Hypersensitivity.ppt

INTRODUCTION
• Hypersensitivity can be defined as a state of altered immune
response against an antigen characterized by hyper reactivity
leading to immunopathology
• Hypersensitivity reactions require a pre-sensitized(immune)
state of the host.
• There are two categories of adaptive hypersensitivities:
–Immediate hypersensitivities refer to humoral
immunity (antigen/antibody reactions)
–Delayed hypersensitivities refer to cell-mediated
immunity(cytotoxic T-lymphocytes, macrophages, and cytokines)

CLASSIFICATION OF HYPERSENSITIVITY
Coomb and Gell in 1963 classified hypersensitivity reactions into
the following four types based on the mechanism involved and
time taken for the reaction.

Type I Hypersensitivity
(IgE mediated anaphylactic hypersensitivity)

Characteristics of Type-I hypersensitivity
• It is also known as immediate or anaphylactic hypersensitivity
and is mediated by IgE.
• The reaction occurs on exposure to allergen second time. The
first exposure (sensitizing dose) results in sensitization of host
to allergen and subsequent exposure (s) (shocking dose) will
cause reaction
• Anaphylactic shock occurs in sensitized animals within
seconds to minutes (15-30 min after exposure to the
allergen) after exposure to the antigen, now called as an
allergen. Sometimes the reaction may have a delayed
onset (10-12 hours).
• In type I hypersensitivity reactions, the allergens are proteins
with a molecular weight ranging from 10 to 40 kDa.
• Diagnostic tests for immediate hypersensitivity include
skin (prick and intradermal) tests resulting in wheal and
flare reaction, measurement of total IgE and specific IgE
antibodies against the suspected allergens by ELISA,
Radioallergosorbent test (RAST)

Mechanism of Type-I hypersensitivity
• The mechanism of reaction involves preferential production
of IgE, in response to certain antigens (allergens).
• Individuals prone to type-I hypersensitivity
preferentially produce IL-4 and IL-13 that favor IgE class switch.
• IgE has very high affinity for its receptor (FcεIII; CD23) expressed
on surface of mast cells and basophils; the Fc portion of
IgE binds to these receptors.
• A subsequent exposure to the same allergen cross links the cell-
bound IgE and triggers the release of various pharmacologically
active substances by a process called as ‘degranulation’; mast
cell degranulation is preceded by increased Ca++ influx, which
is a crucial process.
• These agents cause the early phase of allergic reactions
that appears within minutes after exposure to the antigen.
Cross-linking of IgE Fc-receptor is important in mast cell triggering

Cross linking of IgE by allergen triggers mast cell degranulation

Induction and effecter mechanisms in Type-I Hypersensitivity

Effects of Type-I Hypersensitivity
• The inflammatory agents released or produced cause the
following:
– dilation of blood vessels, which causes local redness (erythema)
at the site of allergen delivery. If dilation is widespread, this can
contribute to decreased vascular resistance, a drop in
blood pressure, and shock.
– increased capillary permeability, which causes swelling of local
tissues (edema). If widespread, it can contribute to decreased
blood volume and shock.
– constriction of bronchial airways, which leads to wheezing and
difficulty in breathing.
– stimulation of mucous secretion, which leads to congestion of
airways.
– stimulation of nerve endings, which leads to itching and pain in
the skin.

Pathology of Type-I hypersensitivity
• The primary cellular component in Type-I is mast cell or basophil.
The reaction is amplified and/or modified by
platelets, neutrophils and eosinophils.
• The reaction may involveskin (urticaria and
eczema), eyes
(conjunctivitis),
bronchopulmonary
(gastroenteritis).
nasopharynx (rhinorrhea, rhinitis),
tissues (asthma) and gastrointestinal tract
The reaction may cause from minor
inconvenience to death.
•In most domestic species, the lungs are the primary target
organs, and the portal-mesenteric vasculature is a secondary
target; this is reversed in dogs.
•In dogs, the major organ affected by anaphylactic shock is
the liver, and signs are associated with constriction of hepatic
veins, resulting in portal hypertension and visceral pooling of
blood. GI signs rather than respiratory signs are more apt to
be seen in dogs.

