HYPERSENSITIVITY
DEFINATION
• Normally immune is protective leading to only subclinical or localized
response
• Sometimes the response becomes exaggerated causing extensive tissue
damage
• Defined as - Injurious consequences in the sensitised host following
subsequent contact with specific antigens.
CLASSIFICATION
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Following contact HS may occur immediately or after a few days.
It may be due to abnormal humoral or cell mediated immune response.
Gell and Coombs classified hypersensitivity reactions into 4 types.
Later a fifth type was also added k/as stimulatory HS
TYPE I REACTION
• Hallmark- production of IgE by sensitized B cells after contact with an
antigen/allergen.
• This in turn leads to degranulation of Mast cells releasing various mediators.
• These mediators cause manifestation like
Vasodilatation
Vascular & smooth muscle contraction
Increased vascular permeability
• These changes lead to either a localised response k/as Atopy or a systemic
response k/as Anaphylaxis.
• The foreign antigens which induce allergy are k/as allergens.
• Common allergens associated with type I HS reactions are:
1. Food
2. Plants and Pollens
3. Proteins
4. Drugs
5.products released during insect bite
6. Others like Mould Spores, animal hair & dander.
Demonstration of type I hypersensitivity
reactions
• P-K reaction
• Schultz Dale phenomenon
• Theobald Smith Phenomenon
Mechanism of type I reaction
• Occurs in two phases:
1. Sensitization phase- occurs when first exposure to antigen occurs
2. Effector phase- occurs during subsequent exposures to same antigen.
• Sensitisation can occur by any route but more effective when introduced
parenterally.
• Allergen is processed by antigen presenting cells (APC)
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Antigenic peptides are presented to the CD4 helper T cells.
Activated TH cells differentiated into TH 2 cells which secrete IL-4
IL-4 induces B cells to differentiate into Plasma cells and Memory cells.
IgE secreted by plasma cells migrates to target sites and coats on surface of
mast cells and basophils.
• Fc region of IgE binds to Fc receptors on mast cells.
• Such Mast cells are k/as sensitised Mast cells and interact with antigen on
subsequent exposure.
• Allergen attaches to the Fab region of IgE coated on mast cells.
• IgE cross linkages initiates degranulation of mast cells and results in release
of chemical mediators.
• Two type of mediators:
1. Primary mediators- preformed, already synthesized by mast cells,
released immediately.
Eg. Histamine- vascular permeability, ECF-A, NCF-A, Proteases-bronchial
mucous secretion
2. Secondary mediators- synthesised by mast cells and released
Eg. Prostaglandins and Leukotrienes, PAF, Bradykinin, Cytokines.
HISTAMINE
• Most important vasoactive amine in human anaphylaxis
• Found in granules of mast cells, basophils and platelets
• Released into skin
• Burning and itching sensation
• Vasodilation and hyperemia (flare effect)
• Odema – increasing capillary permeability (wheal effect)
• Smooth muscle contraction – various organs
Manifestations
• Immediate
• Late
IMMEDIATE
• Systemic anaphylaxis- medical emergency c/by sever dyspnea,hypotension
and vascular collapse leading to death at times
• Occurs within minutes of exposure.
• Wide range of allergens responsible. Eg. Venom fron bee, drugs, antitoxins,
seafoods and nuts
• DOC- Epinephrine
• Loclised Anaphylaxis limited to target site, mostly epithelial surfaces at site
of entry
• These run in families and are inherited.
• They are collectively k/as ATOPY.
• Eg’s. Allergic rhinitis/hay fever
Asthma
Food allergy
Atopic dermatitis
Drug allergy
LATE MANIFESTATIONS
• Immediate response followed 4-6 hrs later by inflammatory response which
leads to tissue damage
Factors influencing type I HS reactions
1. Genetic make up
2. Allergen dose
3. Th1 vs Th2 response
Detection of type I HS response
• Skin prick test
• Radioimmunosorbent test (RIST)
• Radioallergosorbent test (RAST)
Treatment
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Avoiding contact with knowm allergen
Hyposensitization
Monoclonal anti IgE
Drugs like antihistamines, epinephrine, cortisone, theophylline.
