Hypersensitivity

State of heightened reactivity to an antigen

An altered immune state induced by an antigen in which pathological reaction can be subsequently elicited by that antigen Mediated by immunological mechanisms that cause tissue damage

Classification
On the basis of time required for sensitized host to develop clinical rxn upon re-exposure on the antigen, Chase classified them as a. Immediate rxn b. Delayed rxn

Gell and Coombs classification:

Type I IgE mediated (allergy)- anaphylactic rxn Type II Antibody-mediated cytotoxic rxn Type III Immune Complex mediated rxn Type IV Delayed-Type Hypersensitivity (DTH) rxn Types I, II and III are immediate Type IV is delayed

Immediate
Appears & recedes rapidly
Induced by antigen or hapten

Delayed
Appears slow and lasts longer Induced by infection, or by skin contact

Antibody mediated rxn

T cell-mediated rxn

Passive transfer possible with serum

Transfer possible by sensitized T cells

Immediate
Desensitization easy but short lived Lesions are acute exudation; wheal and flare

Delayed
Difficult

Mononuclear cells deposit around blood vessels

Wheal and flare with maximum diameter (in 6 hrs)

Erythema and induration with maximum diameter in 24 to 48 hrs

Type I rxn (allergy; anaphylactic rxn)

An allergic rxn provoked by re-exposure to a specific type of antigen (allergen)

Hallmark is production of IgE against allergens that cause mast cell degranulation
Requires two exposures to an antigen

First exposure to an antigen (Sensitizing dose) Second exposure to same antigen (shocking dose)

Common features
Low mol. wt.

Glycosylation High solubility in body fluids

Anaphylactic rxn
Sensitizing dose: an antigen induces the formation of IgE antibody, which
binds firmly, by its Fc portion to a receptor on mast cells and eosinophils

Shocking dose:
Second contact of Individual with same Ag results in the Ag fixation to cell bound IgE, cross-linking of IgE molecules Release of pharmacologically active mediators from cells within minutes

Mast cell activation

Mediators of anaphytical rxn

Histamine
(biogenic amine; Vasoactive amine)

increase vascular permeability vasodilation smooth muscle contraction (intestine & bronchi) mucus secretion leakage of plasma into tissues

Low mol. wt. compound (preformed and stored in granules) Decarboxylation of histidine

Histamine receptors (H1, H2, H3)

Actions are short-lived Histamine is rapidly removed by amine-specific transport system

Major lipid mediator produced on activation

Prostaglandin D2

Vasodilation, bronchoconstriction neutrophil chemotaxis

prolonged bronchoconstriction mucus secretion increased vascular permeability Chemotaxis & activation of leukocytes bronchoconstriction & vascular permeability

Leukotrienes C4, D4, E4

Platelet-activating factor

Cytokines produced on activation

TNF-, MIP-1 (CCL3) IL-3 IL-4, IL-13 Late-phase rxn (inflammation) Mast-cell proliferation TH2 differentiation

IL-5

Eosinophil production & proliferation

Eosinophils (bone-marrow derived granulocyte)

Major basic protein Eosinophil cationic protein Toxic to helminths & bacteria

Leukotrienes
Cytokines (IL-3, IL-5, GM-CSF, IL-8, IL-10, CCL5)

bronchoconstriction

Eosinophil production & chemotaxis

Atopy
A hereditary allergy produced upon re-exposure esp. by inhalation

to environmental allergens Examples: bronchial asthma, hay fever, allergic eczema There is a strong genetic predisposition

Show higher than average plasma IgE levels

Produce high levels of IgE in response to environmental allergens Rxn occurs within hours of exposure

Clinical manifestations
Allergic rhinitis (hay fever): most common allergic response
Inhaled allergen triggers reaction in nasal mucosa Watery exudate from nose, eyes, upper respiratory tract, sneezing and coughing

Bronchial asthma
Allergic asthma due to inhaled airborne allergens (pollens, dust, fumes etc) An inflammatory disease caused by immediate hypersensitivity and late phase reactions in the lung leading to clinico-pathologic triad; 1. Intermittent and reversible airway obstruction 2. Chronic bronchial inflammation with eosinophils 3. Bronchial smooth muscle cell hypertrophy & hyperreactivity to bronchoconstrictors

Intrinsic asthma triggered by cold, exercise not atopic (30% patients)