Pathology of Type-I hypersensitivity
• The IgE mediated diseases in humans include
systemic anaphylactic shock, asthma, Hay fever (allergic
rhinitis), tropical pulmonary eosionophila, allergic
conjunctivitis, skin reactions (urticaria, eczema), food allergies.
• The IgE mediated diseases in animals include
systemic anaphylactic shock, urticarial reactions (hives), atopic
dermatitis, food allergies, allergic enteritis, atypical interstitial
pneumonia in cattle, chronic allergic bronchitis and pulmonary
infiltration with eosinophilia in dogs, allergic bronchiolitis and
asthma in cats.

Wheal and Flare reaction
Wheal and flare reaction is the characteristic local
cutaneous reaction, developing within 10 to 15 minutes of
injecting an allergen into the skin.
It consists of an elevated, blanched “wheal” surrounded by
a spreading by a spreading “flare” of erythema caused by release
of histamine from mast cells.
Wheal is a raised, itchy (pruritic) area of skin. It reflect
the layer
circumscribed dermal edema (fluid collection in
of skin below the surface). A wheal is also sometimes
called a welt and often a hive.
Flare is an area of redness surrounding wheal
The larger the wheal and flare, the greater the sensitivity.

Mechanism of Wheal and Flare reaction
The mechanism of wheal and flare reaction is expressed by Triple
response of Lewis:
Red spot: due to capillary dilatation
Flare: redness in the surrounding area due to arteriolar
dilatation mediated by axon reflex.
Wheal: due to exudation of fluid from capillaries and venules

Type II Hypersensitivity
(Antibody-mediated cytotoxic hypersensitivity)

Characteristics of Type II Hypersensitivity
• Type II hypersensitivity are antibody mediated cytotoxic
reactions occurring when an antibody binds to antigens located
on the surface of cells (usually RBCs). The reaction time is
minutes to hours.
• It is mediated, primarily, by antibodies of IgM or IgG class.
• The bound antibody can cause cell lysis by activating the classical
complement pathway, promoting phagocytosis (opsonization) or
through ADCC.
• Many different antigens may trigger this cell destruction, but
an infection in a genetically predisposed animal appears to be a
major triggering pathway.
• Antigens are normally endogenous, although exogenous chemicals
(haptens, such as ivy or drugs) that can attach to cell membranes
can also induce type II reactions.
• Autoimmune haemolytic anaemia, Blood transfusion
hemolytic
reactions,
anemia,
Erythroblastosis fetalis, drug-induced
granulocytopenia and thrombocytopenia are examples.

Mechanism of Type II Hypersensitivity
• IgM or IgG antibodies are made against self antigens either as
a result of failure of immune tolerance or cross-
reactive antibodies can develop during infections, which
may bind to normal tissue antigens and trigger
antibody-mediated cytotoxicity.
• Subsequent binding of these antibodies to the surface of host
cells leads to:
–Opsonization of the host cells whereby phagocytes stick to
host cells by way of IgG, C3b, or C4b and discharge their
lysosomes.
–Activation of the classical complement pathway
causing MAC induced lysis.
–ADCC mediated destruction of the host cells whereby NK
cells attach to the Fc portion of the antibodies.

Pathology of Type II Hypersensitivity
• Mediated by Abs directed towards antigens present on
cell surfaces or the extracellular matrix (type IIA) or abs
with agonistic/antagonistic properties (type IIB).
• The most common cells involved are blood cells. The outcome
may be:
– hemolytic anemia if RBCs are involved,
– leukopenia involving WBCs, or
– thrombocytopenia involving platelets.
• Under some circumstances, a cytotoxic attack on vascular
epithelial cells will cause a vasculitis with local vascular leakage.
• The lesion contains antibody, complement and neutrophils

Examples of Type II Hypersensitivity
 AB and Rh blood group reactions (blood transfusion reactions,
erythroblastosis foetalis)
 Autoimmune diseases:
 Rheumatic fever where antibodies result in joint and heart valve
damage;
 Idiopathic thrombocytopenia purpura where antibodies result
in the destruction of platelets;
 myasthenia gravis where antibodies bind to the acetylcholine
receptors on muscle cells causing faulty enervation of muscles;
 Goodpasture's syndrome where antibodies lead to destruction of
cells in the kidney;

 Autoimmune diseases:
 Graves' disease where antibodies are made against thyroid-
stimulating hormone receptors of thyroid cells leading to faulty
thyroid function;
 Multiple sclerosis where antibodies are made against the
oligodendroglial cells that make myelin, the protein that forms
the myelin sheath that insulates the nerve fibre of neurons in
the brain and spinal cord;
Some drug reactions, e.g. penicillin
Bovine Neonatal Pancytopenia

