general-pathology-lecture-notes-1-12.pdf

Pathology Exam 1 Study Guide
Cellular Injury and Adaptation
- Intro to Pathology
o The term pathology is derived from 2 Greek words
§ Pathos = disease
§ Logos = study
o Etiology – the origin of disease including the underlying causes and modifying
factors
o Pathogenesis – the steps in the development of a disease
§ Etiology refers to why a disease arises, while pathogenesis refers to how a
disease develops
o Pathology Divisions
§ Anatomic Pathology
• Autopsy Pathology – dissection and microscopic exam of tissues
removed from cadavers at postmortem exam
• Surgical Pathology – dissection and microscopic exam of biopsies
and surgical specimens removed from living patients to diagnose
tumors or other diseases
§ Clinical Pathology (Laboratory Medicine)
• Clinical chemistry
• Microbiology
• Immunopathology
• Hematology / Hematopathology
• Blood Banking
• Transfusion Medicine
- Intro to Pathology
o Rudolph Virchow (1821-1902)
§ German scientist who introduced the idea that the cell represented the
basic functional unit of the body (cellular pathology)
§ FATHER OF PATHOLOGY
o Sir William Osler (1849-1919)
§ Famous clinician who worked in Baltimore, Philadelphia and Boston – early
1900s
§ Noted that our clinical practice is only as good as our understanding of
pathology
- Overview of Cell Injury and Cell Death
o Homeostasis
§ Homoios – steady
§ Stasis -state
§ The state of balance between 2 opposing pressures operating in and around
a cell or tissue
§ Steady state – when an equilibrium between the cells and their
environment is achieved and maintained

§ External stimuli may alter this equilibrium
• Demands are increased – cell metabolism shifts to a higher level
achieving a new steady state
• Demands are decreased – cell metabolism shifts to a lower steady
state
o Either way, the adaptation is temporary, and the cell may
revert to the original steady state after the external
demands terminate
- Cellular Adaptations
o Prolonged exposure of cells to adverse or exaggerated normal stimuli evokes
various adaptations at the level of individual cells, tissues or organs
o Once the cause is removed, most cells revert to a normal state again
o Cellular adaptations include:
§ Atrophy
• Denotes a decrease in the size of a cell, tissue, organ or the entire
body
• Classifications of atrophy:
o Physiologic atrophy
§ Decreased Work Load
• Immobilization of a limb due to injury
§ Aging
• Certain numbers of brain cells are lost every
day from birth onward, which results in a
decrease in the entire brain
• Bones of elderly people are thin and more
prone to fracture
• Atrophic muscles are thin and weak in the
elderly
• Thymus
§ Loss of Endocrine Stimulation
• Ovaries, uterus and breasts following
menopause
o Pathologic atrophy
§ Inadequate nutrition
§ Diminished blood supply (ischemia)
• Kidneys affected by nephoangiosclerosis
§ Loss of Innervation
• De-inervated muscles after a spinal cord
injury or in muscular dystrophy
• The fundamental cellular changes are identical
o Decreased protein synthesis
o Increased protein degradation (ubiquitin-proteasome
pathway)

§ Hypertrophy
• An increase in size of tissues or organs owing to an enlargement of
individual cells
• Hypertrophy occurs in cells that have a limited capacity to divide
o Pure hypertrophy only occurs in heart and other muscle
• May be physiologic or pathologic
• Limit will be reached beyond which increased size can no longer
compensate for increased burden
o Opposite of atrophy
• Physiologic Hypertrophy
o Caused by increased functional demand or hormonal
stimulation (ex-skeletal muscles in body builders or the
uterus in pregnancy)
§ The uterus during pregnancy (white arrow)
increases in size mainly due to estrogen acting on
smooth muscle estrogen receptors leading to the
increase in smooth muscle cell size (figure C)
compared to smooth muscle cells in a normal
uterus (blue arrow and figure B)
• Cell size increases
• Pathologic Hypertrophy
o Hypertrophy of the heart
§ Increased pressure in the outflow side of the left
ventricle requires more force to be overcome and
its achieved by hypertrophy of cardiac muscle fibers
(ex – hypertensions, aortic stenosis, endocarditis)
• Concentrated myocardial hypertrophy of
the left ventricle wall in a pt with long-
standing hypertension
o Heart cannot make more cells, so
cell size increases
§ Hyperplasia
• An increase in the size of tissues and organs caused by an increased
number of cells
• Occurs in cell populations capable of replication
• Typically occurs as a result of hormonal stimulation (growth factors)
• May occur as a response to chronic injury
• Physiologic Hyperplasia
o Hormonal – female breast at puberty
o Compensatory – resected liver = liver regrows after being
partially removed
• Pathologic Hyperplasia
o Excessive growth factor or hormone stimulation

§ *important point* - the hyperplastic process
remains controlled – if cause is removed the
hyperplasia disappears!!
§ Neoplasia – increased number of cells à tumor, but
even with removal of cause, cells still increase
o Chronic Injury – Induced Hyperplasia
§ Hyperplasia is secondary to chronic injury
• Inflammatory papillary hyperplasia due to
ill-fitting dentures
o Inflammation of tissue – tries to
make denture fit by growing around
the denture!
§ Metaplasia
• A form of adaptation characterized by the change of one normal
cell type into another normal cell type
• One cell type is replaced by another type that is more capable of
handling a particular stress
• Reprogramming of the stem cell to differentiate along a new
pathway**
• Reversible change - when harmful stimulus is discontinued
metaplasia will go away!
• Examples: intestinal metaplasia in Barrett’s Esophagus
o Squamous mucosa transforms into columnar epithelium of
intestinal type
§ Difficult swallowing – squamous epithelium for
protection (white / pale tissue)
• GERD – acid breaks down esophageal walls
à transforms into columnar – lower part of
esophagus changed from squamous to
columnar – can lead to cancer – but should
be reversible
o Ciliated pseudostratified columnar epithelium of bronchial
mucosa changes into squamous epithelium – cigarette
smoke irritant
§ Irritant causes squamous metaplasia to develop in
order to protect the lungs from irritants
• Metaplasia may have some disadvantages
o Important protective mechanisms may be lost – ex – loss of
mucous secretion and ciliary movement in bronchial
epithelium
o Changes that induce metaplastic changes may lead to
malignant transformation
orGERD

• Metaplasia may occur in mesenchymal cells (fibrous tissue, muscle
and fat) but it is generally a pathologic alteration and not an
adaptation to stress
- Categories of Cell Injury
o Overview of Cell Injury and Cell Death
§ Important points:
• Cellular function may be lost long before cell death occurs, and the
morphologic changes of cell injury (death) lag far behind both.
• The events that determine when reversible cell injury progresses to
irreversible injury and then to death are poorly understood
• The 2 events that consistently characterize irreversible cell injury
are the inability to correct mitochondrial dysfunction and inability
to control what comes in and out of cell due to irreversible
damage to the cell membrane
o Ultrastructural – visible with electron microscope
o May not see effect of myocardial infarction until days after
event – will just see plaques not cell death
o Reversible Cell Injury
§ Reversible cell injury – if the adverse environmental influences evoke a
cellular response that remains within the range of homeostasis
• Cessation of injury results in the return of the cell to the original
steady state
• Typically mild or short lived
§ The two main morphologic characteristics of reversible cell injury are
cellular swelling and fatty change
§ Morphologic alterations
• Cellular swelling (hydrophobic- droplets of water in cell or vacuolar
change)
o First manifestation of almost all forms of cellular injury
o Increased influx of water into the cytoplasm
o Membrane bound vacuoles formed from the invaginations
of the plasma membrane and ER
• Plasma membrane – blebbing, blunting and loss of microvilli
• Cytoplasm – myelin figures, lipid vacuoles in the cytoplasm (fatty
change)
• Mitochondrial changes – swelling and the appearance of small
amorphous deposits
• Dilation of ER – detachment of ribosomes and disassociation of the
ribosomes
• Nuclear alteration – clumping of the chromosomes
• Ultrastructural electron micrographs:
o Normal proximal kidney tubule epithelium with microvilli
(top)

o Microvilli are lost and incorporated into apical cytoplasm
(middle)
o Mitochondria were swollen and have undergone
condensation and become electron dense (middle)
o Late injury with markedly swollen mitochondria with
electron-dense deposits of precipitated calcium and
proteins (last)
§ Pathogenesis of Cellular Swelling
• Plasma membranes are selectively permeable membranes that
maintain the gradient in the concentration of minerals (Na, K, CL)
inside and outside the cells
o This is achieved through Na/K ATPase pumps fueled by ATP
• Anoxia (no oxygen) or other forms of energy deprivation cause
dysfunction of these enzyme pumps leading to an influx of Na and Cl
into the cell due to a higher gradient extracellularly
o Water influx follows the Na and Cl leading to cellular
swelling
• Restoration of ATPase function:
o Na and water are pumped out
o Swelling disappears
§ Pathogenesis of Other Functional Alterations
• Swollen mitochondria
o Generates less energy
§ Instead of oxidative ATP production, the cell reverts
to less efficient glycolysis
§ Excessive production of lactic acid
• Cell becomes acidic, which further slows
down cell metabolism
• Dilation and Fragmentation of ER
o RER loses membrane attached ribosomes
§ Decreased protein synthesis
• Swollen Organelles Disintegrate
o Organelle membranes curl up into concentric bodies
(myelin figures)
o Hydrolytic lysosomal enzymes leak from overdistended
phagosomes into the acidic cytoplasm extensively damaging
other cellular components
• Hydropic change is reversible
• Cell will revert to its normal steady state
o Energy source is restored
o Toxic injury is neutralized
o Irreversible Cell Injury
§ Cells exposed to heavy doses of toxins, severe hypoxia or anoxia, or other
overwhelming insults cannot recover from the injury

• Energy production in mitochondria has fallen below the essential
minimum necessary for cell function that cannot be restored to
normal levels
• Plasma membrane functions are irrevocably lost
• Nuclear functions have been disrupted
§ Morphologic Alterations
• Characteristic morphologic changes of the nucleus
o Pyknosis – marked by the condensation of the chromatin
(pyknos = dense)
o Karyorrhexis – chromatin fragmentation into smaller
particles (karyon = nucleus, rrhexis = disruption)
o Karyolysis – dissolution of nuclear structure and lysis of
chromatin by enzymes such as DNAase and RNAase
§ Irreversible Cell Injury à Cell Death
• Dead cells release their contents into the extracellular fluid, reach
the circulation an are washed away
o Cytoplasmic enzymes such as aspartate aminotransferase
(AST- common liver enzyme) and lactate dehydrogenase
(LDH), which are released from dead cells, can be measured
in the clinical chemistry lab and serve as useful signs of cell
injury à determines cell death in body
§ Must look at released enzymes to make a diagnosis
- Cell Death
o All cells in the human body have a finite life span that ends in death
o Some cells may be replaced from stem cells (hepatocytes, epithelium) whereas
others are irreplaceable (cardiac myocytes, neurons)
o Cell death occurs in several forms
§ Necrosis – exogenously induced cell death from toxins or anoxia (necros =
dead) – something kills the cell à inflammation!
• Patterns of Necrosis
o Coagulative*most common*
§ Coagulative – tissue looks like a solid mass of boiled
meat in which the proteins are coagulated by heat
§ The injury denatures structural proteins and
enzymes which blocks the proteolysis of the dead
cells
§ Characteristics of infarctions (ischemic necrosis) in
all solid organs *except the brain*
• Nucleus is gone, red color but cells maintain
their shape
§ Form of necrosis in which the architecture of dead
tissues are preserved for some days
§ The affected tissues exhibit a firm texture

§ Microscopically, eosinophilic (red), anucleate cells
persist for days and weeks
§ More red, inflammation and neutrophils in 2nd
pic!
Cannot see nuclei anymore
o Liquefactive* most common*
§ Characterized by the complete digestion of the
dead cells. The tissue becomes a viscous liquid mass
§ Local bacteria or fungal infections
§ Infarction of the brain
§ Typical of a brain infarct that gets transformed into
a fluid-filled cavity after an ischemic event (stroke)
§ Also seen in focal bacterial and fungal infections
• Microbes stimulate the accumulation of
leukocytes with the liberation of enzymes
from these cells
• Necrotic material is usually creamy yellow
due to the presence of dead leukocytes
(pus)
o Gangrenous
§ This is not a specific pattern of cell death, but the
term is commonly used in clinical practice
§ This usually applies to a limb (lower leg typically)
that has lost its blood supply
§ It undergoes coagulative necrosis; however, it
involves several tissue planes
§ When bacterial infection is superimposed, there is
more liquefactive necrosis due to the actions of the
degradative enzymes in the bacteria and the
attracted leukocytes
§ Wet Gangrene – bacterial infection of coagulated
tissue leads to inflammation and a secondary
liquefaction
§ Dry Gangrene – necrotic tissue dries out and
becomes dark black and mummified.
o Caseous – “cheese” necrosis
§ Typically found in tuberculosis (microbacterial) and
histoplasmosis (fungal)
§ The necrotic tissue is grossly friable, yellow-white
and cheesy
§ The area of caseous necrosis is surrounded by a
distinctive pattern of inflammation known as a
granuloma
• In lung here

§ Granuloma – typical tuberculosis granuloma with
an area of central necrosis surrounded by multiple
Langerhans-type giant cells (arrow), epithelial cells
and lymphocytes
§ Granuloma – a cimcumscribed collection of
epithelial histiocytes (classic definition)
• Barrier around something that the body has
trouble eliminating
o Fat
§ Special form of liquefactive necrosis caused by the
action of lipolytic enzymes
§ It is limited to adipose tissue, usually around the
pancreas
• Occurs in acute pancreatitis
§ Pancreatic enzymes released into the adjacent
adipose tissue degrade the fat into glycerol and free
fatty acids
§ Saponification
• Free FAs rapidly bind with calcium, forming
calcium soaps
• Area of fat necrosis appears like liquefied
fat with white-ish specks of calcium soaps
scattered about.
o Fibrinoid
§ Special form of necrosis usually seen in immune
rxns involving blood vessels
§ Occurs when complexes of antigens and antibodies
are deposited in the walls of arteries
§ Deposits of immune complexes and fibrin that has
leaked from the vessels result in a bright pink,
amorphous appearance to the vessel walls on HE
staining
§ Seen in immunologically mediated vasculitis
syndromes
§ Apoptosis – endogenously programmed cell death (dropping out) – cell is
unnecessary or has injury or genetic change à losing control à suicide
§ Autolysis – death of cells and tissues in a dead organism as a result of
cessation of respiration and heath beat ( autos = self , lysis = dissolution
- General Principles of Cellular Injury
o The cellular response depends on the type of injury, duration and severity
o The consequences of an injurious stimulus depend on the type, status, adaptability
and genetic makeup of the injured cell
o Cell injury results from the functional and biochemical abnormalities in one or more
of several essential cellular components

o Multiple biochemical alterations may be triggered by any 1 insult
§ (Striated muscle will accommodate complete ischemia for 2-3 hours while a
cardiac muscle cell will die in 20-30 minutes.
§ A glycogen rich hepatocyte will tolerate ischemia much longer than one that
is depleted of glycogen.
§ Different variants of cytochrome P-450 will metabolized a toxin at different
rates.)
- Principal Mechanisms of Cell Injury
o Depletion of ATP
§ Major causes:
• Reduced O2 supply
• Mitochondrial damage / dysfunction
o Causes: hypoxia, chemical toxins and radiation
o Results: depletion of ATP due to failure of oxidative
phosphorylation
o Abnormal oxidative phosphorylation leads to formation of
reactive oxygen species (ROS)
o Release of proteins that can activate apoptosis
• Actions of some toxins
§ Widespread effects on many critical cellular systems
• Activity of Na pumps in plasma membrane is reduced resulting in
cellular swelling – more Na and Ca in cell followed by h2O
• Decreased pH due to increase in anaerobic glycolysis (lactic acid)
caused decreased enzyme activity and clumping on nuclear
chromatin – more acidic environment
• Influx of Ca into the cell – swelling
o Influx of calcium
§ Cytosolic free calcium is maintained by ATP-
dependent transporters at 10,000 times lower than
extracellular calcium or calcium sequestered in
mitochondria or ER
§ Increased cytosolic calcium activated a number of
enzymes including:
• Phospholipases – damage membranes
• Proteases – damage membranes and
cytoskeletal proteins
• Endonucleases – DNA and chromatin
fragmentation
• ATPases – hastens ATP depletion
§ Can induce apoptosis
• Decrease protein synthesis
• Accumulation of Oxygen-Derived Free Radicals
o Free radicals are chemical species with a single unpaired
electron in the outer orbital

§ Attack nucleic acids as well as a variety of cellular
proteins and lipids
§ Reactive oxygen species (ROS) – oxygen derived
free radical whose role in cell injury is well
established
§ Balance between free radical production and
removal
o Generation of free radicals is increased by
§ Absorption of radiant energy
• UV light and X-rays
• Enzymatic metabolism of exogenous
chemicals
• Inflammation
o ROS cause injury by 3 main mechanisms
§ Lipid peroxide of membranes
§ Cross-linking and other changes in proteins
§ DNA damage
o Defects in Membrane Permeability
§ Consistent feature in most forms of cell injury that lead to necrosis
§ Important targets:
• Mitochondrial membranes
• Plasma membrane
• Lysosomal membranes
o Need control of what enters/exits the cell or will die!!
o Damage to DNA and Proteins
§ Cells can repair damage to DNA
§ Accumulation of improperly folded proteins
• Both lead to cell death via apoptosis
o Tumor suppressor genes à induce apoptosis! If they are
lost, cancer starts
- Cell Death
o Apoptosis
§ Pathway of cell death in which cells activate enzymes that degrade the cells
own nuclear DNA
§ Energy dependent and requires activation of a specific set of genes and
enzymes (suicide genes)
§ Programmed cell death**
§ The dead cell is rapidly cleared and does not ilicit an inflammatory
response*
§ Initial event could be endogenous or exogenous
• Long-lasting viral infection – chronic viral hep C – exogenous
• Lack of necessary growth factors in a brain cell – endogenous
§ Physiologic Cause of Apoptosis

• Apoptosis occurs in many normal situations and serves to eliminate
potentially harmful cells and cells that have outlived their
usefulness
• Examples – embryogenesis, involution of hormone dependent
tissues upon hormone deprivation
• Cell loss in proliferating cell populations – blood or epithelial
• Elimination of cells that have served their useful purpose
• Elimination of potentially self-reactive lymphocytes à auto immune
diseases
• Cell death by cytotoxic T lymphocytes
§ Pathologic Causes of Apoptosis
• Apoptosis eliminates cells that are genetically altered or injured
beyond repair, it does so without eliciting an inflammatory
response, keeping the extent of tissue damage to a minimum
• Examples
o DNA damage
o Accumulation of misfolded proteins
o Cell injury in certain infections (usually viral)
o Pathologic atrophy in organs after duct obstruction
- Intercellular Accumulations and Calcification
o Intracellular Accumulations
§ Cells may accumulate abnormal amounts of various substances
• Can be harmless or associated with injury
• Can be in many locations in the cell
• May be exogenous or produced by the cell
§ 4 Main Pathways
• Inadequate removal of a normal substance
• Accumulation of an abnormal substance
• Failure to degrade a metabolite
• Deposition and accumulation of an abnormal exogenous substance
§ Fatty Change (Steatosis)

