Understanding immunology for internists 1

Understanding Immunology Dr. Ahmed Elshebiny , MD Lecturer of Internal Medicine Faculty of Medicine, Menoufyia University Former Clinical Research Fellow, Joslin Diabetes Center, Harvard University

Immunology Course Basics: Immune system and disease Diseases: Immunopatholy Applications: Therapeutic applications

Immune system and disease Immunity Immune system Innate Immunity Adaptive Immunity Immune Recognition Cells of the Immune system Complement Immunoglobulins Cytokines Human disease & Immunity Immunopathology Diagnostics Therapeutic applications Structure and Function of The System Cells and Molecules of Immunity Introduction to Clinical Immunology

Immunity is characterized by: Specificity – activated by and responds to a specific antigen Versatility – is ready to confront any antigen at any time Memory – “remembers” any antigen it has encountered Tolerance – responds to foreign substances but ignores normal tissues

History of discovery of immunity “Immune” meaning Noticing immunity centuries ago Small pox Edward Jenner Recent developments

1 st Line defense: Physical and chemical barriers Skin – acts as a barrier to invasion Sweat – has chemicals which can kill different pathogens . Tears - have lysozyme which has powerful digestive abilities that render antigens harmless . Saliva – also has lysozyme . Mucus - can trap pathogens, which are then sneezed, coughed, washed away, or destroyed by chemicals . Stomach Acid – destroys pathogens

Innate Adaptive Immunity Cellular Humoral Cellular Humoral Let us see this video about immunity

Inflammation Inflammation is a nonspecific response of living tissue to localize and eliminate the injurious agent Immune Response

Inflammation The word inflammation means "setting on fire" (16th century), and the process has been known since ancient Egyptian times (c. 2500 B.C) The cardinal signs of redness, swelling, heat, and pain were described by Celsus (first-century A.D.), and loss of function was added by Galen (130-200 A.D)

Acute phase changes characterized by pronounced behavioral, physiologic, biochemical and nutritional changes Acute phase reactants Acute phase proteins

C-reactive protein named for its capacity to precipitate the somatic C-polysaccharide of Streptococcus Pneumoniae. Systemic marker of inflammation produced by hepatocytes, predominantly under transcriptional control by the cytokine IL-6

The Immune system The immune system recognizes, attacks, destroys, and remembers each pathogen that enters the body. It does this by making specialized cells and antibodies that render the pathogens harmless.

Questions ? What Happens during an infection ? How can immune cells distinguish foreign invaders from our own cells ? How can we make 100,000,000 different antibodies with only 30,000 genes ?

Cells of the immune system T-cell development

Polymorphonuclear cells 1- Neutrophils Stored in bone marrow Released in response to infection Have surface receptors for IgG, IgA, complement Phagocytose and destroy bacteria Short lived Dead neutrophils make a part of pus

Polymorphonuclear cells 2-Basophils and mast cells Basophil circulate Mast cells are tissue bound Released in response to infection Have surface receptors for IgE, complement C3, C5 Produce histamine, prostaglandins, leukotrienes and proteases Involved in immune response to parasites Involved in immediate hypersensitivity

Polymorphonuclear cells 3-Eosinophils Allergy Have surface receptors for IgG, complement C3, C5 Also binds to IgE but less than mast cells or basophils Phagocytose antigen antibody complexes

Macrophage In the tissues Long lived Initiate immune responses as they display antigens from the pathogens to the lymphocytes.

Lymphocytes B and T cells mature then circulate in the blood and lymph B-cells mature in bone marrow T-cells mature in thymus

B-Lymphocytes The huge variety is caused by genes coding for abs changing slightly during development. The number of plasma cells goes down after a few weeks Antibodies stay in the blood longer but eventually their numbers go down too.

T-Lymphocytes CD3 in all types CD4 in helper CD8 in cytotoxic

Natural killer cells Large granular lymphocytes Recognize and destroy cells bedaring viral or tumor surface markers

Complement Definition : series of heat-labile serum proteins Site : serum and all tissue fluids except urine and CSF Synthesis : in liver – appear in fetal circulation during 1 st 13 W Function : Responsible for certain aspects of immune response and inflammatory response Activation : antigen-antibody complex or endotoxin, capsule series of proteins activated sequentially Inactivation: inhibitors in plasma (short lived)

Complement system Plasma protein sequence cascade Triggered by Classic pathway Alternative pathway Lectin binding Complement

Complement Activation Classical Pathway C 1 C 4 C 2 C 3 Alternative pathway C 5 C 6 C 7 C 8 C 9 Membrane damage

Classic And Alterenative pathways Classic Pathway Alternative pathway * Specific acquired immunity * Non-specific innate immunity * Initiated by antibody * Bacterial endotoxin, capsule * Interaction of all components * C1, C4, C2 are by-passed * Properdin system not involved * Properdin system is involved

Complement and disease Complement difficiency Difficiency of classic pathway components C3 difficiency Terminal complement protein difficiencies Difficiency of regulatory proteins Heriditary angioedema PNH Complement consumption as in SLE

Functions of Complement Biologically active complement products have 3 main functions Opsonisation …… C3b Chemotaxis and inflammation……C3a, C5a Cell lysis……….. C5,C6,C7,C8,C9

Plasma protein electrophoresis

Antigens Antigens are macromolecules that elicit an immune response in the body. The most common antigens are proteins and polysaccharides. Hapten: incomplete Ag which can be conjugated with a carrier protein to form a complete Ag.

Cytokines hormone-like soluble low molecular weight protein molecules that act, generally in a paracrine fashion, to regulate immune responses They are secreted not only by lymphocytes and macrophages but also by endothelial cells, adipocytes, neurons, glial cells, and other types of cells

Chemokines cytokines that regulate cell movement and trafficking; they attract neutrophils and other white blood cells to areas of inflammation or immune response.

Interferons are potent cytokines that possess antiviral, immunomodulating, and antiproliferative activities Interferon- α , Interferon- β & Interferon- γ Recombinant, natural, and pegylated IFNs currently are available for treatment of condyloma acuminatum, chronic HCV infection, chronic HBV infection, Kaposi's sarcoma in HIV-infected patients, other malignancies, multiple sclerosis

Tolerance It is a specific immunologic unresponsiveness Unresponsiveness to self antigens is known as auto tolerance

Tolerance B-cells become tolerant to self by two mechanisms: 1) Clonal deletion Probably while B-cell precursors are in bon marrow 2) Clonal anergy B cells in the periphery Tolerance in B-cells is less complete than in T-cells The most autoimmune diseases are mediated by antibodies

Factors affecting induction of tolerance Maturity of the immune system Antigen complexity Antigen dose Continuous presence of antigen Immunosuppressive drugs

Clinical importance of tolerance Organ transplantation Tumor development Autoimmune diseases

Autoimmune Diseases Autoimmune diseases occur due to breakdown of the mechanisms that maintain auto tolerance Auto-antibodies and self reactive T-cells are produced, resulting in tissue damage by several mechanisms

References Lecture notes: Immunology 2010 Essential revision notes for MRCP 2009 Merck manual : online textbook Kumar & Klark : Clinical Medicine 2009 Other Web Resources & books

Understanding Immunology(2) Immunopathology

Immunodeficiency Immunopathology Autoimmunity Hypersensitivity Lymphoproliferative Diseases

Understanding Immunology (3) Therapeutic applications

Understanding immunology for internists 1

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