TYPE – III HYPERSENSITIVITY
(Immune complex mediated hypersensitivity)

Characteristics of Type III Hypersensitivity
• In type III hypersensitivity, soluble immune complexes are
formed in blood and are deposited in various tissues (typically
the skin, kidney and joints), activate classical complement
pathway and cause inflammatory damage.
• It is mediated by soluble immune complexes. They are mostly
of IgG class, although IgM may also be involved.
• The reaction takes hours to days (3-10 hours) to develop.
• The antigen may be exogenous (chronic bacterial, viral or
parasitic infections), or endogenous (non-organ specific
autoimmunity: e.g., Systemic Lupus Erythematosus-SLE).
• The antigen is soluble and not attached to the organ involved.
• The prerequisite for the development of immune-complex
disease is the persistent presence of soluble antigen and
antibody.

Mechanism of Type III Hypersensitivity
 Soluble antigen-antibody (IgG or IgM) complexes are normally
removed by macrophages in the spleen and liver.
endothelial cells of blood vessels – specially those in the skin,
joints, and kidneys and become trapped on the surrounding
basement membrane beneath these cells.
 The Ag-Ab complexes then activate the classical complement
pathway; the damage being caused by platelets and neutrophils :
 massive inflammation, due to complement protein C5a;
 influx of neutrophils, due to complement protein C5a , resulting in
neutrophils discharging their lysosomes and causing tissue destruction and
further inflammation;
MAC induced lysis of surrounding tissue cells; and
aggregation of platelets, resulting in more inflammation and the
formation
 On formation of excessive amount or large immune
complexes these gets lodged in capillaries, pass between

Pathology of Type III Hypersensitivity
• The affinity of antibody and size of immune complexes are
important in production of disease and determining the
tissue involved.
• The lesion contains primarily neutrophils and
deposits of
immune complexes and complement.
• Macrophages infiltrating in later stages may be involved in
the
healing process.
• The location of the immune complexes is largely determined by
the route by which antigen enters the body:
– Inhaled antigens give rise to a pneumonitis,
– antigens that enter through the skin cause local skin lesions, and
– antigens that access the bloodstream form immune complexes that are
deposited in renal glomeruli or joints.
• Clinical signs are therefore variable but may include fever,

• Examples in human beings are: serum sickness, Arthus reaction,
polyarteritis, rheumatoid arthritis, Glomerulonephritis, SLE,
allergies to penicillin and sulfonamides, poststreptococcal
glomerulonephritis, meningitis, hepatitis, mononucleosis.
• Examples in animals include:
– Membranoproliferative Glomerulonephritis in dogs
– Hypersensitivity Pneumonitis in large animals(Extrinsic
allergic
alveolitis, Farmer’s lung disease)
– Vasculitis
– Periarteritis Nodosa (Polyarteritis
Polyarteritis)
– Canine Rheumatoid Arthritis
– Plasmacytic-Lymphocytic Synovitis
Nodosa, Necrotizing

• Examples in animals include:
a Streptococcus equi infection; it occurs when immune complexes of
antibody and streptococcal antigen are deposited in vascular
basement membranes.
– Blue-eye disease in dogs is an immune complex–mediated
reaction that frequently occurs in the recovery stage of infectious
canine hepatitis. It is haracterized by anterior uveitis and results
from the reaction of serum antibodies with uveal endothelial cells
infected with canine adenovirus 1.
– Equine recurrent uveitis is associated with immunologic
reactions
to Leptospira or Onchocerca spp.
– Purpura hemorrhagica of horses is a severe non-
thrombocytopenic purpura occurring as a sequelae to

Arthus Reaction
 An Arthus reaction is a localized type III hypersensitivity
reaction characterized by immune complex–mediated
small- vessel vasculitis associated with deposition of
immune complexes and activation of complement, and
consequent organ damage
 Immune complexes form following high local concentration of
vaccine antigens and high circulating antibody concentration.
 It was first observed by Arthus in 1903 following
repeated injections of horse serum into rabbits.
 The formation of immune complexes initiates complement
activation and an influx of inflammatory cells,
followed by thrombus formation and hemorrhagic
infarction in the areas of most intense inflammation; the
types of mediators involved in Arthus reaction
determines the pathological outcome of disease.