• Abnormal accumulations of TAGs most often in liver cells
§ Cholesterol
• Ex-atherosclerosis
§ Proteins
• Russel Bodies (immunoglobulins) in plasma cells, neurofibrillary
tangles in neurons
§ Glycogen
• Poorly controlled diabetes, glycogen storage, diseases
§ Pigments
• Carbon – coal dust (antheacosis) – dark lungs for smokers
• Lipofuscin – wear and tear pigment, accumulates in a variety of
tissues (heart, liver, brain) as a function of age or atrophy
• Melanin – pigment that acts as a screen for harmful radiation
• Hemosiderin – aggregates of ferritin micelles when iron levels are
elevated
§ Types of Calcification
• Dystropic Calcification
o Calcification of necrotic tissue with normal calcium levels –
dead tissue
o Neucrotic tissues attract calcium salts and often undergo
calcification
o Seen in artherosclerotic arteries, damaged heart valves or
necrotic tumors
• Metastatic Calcification
o Deposition of calcium salts in normal tissue the presence of
abnormal calcium metabolism – live tissue
o Feature of metabolic hypercalcemia secondary to
hyperparathyroidism, vitamin D toxcicity, increased
destruction of bone or renal failure
- Cellular Aging
o Individuals age because their cells age
o Cellular aging is the result of a progressive decline in the life span and the functional
capacity of cells
o Main mechanisms
§ Accumulation of DNA damage
§ Decreased cellular replication
• Normal cells have a limited capacity for replication – replicative
senescence – eventually will stop dividing – malignant cells don’t
have replicative senescence and will continue to grow
• Telomeres are short repeated sequences on the end of linear
chromosomes
• Telomeres shorten with each cell division
o Mutated in malignant cells = just keeps being regenerated
• Defective protein homeostasis

Inflammation
- Overview
o A protective response
§ Eliminate the cause of injury (like germs)
§ Eliminate dead cells
o Can cause tissue injury:
§ Severe infection
§ Prolonged cause of inflammation
§ Inappropriate inflammation
• Autoimmunity
• Hypersensitivity
o Components of Inflammation
§ Leukocytes – eliminates microbes or dead tissue
§ Plasma – complement: mediators of inflammation, elimination of microbes
/ clotting factors and kininogens – mediators of inflammation
§ Mast cells – source of mediators
§ Lymphocytes – immune response
§ Monocytes (in vessel) / macrophage (outside of vessel) – elimination of
microbes and dead tissue, source of mediators and role in immune response
§ ECM – repairs the area
o Acute vs. Chronic Inflammation
§ Acute
• Rapid onset and short duration (minutes to days)
• Usually neutrophil-rich inflammatory infiltrate
§ Chronic
• Insidious onset and long duration (days to years)
• Usually mononuclear inflammatory infiltrate
o Signs of Inflammation
§ Rubor (redness)
§ Tumor (swelling)
§ Calor (heat)
§ Dolor (pain)
§ Function laesa = loss of function
o Steps of Inflammation
§ Recognition of injurious agents
§ Recruitment of leukocytes
§ Removal of agent
§ Regulation of response
§ Resolution / repair
- Acute Inflammation
o Vascular and Cellular response
o Rapid response
o Delivers leukocytes and plasma proteins

o Vascular changes
§ Vasodilation (causes rubor – vessels carry more blood) and increased
vascular permeability (vessel leaks out – warmth and swelling)
o Cellular events
§ WBCs (neutrophils) recruited
§ WBCs are activated
o Stimuli for Acute Inflammation
§ Infections
§ Trauma
§ Necrosis
§ Foreign bodies
§ Hypersensitivity reactions
o Vascular Flow in Acute Inflammation
§ Vasoconstriction (seconds)
§ Arteriolar dilation à erythema
§ Increased permeability à fluid in ECM à increased blood viscosityà
decreased blood flow à statis
• Hydrostatic pressure pushes fluid out and osmotic pressure pulls
fluid in
§ Neutrophil margination – as vessel get bigger, neutrophils will go to the
perimeter of the vessel
o Vascular Permeability in Acute Inflammation
§ Increased hydrostatic pressure à transudate (edema – water rich liquid)
§ Endothelial leakage à exudate (protein rich residue)
• Causes of endothelial leakage:
o Cell contraction à intercellular gaps
o Cell injury
§ From original cause of injury
§ From effect of activated WBCs
o Mediator-induced transcytosis of proteins
o Angiogenesis – new blood vessel formation – vessels leak as
they are forming
o Leukocyte Recruitment
§ Margination
• Laminar flow pushes larger WBCs to outside of stream
o Cellular part of inflammation
o Dilated pipe = larger particles (WBCs) go to the perimeter of
the stream
§ Rolling
• Due to selectins
o The WBCs bind to blood vessel walls and roll
o Then, via integrins, WBCs adhere to the vessel wall and then
go through vessel wall via transmigration
§ Adhesion and Transmigration

• Due to integrins on WBCs interacting with ligand on endothelial cell.
§ Migration (chemotaxis – cell motility along a concentration gradient)
• Bacterial products
• Cytokines
• Complement components
• Lipoxygenase and arachidonic and acid metabolites
o Timeline for Acute Inflammation
§ Neutrophils dominate for 6-24 hours
• Very numerous in circulation
• Short-lived
§ Monocytes dominate at 24-48 hours
• Longer survival than neutrophils
§ Very rapid and edema is due to leakage of vessels
o Receptors on Leukocytes
§ Toll-like receptors
• For LPS
• For other bacterial products
§ 7-transmembrane receptors
• For bacterial peptides
• For mediators
§ Cytokine receptors
§ Phagocyte receptors – FYI
o Results of Leukocyte Activation
§ Phagocytosis with intracellular destruction of microbes and dead cells
§ Release of microbicidal substances
§ Production of mediators to amplify reaction
• Neutrophil is activated, eats microbe and leaks mediators –
increases inflammatory / immune response
o Phagocytosis
§ Recognition and attachment of particle to WBC
• Receptors on WBC recognize opsonins (antibodies that coat the
germ) on surface of particle
o Opsonins = IgG, C3 (complement) or collectins
§ Engulfment via a phagocytotic vesicle
o Killing and Degradation
§ Lysosomes fuse with phagosomes
§ Oxidative burst à ROS à kill microorganism
§ Degradation by lysosomal acid hydrolases
• NADPH oxidase makes radicals that will kill the germ in the
phagolysosome
o Secretion of Microbicidal Substances
§ Granules of leukocytes = lysosomes containing:
• Elastase (degrades elastins) or antimicrobial peptides
§ Mechanism of cellular release

• Regurgitation during phagocytosis
• Frustrated phagocytosis à extracellular release
• Membrane damage
o Lysosomes leak out and cause damage in the area
- Pathology of Acute Inflammation
o Mechanisms to kill microorganisms also injure normal cells and tissues
§ Neutrophil Extracellular Traps (NETs)
• Response to: bacteria, fungi or mediators
• Nuclear chromatin and embedded granule proteins leave cell à
trapping of microorganisms
o Neutrophil poops out its nucleus and forms a net that traps
bacterial cocci
o Defective Acute Inflammation
§ Leukocyte (WBCs) adhesion deficiencies (LADs)
• Type 1 and type 2
§ Defective microbicidal activity
• Chronic granulomatous disease
§ Defect in phagolysosome formation
• Chediak-higashi (AR)
o Chronic granulomatous disease = enzyme complex needed
to kill a germ is not there = so never causes germ death à
granuloma
§ Toll-like receptor pathway mutations
- Outcome of Acute Inflammation
o Resolution
o Progression to chronic inflammation – if it failed to kill all of the germs
o Scarring = fibrosis
- Morphology of Acute Inflammation
o Serous inflammation – when transducent (watery) dominates
§ Watery, protein poor fluid accumulation (edema)
• Vesicle (blister)
• Effusion (if inside body cavity)
o Fibrinous inflammation
§ Protein-rich exudate (more vascular permeability than in serous)
§ Fibrinolysis à resolution
• If resolution fails, exudate is organized (fibroblasts enter and make
collagen à adhesions appear between heart and pericardium)
o Ingrowth of blood vessels and fibroblasts
§ Fibrin comes out in the exudate!
§ Bread and butter pericarditis
o Suppurative (purulent) inflammation
§ Neutrophils dominate morphology
§ Large focus = abscess

• PUS = liquefactive necrosis and dead neutrophils make up the
abscess
§ Abscess – large focus of Suppurative inflammation with necrosis due to
impaired drainage
• Must be drained – will not heal without draining because it is dead
tissue and pus!
o Ulcers
§ Loss of epithelium and inflammatory response
• Road rash will be an ulcer
• Can be chronic
• Neutrophils dominate
• Gastric or peptic ulcer – stomach contents eat stomach
- Chemical Inflammatory Mediators
o Produced locally
§ Some sequestered in WBC intracellular granules (histamine)
§ Others synthesized de novo (when needed) at site (prostaglandins and
cytokines)
o Circulating (usually produced by liver)
§ Circulate as inactive form
§ Proteolytic cleavage à activation
o Usually bind receptors on target cells
o Stimulate target cells to release secondary effector molecules
o Under strict and complex regulation
- Cell Derived Mediators (probably no questions about mediators)
o Vasoactive amines = histamine or serotonin
o Arachidoic acid metabolites = prostaglandins, leukotrienes, lipoxins
o Platelet activating factor
o Cytokines = TNF, IL-1, chemokines
o ROS
o Nitric oxide
o Lysosomal enzymes
o Neuropeptides
- Plasma Protein-Derived Mediators
o Circulating mediators
§ Complement system – includes all of these mediators – used to increase
inflammation and to destroy cells
§ Coagulation proteins -
§ Kinins – with complement, overlap with the coagulation cascade – coagulate
blood
• *Some mediators overlap with coagulative system
• Enzyme cascades – used to amplify a cellular signal and thus,
amplify the cellular response – enzymes lower activation energy and
are not consumed so can activate several proteins quickly
o Mediators of Vasodilation

§ Prostaglandins
§ Nitric oxide
§ Histamine
o Mediators of Vascular Permeability
§ Histamine, serotonin, C3a, C5a, bradykinin, leukotrienes C4, D4 and E4, PAF,
Substance P
• Causes leaky vessels
o Mediators of WBC Recruitment and Activation
§ TNF, IL-1, chemokines, C3a, C5a, leukotriene B4, bacterial products
o Mediators of Fever
§ IL-1 - interleukin
§ TNF – tumor necrosis factors
§ Prostaglandins
o Mediators of Pain
§ Prostaglandins
§ Bradykinin
§ Neuropeptides
o Mediators of Tissue Damage
§ WBC lysosomal enzymes
§ ROS
§ Nitric Oxide
o Major Cytokines – guess TNF, then IL-1, then IL-6
§ TNF is in everything but the liver
§ IL-1 is in everything but the endothelium and heart
- Chronic Inflammation
o Prolonged duration (weeks to years)
§ Acute inflammation
§ Tissue injury
§ Healing
o Characterized by:
§ Mononuclear (lymphocytes, plasma and macrophages) inflammatory
infiltrate
§ Tissue destruction
§ Repair (angiogenesis and fibrosis)
o Setting of Chronic Inflammation
§ Persistent infections
§ Immune-mediated diseases (hypersensitivity)
§ Prolonged exposure to toxic agents
o Chronic Inflammatory Cells
§ Macrophages (derived from monocytes)
§ Lymphocytes
• T and B cells
§ Plasma cells
§ Eosinophils (usually IgE mediated inflammation)

• Not always considered a chronic inflammation cell
§ Mast cells (usually IgE mediated inflammation) – don’t care right now
o Granulomatous Inflammation
§ Specialized subtype of chronic inflammation
§ Defined by presence of granuloma
• Granuloma = circumscribed collection of epithelioid histiocytes
o Can have multinucleated giant cells
o Can have peripheral cuff of lymphocytes
§ Small collections of activated macrophages
(cytoplasm is huge and nucleus is smaller so it looks
like squamous epithelium)
§ Causes of Granulomatous Inflammation:
• Mycobacteria
• Many fungi** (not all)
• Foreign bodies
• Sarcoidosis – not well understood, pt has granulomas but has ruled
out everything that typically causes granulomas = idiopathic
granulomas
§ Pic = well-formed caseous granuloma
• Middle = dead caseous necrosis
• Histocytes – blobs
• Blue = cuff of lymphocytes around histocytes
• 3-4 cells hugging = granuloma
• Red is dead = necrotic tissue picks up eosinophil well
• Blue is bad = neoplasia – nucleus gets bigger in cancer cells
- Systemic Effects of Inflammation
o Acute-phase reaction = systemic inflammatory response system
o Largely mediated by cytokines
§ TNF, IL-1 and IL-6
• All from the liver!
o Acute Phase Response
§ Fever
§ Increased levels of plasma “acute phase” proteins
§ Leukocytosis
§ Increased heart rate
§ Increased blood pressure
§ Decreased swelling
§ Chills and rigors (shivering)
§ Anorexia – no appetite
§ Malaise and somnolence
• Increases WBCs
o Severe Acute-Phase Responses
§ Cachexia (wasting of tissues)
• Largely due to TNF (aka cahexin)

o Can happen in cancer or severe inflammatory response
§ Septic shock
• Shock = blood isn’t flowing
o Due to heart not pumping, no fluid or vessels are too dilated
• DIC
o Disseminated intravascular coagulation – small blood clots
everywhere but mainly in capillaries – exhausted the
coagulation proteins and now will bleed to death with
minor trauma
• Hypoglycemia – low blood sugar
• Hypotensive shock – vessels are too dilated
Repair (wound healing)
- Overview
o Regeneration
§ Proliferation of uninjured cells
§ Typical of epithelia and liver
o Scarring (Fibroplasia)
§ Replacement of cells by collagen
§ Typical of
• Severe damage and many solid organs
o *both processes require close interaction between cells and ECM***
- Cell and Tissue Regeneration
o Proliferating Cells in Repair
§ Remnants of injured tissue - to restore normal structure
§ Endothelial cells – to make new blood vessels
§ Fibroblasts – to make collagen
o Cell Cycle
§ Growth factors drive transitions
§ Cyclins regulate progression
• Labile = cells that constantly divide (skin, gut, marrow)
• Quiescent = stable cells, usually in G0
• Permanent = cells incapable of regeneration, will only heal by
scarring – neurons, and striated cardiac muscle
o Stem Cells
§ Important properties
• Asymmetric replication
o Division à differentiated cell and stem cell
• Self-renewal
§ Types
• Embryonic stem cells (ES cells) – can become any type of cell
• Adult stem cells (aka tissue stem cells)
o Regenerative Medicine

§ Introduce genes from stem cells into patient’s cells à induced pluripotent
stem cells (iPS cells)
• Can grow a new liver if you need one
o Growth Factors: Functions
§ Promote entry of cell to cell cycle
§ Relieve block on cell cycle progression (stimulate G0 cells to go to M cycles)
§ Prevent apoptosis
§ Enhance synthesis of proteins for mitosis
o Growth Factors in Repair
§ VEGF (vascular endothelial growth factor) and FGF (fibroblast growth factor)
• Both involved in wound healing and will make new blood vessels via
angiogenesis
o Growth Factor Effects
§ Autocrine – GF signals the same cell that produced it
§ Paracrine – GF signals cell nearby
§ Endocrine – GF signals cell far away
o Types of GF Receptors
§ Receptors with intrinsic kinase activity
• Ligand binds receptor à dimerizes and receptor subunit is
phosphorylated = creates an enzyme cascade by binding and
activating intracellular proteins
§ G-protein-coupled receptors (7 transmembrane receptors)
• Ligand binds receptor à associate with G-proteins, GDP is replaced
by GTP à activation
§ Receptors without intrinsic enzyme activity
• Ligand binds extracellular part of receptor à conformational
change of intracellular part
• Intracellular part associated with Janus kinases (JAKs)
o Extracellular Matrix in Repair
§ Regulates cells proliferation, movement and differentiation by:
• Providing substrate for cell adhesion and migration
• Sequester water à turgor pressure
• Sequester minerals à tissue rigidity
• Serves as a GF reservoir
o ECM is needed for wound healing – reservoir and scaffold
for regenerating cells and repair
o If ECM is damaged or damage to heart or brain = scarring!
§ 2 forms of ECM
• Interstitial matrix
o 3D amorphous gel
§ Collagens, fibronectin, elastin, proteoglycans,
hyaluronate ect.
o Bulk of ECM
• Basement membrane

o Plate-like mesh
§ Collagen 4 (non-fibrillar) and laminin
o Located under epithelium usually
§ Major ECM components
• Structural proteins
o Tensile strength and recoil
§ Collagens – 30 types, rope-like triple helix that
provides tensile strength
• Fibrillar (1, 2,3,5)
• Non-fibrillar (4,7,9)
o Collagen 1 (wound healing) and 4
(basement membrane)
§ Elastin – provides elastic recoil – in aorta
• Hydrated gels
o Resilience and lubrication
§ Proteoglycans = glycosaminoglycan and protein
core
• Resilience, lubrication and GF reservoir
o Proteoglycans = look like cleaning
brushes = makes tissue resilient to
trauma
§ Hyaluronan (hyaluronic acid)
• Mucopolysaccharide without a protein core
o Binds with water to make gelatin-
like matrix
• Adhesive glycoproteins
o Connect ECM components to each other
o Connect ECM components to cells
o Fibronectin - binds many ECM components and attaches to
integrins
o Laminin – connects cells to type 4 collagen and heparin
sulfate
o Integrins – binds cells to ECM
§ ECM Functions
• Mechanical support
o For cell anchorage, migration and to maintain cell polarity
• Control of cell proliferation
o By binding and displaying GF and by integrin signaling
• Scaffolding for tissue renewal
o Basement membrane is required for regeneration
• Establishment of tissue microenvironments
o Regeneration in Repair
§ Labile tissues
• Regeneration if basement membrane scaffold is intact

