HYPERSENSITIVITY REACTIONS

Dr. SOMESHWARAN RAJAMANI, MBBS, MDAssistant professor, Department of Microbiology,

Karpagam Faculty of medical sciences and Research.

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INTRODUCTIONImmunity – protective – overcome infectious agents (antigens) and toxins

Immune response – may also be injurious to host

Sensitised individual respond to specific antigenic stimuli in an inappropriate or exaggerated manner

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In protective part of immunity – antigen is the focus of attention and what happens to it

Example: Bacteriolysis, Toxin neutralization

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In hypersensitivity antigens are of little concern and often innocuous or bland substances such as serum proteins or pollen

Hypersensitivity is concerned with what happens to host as a result of immune reaction

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DEFINITIONInjurious consequences in the sensitized host, following contact with specific antigens.

Deals with injurious aspect of heightened and exaggerated immune response leading to tissue damage, disease or even death

Concerned with what happens to the host rather than what happens to the antigen.

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Essentials for Hypersensitivity

Contact with allergen

Sensitizing/priming dose

Induction of AMI/CMI

Shocking dose

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CLASSIFICATION TRADITIONAL CLASSIFICATION

COOMB AND GELL (1963) CLASSIFICATION

Traditional classification is based on the time required for a sensitized host to develop clinical reactions on re-exposure to the specific antigen

Coomb and Gell classification is based on mechanism of pathogenesis

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TRADITIONAL CLASSIFICATION IMMEDIATE HYPERSENSITIVITY: (B cell or antibody mediated)

Anaphlaxis Atopy Antibody mediated damage Arthus phenomenon Serum sickness DELAYED HYPERSENSITIVITY Infection (Tuberculin) type Contact dermstitis type

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IMMEDIATE HYPERSENSITIVITY DELAYED HYPERSENSITIVITY

Appears and recedes rapidly Appears slowly and lasts longer

Induced by antigens or haptens by any route Antigen or hapten intradermally or with Freund’s adjuvant or by skin contact

Circulating antibodies present and responsible for reaction; ‘antibody mediated’ reaction.

Circulating antibodies may be absent and not responsible for reaction; ‘cell mediated’ reaction

Passive transfer possible with serum Cannot be transferred with serum; but possible with T cells or transfer factor

Desensitisation easy, but short-lived Difficult, but long-lasting

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COOMB AND GELL CLASSIFICATION (4 types)1. Type l : IgE mediated2. Type ll : Cytolytic & Cytotoxic3. Type lll : Immune complex4. Type lV : Delayed hypersensitivity

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AtopyAnaphylaxis

Arthus reactionSerum sickness

Autoimmune anemiaHemolytic disease of

newbornGrave’s disease

Myasthenia gravis

Contact dermatitisTuberculin reaction

Schwartzmann reactionCutaneous basophil

hypersensitivity

I III

II IV

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COOMBS & GELL CLASSIFICATION (1963)Type of reaction

Clinical syndrome Time required for manifestation

Mediators

Type l AnaphylaxisAtopy

Minutes IgE: histamine & other pharmacological agents

Type ll Ab mediated damage- thrombocytopenia, hemolytic anemia

Variable : hours to days

IgG : Igm, C

Type lll Arthus reactionSerum sickness

Variable : hours to days

IgG : Igm, C, leucocytes

Type lV Tuberculin Contact dermatitis

Hours to days T cells; lymphokines; macrophages

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TYPE I REACTIONS IgE dependant/ Reagin , mediated Occur in 2 forms:1. Anaphylaxis – acute, potentially fatal,

systemic form.

2. Atopy – chronic or recurrent, non fatal, localized form.

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ANAPHYLAXISAna- without, Phylaxis-protectionClassical immediate hypersensitivity reactionSensitization

Most effective when Ag is introduced parenterally

Minute quantities are enoughInterval of 2-3 weeks needed between sensitizing & shocking dose

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ANAPHYLAXISOnce sensitized it remains so for long time

Shocking dose most effective by IV route then IP, then SC then ID

The shocking Ag must be same or similar to Sensitizing Ag

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ANAPHYLAXIS Mechanism: Cytotropic IgE – IgE antibodies bound to surface of mast cells and basophils

FcER receptors analogous to TCR is present in these cells

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ANAPHYLAXIS IN VITROSchultz Dale phenomenon:Intestinal or uterine muscle strips – from sensitized guinea pigs – kept in a bath of ringer’s solution – contarct vigorously on addition of specific antiserum

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ANAPHYLAXISPrimary mediators:Histamine, Serotonin, Chemotactic factors

Secondary mediators: Prostaglanins and Leukotrienes, Platelet activating factor (PAF)Others: anaphylatoxins, bradykinin

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Theobald-Smith phenomenon: Guinea pigs - Sublethal load of sea anemones – toxin - immune

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ANAPHYLACTOID REACTIONIntravenous Trypsin or peptone - HS

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B cell

Histamine, tryptase,

kininegenase, ECFA

Leukotriene-B4, C4, D4, prostaglandin D,

PAF

Newly synthesized mediators

TH2IL13

Sensitization against allergens and type-I hypersensitivity

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Type I ReactionsHumans – Itching of scalp & tongue,

flushing of skin, difficulty in breathing, nausea, vomiting, diarrhea, acute hypotension, loss of consciousness, death (rare)

Causes Serum therapy, antibiotics,

insect stings Treatment

Adrenalin 0.5 ml (1 in 1000 solution) SC/IM repeated up to 2 ml in 15 min

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CUTANEOUS (LOCAL) ANAPHYLAXIS Follows I.D. injection (small shocking dose) – a

local wheal & flare response is seen. Wheal – central pale area of puffiness due to

edema Flare - surrounds wheal, caused by hyperemia

and subsequent erythema. Uses : - Testing for hypersensitivity Precaution – Keep adrenalin injection ready to

combat severe fatal reaction.