Arthus Reaction
Arthus reaction is characterized by pain, swelling, induration, and
edema beginning several hours after immunization and
usually reaching a peak 12 to 36 hours after immunization.
It is self-limiting, resolving over the course of a few days.
The frequency and severity can be
more widely, as has been
lessened by spacing
immunizations recommended for
tetanus-diphtheria toxoid booster injections.

Serum Sickness
Serum sickness is a systemic type III hypersensitivity reaction that
results from the injection of heterologous or foreign protein
or serum.
Von Pirquet and Schick first described the syndrome in 1905, in
regions draining the site of injection after patients were
given antitoxin in the form of horse serum, hence the name
serum sickness–like reactions.
These reactions typically occur 1 to 3 weeks after exposure to the
drug, but may occur as early as 1 to 24 hours afterward.
Clinical manifestationsincludegeneral malaise,
fever, urticaria,
artheralgia, eosinophilia, splenomegaly and lymphadenopathy.
Certain medications (eg, penicillin, nonsteroidal anti-
inflammatory drugs [NSAIDs]) have also been associated with

Serum Sickness
On exposure to a foreign serum protein, 6-10 days later
antibodies and form antigen-antibody complexes.
If the macrophage activating system is not functioning properly,
these complexes will become saturated in the circulation, leading
to immune complex deposition, most commonly in parenchymal
tissues and synovial joint fluid.
The deposition of immune complexes may activate the classical
complement pathway, which will trigger histamine release
and increase vascular permeability, which leads to an
inflammatory response in the tissues and joints.
The mediation of injury in serum sickness appears to
involve several mechanisms, such as vasoactive amines,
infiltration of neutrophils, and cytokines, in particular TNFα) and
IL-1

Pathogenesis of Serum Sickness

Arthus reaction versus Serum Sickness

TYPE – IV HYPERSENSITIVITY
(Cell mediated hypersensitivity)
(Delayed type hypersensitivity)

Characteristics of Type IV Hypersensitivity
• Type IV hypersensitivity is often called delayed type
hypersensitivity as the reaction takes more than 12 hours to
develop. Typically the maximal reaction time occurs between
48 to 72 hours
• It is mediated by cells that cause an inflammatory reaction to
either exogenous or autoantigens
• The major cells involved are T lymphocytes
and
monocytes/macrophages.
• This reaction to exogenous antigens involves T cells and also
antigen-presenting cells (APC), all produce cytokines that
stimulate a local inflammatory response in a
sensitized individual.
• DHR cannot be transferred from an animal to another
by means of antibodies or serum. However, it can be
transferred by T cells, particularly CD4 Th1 cells.

Mechanism of Type IV Hypersensitivity
• CD8 cytotoxic T cells and CD4 helper T cells recognize antigen
in a complex with either type I or II MHC antigens
• The antigen-presenting cells in this case are macrophages and
they release interleukin 1, which further stimulates
the proliferation of CD4 cells.
• These cells release IL-2 and IFN-λ, which together regulate
the
immune reaction; other lymphokines involved in delayed
chemotactic
hypersensitivity reaction include monocyte
factor, TNF α etc.
• Cytokines produced by keratinocytes, APC, and T cells recruit
antigen-nonspecific T cells and macrophages to participate in
a local inflammatory reaction.
• Activated CD8 cells destroy target cells on contact, while
activated macrophages produce hydrolytic enzymes
and, transform into multinucleated giant cells.

Mechanism of Type IV Hypersensitivity

Pathology of Type IV Hypersensitivity
• Type IV hypersensitivity is involved in the pathogenesis of many
autoimmune and infectious diseases (tuberculosis,
leprosy, blastomycosis, histoplasmosis, toxoplasmosis,
leishmaniasis, etc.) and granulomas due to infections and
foreign antigens.
• There are three variants of delayed hypersensitivity as
listed below and their maximal reaction time appears in
brackets:
– Contact (48 to 72 hours)
– Tuberculin (48 to 72 hours)
– Granulomatous (21 to 28 days)
• The delayed hypersensitivity lesions mainly contain monocytes
and a few T cells.
– Contact: mononuclear cells infiltrates present in both dermis and
epidermis.
–Tuberculin: dermal infiltrate of leukocytes
–Granulomatous: typical epithelioid-cell granuloma and giant cells in the
center of the lesion surrounded by a cuff of lymphocytes.

Delayed Hypersensitivity Reactions

Contact Dermatitis Tuberculin type
Granuloma (T.B)

Comparison of Types of Hypersensitivity

Hypersensitivity.ppt

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