§ Stable tissues
• Limited regeneration in many parenchymal organs
o Liver is excellent at regeneration!
§ Permanent tissues
• No regeneration
- Scar Formation
o Steps in Scar Formation
§ Inflammation – begin to clear dead cells
§ Angiogenesis – make new blood vessels from existing vessels
• Steps
o Vasodilation
o Separation of pericytes
o Migration of endothelial cells
o Proliferation of endothelial cells
o Remodeling into tubes
o Recruitment of pericytes and smooth muscle cells
o Suppression of proliferation and migration
o Deposition of basement membrane
• Angiogenesis Growth Factors
o VEGF family – migration and proliferation of endothelial
cells
o FGF family – proliferation of endothelial cells
§ Migration of: macrophages, fibroblasts and
epithelial cells
o Angiopoietins (Ang1 and Ang2) (don’t care yet)
§ Structural maturation of new vessels
§ Migration and proliferation of fibroblasts – make collagen!
• Driven by GFs (mostly from macrophages)
o PDGF, FGF-2 and TGF-beta***
§ Tell fibroblasts to divide and make ECM
• New blood vessels will go away after
healing
§ Collagen synthesis
• Fibroblasts synthesize ECM (especially collagen)
• Progressive regression of vessels
§ Remodeling (maturation and reorganization)
• Matrix metalloproteins (MMPs) degrade collagen and other ECM
components
• MMPs turned off by tissue inhibitors of metalloproteinases (TIMPs)
• Wound contraction (due to myofibroblasts)
o Making scar stronger!
§ * Angiogenesis and the migration and proliferation of fibroblasts form
granulation tissue!!!****
• Granulation tissue is the HALLMARK OF WOUND HEALING

o Scabs = blood leaking out of new vessels = healing
o Blue = collagen 1
• Left pic = still edema
• Right = later so some vessels and more
collagen
- Factors that Influence Tissue Repair
o Antagonists of Wound Healing
§ Infection – most important cause of delayed healing***
§ Inadequate nutrition (ex- lack of vitamin C = scurvy – hydroxylating collagen)
§ Mechanical forces (ex-causing dehiscence = when sutures are
broken/ripped out ) or need a cast
§ Poor perfusion (diabetics have crappy circulation)
§ Foreign bodies – no blood flow in foreign bodies
o Abnormal Wound Healing
§ Keloid = hypertrophic scar due to excessive collagen production
• More common in African Americans = will keep coming back and
needs plastic surgery
§ Proud Flesh – excessive granulation tissue – horses
§ Contracture – wound contraction reduces range of motion
• Myofibroblasts pull the wound together = lesion contracture
(sometimes from burns) – scars are pulled too tightly over a joint
and limits motion
§ Stricture – wound contraction in viscus à obstruction
• Lesion in pipes
- Clinical Examples of Repair
o Healing of skin wounds
o Fibrosis of parenchymal organs
o Healing by First Intention
o Healing of an incised wound with approximated edges
Primary = sew edges of wound together
• Day 0 = surgeon’s incision
• Day 1 = neutrophils appear, basal cells divide
• Day 2-3 = macrophages replace neutrophils, granulation tissue
invades wound space, vertical collagen fibers
• Day 4-5 = peak of neovascularization, collagen fibers bridge wound,
epithelium of normal thickness
• 2nd
week = continued collagen formation, regression of vascular
channels, dissipation of inflammation
• 1st
month = scar
o Healing by Second Intention
§ The healing of a wound without approximation of edges
• Same as healing by first intention but with the following differences:
o Larger amount of necrotic debris, exudate and fibrin to
remove

o Greater volume of granulation tissue leading to (early) large
scar
o Wound contraction* - due to myofibroblasts – can shrink
scar 90-95%
• Only difference is that the edges of the wound are not put together
– huge wound, so cannot put a timeline with it
• Wound contraction is primary but more obvious with a bigger
wound
o Wound strength
§ Sutured = 70%
§ 1 week (no suture) = 10%
§ 3 months = 70-80%
§ Will never go back to 100%***
o Parenchymal Organ Fibrosis
§ Same mechanisms as scar formation (including wound contraction)
Hemodynamic Disorders – bleeding issues
- Cardiovascular Disease
o Most important cause of morbidity and mortality in Western society
o Divided into diseases that affect the heart, the vessels and the blood components.
o Blood components: water, salt, protein, and elements of coagulation (platelets and
factors), WBCs and RBCs
o Disorders lead to adaptation and further abnormalities
§ Centrifuge blood
• RBCs
• Buffy coat? – WBCs and plasma
• Plasma – water and salt ect.
- Edema
o Normal hydrostatic pressure is equal to the plasma colloid osmotic pressure
o Net fluid into interstitial drains into lymphatic returns to blood stream via thoracic
duct
o Elevated hydrostatic pressure or diminished colloid osmotic pressure = increased
movement of fluid out of vessels
§ Hydrostatic = pushes water out
§ Osmotic = caused by proteins pulling water in
o Edema – fluid in the tissue (swelling)
§ Increased hydrostatic pressure and low osmotic pressure
o Effusion – fluid in body cavities
- Edema (cont)
o Non-inflammatory
o Inflammatory
o Exudate (opaque)
§ Protein rich plasma inflammatory mediators
§ Local vs. sepsis

§ Generally high values
o Transudate (translucent)
§ Protein-poor plasma
§ Heart failure, liver failure, severe nutritional disorders
§ Generally low values
§ Pitting edema à
- Renin – Angiotensin System
o Prominent for hypertension
o Kidneys sense low blood volume or pressure due to severe blood loss (trauma) and
secretes renin which converts angiotensin to angiotensin 1 which is converted to
angiotensin 2 in the lung which stimulates the adrenal gland to make aldosterone
which tells kidney to absorb salt and water follows to increase blood pressure
o Sodium and Water Retention
§ Increased salt retention with associated water – at kidney with renin-
angiotensin pathway
§ Increased hydrostatic pressure and decreased colloid pressure
§ Decreased renal perfusion
- Increased Hydrostatic Pressure
o Disorders that impair venous return
o Localized – deep vein thrombosis
o Systemic – congestive heart failure
§ Increased blood pressure and hydrostatic pressure = liver disease
- Reduced Plasma Osmotic Pressure (comes from proteins)
o Albumin – half of the total plasma protein – low albumin = liver disease, liver makes
albumin
o Inadequate synthesis or increased loss
o Severe liver disease
o Nephrotic syndrome – holes in glomerulus so peeing out proteins!
o Secondary hyperaldosteronism
- Lymphatic Obstruction
o Disruption of lymphatic drainage
§ Trauma
§ Fibrosis
§ Invasive Tumors
§ Infectious agents – parasitic filariasis
• Lymph edema – parasite gets into lymphatic system and obstructs
the flow of the lymph
• Breast cancer – metastasizes to the lymph nodes and causes edema
- Edema and Effusions
o Edema = fluid build-up in skin
o Effusion = fluid build-up in organs – fluid in interstitial space of organs
§ Heart = pericardial effusion
§ Lungs = pleural effusion
§ Abdomen = ascites

- Hyperemia and Congestion
o Hyperemia (active)
§ Arteriolar dilation
§ Erythema
§ Inflammation
§ Skeletal muscle during exercise*
o Congestive (passive)
§ Reduced outflow
§ Systemic – CHF
§ Localized – Isolated venous obstruction
• Liver with chronic passive congestion = nutmeg liver (left)
• Centrilobular necrosis with degenerating hepatocytes and
hemorrhage = liver disease and failure
- Hemostasis
o Hemostasis – process blood clots form at sites of vascular injury
o Hemostatic Abnormalities:
§ Hemorrhagic Disorders –excessive bleeding
§ Thrombotic Disorders – blood clots form within vessels in cardiac chambers
o Arteriolar Vasoconstriction
§ Mediated by neurogenic mechanisms
§ Endothelium
o Primary Hemostasis
§ Formation of the platelet plug*
§ Exposure of vWF
§ Shape changes
§ Release of granules
§ Aggregation
o Secondary Hemostasis – need more than just a platelet plug
§ Formation of fibrin clot*
§ Coagulation cascade
§ Thrombin cleaves fibrinogen into fibrin
• If bleeds, then stops then bleeds again may have disorder of
secondary hemostasis
o Clot Stabilization and Resorption
§ Polymerized fibrin and platelet aggregated a solid, permanent plug
§ Tissue plasminogen activator, t-PA – limits clot and leads to resorption and
repair
• Can have issues if clot doesn’t dissolve
o Platelets
§ Platelets play an integral role in hemostasis
§ Anucleate fragments shed from megakaryocytes
§ Platelet adhesion – vWF and GpIb
§ Contractile cytoskeleton
§ Secretion of granule content

§ Platelet aggregation
o Coagulation Cascade
§ Thrombin activates the cleavage of fibrinogen to fibrin to form clots!
• 2 Hemostasis = ends with fibrin clot from coagulation cascade
§ Intrinsic vs extrinsic
§ Enzyme – substrate – cofactor à coagulation test?
§ Prothrombin time (PT) – measure extrinsic
§ Partial thromboplastin time (PTT) – measures intrinsic
§ Thrombin
• Thrombin is most important
• Conversion of fibrinogen into crosslinked fibrin*
• Platelet activation
• Pro-inflammatory effects
• Anticoagulation effects – breaks the clot!
o Fibrinolysis
§ Counter regulatory mechanisms
§ Fibrinolytic cascade
§ Enzymatic activity of plasmin, generated by activated plasminogen*
• Breaks down fibrin*
• Fibrin split products (D-dimers) *
• Factor XII-dependent pathway
• Plasminogen activators – t-PA**
o Given to pts within 30 min of a stroke to break the clot – if
later then angioplasty – but cannot administer both!
o Anticoagulant Effects
§ Antithrombotic effects
• Platelet inhibitory: prostacyclins*, nitric oxide, adenosine
diphosphotase
• Binds and alters activity of thrombin*
§ Anticoagulant effects
• Thrombomodulin*
• Endothelial protein C receptor – protein C/protein S complex ** -
breaks down clots!
• Heparin-like molecules
• Tissue factor pathway inhibitor
§ Fibrinolytic effects
• t-PA
- Hemorrhagic Disorders
o Abnormal bleeding
§ Massive bleeding secondary to rupture - dissection
§ Subtle defects in clotting – vWF defects
§ Coagulation factor hemophilias
o Defect of primary hemostasis – cannot make platelet plug! Issues with platelets!
§ Platelets of vWF

§ Petechiae or purpura (minute hemorrhages) – tiny bruising – platelets are
used and small clots everywhere!
§ Epistaxis, GI bleed or menorrhagia, intracerebral hemorrhage
• Hemorrhagic stroke – vessels burst open due to hypertension!
• TIA = clot!
o Defects of secondary hemostasis – issues with proteins of clotting cascade – cannot
clot!
§ Coagulation factors
§ Hemarthorosis following minor trauma
- Thrombosis
- Virchow’s Triad:
- Endothelial Injury
o Injury may trigger thrombosis exposure of vWF and tissue factor
o Prothrombotic environment – promotes thrombosis including infectious agents,
metabolic abnormalities, toxins absorbed in cigarettes: “endothelial activation or
dysfunction”
§ Trauma, infection, autoimmunity or diabetes
§ Hypercholesterolemia
§ Vessels rupture and clot forms
- Abnormalities in Blood Flow
o Atherosclerotic narrowing
o Statis – clot formation
o Atrial fibrillation, bed rest, airplanes
o Turbulence
o Artherosclerotic vessel narrowing
- Hypercoagulability
o Thrombophilia
o Disorder of the blood that predisposes to thrombosis
o Primary or Secondary
o Factor V Leiden (**MOST COMMON**) **
§ Single-nucleotide mutation in factor V
§ Factor V resistant to cleavage and inactivation of Protein C à cannot break
clot!!**
§ Heterozygotes have a 5x increase of thrombosis and homozygotes have a
50x increase
§ Inherited
§ Acquired = disseminated cancer – a lot of clots – can cause edema and
embolism
- Heparin-Induced Thrombocytopenia (low platelets)
o Follows administration of unfractionated heparin*
o Induce antibodies that bind to heparin and platelet factor 4 on the surface of
platelets or endothelial cells
o Platelet activation, aggregation and consumption
o Prothrombotic state (while on heparin)

o Low-molecular weight heparin – less frequent HIT
- Antiphospholipid Antibody Syndrome
o Previously called Lupus Anticoagulant syndrome*
o Recurrent thrombosis, repeated miscarriages, cardiac valve vegetations,
thrombocytopenia*
o PE (pulmonary embolisms), pulmonary hypertension, stroke, bowel infarct,
renovascular hypertension
o Antibody targets β2-glycoprotein* I, protein that associated with the surfaces of
endothelial cells and trophoblasts and thrombin
§ In vivo – induce hypercoagulable state
§ In vitro – induce prolonged coagulation antibodies interfere with
phospholipids
§ False-positive for syphilis because the antigen in assay is embedded in
cardiolipin
- Thrombi
o Arterial thrombi tend to grow retrograde - develop on endothelium
o Venous thrombi extend in the direction of blood flow – blow propagate to heart à
lungs**
o Clots have Lines of Zahn*** – pale platelet and fibrin deposits with alternating
darker red cell-rich layers
o Postmortem clots: gelatinous and dark red dependent portion, “chicken fat” upper
portion, usually not attached to underlying vessel wall
o Pic à clot made with blood and laminar flow, post-mortem clots don’t have this or
lines**
- Fate of a Thrombus
o Propagation
o Embolization à systemic!
o Dissolution
o Organization and recanalization
§ Make a new, reduced, lumen of the vessel
- Clinical Features of a Thrombus
o Venous thrombosis
o Arterial and cardiac thrombosis
- Embolism
o Embolus is a detached intravascular solid, liquid or gaseous mass carried by the
blood from its point of origin to a distant site**
o Can cause tissue dysfunction or infarction
o Types of Embolism
§ Thromboembolism: Pulmonary and Systemic
• Pulmonary Embolism
o Dislodged thrombi
o Causes 100,00 deaths a year
o Originates from deep venous thrombosis to the right heart
and into the right pulmonary artery

o One large – saddle embolus or multiple emboli ** stuck in
bifurcation of lung! = sudden death!
§ Pic = saddle embolism caused via DVT to lungs
o Usually clinically silent however sudden death, right heart
failure occurs with 60% obstruction
o Vascular rupture results in pulmonary hemorrhage but not
usually cause pulmonary infarction due to dual blood supply
• Systemic Thromboembolism
o 80% arise from intracardiac mural thrombi: 2/3rds from left
ventricular wall infarcts, 1/4th atrial fibrillation
o Emboli lodge into various sites – lower extremities (75%),
brain (10%), intestines, kidneys, spleen &upper extremities
§ Heart à arterial fibulation and turbulent flow or
erythema all can cause clots that go everywhere!
§ DVT à embolism à lung BUT, if there is a hole in
the heart, DVT can go to brain via paradoxical
embolism**
o Consequences depend on
§ Vulnerability of tissue ischemia
§ Caliber of occluded vessel
§ Collateral circulation **kidney doesn’t have this!**
§ Fat and Marrow Embolism – usually trauma from broken bones
• Fat globules found in the pulmonary vasculature after fracture of
long bones, trauma or burns*
• Fat embolism syndrome: minority of symptomatic patients
o Pulmonary insufficiency, neurologic symptoms, anemia and
thrombocytopenia
o Fatal in 5-15% of cases
o 1-3 days after injury, develop tachypnea, dyspnea,
tachycardia, irritability and restlessness
o Diffuse petechial rash*
§ Amniotic Fluid Embolism – rare, mom fatality
• 5th most common cause of maternal mortality worldwide*
• Ominous complication of labor and immediate postpartum period
• 1/40,000 deliveries – 80% mortality
• Infusion of amniotic fluid or fetal tissue in the maternal circulation
via a tear in the placental membranes or rupture of uterine veins
• Sudden severe dyspnea (difficult breathing), cyanosis (blue) and
shock followed headache to seizures and coma
• Pulmonary edema and disseminated intravascular coagulation
• Biochemical activation of coagulation factors rather than
mechanical obstruction
§ Air Embolism

• Gas bubbles within the circulation can coalesce to form froth
masses that obstruct flow and cause ischemic injury
• Decompression sickness: sudden decreases in atmospheric pressure
• High pressures, increased nitrogen gas is dissolved in blood and
tissue, if ascend to rapidly, the nitrogen can form gas bubble within
skeletal muscle – “the bends”
o Scuba divers, or air in IV system
• Treatment in a decompression chamber
§ Others: cholesterol, tumor fragments, foreign bodies
- Infarct
o Area of ischemic necrosis caused by occlusion of arterial supply or venous drainage*
o Classified according to color and +/- infection
o Red infarcts
§ Venous occlusion*
§ Loose, spongy tissues where blood can collect
§ Tissues with dual circulations à GI and Lungs!
§ Tissues previously congested by venous overflow
§ Flow is reestablished to a previous site of occlusion and necrosis
o White infarcts
§ Occlusion of end-arterial circulation*
§ Compact tissues
• Myocardial infarctions*
o Wedge shaped – occluded vessel at apex
o Microscopic- ischemic coagulative necrosis (MOST INFARCTS ARE COAGULATIVE)
§ <4 hours no changes
§ 4-12 hours’ frank necrosis, acute inflammation – increased neutrophils!
§ Most infarcts a replaced by scar
o Liquefactive necrosis – brain
o Septic infarcts – infected cardiac valve vegetations embolize or when microbes seen
necrotic tissue
o Factors that Influence Infarcts:
§ Anatomy of the vascular supply
§ Rate of Occlusion
§ Tissue vulnerability to hypoxia
• fibroblasts<cardiac myocytes<neuron
o fibroblasts handle hypoxia best!
o Pics = lung infarct, spleen infarct and kidney infarct (depressions = fibrous scar
tissue)
§ Hypoxemia
- Shock
o A state in which diminished cardiac output or reduced effective circulating blood
volume impairs tissue perfusion and leads to cellular hypoxia
§ Heart cannot pump fast enough to supply blood to body!
o Septic Shock – systemic inflammation

§ Incidence rising to improvements in life support and growing risks of
immunocompromised patients
§ Increase prevalence of multidrug resistant organisms*
• Bacteria cause vasodilation and activate clot cascade causing a lack
of blood to systemic vasculature and organs
• DIC = body uses all of clotting factors
§ Most frequently triggered by gram-positive bacterial infections, followed by
gram-negative bacteria and fungi**
§ Host response to bacterial, viral or fungal infections
§ Systemic inflammatory conditions
• Endothelial activation
• DIC
• Metabolic derangements
• Organ failure and death
o Stages of Shock
§ 1) Nonprogressive phase – reflex compensatory mechanisms with organ
perfusion maintained
• Neurohumoral mechanisms: tachycardia, peripheral
vasoconstriction, renal conservation of fluid
§ 2) Progressive stage – tissue hypoperfusion, lactic acidosis
• Widespread tissue hypoxia
§ 3) Irreversible stage
o Morphology of Shock
§ Hypovolemic and cardiogenic – hypotension; weak, rapid pulse; tachypnea
and cool clammy cyanotic skin
• MI or trauma with heart not working!
§ Septic shock – initially be warm and flushed because of peripheral
vasodilation
• Hypertension
§ Cardiac, cerebral and pulmonary dysfunction, followed by electrolyte
disturbances
§ Renal insufficiency and fall in urine output
§ Coagulopathy – DIC = disseminated intravascular coagulopathy = no
platelets and no coagulation
§ 90% survival of hypovolemic shock in young patients, worse mortality rates
with septic shock
o Clinical Consequences
§ Hypovolemic / Cardiogenic
• Hypotension with weak, rapid pulse, tachypnea and cool, clammy
cyanotic skin
§ Septic Shock
• Hypotension – warm and flushed