Food allergies
Ingestion of food allergens Vomiting and diarrhea If allergens are absorbed into bloodstream, reactions can occur where allergen deposits asthma-like symptoms Urticaria (hives, wheal & flare response)

Atopic Dermatitis (allergic eczema)

Often occurs in young children Red skin rash Strong hereditary predisposition

 Systemic anaphylaxis
Systemic presence of allergen Edema in many tissues Vasodilation bronchial constriction GI and bladder smooth muscle contraction Dyspnea Fall in blood pressure, shock Death within minutes if untreated

Type 1 Hypersensitivity tests

Allergy test: Skin testing

Intra-dermal injection of allergens into forearm Wheal and flare response develops within hours to 24 hrs

Type 1 Hypersensitivity test

Radioimmunosorbent test (RIST): Radioimmunoassay
Detection of total serum IgE antibodies Highly sensitive; detect nanomolar levels of IgE

125 I-labeled

anti-IgE

Type 1 Hypersensitivity tests

Radioallergosorbent test (RAST)

Detection of serum level of IgE specific for given allergen

Type II Hypersensitivity
Antibody-mediated cytotoxic reaction Antibodies (IgM or IgG) bind to cell surface antigens and may lead to: Complement activation lysis Antibody-dependent cell-mediated cytolysis Opsonization phagocytosis

 Examples:
Transfusion reactions (Rh incompatibility) Hemolytic disease of the newborn (erythroblastosis fetalis) Drug-induced hemolytic anemia (penicillin) Hashimotos Thyroiditis

Type III Hypersensitivity

Immune Complex Disease
Antibody (IgG) attaching to soluble antigen leads to complex formation
Immune complexes may deposit in:
Blood vessel walls (vasculitis) Synovial joints (arthritis) Glomerular basement membrane (glomerulonephritis)

Type III Hypersensitivity

Autoimmune Diseases
Systemic lupus erythematosus Rheumatoid arthritis Goodpastures syndrome

Infectious Diseases
Post-streptococcal glomerulonephritis Meningitis Hepatitis Malaria Trypanosomiasis

Drug Reactions
Allergies to penicillin & sulfonamides

Arthus reaction:

Localized reaction

Anaphylatoxin (C3a, C4a, C5a) release due to complement activation attracts neutrophils, and causes mast cell degranulation

Neutrophils can not phagocytose stuck immune complexes, so they release their granule contents leading to inflammation

Generalized reaction
Serum sickness
Administration of horse anti-tetanus or anti-diphtheria toxin induces production of antibodies against foreign serum proteins
Antibodies form circulating immune complex and within days or weeks, recipient begins to manifest clinical manifestations Fever, weakness, generalized vasculitis, edema and erythema, lymphadenopathy, arthritis, and sometimes glomerulonephritis

Type IV Hypersensitivity (Delayed type hypersensitivity)

When activated TH1 cells encounter certain type of antigens, they secrete cytokine that mediate localized inflammatory reaction, known as delayed type hypersensitivity (DTH) Hallmarks: large number of macrophages at reaction site & it takes an average of 2-7 days to manifest after repeat exposure First noticed by Robert Koch (in 1890) with reaction to tuberculosis bacteria (tuberculin reaction)

TH cells that have been sensitized by an antigen develop into TH1 T cells

TH1 cells induces macrophage recruitment and activation

Contact Dermatitis: DTH

Small molecules that can form complex with skin proteins

Protein complex is processed by Langerhans cells & presented to TH1 cells

A subsequent exposure will elicit activation of TH1 cells & induce cytokine production

Cytokines activate macrophages & release of lytic enzymes that result in redness and pustules

Delayed Type Hypersensitivity test: skin test Tuberculin rxn

To determine whether an individual has been exposed to M. tuberculosis, PPD, a purified protein derivative (cell wall of mycobacterium), is injected intradermally Development of a red, swollen, firm lesion at the site between 48 and 72 h later indicates previous exposure Skin lesion results from intense infiltration of macrophages to the site of injection during a DTH reaction

80%90% of these cells are macrophages

Interpretation
A region of swelling 10 mm (0.4 inch) or greater in diameter, usually
accompanied by redness, occurs within 48 hours at the site of injection

+ve reaction +ve reaction indicates that the individual was previously exposed to
the tubercle bacillus, but it does not necessarily indicate that active clinical tuberculosis is present Clinical diagnosis (chest X-ray) is recommended