TYPE II HYPERSENSITIVITY REACTION
• Host injury mediated by antibodies which interact with various types of
antigens.
Eg’s: 1. host cell surface anigen
2. Extracellular matrix antigen
3. Exogenous antigens absorbed on host cells
• The antibody associated is mostly IgG & rarely IgM.
• Ag-Ab bind, Fc region of antibody initiates the reaction by the following 3
broad mechanisms:
1. Complement dependent reactions
2. Antibody dependent cellular cytotoxicity (ADCC)
3. Autoantibody mediated OR Antibody dependent cellular dysfunction
COMPLEMENT DEPENDENT REACTIONS
• The Fc region of bound antibody activates classical complement pathway
and leads to host cell injury mediated by following mechanisms:
1. Complement dependent cytolysis- MAC(C5-C9) formed during activation of classical
pathway, produces pores which lead to lysis of target cells.
2. Complement dependent inflammation- Byproducts of complement pathway like C3a
& C5a which act as chemoattractants, induces inflammatory response leading to tissue
injury.
3. Opsonisation- Byproducts like C3b & C4b acts as opsonins. They get deposited on
target cells. These complement coated target cells are engulfed by macrophage and
neutrophil.
• Clinical conditions in which type II hypersensitivity:
1. ABO incompatibility/ Transfusion reaction
2. Erythroblastosis fetalis/ Rh incompatibility
3. Autoimmune haemolytic anaemia- due to production of autoantibodies to individuals
own membrane antigens of RBC’s/granulocytes/platelets.
4. Drug induced haemolytic anaemia- drug or its metabolized product gets adsorbed
onto RBCmembrane. If antibodies against drug are formed, they will bind to the
adsorbed drug and cause complement mediated lysis of RBC’s. eg. Quinine, penicillin.
5. Pemphigus vulgaris- autoantibodies against desmosomal protein result in disruption
of epidermal intracellular junction.
ABO Blood Groups
Antibody against rbc antigen binds and
mediates killing of rbcs via C’or ADCC
causes systemic inflammation.
ERYTHROBLASTOSIS FETALIS
Autoimmune Hemolytic Anemia
DRUG INDUCED HEMOLYTIC
ANAEMIA
ANTIBODY DEPENDENT CELLULAR CYTOTOXICITY
(ADCC)
• Involved in destruction of target that are too large to be phagocytosed
• Typically mediated by IgG but rarely by IgE.
• IgG coat on target cells by interacting with surface antigen through Fab
region .
• Fc portion binds to receptors on various cells and results in destruction of
target cells.
Antibody dependent cellular dysfunction
• Autoantibodies bind and disturb the normal function of self antigens
• Anti receptor antibody. Eg’s Graves disease, Myasthenia grevis
• Other examples: good pasture, pernicious anaemia, rheumatic fever.
Autoantibody mediated cellular dysfunction
TYPE III HYPERSENSITIVITY
REACTIONS
• Result of excess formation of immune complexes, which initiate
inflammatory response through activation of complement.
• Can involve exo or endogenous antigens
• Under normal conditions immune complexes rapidly cleared.
• In some conditions immune system exposed to excess antigen over long
period of time. This leads to excessive formation of immune complexes.
Mechanism of tissue injury
1. Classical complement activation- C3a, C5a act as anaphylotoxin &
chemoattractant. Also neutrophils play a role.
2. Platelet activation- IC bind t Fc receptor platelets and activates them.
Aggregation and vasoactive amines released cause tissue ischaemia.
3. Activation of Hageman factor leads to activation of kinin causing
vasodilation and oedema
Localised Arthus Reaction
• Localised area of tissue necrosia due to vasculitis.
• Seen following insect bite, during allergic desensitization
• Also occurs due to inhalation of bacteria fungi, spores. Eg’s Farmer’s lung,
Bird fancier’s disease
Generalised reaction
• Occurs in 2 phases: formation of small sized soluble IC and induction of
inflammatory immune response.