Disease of The Immune System
- Innate and Adaptive Immunity
o Innate
§ Natural or Naïve
• Includes: Epithelium, neutrophils, macrophages, NK cells and
Complement (drills holes in germs)
• Occurs within hours
o Adaptive
§ Acquired or Specified
• Humoral
o Attacks extracellular microbes
o Antibodies from B-Cells
• Cell-Mediated
o Attacks intracellular microbes
o T-Cells
- Cells and Tissues of the Immune System
o Lymphocytes
§ T-cells
• Mature in the Thymus
• Locations
o Blood (60-67% of blood lymphocytes)
o Spleen (periarteriolar)
o Lymph nodes (interfollicular)
o Tonsils (interfollicular)
• Surface T-Cell Receptor recognizes antigen displayed by APCs
o On T-cell surface
o Recognizes antigen on APCs
o Composition:
§ Alpha and beta heterodimer
§ Non-covalently linked to 5 other proteins for signal
transduction
• CD3 (y, s and e proteins)
• 2 C proteins
• 2 Subtypes
o CD4+ = T-helper cells
§ CD4 binds to MHC II on APC
§ Cytokine Secretion
• Stimulate B cells à antibody production*
cross-talk*
• Stimulate macrophages
o CD8+ = Cytotoxic T-cells
§ Binds to MCH I on APC
§ Cytokine secretion

• To kill cells!
• Major Histocompatibility Complex = MHC = all need APCs*
o MHC I
§ Encoded by HLA – A, B and C genes
• Human Leukocyte Antigen = HLA
§ On all nucleated cells
§ Binds to CD8 (on killer cells)
§ Favors peptides made within the cell
o MHC II
§ Encoded by: HLA – DP, DQ and DR genes
§ On APCs
§ Binds to CD4 (on helper cells)
§ Favors peptides made outside the cell
o MHC III
§ Complement proteins
• C2, C3 and Bf
§ Tumor necrosis factor (TNF)
§ Lymphotoxin
• HLA – Human Leukocyte Antigen
o Each person has 6 HLA I classes (3 maternal and 3 paternal)
o Each person has up to 20 HLA II classes (due to mixing of
alpha and beta chains)
o Haplotype
§ The combination of HLA alleles in each individual
§ Implicated in transplantation complications
(rejection)
• Stimulates the immune system to attack
transplants
o HLA and Disease
§ HLA-B27 associated with:
• Ankylosing spondylitis (joints)
• Several post-infectious arthropathies
§ Some HLA-DR alleles associated with autoimmune
diseases
§ B-cells
• Mature in Bone Marrow
• Location:
o Blood (10-20% of blood lymphocytes)
o Spleen (follicles)
o Lymph nodes (follicles)
o Tonsils (follicles)
o Mucosa (MALT)
• Surface IgM or IgD recognizes antigen

o Does not require antigen association with MHC molecule, in
contrast to TCR on T-cells
o Don’t need APC – can see naked antigen!
• Immunoglobulins (Ig)
o Some (IgM, IgD) expressed on B-cell membrane
o Most (all but IgD) secreted by plasma cells (terminally
differentiated B-cells)
o 5 Classes of Immunoglobulins (correlates with heavy chain)
§ IgG (in blood- can cross placenta) *
§ IgA (major secretions and blood) *
§ IgM (on B cells and in blood)
§ IgE (attached to mast cells and in blood)
§ IgD (only on B-cells, not secreted)
o Structure: 2 heavy chains and 2 light chains (kappa or
gamma) with FC region that is recognized by other cells
§ NK cells (innate)
• Natural Killer Cells
o Part of innate system
o Do not express highly variable antigen receptors
o Recognize cells with DNA damage, then kills them
o Antigen Presenting Cells (APCs)
§ Dendritic cells
• The major cells to display antigens to T-Cells
• 2 types
o Interdigitating dendritic cell (in T-cell zones of lymphoid
tissues – between germinal centers)
o Follicular dendritic cell (in B-cell zones of lymphoid tissue –
in germinal centers of follicles)
§ Others – macrophages and B-cells
o Effector Cells
§ Mature B and T cells
§ Plasma cells (terminally differentiated B-cells)
o Tissues
§ Lymphoid Tissues
• Generative (primary): where maturation occurs
o Thymus
o Bone marrow
§ Hematopoietic and adipose tissues
§ 100 – age = % of hematopoietic tissue you should
have
• Peripheral (secondary) – where adaptation develops
o Lymph nodes
o Spleen
o Tonsils

o MALT
- Overview of Normal Immune Response
o Innate immune response
§ Early
• Epithelia = 1st
line of defense
• Phagocytes
o Neutrophils and Macrophages
• NK cells
• Complement system
o Capture and display of antigens
§ Dendritic cells in epithelium capture microbes and their antigens
§ Dendritic cells with antigens travel to lymph nodes to serve as APCs to naïve
T-cells
• MHC 1 present to CD8
• MHC 2 presents to CD4
§ Antigens not in APCs are recognized by B-cells
§ APCs are in the lymph nodes*
o Cell-mediated immunity
§ Antigen presentation activates T-cells
• Activated T-cells proliferate, differentiate into effector and memory
cells, effector T-cells migrate to site of antigen, secrete cytokines
o Activated cells make more cells with receptors à leave cells
and go to circulation
o CD4 = helper – finds antigen on APC – innate immune
response will enter and kill antigen
§ Effector Functions of CD4 T-cells (helper)
• Secrete IL-2, express receptor for IL-2
• Interaction of IL-2 and its receptor à
proliferation of antigen specific T-cells
(effector and memory cells)
o TH1 and TH2 = subcategories of
CD4 T-cells = hypersensitivity
o TH1
§ Produces IFN-y à
§ Activation of macrophages
§ Stimulation of B-cells to
make antibodies
o TH2 (worms)
§ Produce IL-4 à stimulation
of B-cells to become IgE –
secreting plasma cells
§ Produce IL-5 à activation
of eosinophils

§ Produce IL-13 à mucous
secretion
o CD8 = kills cells with antigen stat
§ Effector functions of CD8 T cells
• Activated CD8 T-cells differentiated into
cytotoxic T lymphocytes (CTLs)
• CTLs kill cells containing microbes
§ Cytokines
• Polypeptide products of many cells (esp. activated lymphocytes and
macrophages)
• Mediate inflammation and immune responses
• Pleiotropic – one cytokine affects many cell types
• Redundant – many cytokines induce same response
• Cytokines of innate immunity and inflammation
o TNF, IL-1, chemokines, IL-12, IFN-y
• Cytokines regulating lymphocytes in adaptive immunity
o IL-2, IL-4, IFN-y, IL-5
• Cytokines stimulate hematopoiesis
o Colony stimulating factors (CSFs)
o Humoral immunity (B-cells)
§ IgM and IgD on naïve B-cell surface recognize antigen à activation of B-cell
§ Helper T-cells and activated B-cells à B-cell proliferation
§ B-cells differentiate into plasma cells
§ Plasma cells secrete Igs
§ Antibody actions
• Neutralize microbes by binding to them
• IgG coats (opsonizes – target for phagocytosis) microbes, targeting
them for phagocytosis
• IgG and IgM activate complement
• IgA in secretions neutralizes microbes in Lumina of gut, respiratory
tract et al
• IgG is the only antibody that can cross placenta
• IgE coats helminths (worms), allowing mast cells and eosinophils to
kill (IgE à TH2 à kill worms)
o Virus not attached to cell when attacked by B-cell – more B-
cells make antibodies – plasma cells secrete antibodies
•
o Immune decline and immune memory
§ Decline of Immune Response
• Infection eradicated à death (apoptosis) of effector cells
• Memory cells (antigen specific) persist à more rapid immune
response on next exposure (why vaccines work)
- Hypersensitivity Reactions
o Causes of Hypersensitivity

§ Reactions against self-antigens = autoimmunity (low self-tolerance)
§ Reactions to microbes
§ Reactions to environmental antigens
o Hypersensitivity = host injury due to mechanisms that normally work to eliminate
infections
o Types of Hypersensitivity
§ 1 = immediate
• Allergies
• Inherited propensity for increased TH2 response à IgE production
(worms)
• IgE binds mast cells (sensitization)
• On re-exposure to antigen, antigen binds IgE on mast cell surface à
activation of mast cells (allergic reaction)
o Antigen / Allergen à TH2 à B-cell à Plasma à IgE à
Mast Cell à allergic reaction
• Allergic Reaction – Type 1
o Vasodilation and increase vascular permeability due to:
§ Histamine, PAF, LT C4, D4, E4, proteases and PGD2
o Smooth Muscle Spasm due to:
§ LTC4, D4 and E4, histamine, PGs, PAF, adenosine
o Cellular Infiltration (late-phase reaction) due to:
§ Cytokines, LT B4, eosinophil and neutrophil
chemotactic factors
• Mast Cell Mediators (pic)
• Early Phase Reaction
o Starts within 5-30 minutes
o Ends by an hour
• Late Phase Reaction
o Starts 2-8 hours later
o Ends within several days
§ Neutrophils are recruited by chemokines
§ Lymphocytes (TH2)
§ Eosinophils are recruited by eotaxin et al
• Produce
o Major basic protein à epithelial
cell injury
o LTC4 à increased inflammation
o PAF à increased Inflammation
• Clinical Type 1 Hypersensitivity
o Systemic Reaction
§ Anaphylaxis à shock
o Local Reaction
§ Skin à urticaria (hives)
§ Gut à vomiting and diarrhea

§ Lung à bronchoconstriction = hay fever or asthma
§ 2 = antibody -mediated
• Antibodies vs. antigen or cell surface or ECM (ab against RBCs)
• Opsonization of cells àphagocytosis (often in spleen)
o Hemolytic anemia or thrombotic thrombocytopenic purpura
(TPP) = antibodies against platelets)
• Complement Activation à recruitment of inflammatory cells
o Goodpasture syndrome (lung and kidney), acute rheumatic
fever, ANCA vasculitis
• Antibody mediated enzyme activation
o Pemphigus vulgaris (blisters)
• Antibody Mediated Cellular Dysfunction
o Mysasthenia gravis, graves’ disease (increase thyroid) and
hashimoto thyroiditis (decrease thyroid) , insulin resistant
diabetes mellitus and pernicious anemia
§ 3 = immune-complex mediated
• Normally, antigen – antibody complexes are phagocytoses and
removed
• Type 3 hypersensitivity occurs when the # of antigen-antibody
complexes overwhelms the systems à deposition of complexes à
inflammatory response
o Systemic immune complex disease
§ Pathogenesis
• Formation of complexes in circulation
• Deposition of complexes in various tissues
(vessel walls)
• Inflammatory reaction to deposits
§ Prototype = acute serum sickness
o Local immune complex disease
§ Prototype = Arthus Reaction
• Pre-formed antibodies in circulation
• Injection of antigen to skin
• Antigen-antibody complexes form at
injection site and diffuse into vascular walls
• Peak inflammatory response within 4-10
hours
• Type 3 Hypersensitivity Diseases
o Systemic lupus erythematosus, Post-infection
glomerulonephritis, Membranous glomerulonephropathy,
IgA nephropathy, Polyarteritis nodosa, reactive arthritis,
serum sickness, arthus reaction
§ 4 = T-cell mediated
• CD4 T-cells à type 4 hypersensitivity, delayed
o Prior antigen exposure à memory CD4 TH1 cells

o Re-exposure à recruitment of memory TH1 cells
o TH1 cells secrete IFN-y à macrophage activation
§ Activate macrophages
• Have increased phagocytic activity
• Have increased microbicidal activity
• Secrete à PDGF and TGF-beta à fibrosis =
recruit fibroblasts
o TH1 cells also secrete
§ IL-2 à T-cell proliferation
§ TNF à various effects on endothelium
§ Lymphotoxin à various effects on endothelium
o If prolonged à granuloma formation*
§ Granuloma = circumscribed collection of *
histocytes
o Examples of delayed type 4
§ Tuberculin skin test (PPD), tuberculosis,
histoplasmosis, leprosy, contact dermatitis (poison
ivy and oak)
• CD8 T-cells type 4 hypersensitivity, cytotoxic
o Exaggerated CD8 cytotoxic T-lymphocyte (CTL) response
§ Type 1 diabetes mellitus
- Rejections of Allographs
o Mechanisms of Rejection
§ Direct
• Host T-cells recognize graft MHC molecules as foreign with graft
dendritic cells as APC
o Host CD4 T-cell and graft MHC II à delayed type 4
hypersensitivity reaction
o Host CD8 T-cell and graft MHC I à cytotoxic type 4
hypersensitivity reaction (T-cell differentiation to CTL)
§ Indirect
• Host T-cells recognize graft MHC molecules as foreign with host
dendritic cells as APC
o Effector Mechanisms of Graft Rejection
§ T-cell mediated
• CTLs kill graft cells (esp. endothelial cells à thrombosis and
ischemia)
• CD4 T-cell secretes cytokines à delayed type 4 hypersensitivity
reaction
§ Antibody Mediated
• Host antibody vs. graft MHC antigen (and others) à antibodies bind
to endothelium à complement activation and WBC recruitment à
injury (like type 2 hypersensitivity reaction)

• Can be hyperacute if antidonor antibodies are pre-formed (rejection
within minutes to hours)
o Hyperacute = host kills the graft
o Improving Graft Survival
§ HLA Matching
• Living-related donor kidney
§ Immunosuppression = increased risk of infection! = must take meds forever!
• Complications of immunosuppression
o Infection
§ Bacteria, including opportunists
§ Fungi, including opportunists
§ Viruses
o Cancer
§ Lymphoma (EBV-related)
§ SCCA (HPV-related)
§ Kaposi Sarcoma (KSHV-related)
o Allogenic Bone Marrow Transplantation
§ Chemotherapy and or radiation à death of tumor cells and marrow
§ Donor bone marrow or stem cells then transplanted
• Gives person a new immune system
o Autogenous – given back your own marrow
§ Bone Marrow transplantation complications
• Rejection
o Host T-cells and host NK cells resistant to radiation /
chemotherapy
• Graft vs. Host disease (graft rejects (kills) host) – liver transplants
o Not limited to bone marrow transplantation
• Prolonged immune deficiency = increased infections
- Autoimmune Diseases
o ß Immunologic Tolerance (avoiding autoimmune disease)
§ Central
• Apoptosis of T and B cells that recognize self-antigen (not 100%
effective)
o T cells receptors and antigen receptors of B cells – don’t
want them to recognize self – if they do = apoptosis
§ Peripheral
• Anergy – inactivation of offending T or B cell
• Suppression of offending T or B cell
o Mediated by regulatory T-cells
• Activation – induced cell death
o Mechanisms of Autoimmunity
§ Genetic – inheritance of certain MHC / HLA alleles à
• Associations with MLC and MHC
§ Infection – antibody vs. microbe antigen cross reacts with self-antigen

• Determines when it declares itself – acquired
o Autoimmune Diseases
§ Rheumatoid arthritis (RA), Seronegative spondyloarthropathies,
polyarthritis nodosa and other vasculitis
§ Systemic Lupus Erythematosus (SLE)
• Multisystem disease, affects:
o Skin, kidney, serosal membranes, joints and heart
• Widely variable signs and symptoms
• Unpredictable clinical course
• Incidence = 1 in 2500
• More women than men, more black than white*
• SLE Criteria for Diagnosis
o Not defined by appearance – A TON ON SLIDE
o *Need at least 4 criteria required for diagnosis (not
necessarily simultaneous)
o ANA is a screen for lupus – antinuclear antibodies à
• SLE Autoantibodies – detected in lab – type 2 or type 3
hypersensitivity!
o Antinuclear antibodies (ANA) vs.
§ DNA, Histones, Non-histones bound to RNA,
nucleolar antigens
o Other autoantibodies vs.
§ Blood cells, phospholipids (lupus anticoagulant)
*misnomer*
• Prothrombic state
• Antibodies against thrombus = makes them
more susceptible to blood clots!
• SLE Variables
o Genetic
§ 25% monozygotic twin concordance
§ 1-3% dizygotic twin concordance
§ Family members have increased risk
§ Association with HLA-DR2 and DR3 alleles
§ 10% with complement deficiency
o Non-genetic
§ UV light exacerbates skin lesions
§ Cigarette smoking
§ Can be drug-induced
• Procainamide, hydralazine or female
hormones
• ß SLE Morphology
o Acute necrotizing vasculitis
o Red is dead!
o Lupus patients have issues in kidney

o Glomerulonephritis * don’t memorize*
§ Class 1 – normal LM
§ Class 2 – mesangial
§ Class 3 – focal proliferative
§ Class 4 = diffuse proliferative
§ Class 5 – membranous
§ Class 6 – end-stage
§ Class 3 and 5
§ Class 4 and 5
o Skin
§ Malar rash (butterfly rash)
§ Discoid rash
§ Photosensitivity – UV light sensitivity
o Joints
§ Usually not striking morphology
o CNS
§ Small vessel angiopathy (intimal proliferation)
§ Thrombosis (antiphospholipid syndrome)
• Lupus anticoagulant
• If in brain = stroke
§ Microinfarcts
§ Premature atherosclerosis
o Spleen
§ Splenomegaly*, thickened capsule, follicular
hyperplasia, perivascular “onion skin” fibrosis ß
• Concentric layers of fibrosis
o Serosal Membranes
§ Effusions (too much fluid – pleural and peritoneal
caivities) and Exudates (protein-rich effusions)
o Heart
§ Pericarditis, myocarditis and or Libman -Sacks
Endocarditis – thrombi on surface of valves =
vegetations! Sterile endocarditis = no bacteria but
can embolize*
o Lung
§ Interstitial fibrosis
• SLE Clinical Course
o Highly variable – can have flare ups
§ Mild to death within months
o Usually remissions and relapses
o Survival
§ 90% 5-year survival
§ 80% 10-year survival
o Death usually due to: renal failure, infection or diffuse CNS