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ATOPY Refers to naturally occurring familial

hypersensitivities of human beings : - Hay fever - Asthma Antigens involved in atopy can be 1. Inhalants – pollen, house dust 2. Ingestants – eggs, milk3. Contact allergens.

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Type-I hypersensitivity

The common allergy

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DIAGNOSIS1. Skin tests (ID injection ) - with allergens like pollen, cat or dust mite Children - 3x3 mm wheal Adults – 4x4 mm wheal +ve test takes 5 -15 mins to develop, persist for 30 mins or

more – IMMEDIATE RESPONSE.

2. Radioallergosorbent test (RAST) - to measure the levels of Ig E in serum.

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TYPE II (CYTOTOXIC) REACTIONS

Involve activation of complement by IgG or IgM binding to an antigenic cell.

Antigenic cell is lysed.

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Type II Hypersensitivity

Role of complement and phagocytes

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TYPE II HYPERSENSITIVITY REACTIONS

Reactions against blood cells & platelets1. Incompatible blood transfusion. 2. Hemolytic disease of the newborn.3. Autoimmune hemolytic anemias,

thrombocytopenia.

• Reactions against Tissue Antigens1. Myasthenia gravis & LATS in Grave’s

disease2. Pemphigus vulgaris

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Type II hypersensitivity induced by exogenous agents

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Involve reactions against soluble antigens circulating in serum.

Usually involve IgA antibodies.Antibody-Antigen immune complexes are

deposited in organs, activate complement, and cause inflammatory damage.

Glomerulonephritis: Inflammatory kidney damage.Occurs when slightly high antigen-antibody ratio

is present.

TYPE III (IMMUNE COMPLEX) REACTIONS

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APC

TH2

B cell

Sensitization for Type III hypersensitivity

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Immune Complex Mediated Hypersensitivity

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SERUM SICKNESSSystemic form of type lll HS. Appears 7-12 days following the injection of large doses of foreign serum (Diphtheria antitoxin).

ICs are deposited on the endothelial lining of blood vessels in various parts of the body.

Features – fever, LN pathy, splenomegaly, arhthritis, glomerulonephritis, endocarditis, rashes, abdominal pain, nausea & vomiting.

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Serum sickness

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ARTHUS REACTIONLocal reaction consisting of edema, induration & hemorrhage.

Followed by repeated SC injection with a foreign serum/ normal horse serum.

Intense local reaction – edema, induration, hemorrhagic necrosis

Reaches peak after 4 - 10 hrs, disappears by 48 hrs.

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TYPE 4: DELAYED HYPERSENSITIVITY

Takes more than 12 hrs to develop. Involve CMI reactions. Provoked by intracellular microbial infections

or haptens like simple chemicals Varieties of Delayed HS :1. Contact 48-72 hrs2. Tuberculin 48-72 hrs3. Granulomatous 21-28 days

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CONTACT DERMATITIS Eczematous reaction at the point

of contact with an allergen, like1. Metals – nickel, chromium2. Simple chemicals – dyes3. Drugs – Penicillin

• Cells involved in Contact HS1. Langerhans cells2. Keratinocytes

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CONTACT DERMATITISLesions – vary from macules & papules to vesicles that break down leaving behind raw weeping areas

Detected by ‘Skin Patch Test’ * Allergen is applied to the skin under an adherent dressing. * Itching appears in 4- 5 hrs. * Local reaction after 24- 48 hrs: Erythema to vesicle or blister formation

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Clinical & Patch test appearance of contact hypersensitivity

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Tuberculin Type HypersensitivityTuberculin type – ID inoculation of PPD in sensitized

individual leads to induration & inflammation in 48-72 hrs. This is not the same as skin test done for Type I hypersensitivity.

Used for diagnosis / exclusion of diagnosis of many bacterial / fungal / parasitic / viral and autoimmune diseases.

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DISEASES MANIFESTING GRANULOMATOUS HS

LeprosyTuberculosisSchistosomiasisSarcoidosisCrohn’s disease

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SCWARTZMANN REACTION

Not an immune reactionPertubation in factors affecting intravascular coagulation

Ex: Waterhouse Freiderichsen syndromeMeningococcal septicemia

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Type-IVType-IIIType-IIType-Icharacteristic

Comparison of hypersensitivity reactions

TB test, poison ivy, granuloma

farmers’ lung, SLE

pemphigus, Goodpasture

hay fever, asthma

examples

antibody IgE IgG, IgM IgG, IgM noneantigen exogenous cell surface intracellularsoluble

response time

15-30 min. Min.-hrs 3-8 hours 48-72 hoursor longer

appearance Weal & flare Lysis & necrosis

Erythema & edema

Erythema & induration

baso- and eosinophils

Ab and complement

histology PMN andcomplement

Monocytes & lymphocytes

T-cellsantibodyantibodyantibodytransfer with

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SUMMARYHypersensitivity – injurious4 types – Type I, II, III, IVI, II, III – ImmediateIV- DelayedDifferences between immediate and delayed HS

Examples for Type I, II, III and IV HS

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THANK YOU