• Prototype is serum sickness
Disease associated with generalised type III
reactions
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SLE
RA
PAN
Parasitic diseases
PSGN
M. leprae
HBV, HCV, IM, Dengue
Graft rejection
TYPE IV HYPERSENSITIVITY REACTIONS
• Also k/as “Delayed Hypersensitivity type of reaction” occurs 48-72 hrs
after Ag exposure
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Its cell mediated: TDTH (delayed type hypersensitivity cells) are the main
mediators
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Tissue injury predominantly due to activated Macrophages
Mechanisms of Type IV reactions
• 2 phases
• Sensitization phase:
Initial 1-2 weeks following Ag exposure
APCs present antigen along with MHC II to helper T cells
These differentiate to form TDTH cells
Effector phase:
TDTH cells on subsequent contact with the Ag secrete variety of CYTOKINES
Attract & recruit macrophages, inflammatory cells to site of reaction
INF-γ: activates Macrophages for microbial killing
IL: 2 stimulates proliferatio of TDTH cells
Monocyte chemotactic factor
Examples of DTH
Intracellular pathogens inducing DTH
Intracellular bacteria:
• M.Leprae
• M.Tuberculosis
• Listeria monocytogenes
• Brucella abortus
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Intracellular viruses
• HSV, Smallpox virus
• Measles virus
Other examples of DTH
• Multiple sclerosis
• Hashimotos thyroiditis
• Chronic transplant rejection
Intracellular fungi:
Pneumocystis jerovecii
Candida albicans
Histoplasma capsulatum
Crytococcus neoformans
Contact dermatitis: following exposure to nickel, poison ivy
Role of DTH: protective Vs tissue damage
• Through DTH host attempts to provide protection
• Protective response: Pathogens usually cleared with little tissue damage by
macrophages
• Tissue damage response: when IC pathogens escape macrophage killing, enhanced
phagocytic activity & release of lytic enzymes : tissue damage
Pathology of DTH reaction:
Granuloma formation
• Continuous DTH response for killing persistent /non degradable Ags leads to
granuloma formation (TB, Leprosy)
Macrophages transform into flat epithelioid
cells
Epitheiliod cells fuse : multinucleated giant
cells (IFN-γ)
Granuloma: inner zone: epithiliod cells,
surrounded by lymphocytes rim of
fibroblasts
Clinically important Delayed Hypersensitivity reactionsA. Contact dermatitis:
• Cell mediated hypersensitivity occurs after contact with simple chemicals like nickel,
formaldehyde, plant materials – poison ivy, poison oak, topically applied drugs like
sulfonamides, neomycin, sometimes cosmetics, soaps and others.
• Most of these are haptens, attach to skin proteins to become complete antigen:
immunogenic
• Hapten alters the skin protein & immune system starts recognizing it as foreign:
internalized by APCS presented to T-helper cells: induce DTH
• Activated macrophages: release lytic enzymes : skin lesions
B. TUBERCULIN TEST• A patient previously exposed to M.tuberculosis is injected with a small amount of
Tuberculin (PPD) intra-dermally.
• Local reaction develops gradually (induration and redness) 48-72 hours, suggestive of
a Positive test.
• A positive skin test indicates the person has been infected with the agent but it does
not confirm the presence of current disease.
• But if skin test converts from negative and positive, it suggests that the patient has
been recently infected.
• Infected persons need not always have a positive skin test. E.g.
overwhelming infections, disorders which suppresses Cell
Mediated Immunity like uremia, measles, Sarcoidosis, lymphoma
and AIDS or administration of immune-suppressive drugs like
corticosteroids, anti-neoplastic agents can cause anergy.
A positive skin test response assists in diagnosis – supports chemoprophylaxis or
chemotherapy
Examples• 1. Leprosy – Lepromin test• Positive test indicates Tuberculoid type with competent CMI.
• Negative test indicates Lepromatous leprosy with impaired CMI.