§ Sjogren syndrome disease
• Dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia)
• Due to immune-mediated destruction of lacrimal and salivary glands
o Destroy salivary and lacrimal glands*
• 2 forms
o Primary (sicca syndrome) – no salivary or lacrimal glands
o Secondary
§ Associated with: RA, SLE, polymyositis, systemic
sclerosis, vasculitis and thyroiditis
• Clinical Course
o About 90% in 35-45-year-old women* autoimmune = more
common with women!!
o About 60% with other autoimmune disorder
o Extra glandular manifestations
§ Synovitis, pulmonary fibrosis, peripheral
neuropathy
§ 40X increased risk of B-cell lymphoma (b-cell
cancer)
§ Systemic Sclerosis (Scleroderma) (SS)
• Excessive fibrosis throughout body (not just skin) – systemic!
o ß Diffuse atrophy!
o Limited (mostly skin, till late in course) = CREST syndrome*
§ Calcinosis
§ Raynaud phenomenon – response to cold air
§ Esophageal dysmotility – difficult swallowing
§ Sclerodactyly – hardness of fingers
§ Telangiectasia – vessels
• Systemic Sclerosis Morphology
o Skin
§ Diffuse sclerotic atrophy
§ Histology
• Edema, perivascular inflammation,
thickened vascular basement membranes
(capillaries and small arteries)
• Eventual replacement of edema by fibrosis
• Less glands, more fibrosis
o Alimentary Tract (in about 90%)
§ Atrophy and fibrous replacement of Muscularis
propria (drives peristalsis) à stiffness
§ Especially affects esophagus à GERD
o Musculoskeletal system
§ Synovial hyperplasia and inflammation
§ Subsequent fibrosis*

§ About 10% with myositis* - inflammation of skeletal
muscle
o Lungs (less than 50%)
§ Pulmonary hypertension, interstitial fibrosis
• High BP
o Kidneys (about 66%)
§ Interlobular artery intimal fibrosis, hypertension
• High BP
o Heart
§ Patchy myocardial fibrosis*, arteriolar thickening
o *sclerosis = made harder with deposition of collagen,
fibrosis = deposition of collagen*
• SS Clinical Course
o 1 men to 3 women = more women!
o 50s to 60s
o Most have Raynaud phenomenon
§ Cold-induced arterial reversible vasospasm
• Finger will change from White à blue à
red when cold
• No blood flow to digits
o Course difficult to predict
o 35-70% 10-year survival
§ Inflammatory Myopathies (don’t care)
• Polymyositis – skeletal muscle
• Dermatomyositis – skin and muscle
• Inclusion body myositis - common
§ Mixed CT Disease
• Presentation with features of SLE, polymyositis and SS
o Arthritis, hand edema, Raynaud phenomenon, esophageal
dysmotility, myositis, deceased RBC and WBC, fever,
lymphadenopathy, hypergammaglobulinemia
§ Polyarteritis Nodosa and other Vasculitides
• Necrotizing inflammation of blood vessels with probable immune
pathogenesis
• More to come (when blood vessel disease is covered)
- Immunodeficiency Diseases
o Primary – uncommon, inherited, typically present in childhood – iatrogenic = caused
by meds – meds to decrease immune system
§ X-linked agammaglobulinemia (XLA, Bruton Disease)
o Alpha beta and gamma regions of gel electrophoresis = no
gamma immunoglobulins or other gamma proteins in
blood! *
• Pre-B-cells cannot become B-cells
• No immunoglobulin production (agammaglobulinemia)

• Decreased B-cells in blood – not in lymphoid germinal centers
• Absent plasma cells
• Underdeveloped germinal centers
• Normal T-cell mediated responses
• Presents after 6 months of age (after mom’s abs are gone) passive
IgG is gone! Nursing = IgA passive after = unable to make own abs
o Recurrent bacterial infections
o Some viral infections
o Giardiasis
• X-linked Disease = so more men than women***
• Therapy – intravenous immunoglobulin
• 20% have associated autoimmune disease
• Genetic cause BTK mutation – single gene mutation***
§ Common variable immunodeficiency
• Heterogenous group of disorders with a low Ig production = not a
single gene = BTK is normal! – not making antibodies
• Men = women
• Presentation in teens or 20s*
• Clinical manifestations similar to XLA
• Associated with autoimmune disorders
• Associated with lymphoma
• Most with unknown genetic cause
§ Isolated IgA deficiency – cannot class switch*
• The most common primary immunodeficiency***
• MOST COMMON immunodeficiency is IgA deficiency******
o Incidence = 1 in 700 white
• Increased sinopulmary and GI infections
• Associated with autoimmune diseases
• Unknown genetic cause
§ Hyper IgM syndrome – IgM cannot change to IgG (targets cells for
phagocytosis)
• Impaired heavy-chain class (isotype) switching – failure of class
switching!
o Normal or increased IgM*
o Absent IgG à recurrent pyogenic infections (no
Opsonization)
o Absent IgA and IgE*
• About 70% X-linked (gene for CD40L)*
• Also decreased cell-mediated immunity à recurrent intracellular
pathogen infections
§ Thymic hypoplasia (DiGeorge)
• *Congenital defect in thymus development à absence of T-cells –
where T cells mature*

o B-cells and Ig are unaffected
• Can be parathyroid hypoplasia à decreased Ca+2
• CATCH-22***
o Cardiac abnormality (tetralogy of Fallot) – 4 probs in heart
o Abnormal facies
o Thymic aplasia *** main problem!
o Cleft palate
o Hypocalcemia / Hypoparathyroidism *
o 22q11.2 deletion – long arm of 22 chromosome
§ Severe combined immunodeficiency (SCID)*
• Genetically Heterogeneous – not single gene disorder – prevent
from cd8 or cd4 – combined because CD4 cant help B side – so,
hurts both sides of immune system
o About 50% are X-linked
§ Gene mutations for y chain of cytokine receptor
o 40-50% are autosomal recessive (AR)
§ Adenosine deaminase deficiency (50%)
§ Various other genetic causes (50%)
o Defects in humoral and cell mediated immunity
• Hypoplastic Lymphoid Organs
o Thymus, lymph nodes, tonsils, MALT
• Severe and recurrent infections
o Bacteria, viruses, fungi, protozoa
• Therapy: bone marrow transplantation*
§ Wiskott-Aldrich Syndrome exist
§ Innate immunity deficiencies
• Complements = drill holes in germs*
• Complement Abnormalities exist
• Phagocyte Deficiencies
o Chronic granulomatous disease***
§ NAPDH oxidase deficiency à impaired neutrophil
killing activity
§ Respiratory burst that releases free radicals –
neutrophil eats germ but cant kill it* pusà
granuloma!
o Leukocyte adhesion deficiencies à impaired phagocytosis
• Acquired Immune Deficiency Syndrome (AIDS)****
o Caused by human immunodeficiency virus (HIV) =
retrovirus*
§ Targets CD4+ cells! – assists T and B cells
o Infection of CD4 T-cells è decreased CD4 T-cells
o About 5,000,000 new cases each year
o 5th
most common cause of death in USA for 25 – 44 yr
olds**

o Transfusions = for hemophiliacs – need more proteins so
transfusions from more than one person
o Common in asia and Africa
o AIDS is decreasing = good therapy
o HIV Transmission
§ Sexual
• 75% of HIV infections are sexually
transmitted
• More male to male or male to female*
than female to male
o Harder for women to spread it!
• Virus in semen (lymphocytes and
extracellular) and vaginal and cervical cells
§ Parenteral
• Drug abuse – sharing needles
• Hemophiliacs receiving factor 8 or 9
concentrates
o Now we synthesize factors 8 and 9
• Blood product transfusion
o Risk = .00014% or 1 in 676,000 ****
• Needle stick injury
o Risk = .3% (1 in 3,300)
§ Hep B = 30%
§ Mother to infant
• Transplacental, intrapartum or breast milk
o Utero, delivery or nursing
o HIV genome
§ Retrovirus = so uses RNA à DNA with reverse
transcriptase enzyme
• Gp41 (stick) and gp120 (candy)
§ Viral polymerase makes mistakes (1/10^5
nucleotides)
• Mistake with outer coating
• A lot of errors with stick things – so virus is
hard!
§ Most mistakes in coding section for envelope
glycoproteins à variability of the envelope
• Since envelope is target of immune system,
vaccine is difficult
o HIV Subtypes / clades
§ Group M (Major)
• More common than group O
• Divided into subtypes called clades (A-J)
• Clade B = most common in Europe and USA

• Different clades have differing abilities to
infect dendritic cells à variable
transmission rates
§ Group O (outlier)
o HIV / AIDS Pathogenesis
§ Viral gp120 binds to host CD4 (receptor for this
virus!!)*** à gp120 changes conformation
§ Viral gp120 binds to CXCR4 (T-cells - coreceptor) or
CCR5 (macrophages)
§ Viral gp41 inserts into host cell membrane
§ Virus fuses with host cell membrane à viral
genome (RNA) enters cell – genome injected into
cell!
§ Reverse transcription* à proviral cDNA
• cDNA can remain in cytoplasm
• in dividing T-cells, cDNA is integrated into
host genome
o can remain latent (non-transcribed)
for months-years
o can be actively transcribed à
formation of new viruses
o Resistance to HIV
§ Defective CCR5 à decreased infectivity
• In USA
o 20% white are heterozygous for
defective CCR5 (co-receptor*) *
o 1% whites are homozygous for
defective CCR5
o HIV: Mechanisms for killing CD4 T-Cells
§ Viral replication à infected cell lysis
§ Infected T-cells killed by CTLs (CD8s kill CD4s)
§ HIV antigens cause activation (and subsequent
apoptosis) of uninfected T-cells
§ Uninfected T-cells bind soluble gp120 (candy) à
aberrant signaling à apoptosis
§ CD4 to CD8 goes from 2:1 to 1:2 **
§ Precursor T-cells can be infected and die à
decrease ability to replace lost cells
o HIV and Macrophages
§ HIV can replicate in nondividing macrophages (not
true in T-cells)
• Macrophages also have CD4s! and don’t
really lyse = so reservoir for more virus even
if all CD4s are killed!

§ Infected macrophages shed few virions but contain
many
• Also, resistant to lysis
o Macrophage serves as virus
reservoir
o HIV and Dendritic Cells
§ Infected mucosal (interdigitating) dendritic cells
transport virus to lymph node à
• Infection of CD4 T-cells
• Infection of follicular dendritic cells
o Follicular dendritic cells become
virus reservoirs
o Follicular dendritic cells infect CD4
T-cells
o HIV and B Cells
§ Polyclonal B-cell activation à
• Hypergammaglobulinemia** too many
abs!! – gel electrophoresis gamma
• Circulating immune complexes
§ Impaired B-cell response (mult. causes, including
decreased T-cell help) à increased infection with
encapsulated bacteria
o HIV CNS Pathogenesis
§ Poorly understood, morphology less striking than
clinical Sx
§ Main CNS cells infected: macrophage and
microglia**
o HIV Natural History
§ Acute Phase (in 50-70%)
• 3-6 weeks after infection
• Nonspecific viral illness
• Seroconversion (ex- detectable production
of anti-HIV abs) occurs 3-17 weeks after
exposure à end of acute phase ***
§ Chronic Phase (100%)
• Progressive CD4 T-cell loss
• Continued viral replication
• Can last several years
• Development of persistent
lymphadenopathy (enlarged lymph nodes –
immune system crashes) heralds evolution
to next phase
§ Crisis Phase (AIDS)*** name change!

• Decreased host defense à increased
infections
• Increased viremia
• CD4 count < 500
§ Most reach crisis phase (AIDS) in 7-10 years
§ Rapid progressors reach crisis phase in 2-3 years
§ Nonprogressors (<5%) are asymptomatic with
stable CD4 counts > 10 years
o CD4 Counts****
§ > 500 = usually asymptomatic
§ 200-500 = early symptoms
§ <200 = severe immunosuppression = AIDS defining
finding **** - CD8 plummets too!
o AIDS-Defining Illnesses in HIV and person
§ Protozoal and helminthic
• Cytosporidiosis, isosporidiosis,
pneumocystosis, toxoplasmosis
§ Fungal
• Candidias, crytococcosis (CNS),
coccidiomyocosis (disseminated),
histoplasmosis (disseminated)
§ Bacterial
• Mycobacteriosis, nocardiosis, Salmonella
infection – tuberculosis
§ Viral
• CMV, HSV- herpes simplex virus, VZV-
chicken pox, progressive multifocal
leukoencephalopathy (JC virus)
§ Neoplastic
• Kaposi sarcoma, Burkitt/immunoblastic
lymphoma, primary CNS lymphoma* only
happens here**, uterine cervical cancer
§ Laboratory Finding
• CD4 < 200 **** diagnosed as AIDS
o Secondary – common, often iatrogenic
§ Malnutrition, infection, cancer, renal disease, sarcoidosis, therapeutic, AIDs
- Amyloidosis
o Diverse group of diseases with extracellular deposition of amyloid à tissue damage
and decreased function
o Amyloid (means starch-like* misnomer)
§ misfolded proteins forming insoluble fibrils
§ > 20 different proteins can misfold to form amyloid
§ Randomly oriented, nonbranching fibrils**
§ Fibril diameter of 7.5 – 10 nm*

§ Fibrils = polypeptide chains (in beta pleated sheet formation) wound
together in groups up to 6
§ Staining characteristics led to the misnomer meaning starch like
o Amyloidosis Pathogenesis
§ High conc. Of misfolded forms – 20 proteins misfolding into beta sheets****
• With aging (senile amyloidosis)
• With increased production of the protein (chronic inflammation)
• With decreased excretion of the protein (dialysis associated)
• Mutation à protein with tendency to misfold (hereditary)
• Limited proteolysis à protein that misfolds (Alzheimer’s disease)
o Amyloid Morphology
§ Light Microscopy
• Extracellular hyaline, congophilic with apple green birefringence***
o Appear hyaline under LM = use congo red stain for
amyloids!
• Polarize filter = something in tissue rotate plane of polarization! –
rotate light and add green color****
§ Electron Microscopy
• Nonbranching, randomly oriented fibrils (pickup sticks), fibril
diameter = 7.5-10nm
§ Amyloid in the Kidney
• Mostly nodular glomerular deposition – pt keeps peeing proteins!
• Also interstitial and perivascular
§ Amyloid in the Spleen
• Moderate to marked splenomegaly
• 2 patterns
o Sago spleen = deposition in follicles (gross appearance is
tapioca granules)
o Lardaceous spleen = deposition in splenic sinuses
§ Amyloid in the Liver
• Massive hepatomegaly
• Pale, gray, waxy cut surface
§ Amyloid in the heart – feels like candle wax
• Diffuse deposition between myofibers
o Amyloid Proteins
§ ***AL protein (from amyloid light chain) – called primary but clearly
secondary!
• Produced / made by plasma cells
• Composed of Ig chains (complete or partial)
• Associated with B-cell proliferations (mult. myeloma** - plasma cell
cancer) – misfolded protein is part of light chain of antibody*
§ ****AA Fibril (amyloid-associated)
• Derived from serum amyloid associated (SAA) protein
o Made in liver as part of “acute phase reaction”

• Associated with long-standing chronic inflammatory diseases
o Inflammatory response – liver pumps out proteins = acute
phase reactants = SAA which misfolds as AA = amyloid **
§ A-beta-amyloid
• Derived from glycoprotein amyloid precursor protein (APP)
• Found in cerebral lesions of Alzheimer’s disease*
§ ATTR
• Abnormal form of transthyretin (TRR)*
• Results from gene mutation
• Typical of familial amyloid polyneuropathies
§ A-beta-2 microglobulin
• Part of MHC I molecule*
• Normally excreted through kidney
• Associated with dialysis-related amyloidosis – dialysis machine
cannot get rid of it well*
§ A Cal
• Precursor protein is calcitonin
• Associated with medullary thyroid cancer
§ AIAPP
• Precursor protein is islet amyloid peptide
• Associated with pancreas amyloid in diabetes mellitus
§ AANF
• Precursor protein is atrial natriuretic factor
• Found in isolated cardiac atrial amyloidosis
o Classification of Amyloidosis
§ By organ involvement
• Systemic (generalized)
• Local
o Single organ deposition of amyloid
o Often associated with chronic inflammatory infiltrate
o Typically, AL amyloid
o Endocrine Amyloid
§ Associated with endocrine neoplasms
• Medullary carcinoma of the thyroid – 10s?
• Islet cell tumor of pancreas
• Pheochromocytoma
• Undifferentiated carcinoma of stomach
§ Associated with diabetes mellitus type 2
• Amyloid deposition in the islets of
Langerhans
o Amyloid of Aging
§ Senile systemic amyloidosis

• Heart disease is main clinical problem,
therefore, senile cardiac amyloidosis*
• ATTR
§ By clinical setting
• Primary amyloidosis
o Associated with immunocyte abnormality (mult. myeloma =
plasma cell cancer)
o Typically, systemic deposition of AL amyloid*
o Associated with Bence Jones Proteins (Ig light chains) in
urine
• Secondary amyloidosis
o Reactive amyloidosis
o Typically systemic deposition of AA protein*
o Associated with prolonged chronic inflammation
§ Autoimmune diseases (RA)
§ Skin popping = form of drug abuse* IV drug abuse –
small amount in subcutaneous = more sustained
but less intense*
§ Infectious Disease
• Tuberculosis, bronchiectasis, osteomyelitis
• Hereditary
o Familial amyloidosis
o More than 1 form, typically rare and geographically limited
§ *Familial Mediterranean fever (autosomal
recessive)
• Mutation in gene for pyrin à increased
inflammation following minor trauma* à
AA amyloidosis
• AA protein (same as reactive amyloidosis)**
§ Amyloid polyneuropathies (autosomal dominant)
• ATTR
o Amyloidosis Clinical Features
§ Can be unsuspected finding at autopsy
§ Renal involvement à proteinuria
§ Liver involvement à hepatomegaly = usually no clinical dysfunction
§ Spleen involvement à splenomegaly = usually no clinical dysfunction
§ Cardiac involvement à cardiomegaly
• Conductive disturbance à arrhythmia
• Restrictive cardiomyopathy
o Amyloidosis Diagnosis and Prognosis
§ Diagnosis requires biopsy (tissue is the issue) *** LM and EM
§ Diagnosis à additional workup
• To determine subtype of amyloidosis
• To diagnoses underlying cause

§ Mean survival (general amyloidosis) = 1-3 years usually AL
Environment and Nutritional Pathology
- Environmental Diseases
o Lesions and diseases caused by chemical or physical injuries or nutritional origin
o Voluntary or Involuntary
o Major Public Health Concern
- Tobacco
o Cigarettes, cigars, pipes & snuff
o Most preventable cause of death
o More morbidity/mortality
§ 390,000 premature deaths/year in the US
§ 10 million cases of chronic diseases
o Dose-dependent survival in pack years
o PACK YEARS = # packs x # of years = how to quantify smoking habit
o Noxious chemicals, >2000, >60 carcinogens
o Nicotine – addictive and acute effects of smoking
§ Smoking is a gateway to other cancers
o 70 carcinogens and polyaromatic hydrocarbon = main carcinogen in many cancers*
o Smoking consists of two chronic diseases
o Lung disease à COPD – chronic bronchitis and emphysema
§ Pure chronic bronchitis
• Large airways (trachea and bronchi) – chronic bronchitis
o Mucous hypersecretion
§ Mucous blocks airways
o Inflammation
• Small airways (bronchioles) – chronic bronchioles
o Peribronchiolar fibrosis
o Airway obstruction
§ Pure emphysema
• Acinus (respiratory bronchiole, alveolar ducts and alveoli)
o Loss of elastic recoil
o Emphysema
o Air exchange is difficult due to damaged alveoli
§ à emphysema on top à
• Neutrophil Elastase
o Increased due to smoking à tissue damage and increased
neutrophils and macrophages that break down tissues
o Atherosclerosis and Heart Disease
§ Increased platelet aggregation – clots
§ Decreased myocardial oxygen supply
§ Myocardial infarction
§ Multiplicative effect with hypertension and hypercholesterolemia
o Lung Cancer

§ Related to "pack history"
§ Carcinogens in cigarettes - polycyclic aromatic hydrocarbons
§ Causes 80-90% of all lung cancer – NSCL (non-small cell lung carcinoma)/SC
(small cell lung carcinoma)
• Different treatments but smoking usually gives you both
§ Synergistic affect with other environmental exposures
o Smoking and Cancer
§ Oral cavity
§ Larynx
§ Esophagus
§ Bladder
§ Pancreas
• Can also cause other cancers
o Second-Hand Smoke
§ Relative risk of lung cancer in nonsmokers exposed to smoke is 1.3 X
unexposed
§ Increased risk of ischemic heart disease, MI, respiratory infections and
asthma
o Fetal Tobacco Syndrome
§ Increases the risk of spontaneous abortions and preterm birth
§ Placental abruption
§ Intrauterine growth restriction (SGA)
§ SIDS
- Lead Toxicity / Poisoning
o Lead sources: air and food
o Absorption: Lungs and GI tract*
o Occupational Exposure
§ Mines, foundries, batteries, and spray paints
o Non-occupational Exposure
§ Flaking lead paint – houses before 1978
o 80% absorbed in bones, developing teeth
o 5-10% remains in blood
o Excreted in kidneys
o Major anatomic targets:
§ Bone marrow and blood
§ Nervous System
§ GI and Kidneys
o Skeleton and Lead Toxicity
§ Competes with calcium and binds phosphates
• Lead is absorbed as a dysfunctional calcium depositions = called
lead lines
§ Half-life of 20-30 years
§ Radiographic lead lines
§ Growth

o Hematopoietic System
§ High affinity for sulfhydryl groups
§ Interferes with 2 heme synthesis enzymes
• Lead interferes with heme synthesis à develop anemia with
basophilic stippling*** - have low RBCs due to crappy hemes
§ Increased free protoporphyin
• Lesions on RBCs = basophilic stippling = clumps of ribosomes
• Measure increased protoporphyin = lead poisioning
§ ß Anemia with basophilic stippling
o GI and Kidney – Lead Toxicity
§ GI: Lead "Colic" (stomach pain) by extremely severe, poorly localized
abdominal pain
§ Kidneys: proximal tubular damage with intranuclear inclusions.
§ Chronic damage - interstitial fibrosis and renal failure
o Nervous System
§ Young children - sensory, motor and psychological impairments
§ Severe changes in CNS: brain edema, demyelination of white matter and
necrosis
§ Adults: peripheral demyelinating neuropathy. Extensor muscles of the
wrist and fingers, wrist drop and foot drop
• Children are affected more acutely* due to 50% absorption of
eating lead paint – IQ problems or encephala = brain swelling /
inflammation
• Adults = usually more at work, myelin is screwed up and messes
with nerves
• Brain, digestive, kidneys and cardio
o Lead Paint Laws
§ Congress passed the Residential Lead-Based Paint
§ Hazard Reduction Act of 1992, also known as Title X
§ 5ug/ml = LEAD POISIONING
§ 1 cm^2 lead paint chip = 175,000 ug
- Carbon Monoxide
o Systemic asphyxiate (suffocation) that is an important cause of accidental and
suicidal death.
o Colorless, odorless gas made during incomplete combustion of fossil fuel, tobacco.
o Carbon-based gas
§ Hemoglobin – 4 spots for O2, CO2 binds to hemoglobin with a 200X more
affinity, impairs release of O2
o CO has 200 fold higher affinity for Hgb than O2, increases heme affinity for O2,
impairs release of O2 from Hgb
o Chronic exposure in tunnel and underground garage workers, highway toll booths
o In a small, closed garage, the average running car can produce sufficient CO to
induce coma or death within 5 minutes
§ More CO = more symptoms

o Acute and chronic symptoms
o Cherry red lividity – post-mortem finding = blood pooling
o Necrosis of globus pallidus = CO has a high affinity for this part of the brain
o
- Alcohol Abuse
o Half of Western adults drink alcohol
o 5-10% are chronic alcoholics.
§ >10,000,000 chronic alcoholics in US
o Causes > 100,000 deaths/year in US.
§ 50% are accidents, homicides, suicides.
§ 25% are due to cirrhosis of the liver
o 1.8 million deaths/year worldwide are due to alcohol use.
o Chronic alcoholics shortened life due to damage to liver, G.I., CNS, cardiovascular
system and pancreas.
o Alcohol Metabolism
§ Absorbed unaltered in the stomach and small intestine
• Amount exhaled = amount in bloodstream because it is absorbed
unaltered
§ Distributed to all tissues in direct proportion to the blood level
§ Less then 10% is excreted unchanged in urine, sweat or breath
§ Amount exhaled is proportional to the blood level
o Blood Alcohol Levels
§ Effects vary by age, sex, body fat.
§ 80 mg/dL is legally drunk driving:
§ 8 beers, 12 oz wine, 6 oz whiskey
§ 200 mg/dL drowsiness
§ 300 mg/dL stupor.
§ >300 mg/dl can cause coma, respiratory arrest.
§ Chronic alcoholics tolerate 700 mg/dL because induction the metabolism by
cytochrome P450 system.
§ The effects of alcohol also vary by age, sex, and body fat.
• Can be due to fat distribution and metabolism
o Alcohol Metabolism (cont)
§ Alcohol oxidized to acetaldehyde by 3 enzyme systems in the liver.
§ Acetaldehyde metabolized by acetaldehyde dehydrogenase to acetate.
• All occurs in the liver
• ADH and ALDH
o Variations in Metabolism
§ Half of Asians have mutation in gene that encodes for acetaldehyde
dehydrogenase
§ Results in low enzyme levels
§ Homozygous state causes flushing, tachycardia, hyperventilation after
drinking alcohol due to accumulation of acetaldehyde
• Accumulation of acetaldehyde = ASIAN FLUSH!

o Acute Alcoholism
§ Mainly CNS effects
• Stimulation and disordered activity
• Depression of medullary centers – regulate respiration leading to
respiratory arrest
§ Acute gastritis and ulceration
§ Hepatitic steatosis (reversible) = FATTY LIVER
o Chronic Alcoholism / Alcohol Pathology
§ Liver
• Fatty change/steatosis with even moderate alcohol intake.
• NAD is required for fatty acid oxidation in the liver
• Alcohol oxidation by ADH depletes NAD+
required for fatty acid
oxidation.
• Accumulation of fat in the liver of alcoholics.
• Increase in the NADH/NAD ratio leads to lactic acidosis.
• Chronic alcohol use causes alcoholic hepatitis and cirrhosis.
• Cirrhosis (fibrosis of liver) is associated with portal hypertension,
risk of hepatocellular carcinoma.
o Portal hypertension à esophageal bleeding
§ Heart
• Dilated cardiomyopathy (alcoholic cardiomyopathy)
• Increased incidence of hypertension
• Liver injury decreases HDL
o Thin myocardium and ventricles are dilated
§ Esophagus
§ GI
• Acute gastritis, ulcer
• Esophageal varices due to portal hypertension/cirrhosis
• Pancreatitis
§ Pancreas
§ Brain
• Cerebral atrophy
• Cerebellar degeneration
• Optic neuropathy
• Necrosis of Mammillary Bodies
o Brain of alcoholic resembles a dementia pt.
§ Nutritional deficiencies
§ Cancers
• Oral cancer (related to acetaldehyde), esophagus, liver, possibly
breast cancer in women.
• Risk increased by concurrent smoking and use of smokeless
tobacco.

• Acetaldehyde associated with alcohol-induced laryngeal and
esophageal cancer
• Patients heterozygous for ALDH2*2 allele who drink have higher risk
of developing cancer of esophagus.
o Vitamins and Alcohol
§ Alcohol is an empty source of calories
§ Malnutrition and deficiencies particularly of B vitamins.
§ Thiamine (B1) deficiency causes peripheral neuropathy, Wernicke-Korsakoff
syndrome. – BeriBeri!!
• Wernicke’s Syndrome
o Neuro-psychiatric disorder
o ophthalmoplegia (paralysis of eye movements),
o abnormal stance and gait
o markedly deranged mental function
o Fetal Alcohol Syndrome
§ Microcephaly
§ Growth retardation
§ Facial abnormalities in the newborn
§ Reduction in mental functions as the child grows older
§ Consumption during 1st
trimester most harmful.
§ Prevalence of frequent/ binge drinking among pregnant women is
approximately 6%
§ FAS affects 1 to 4.8 per 1000 children born in the US.
- Thermal Injury -Burns
o 450,000 persons per year
o 80% by fire or by scalding
o 3,500 persons die each year
o 45,000 hospitalizations – 95% survival
o Depth
o % surface area
o Internal injury from inhalation hot toxic fumes
o Promptness of therapy (fluid electrolyte, infection control).
o Over 50% of body surface is
o potentially fatal
o Burn Depthless
§ Superficial burns (formerly known as first-degree burns) are confined to the
epidermis.
§ Partial thickness burns (formerly known as second-degree burns) involve
injury to the dermis.
• Pink or mottled with blisters – painful
§ Full-thickness burns (formerly known as third-degree burns) extend to the
subcutaneous tissue and beyond
• White, charred, dry and painless burns
o Burn Physiology

§ Rapid (within hours) shift of body fluids into the interstitial compartments
§ Widespread vascular leakiness leads to pulmonary edema
§ Hypermetabolic state – excess heat loss and need for nutritional support
§ Shock, sepsis, and respiratory insufficiency - greatest threats to life in burn
patients.
§ Airway and lung injury develops within 24-48 hours
§ Direct effect of heat, inhalation of heated air and noxious gas
§ Inflammation and swelling
§ Partial or complete airway obstruction
§ Pneumonitis formed from burning plastics
o Burns
§ Burn site ideal for growth of organisms, colonization of bacteria
§ Most common cause – P. Aeruginosa, S. aureus and Candida
§ Direct bacteremic spread and release of toxic substances
§ Pneumonia or Septic Shock, Renal Failure and Acute Respiratory Failure
- Hyperthermia
o Heat cramps – loss of electrolytes via sweating
o Heat exhaustion – most common hyperthermic syndrome
§ Prostration and collapse
§ Failure of the CV to compensate for hypovolemia
§ Decreaed fluid intake, increased heat exposure, increased activity, body
temp drops* - attempt to cool off body, headache, weakness, skin moist,
cool and clammy, decreased bp, increased pulse, anxiety and confusion
o Heat stroke
§ Thermoregulatory mechanisms fail
§ Sweating ceases
§ Core body temp rises to more than 40 degrees
§ Multiorgans failure rapidly fatal
§ Rhabdomyolysis – muscle necrosis, sustained contractions of skeletal
muscle = skeletal muscles break down!
§ Malignant hyperthermia
• No more sweating
o Associated with high ambient temperature, high humidity and exertion
o Older adults
o Intense physical stress
o Persons with CVD at high risk
- Ionizing Radiation – skip!
- Clinical Case
o A 54 year-old woman presented with a 2-day history of a painful enlarging rash over
her face, ears, breasts and extremities.
o Arthralgias of his hands but denied fever, chills, sore throat and cough
o History of chronic back pain, chronic Hep C infection, intermittent cocaine use.
o No drug allergies
o Only medications – ibuprofen for pain

o Lab Studies
§ Laboratory studies showed
§ Neutropenia, Lymphopenia
§ Detection of antineutrophil cytoplasmic antibodies (ANCA) by IF were
positive for p-ANCA and c-ANCA
§ Proteinase-3 Ab titer was 1:320
• Biopsy à
§ Toxicologic screening of the urine was positive for cocaine and opiates
§ Treatment with prednisone and methylprednisone did not improve
condition
§ Patient underwent extensive debridement of necrotic tissue
o Clinical Toxicology
§ Hundreds of thousands of clinical toxins
§ 24 drugs or agents account for 80% or more of intoxications treated
§ Frequency of certain drugs is location dependent
§ Scope of clinical toxicology depends on
• Pattern of local drug use
• Available resources of institution
o Clinical Considerations
§ Time and date of the suspected exposure along with the time and date of
sample collection
§ History from the patient or witness
§ Assessment of the physical state
o Analytical Considerations
§ No single analytical technique is adequate
§ Several approaches in combination are required
§ Simple, inexpensive and rapid spot tests – immunosassays and
chromatographic and/or mass spectrometric techniques
§ Speed of analysis (TAT)
§ Quantitative determinations guide management
§ Knowledge of pharmacology and pharmokinetics
§ (1) acetaminophen, (2) carbamazepine, (3) digoxin, (4) ethanol, (5) ethylene
glycol, (6) iron, (7) isopropanol, (8) lithium, (9) methanol, (10)
phenobarbital, (11) phenytoin, (12) salicylate, (13) valproic acid, and (14)
theophylline, and in whole blood, (15) carboxyhemoglobin and (16)
methemoglobin.
o Toxic Syndromes
§ Toxidromes
§ Clinical syndromes that help recognize a poisoning pattern
§ Most common
• Anti-cholinergic
• Cholinergic
• Opioid
• Sedative-hypnotic

• Sympathomimetic
§ Central nervous system excitation (anxiety, tremors, delusions, paranoia),
hypertension, tachycardia, seizures, mydriasis, hyperpyrexia, diaphoresis
§ Amphetamines, cocaine, phencyclidine, ephedrine, cathine,
pseudoephedrine
o Cocaine
§ Alkaloid found in Erythroxylon coca, grows in northern South American
Andes, India, Africa and Java
§ Clinical medicine – local anesthesia and vasoconstriction in nasal surgery;
dilate pupils in ophthalmology
§ 2.1 million users reported in 2007, stable since 2002
§ Hydrocholoride salt (powder)
• Nasal insufflation, intravenously
§ Free-base “crack”
• Has not been neutralized by acid to to make the salt
• Heated and vapors smoked, crackling sound
§ Pharmacologic Response
• Cardiovascular effects
• Potent CNS stimulant: euphoria and alertness
• Blocks dopamine reuptake at nerves synapses, prolonging the
action of dopamine
• Blocks reuptake of norepinephrine at the presynaptic nerve
terminals – sympathomimetic response
§ Chemical Components
• Cocaine is methylbenzoylecognine (COC)
• Complex metabolisms via nonezymatic hydrolysis and enzymatic
transformation in the plasma and liver
• Rapidly metabolized to benzoylecgonine (BE) and ecogonine methyl
ester, both are inactive
• BE further metabolized to minor metabolite
§ ß Cocaine Metabolism and Screening
• Half-life of COC 0.5-1.5 hours
• BE 4-7 hours, ecgonine methyl ester 3-4 hours
• Initial screening: BE immunoassay 300-ng/mL cutoff***
o Test BE because it has a longer half life than cocaine
• Confirmation: parent drug and metabolite
• GC-MS
• LC-MS/MS
§ The rash is caused by:
§ Levamisole
• Antihelminthic agent
• Increases T-cell activation and proliferation, neutrophil mobility,
adherence and chemotaxis

• Acts as a hapten, triggers an immune response resulting in
opsonization and destruction of leukocytes
o Anti-parasitic drug, now only for animals, Added to cocaine
for weight
• Detected by US Drug Enforcement Agency in 2003
• 2008 – 44% drug specimens
• 2009 – 73% drug specimens
• Widely available, cheap white powder thought to increase euphoric
and stimulatory effects of cocaine
• Life-threatening agranulocytosis, leukoenephalopathy and
cutaneous vasculitides
o No neutrophils and low lymphocytes
• Can be measured in a lab
- Opiates (Opiods)
o Pain management: post-surgical analgesia, relieving moderate to severe chronic
pain (cancer vs noncancer-related)
o Substantial addictive capacity and potentially life-threatening side effects
o Development of tolerance and risk of prescription diversion complications
o Types
§ Natural opium alkaloids
§ Semisynthetic opiates
§ Fully synthetic opioids
§ Opioid antagonists
§ Mixed agonist/antagonists
o ß Effects of Opioids
- Nutritional Diseases
o Diet must supply sufficient energy, carbohydrates, fat, protein, essential amino
acids and fatty acids, vitamins and minerals
o Under nutrition (insufficient diet)
§ Protein-energy malnutrition (PEM)
§ Common in third world
§ 25% of children affected.
§ Child at weight < 80% normal malnourished.
§ Marasmus and Kwashiorkor
• Protein / somatic stores = muscle
• Viscerla stores = liver = makes albumin = decreased albumin =
edema
o Kwashiorkor
§ “the sickness the baby gets when the new baby comes”
§ Primary PEM in children
§ Protein deprivation greater than reduction in calories
§ 60-80% of normal weight
§ Severe loss of visceral protein compartment = LIVER!
§ Listless, apathetic

§ Clinically more severe than Marasmus
§ Hypoalbuminemia, generalized edema
§ Spares fat, muscle
§ Skin hyperpigmentation alternates with hypopigmentation, “flaky paint”,
loss of hair color
§ Hepatomegaly, steatosis, due to reduced synthesis of lipid carrier proteins
§ Immune defects
§ Children with kwashiokor break down fat, oxidize fatty acids less efficiently
than children with marasmus
• Marasmatic kwashiorkor = both forms of malnutrition
§ May explain better survival rate in marasmus
§ Would limit energy supply essential for survival when dietary intake is
inadequate
o Marasmus
§ Primary PEM in children
§ Due to severe reduction in caloric intake
§ Less than 60% of normal weight
• Big head – losing somatic muscle stores!
§ Growth retardation, loss of fat and muscle due to catabolic depletion of
somatic proteins
§ Emaciated, head appears too large for body
§ Anemia, normal – decreased albumin, cell-mediated immune deficient
§ Secondary Marasmus-like
• Occurs with chronic illness – like cancer
• Weight loss, muscle wasting, loss of subcutaneous fat
• Cachetic wasting due to loss of appetite, elevated BMR, catabolic
cytokines (IL-1, TNF, IL-6) made by tumor
o Due to elevated catabolic cytokines
o Undernutrition
§ Secondary to systemic disease
§ Anorexia nervosa
§ Like marasmus
o Overnutrition
§ When food-derived energy chronically exceeds energy expenditure, excess
calories stored as triglycerides in adipose tissue.
§ Obesity
• Increased weight, due to increased adipose
• 65% of US adults are overweight or obese, 15% of children
• Genetic, metabolic, environment, psychological factors
• Obesity Related Diseases
o Atherosclerosis, hypertension, diabetes, liver and biliary
tree, hypoventilation (sleep apnea), osteoarthritis
§ Hypertension – if bigger than heart needs to work
harder

o Hypertension: Increased risk in normotensive person
proportional to increase in weight
o Type II Diabetes
§ Hyperinsulinemia, insulin resistance
§ Increased lipids increase risk of coronary artery
disease
• Low HDL cholesterol
• Hypertriglyceridemia
o Hypoventilation (Pickwickian) syndrome: Hypersomnolence
associated with sleep apnea, polycythemia, right-sided
heart failure. – pickwick = Charles Dickens
o Osteoarthritis: Wear and tear on joints
o Liver and biliary tree
§ Cholelithiasis: Increased cholesterol, augmented
biliary excretion predisposes to cholesterol stones.
• Increased gallbladder stones
§ Nonalcoholic steatohepatitis (NASH) can progress to
fibrosis.
• NASH = cirrohis similar – kids are getting it
now, lose weight à reverses
§ Diet and Systemic Diseases
• High animal fat + low fiber intake may cause colon cancer.
o Increased bile acids modifies flora, favoring microaerophilic
bacteria. Bile acid metabolites made by bacteria may be
carcinogen or promoter.
• Increased BMI associated with cancer-related mortality
• There is no definite proof that diet can cause or protect against
cancer.
o Daily fiber Intake
§ Woman = 25
§ Man =26
o Apple = 3g
o High fiber = plant based diet is best
o Obesity and Cancer
§ Mediated by hyperinsulinemia and insulin resistance with increased IGF-1
§ In Men
• 4% of cancers associated with obesity
• BMI>25kg/m2
increased adenocarcinoma of esophagus, thyroid,
colon and kidney cancer
§ In Women
• 7% of cancers associated with obesity
• BMI>25kg/m2
increased adenocarcinoma of esophagus,
endometrial, gallbladder, kidney cancer
o Diet and Systemic Diseases

§ Hypertension reduced by restricting sodium
§ Dietary fiber prevents colonic diverticulosis
§ Low sugar diet
• Colonic = outpouching of colon à perforation and infection
Introduction to Neoplasia
- Introduction
o Terms
§ Neoplasia = process to get neoplasm
• Generalizations of neoplasia
o Benign Neoplasm
§ Localized (non-invasive)
§ Cannot metastasize
§ Excision à cure with survival
o Malignant Neoplasm = cancer
§ Invades local tissues
§ Can metastasize
§ Will kill patient without treatment (and maybe
despite treatment)
§ Neoplasm = new growth
• RA Willis Definition
o A neoplasm is an abnormal mass of tissue, the growth of
which exceeds and is uncoordinated with that of normal
tissue and persists in the same excessive manner after
cessation of the stimuli which evoked the change
• Henry Pilot Definition
o A neoplasm is a heritably altered, relatively autonomous
growth of tissue
§ Tumor = swelling or neoplasm
§ Oncology = study of cancer
- Nomenclature
o Parenchyma
§ The clonal proliferation
• Neoplasms = monoclonal – 1 cells screws up everything!
§ Determines name of the neoplasm
o Stroma
§ Nonclonal supporting tissue
• Connective tissue
• Blood vessels
§ May add qualifier to name of tumor
§ Desmoplasia – neoplasms that evoke a fibrosis response
§ Manifestations of Stroma
• Neoplasm with little stroma = soft
• Neoplasm with dense stroma = hard (scirrhous)

o Burkitt lymphoma (little stroma) – fish skin
o Breast cancer (abundant stroma) – stoma between glands
o Basic nomenclature
o Mesenchymal Neoplasms
§ Lipoma = benign fat neoplasm
§ Liposarcoma = malignant fat neoplasm with lipoblast present
§ Hemangioma = benign
§ Angiosarcoma = malignant
o Epithelial Neoplasms
§ Papilloma = wart based on architecture
§ Glandular = has tubules
• Adenoma = liver or kidney
• Cystadenoma
• Villous adenoma – large intestine
§ Squamous papilloma = benign

§ Squamous cell carcinoma = malignant and unorganized, more inflammatory
response
§ Tubular adenoma = benign
§ Adenosarcoma = malignant, dirty necrosis with dead crap in glands
•
o Other Neoplasms
§ Epithelial and mesenchymal
• Benign – mixed tumor
• Malignant – carcinosarcoma
§ Teratoma = more than 1 germ layer (endo,ecto,meso-derm) – monster
• Ovarian Teratoma = cystic, mature tissues, favors skin accessories =
dermoid cyst, can include any type of tissue
o Breaking the Rules
§ Locally invasive but not capable of metastasis
• Act like metastatic but really benign
§ Brain neoplasms
§ Borderline tumors
• Not really malignant or benign – low malignancy
§ Sloppy nomenclature
• Lymphoma = malignant
• Other bad names
o Malignant
§ Lymphoma, melanoma, seminoma, hepatoma
(hepatocellular sarcoma), hydaitidiform mole
(placental neoplasia), melanocytic nevus, leukemia
(WBCs),
o Choristoma = not malignant = bump of tissue, hamartoma =
normal tissue but abnormal architecture, hematoma =
blood in interstitial matrix
- Epidemiology
o Skin cancer tops all! But higher number of deaths is from lung cancer!
o Cancer incidence varies and is not a single disease = spreads!
o Used to be heart disease, but today cancer will kill you
o Every cancer is different and some are more fatal than others
o Environment can cause cancer!
o Cancer Risk Factors
§ Obesity
• Increased death rate
o Males by 52%, females by 62%
§ Alcohol
• Increased incidence
o Oropharynx
o Esophagus
o Liver

§ Sexual Activity
o Uterine and cervix
§ Smoking
o Lung / bronchus, mouth, pharynx, larynx. esophagus,
pancreas, urinary bladder
§ Age
• Tumor-specific variation in incidence and death rate
• Each cancer can target specific ages
• Adults
o Carcinoma à leukemia (WBCs in bone marrow) /
lymphoma (WBCs in lymph nodes – on non-marrow sites)
à sarcoma
o Main cause of death in 60-79 year old men and 40-79 year
old women
• Children
o Leukemia à CNS à sarcoma à carcinoma (but not very
common)
§ Genetic Predisposition
• Autosomal dominant cancer syndromes
o TSG point mutation (except as indicated)
§ Retinoblastoma (RB mutation)
§ Familial adenomatous polyposis (APC mutation)
• Large intestine with benign neoplasm but
pt. will get colon cancer
§ Li-Fraumeni (P53 mutation)
§ MEN 1 (MEN 1 mutation)
§ MEN 2 (RET mutation) (oncogene)
§ HNPCC (genetic heterogenicity) (mismatch
repair*** = autosomal dominant
• Defective DNA repair cancer syndromes -autosomal recessive
o Xeroderma pigmentosum
§ UV repair is gone so 100X increased risk for skin
cancer
o Ataxia telangiectasia
o Bloom syndrome
o HNPCC (autosomal dominant) *
• Familial Cancers
o Probably polygenic (except as indicated)
§ Colon, breast (BRCA1 and 2 mutation), ovary, brain,
skin (melanoma)
o Usually earlier age of onset than non-familial

o Frequently multiple and/or bilateral cancers (paired organ
cancers)*
o Less than or equal to 2 close relatives with the same cancer
§ Nonhereditary predisposition to cancer
• Most benign neoplasms do not undergo “malignant transformation”
o Some do – FAP!
• Some diseases increase risk factors for cancer
o Idiopathic inflammatory bowel disease
§ Ulcerative colitis
§ Chron disease
o Helobacter pylori gastritis
o Viral hepatitis – liver cancer
o Chronic pancreatitis
o Chronic atrophic gastritis – stomach cancer
o Actinic keratosis – sun-skin lesion
o Leukoplakia – white plaque
Clinical Aspects of Neoplasia
- Effects of neoplasms on the host
o Signs and symptoms of neoplasia
§ Palpable or otherwise detectable mass
• Verrucae = warts
• Melanocytic nevus = moles
• Basal cell carcinoma = very common
• Malignant melanoma
• Subcutaneous neoplasms
o Lipoma
o Burkitt lymphoma
o Neurofibroma
• Congenital Teratoma
o Usually sacral coccygeal or oral / nasal pharynx
§ Critical location effect
• Laryngeal cancer – affects speech
• Intussuception (burkitt lymphoma)
o Eventually causes colon obstruction – telescoping of gut
§ Ulceration
• Stomach and skin
§ Infarction
• Ovarian teratoma with torsion causing infarction
o Twists and dies,
o Causes hemorrhagic necrosis
§ Rupture
• Ruptured HCCA
§ Functional Endocrine Activity

• Cushing Syndrome - Too much from adrenal gland
§ Cahexia
• Wasting away from cancer, active degradation of tissues
- Paraneoplastic syndromes (PNS) – doesn’t make sense with neoplasm
o Seen with benign and malignant neoplasms
§ 10% cancer patients have a PNS
o Signs and symptoms not explainable based on
§ Local disease, distant spread and hormones indigenous to tissue of origin
o Clinical significance of PNS
§ Can be 1st
sign of neoplasia
§ Can cause significant morbidity
• Effective treatment provides palliation
§ Can cause death
§ Can stimulate metastatic disease
§ May involve tumor marker
§ Erroneous diagnosis of PNS can prevent treatment of non-PNS complication
o Endocrinopathy
§ Cushing syndrome
• Ectopic secretion of
o ACTH and ACTH-like peptides
• Common causes
o Small cell lung cancer
o Thymoma
o Pancreatic carcinoma
• Increased calcium = from lysis of bone tissue due to metastasis of
bone
o Ectopic secretion of PTH and PTH-rp
o Hypercalcemia in cancer patients is usually due to bone
metastasis rather than PNS**
o Effects of hypercalcemia
§ Acute renal failure, Cardiac arrhythmia, Stupor,
Coma
§ As PNS, hypercalcemia can be an oncologic
emergency**
o Common causes
§ SCCA lung, lymphoma, kidney CA, uterine/cervical
cancer, breast cancer
o Hypercalcemia in cancer pts is usually due to bone
metastasis rather than PNS
• Decreased sodium
o Ectopic secretions of: ADH and atrial natriuretic hormones
o Common causes: small cell lung cancer and intracranial
neoplasm
• Decreased glucose

o Ectopic secretion of insulin and insulin-like factors
o Common cause: sarcoma and hepatocellular carcinoma
• Carcinoid syndrome (lung and gut)
o Paroxysmal flushing, wheezing, right-sided heart failure,
diarrhea and abdominal pain**
o Ectopic secretion of serotonin, bradykinin, histamine
o Common cause: carcinoid tumor with liver metastases
• Polycythemia
o Ectopic secretion of erythropoietin (from kidney)
o Common causes: renal cell carcinoma, cerebellar
hemangioma, hepatocellular carcinoma
§ When hematocrit (red) is too much! Hematocrit =
height or red/ height of column
o Neuromyopathic
§ Myasthenia (eaton-lambert) syndrome
• Common causes: small cell lung cancer, other lung cancer, thymoma
• Antibody (directed to tumor antigen) reacts with other (non-tumor
cells)
• CNS white matter degradation
o Common cause = lymphoma
• Peripheral neuropathy
o Common cause = lung cancer and breast cancer
o Dermatologic
§ Acanthosis nigricans
• Common causes = lung cancer, stomach cancer, uterus cancer,
breast cancer
• Groin or axilla
§ Dermatomyositis – skin and muscle inflammation
• Common causes: lung cancer, breast cancer, gut cancer
o Hypertrophic Osteoarthopathy
§ Periosteal new bone formation
• Distal long bones
§ Arthritis of adjacent joint
§ Digital clubbing
§ Common cause = lung cancer*
o Hematologic and Vascular
§ Migratory thrombophlebitis – blood coagulates – Dr.diagnosed himself
• Pancreas cancer
• Other mucinous cancer
§ DIC – micro clots everywhere in capillaries, exhaust coagulation factors and
bleed to death with minor trauma
• APL, mucinous cancer (lung, pancreas), prostate cancer
§ ß Non-bacteria thrombotic endocarditis (marantic endocarditis)
• Advanced (mucinous) cancer

§ Anemia
• Aplastic = thymoma
• Hemolytic = CLL and lymphoma
§ Polycythemia = hormonal and previously discussed
§ *cytopenia in cancer usually reflects bone marrow replacement rather than
PNS* = metastasis to marrow
§ Thrombocytosis = too many platelets
• Carcinoma, lymphoma, thymoma
§ Granulocytosis
• Thymoma
§ Eosinophilia – too many eosinophils
• Hodgkin disease
• T-cell lymphoma
o Renal
§ Nephrotic syndrome and glomerulonephritis = many neoplasms
- Lab diagnosis of cancer
o Clinical data
§ Radiation effect on epithelium mimics carcinoma
§ Fracture callus mimics osteosarcoma
§ Verrucous carcinoma looks histologically benign
o Morphology
§ Procuring tissue
• Incisal biopsy
• Excisional biopsy – take out
o Necropsy – look at dead
o Biopsy – look at living tissue
• Fine needle aspiration biopsy
o Need enough cells
o No tissue, very small needle used for palpable skin lesions
• Exfoliative cytology
o Centrifuge fluid or pap smear to look at cells
§ Specimen Dissection
§ Section submission – in a cassette
§ Tissue fixation – buffered in formalin (10% liquid form of formaldehyde
(gas)) – 24 hours fixes tissue, kills and stiffens to help cut thinner slices
§ Tissue processing - The tissue processor = overnight
• Formalin à alcohol - pulls water out of tissueà xyline- mount
tissue
§ Tissue embedding – in paraffin wax to make a tissue block
§ Microtome sectioning of the block – cutting a ribbon = 5-6um
§ Floating the ribbon in water
§ Mounting the ribbon on the slide
§ Staining the slides, melt wax away and stain with H and E
§ Cover-slipping the slide

§ Specimen to Slide Turnaround time
• Small specimen = submitted same day
o Routine = slides by next morning (day 2)
o Rush = slides within 4-5 hours (day 1)
• Large specimen = submitted next day
o Routine = slides by second morning (day 3)
o Rush = not possible
§ If need it faster = use frozen section
• 20 minutes but wrinkles with frozen artifacts
§ Immunohistochemistry
• Difficult to ID cancer so use antibodies
• Categorize undifferentiated neoplasm
• Subclassify leukemia / lymphoma
• ID primarily when examining metastasis
o Use mouse antibodies tagged with chromagin = usually
brown, blue is counterstain**
• Use immunoperoxidase stains
• Stains
o Vimentin – non-carcinoma
o Keratin – carcinoma
o Desmin – muscle
o GFAP – glia
o LCA – lymphoma**
o HMB-45 – melanoma
• Immunohistochemical staining helps ID cell / tissue type
• Immunohistochemical staining does not indicate whether benign or
malignant
• Transmission electron microscopy
o Characterize cell type by ID of cytoplasmic organelles,
matrix constituents, and other structures below LM
resolution
o Sampling error
o Cannot distinguish benign from malignant*** - zoomed in
too much!
§ Staining is easier!
o Use electrons for greater resolution = 2 pts are separate**
o Molecular technique
§ Karyotype – photo of cell at metaphase
• N-MYC gene and Neuroblastoma
§ Fluorescence in situ hybridization (FISH)
• MYC and Burkitt Lymphoma
o Myc oncogene and Ig gene switch places = translocation*
§ Spectral karyotyping
• Colorful

§ Polymerase Chain Reaction (PCR)
• Make more DNA from a small sample, amplify 1 section of DNA
• Amplify DNA sequences specific to tumor DNA
§ Cancer fingerprinting
• DNA microarray analysis – look at mult. genes at the same time
§ Gene sequencing
o Flow cytometry
§ Diagnostic flow cytometry
• Immunofluorescent labeling of single cell suspension
• Computer-assisted counting
• Evaluation of leukemia / lymphoma
• Requires fresh / non-fixed material
o React antibody linked to fluorescent to look for antigen on a
cell
• Single cells file through a tube and measures with computer
• Only used for lymphoma leukemia = cells don’t stick together so can
be used here! ****
§ DNA flow cytometry
• Quantify DNA content of cells
• Can be done on fresh, frozen or fixed tissues
o Despite the numerous ancillary techniques available, light microscope examination
remains the cornerstone of neoplasia diagnosis**
- Tumor markers
o Substances in the blood or body fluid indicating the presence of cancer
§ Cells surface antigens, cytoplasmic proteins, enzymes, hormones
§ List of tumor markers = prostate acid phosphatase = a lot of false positives
o Clinical utility of tumor markers
§ Follow levels in known cancer patients
• Evaluate response to therapy
• Diagnose recurrence
o Increased CEA for colon cancer, tumor needs a marker to be
monitored
§ Screen high-risk populations
• AFP (alpha fetal protein) in cirrhosis (high risk of HCCA) – hepatic
cancer
§ Screen general population
• Would be ideal, if it worked
o Doesn’t really work though, because prostate cancer only
affects older men
o PSA is not a tumor marker
- Grading and staging – with malignant for prognosis
o Grade
§ Degree of differentiation (+/- mitotic rate)
• Low grade – well differentiated

• High grade = poorly differentiated = worse prognosis!
§ Rules vary by neoplasm but generally are numbered 1-3 or 1-4
§ Generally, less useful than stage
• Depends on tumor mitotic rate
• Adenocarcinoma = high grade = hard to see glands
o Signant ring = for stamps, in high grade with mucin ring
o Stage – more powerful tool to determine aggressiveness
§ How much cancer is in the pt?
§ Extent of disease
§ TNM = tumor, number of lymph nodes, other metastases
• T = size of primary lesion
• N = extent of regional lymph node metastases
• M = presence or absence of distant metastases
§ Stage I (least advanced) through IV (most advanced
§ à staging of thyroid cancer
• Get 3 scores and then determine stages
• Each grade is specific to each cancer
• Stage 4 is consistent = just 1 other metastasis in another location!
§ Stage as predictor of outcome in small cell lung cancer
• Stage 1 is best, stage 3b and worse dies
The Biology of Neoplasia
- Introduction
o Adaptation vs. Neoplasia
§ Adaptation
• Increased cell number = reversible (hyperplasia)
o Driven by a stimulus, when removed will go back to normal
• Change in differentiation = reversible (metaplasia)
§ Neoplasia
• Increased cell number = irreversible
• Change in differentiation = irreversible
o Removing stimulus wont change anything
- Biology of neoplastic growth
o Characteristics of neoplasms
§ Abnormal growth
• Monoclonal growth (from 1 cell), increased growth rate
§ Abnormal differentiation
• Dysplasia
o Pleomorphism – variable cell appearance
o Nuclear abnormalities = hyperchromasia (nucleus stains
blue), enlarged nucleus with increased N:C (nucleus to
cytoplasm) ratio à red is dead! Blue is bad = cancer!**
o Nucleoli
o Mitotic figures

o ß Loss of polarity = cell loses directionality, don’t
differentiate correctly
§ Cells making keratin pearls!, weird mitosis, ect.
• Anaplasia – most severe dysplasia
o tumor giant cells = many neoplastic cells
o necrosis
§ cells can make new antigens, unexpected hormones
ect.
• Pleomorphism
o Variable cell shape and size
• Anomalous differentiation
o Unexpected cell behavior
§ ß Tumor growth simplifies
• 10^6 cells = usual size of neoplasm – 1mg, 20X doublings – new
blood supply
• 10^9 cells = 1g = smallest detectable cancer = 30X doublings
• 40X doublings = 1kg = max. size compatible with life
§ New characteristics
• Neoantigens
• Oncofetal antigens
• Ectopic hormone production
o Tumor growth rate variables
§ Length of cell cycle – relatively constant
§ Number of cells in cell cycle
• Variable
o Early = majority of cells
o Late = minority of cells (<20%)
§ Rate of cell loss = variable
• Necrosis and apoptosis
§ *Growth fraction = cell proliferation / cell loss *
• If proliferation and loss are equal = not growing very quickly
o Tumor growth generalizations
§ Malignant growth (grows faster) > benign growth
§ Poorly differentiated growth (grows faster) > well differentiated growth
• Crap in cytoplasm slows down mitosis
§ Growth rate not constant but influenced by:
• Hormonal stimulation, adequacy of blood supply, change in
frequency of apoptosis, other influences
o Cancer stem cells
§ Tumor-initiating cells (T-ICs) are the neoplastic equivalent to stem cells
§ T-ICs have been ID in some neoplasms
• New studies
o Transformation (in vitro) – technically lab term – carcinoma*
§ Loss of

• Contact inhibition
• Density inhibition
• Finite replicative life span
o Eventually normal cells will dies, cancer is immortal
o Henrietta X?
• Anchorage-dependent growth
• Grow as tumor in animal * = transformation*
o Cancer doesn’t stop growing!
o Benign vs. Malignant Generalizations of Morphology à
§ Benign pushes things out of the way and has capsule, malignant = may or
may not have capsule
o Metastasis
§ A focus of neoplasm discontinuous with the primary tumor
§ Nearly always indicates malignancy
§ Most malignant neoplasms can metastasize
§ Risk of metastasis increased if
• Rapid growth rate, large size and aggressive local growth
§ *30% solid cancers have metastasis at time of diagnosis* = distant
metastasis = stage 4! (solid = not leukemia or lymphoma)
§ Routes of metastasis
• Direct seeding of body cavities
o Peritoneal implants of ovarian carcinoma
• Via lymphatics
o Carcinoma > sarcoma = fake news
o Follows patterns of lymph drainage
o Initially to regional lymph nodes
• Via blood vessels
o Carcinoma < sarcoma = fake news
o Follows pattern of venous drainage*
o Frequently to liver and/ or lung
- Molecular basis of carcinogenesis
o Carcinogenesis
§ A *multistep process brought about by non-lethal genetic damage*
resulting in monoclonal (1 ahole cell) expansion of abnormal cells
o Evidence of monoclonality à
o Targets of genetic damage – X-chromosome is bigger – lionization = 1 X is turned off
in females!
§ Protooncogenes (growth-promoting) / oncogene
• Mutation results in oncogene which turns up growth promoting
effects
• Dominant
o Promote cell growth – but does it too well in cancer
§ Tumor suppressor genes (growth inhibiting) (TSG)*
• Mutation turns down growth-inhibiting effects

• Recessive
o Depressing growth of tumor cells
o Cytoplasm or nucleus
§ Genes that regulate cell death / apoptosis
• Recessive or dominant
o Can activate or repress
§ mitochondria
§ DNA repair genes
• Usually recessive
o Nucleus
• *Gene = italics!!
o Fundamental malignant changes (add defective DNA repair to pic)
§ 1-6 from pic**
o Cell cycle
§ G1
§ Pause = is DNA okay?
§ S1 = synthesis
§ G2 =
§ Pause = replication complete?
§ M = mitosis
§ ß Green = pauses in cell cycle
o Cyclins (made when needed) and CDK’s = at pauses
§ Cyclin-dependent kinases = CDKs
• Constitutively expressed but inactive
§ Cyclins
• Synthesized at specific times
§ *Cyclin and CDK = cyclin-CDK complex
• Phosphorylates critical target proteins à progression of cell cycle**
o Protooncogenes and oncogenes
§ Protooncogenes = normal* genes that are growth-promoting
§ Oncogenes = mutated* protooncogenes that lead to excessive growth
promotion
• Act on any of the steps in cell proliferation
• Dominant cancer genes = only activation of 1 gene will express the
phenotype
o All growth promoting
o Steps of cell proliferation (review)
§ Growth factors binds to receptor on cell surface
§ Receptor is transiently activated, leading to signal transduction
§ Signal is transmitted to the nucleus
§ Nuclear regulatory factors are activated, initiating DNA transcription
§ Cell progresses through cycle, resulting in cell division
o Oncogenes at Growth Factor (GF) level – usually just over-expressed genes
§ Mutation causes increased expression of GF

• Probably not sufficient for transformation but à high risk of
mutation*
§ Most GF genes are not mutated, rather, they are overexpressed due to
mutations of signal transduction genes
o Oncogenes at receptor level ß proteins are receptors for growth factors
o Oncogenes at signal transduction level à **RAS AND ABL**
§ Mutations in the RAS family of genes are the most common oncogene
abnormality in human neoplasms (present in 30%)
• **Most commonly mutated in cancer = RAS****
§ Normal RAS protein is transiently activated (should turn itself off) leading to
activation of regulators of cell proliferation
§ Mutant RAS protein stays activated
§ RAS protein à
• GTP à GDP =
• Protein loses enzymatic activity
• DNA keeps making proteins!
§ ABL**
• ABL protein = plasma-membrane associated signal transducer
• ABL gene = regulated in its normal location on chromosome 9
• BCR-ABL gene = unregulated hybrid gene (from translocation of ABL
to the BCR region of 22)
• BCR-ABL protein = a potent tyrosine kinase that sends growth-
promoting signals to the nucleus
o 9 and 22 switch! ABL next to BCR à hypergene that makes
a tyrosine kinase that tells nucleus to make more DNA
o Oncogenes at nuclear transcription level
§ MYC** (N-MYC = ped. Cancer)
• The MYC protein binds DNA and activates transcription of growth-
related genes
o MYC protein levels decrease when cell enters cycle
• *MYC translocated (from 8-14) à overexpression of the protein
(due to translocated gene’s proximity to Ig heavy chain gene)* so, if
Ig is activated, then MYC will be turned on by accident and cause
issues
o Oncogenes at the cell cycle level
§ *Cyclin overexpression à increased activation of CDKs à easier G1 à S
and G2 à M transitions
• Smaller hurdles/ pauses = cell cycles too quickly à errors
§ CDKs can be overexpressed or expressed as overactive mutants, allowing
easier G1à S and G2 à M transitions
§ Cyclins and CDKs
§ Oncogenes at cell cycle level
§ Tumor suppressor genes (TSGs)
• TSGs are normal genes that are growth-inhibiting

• Mutation turns down inhibition, allowing proliferation
• TSGs act on any of the steps in cell proliferation
• Recessive cancer genes
• *TSG Prototype = RB
o Gene RB is named after retinoblastoma*
§ Retinoblastoma = malignant retina neoplasm
§ 60% sporadic and 40% familial
o Need 2 mutant alleles for neoplasm
§ ß *2 hit hypothesis = if 2 mutant cells in 1 cell =
issues** à retinoblastoma
• Autosomal dominance of RB
§ Loss of heterozygosity
• Loss of red eye in pics!
o RB loss also in other cancer
• TSG at cell cycle level: RB
o RB is expressed in nearly every cell
o RB protein has active and inactive state
§ Active (cell in G1) = RB binds transcription factor,
preventing transcription***
§ Inactive (following GF stimulation - phosphorylated)
= RB not bound to transcription factor, allowing
transcription**
o *An exception to the phosphorylation = activation rule**
• ß RB protein function
o Right = active = holds E2F = blocks transcription*
o Left = phosphorylates and inactive = releases TF and
transcription occurs*
o Lose RB = lose ability to block transcription à proliferation*
• *TSG at cell cycle level” p53 * pivotal protein! MOST COMMON
GENE! – guardian of the genome = many functions
o Normal = DNA damage à increased p53 protein
§ P53 protein induces transcription of p21 (encodes
CDK inhibitor that activates RB (stops transcription),
preventing G1 à S)
§ P53 protein induces expression of GADD45 (DNA
repair enzyme) * can stop cell cycle for DNA repair
• Repair successful – MDM2 expression
(protein degrades p53) *
• Repair unsuccessful à p53 activates
apoptosis genes *
o Abnormal = DNA damage goes unrepaired, cell division
process
§ *p53 = most common target for genetic aberration
in human neoplasms*

o ß P53 protein function
o Genes that regulate apoptosis = major target for chemotherapy!!
§ Named by 3 letters, the first of which is B*
§ BCL-2 is anti-apoptotic
• Translocation from 18 to 14 allows overexpression protecting cells
from apoptosis
• The pathway of BCL-2 and its protein is complex
o The pathway involves MYC (oncogene)
o The pathway involves p53 (TSG)
§ These genes are major chemotherapy targets
o Alternate Nomenclature
§ Some classification of genes split apoptosis genes into subtypes of
oncogenes or TSGs
• Pro-apoptosis gene = TSG*
• Anti-apoptosis gene = oncogene*
o DNA repair genes
§ DNA repair system
• Mismatch repair**
o Hereditary nonpolyposis colorectal cancer (HNPCC)
syndrome
§ AD inheritance of large intestine cancer and other
extra intestinal cancer
§ Genetic heterogeneity
• MSH2, MLH1, PMS, PMS2
o *Microsatellite instability = repeated codes are
microsatellites, usually repeats are consistent but the
tandem repeats increase = mismatch repair issue***
• Base excision repair
• Nucleotide excision repair = removes UV caused thymine dimers!
§ AR inheritance of 2000X increased skin cancer*
§ genetic heterogeneity – different genes lead to this
• Homologous recombination repair
o Ataxia telangiectasia – ATM mutation
o Bloom syndrome = BLM mutation
o Fanconi anemia = genetic heterogeneity
o Familial breast cancer = BRCA1 mutation, BRCA2 mutation
• End-joining repair
§ Defects in DNA repair system à mutator phenotype
§ DNA repair systems to be discussed
o Telomeres, Telomerase and Limitless replicative potential
§ *Telomeres = structures at the end of chromosomes, necessary for cell
division*
§ With each cell division, telomere is shortened*

§ When telomere is too short, further replication is not possible*
§ *Telomerase = lengthens telomers where necessary (germ cells)
§ About 90% human neoplasms show telomerase reactivation
• Part of how cancer cells are immortal! Cancer turns on telomerase
so can never stop replicating!
o Development of sustained angiogenesis
§ Needed at 1mg or more (more or equal to 10^6 cells)
§ Major players = bFGF and VEGF
§ A balancing act of activators and inhibitors
o The angiogenic switch
§ Neoplasm gets another blood source and can keep growing!
§ Similar to granulation tissue*
o Invasion
§ Loosening of intercellular junctions of epithelial cells
§ Degradation – cells secretes enzyme to degrade type 4 collagen
§ Attachment – fibronectin and laminin helps cell attach
§ Migration – autocrine activity! Pulls cell down! Goes through basement
membrane! = officially cancer!
• If not broken through basement membrane = in situ lesion = not
malignant
o Metastasis
§ Invasion
§ Enter vascular lumen
§ Travel – blood or lymphatics
§ Reverse invasion
o Metastatic Sites
§ Common = lymph nodes, liver, lung, bone, brain
§ Uncommon = spleen, heart and striated muscle
o Classic metastatic sites
§ Colon à liver (portal system) * and lung
§ Lung à brain, liver, bone, lung
§ Breast à bone, lung, liver
§ Melanoma à lung, liver, brain
o Unexpected Metastatic Sites – but occur!
§ Bronchial cancer à adrenal
§ Breast ductal cancer à liver
§ Beast lobular cancer à peritoneal seeding
§ Breast à bone and ovary
§ Lung à brain
§ Ocular melanoma à liver
§ Prostate à bone
§ Melanoma à brain
o Seed and soil – cancer does what it wants!
§ Chemotactic factors / receptors

§ Adhesion molecules
§ Local growth factors
§ Anatomic arrangement
o *Batson Venous System – valveless venous plexus that goes sacrum to skull!
§ How prostate cancer can go to the brain ** avoid lungs
o Mechanisms of Genetic Damage
§ Change in gene structure
§ Change in regulation of gene expression
§ Increase in number of gene copies
§ Loss of genes
o Cytogenetic alterations
§ P = petite
§ Q = larger
§ Isochromosome = 2ps or 2 qs
§ Centromere names the chromosome
o Translocation
§ Usually protooncogene à oncogene
• Change in gene structure
o T(9,2) BCR-ABL, CML
• Change in regulation of gene expression
o T (8,14), MYC, Burkitt lymphoma
o FISH = if know where translocation is = label both sides!
o Gene amplification – too many copies of gene!
§ Usually protooncogene à oncogene
• Increase in structurally normal growth – promoting protein
o N-MYC, neuroblastoma (ped. Tumor) **
• Karyotype findings
o HSRs – homogenous staining region
o Double minutes = tiny pieces!
o Deletion
§ Usually inactivation of TSG**
§ Decrease in growth-inhibiting protein
• *RB, retinoblastoma, osteosarcoma, breast cancer, small cell lung
cancer, brain tumors
o Epigenetic change
§ Usually inactivation of TSG
§ **Change in methylation of promoter sequences (not actual gene mutation)
o miRNAs – micro RNAs
§ miRNAs = post-transcriptional gene silencing**
§ decreased translation
§ cleavage of mRNA
o miRNAs and Cancer
- Molecular basis of multistep carcinogenesis
o No single oncogene can fully transform non-immortalized cells in vitro

o Usually, activation of several oncogenes and loss of 2 or more TSGs
o *Multistep carcinogenesis**
o Gatekeepers and caretakers*
§ Gatekeeper genes = oncogenes, TSGs and apoptosis genes
§ Caretaker genes = DNA repair genes
o Tumor progression and heterogeneity
§ Usually, increased malignant behavior over time
§ Due to sequential appearance of subpopulations
§ *Monoclonal but genetically heterogeneous
§ Genetical heterogeneity begins early
• Lose p53 = more issues in cells! = why metastasis is larger than
primary = more different types of cells = tumors get worse over
time*** - oncogene activated, TSGs turned off à cancer!
• Cancer karyotype! Trisomys, translocations, ect.
- Carcinogenesis
o 18th
century scrotal cancer – chimney sweeps – chemical cancer = not bathing, and
soot has carcinogen = rugae of scrotum holds carcinogens from soot
o Carcinogens
§ Chemicals
• Initiators – occurs first = mutation* = X
o Direct = carcinogens = chemical directly causes canver
o Indirect = procarcinogens = body metabolizes chemical so
that it causes cancer
• Promoters = cocarcinogens = making mutated cells* = triangle
o Promotion = reversible
§ Stimulation of cell proliferation
• Direct
• Indirect = cause cell death
§ Cell proliferation = increased risk of mutagenesis
• Ames test
o Bacteria to chemical and add mammal metabolism system =
so if carcinogens or procarcinogens = growth will occur
§ Radiant energy
• Ionizing Radiation
o Creates free-radicals which attack DNA**
o Radiation hits water making free radicals
§ Microorganisms
• ß HPV – prevents apoptosis and growth arrest
o DNA virus
o Over 70 types
o 1,2,4,7 (low risk) à squamous papilloma
o 6,11 (low risk) à genital wart
o 16,18,31,33,35,51 (high risk) à SCCA
o Cariogenic effect due to expression of E6 and E7

o HPV carcinogenesis
o HPV neoplasms: benign
§ Condyloma
§ Sinonasal papilloma
§ Papilloma (oral cavity)
§ Verruca vulgaris
o HPV neoplasms = malignant
§ **Squamous cell carcinoma (uterine cervix)*
• Epstein-Barr Virus (EBV)*
o DNA virus
o Associated neoplasms
§ Burkitt lymphoma (Africa)*
§ B-cell lymphoma (immunosuppression)*
§ Hodgkin disease* = owl eyes
§ Nasopharyngeal carcinoma*
o Enters via CD21
o Viral LMP-1 mimics CD40 à proliferation and survival
o Can immortalize cells
o EBV Malignancies
§ Hodgkin disease
§ Nasopharyngeal carcinoma
• Hepatitis B Virus (HBV)*
o DNA virus
o Hepatocellular carcinoma à
§ *Most likely promoter effect
§ Keep making hepatocytes
• Kaposi Sarcoma Herpesvirus (KSHV)*
o DNA virus
o Kaposi sarcoma
§ Unclear mechanism
• Hepatitis C Virus (HCV)*
o RNA virus
o Hepatocellular carcinoma
§ Most likely promoter effect*
• Human T-cell Leukemia Virus Type 1 (HTLV-1)*
o RNA virus (retrovirus)
o CD4 positive T-cell tropism
o Leukemia / lymphoma in 3-5% - 40-60 years latency
between infection and phenotype
§ Most likely promoter effect
• Helicobacter pylori
o Gram negative bacillus
o Gastric lymphoma = most likely promoter effect
o Gastric carcinoma – most likely promoter effect

- Tumor immunology
o Tumor specific antigens = immune system can recognize
§ Product of oncogene
§ Product of mutated TSG
§ Product of other mutated gene
§ Overexpressed protein
§ Aberrantly expressed protein
§ Viral proteins
§ Oncofetal antigen
§ Altered cell-surface glycolipid / glycoprotein
§ Cell type-specific CD antigen
o Tumor associated antigens
§ Tumor antigens recognized by *CD8* and T-cells (tumor immunity)
• Other tumor immunity cells
o NK cells, activated macrophage, B—cell
o Immune surveillance
§ (Cancer risk) immunodeficient = 20X (cancer risk) immunocompetent
• So, immune system does something to prevent cancer!
• If cancers related to infectious disease = worse with immune-
compromised!
§ Mechanisms to evade immune system
• Outgrowth of ag-negative variants
• Decreased MHC expression
• Tumor-cell-product induced immunosuppression
• Antigen masking by glycocalyx
• Induction of CTL apoptosis
o Cancer immunoediting
§ Common neoplasms in immunocompromised hosts
§ Making cancer worse!
• Lymphoma = EBV
• Kaposi sarcoma = KSHV
• Uterine cervical carcinoma = HPV
• Gastric carcinoma = helicobacter pylori

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