HYPERSENSITIVITY

Seminar By- SALMAN KHANII sem M.Sc (bt)

Hypersensitivity Reactions

Allergies Greek = altered reactivity

1906 – von Pirquet coined term: hypersensitivity

Hypersensitivity reactions – ‘over reaction’ of the immune system to harmless

environmental antigens

Definition

• Hypersensitivity refers to undesirable (damaging, discomfort-producing and sometimes fatal) reactions produced by the normal immune system.

• Hypersensitivity reactions require a pre-sensitized (immune) state of the host.

• Nearly 45 years ago Gell and Coombs proposed a classification scheme which defined 4 types of hypersensitivity reactions

• Hypersensitivity reactions -four types: type I, type II, type III and type IV, based on the mechanisms involved and time taken for the reaction.

TYPES OF HYPERSENSITIVITYThe four types of hypersensitivity are:

I. Type I Hypersensitivity- IgE mediated(classical immediate hypersensitivity)

II. Type II Hypersensitivity- Antibody mediated(cytotoxic hypersensitivity)

III. Type III Hypersensitivity- immune complex(immune-complex mediated hypersensitivity)

III. Type IV Hypersensitivity- cell mediated(mediated or delayed hypersensitivity)

The first three are mediated by antibody, the fourth by T cells.

Hypersensitivity reaction depends on:

1) chemical nature of allergen2) route involved in sensitization i.e.

inhalation, ingestion, injection…3) physiological state of individual / genetic

potential

Type I• Common among population in developed nations• Prerequisite: need prior sensitization to antigen• the binding of antigen to antigen specific IgE bound

on mast cells• Rapid liberation of active chemicals such as

histamine and serotonin• A hypersensitivity due to excessive production of the

class of antibody known as IgE. Reactions between allergens and IgE bound to mast cells and basophiles cause a greatly heightened inflammatory response.

Pollen grain entry into nasal cavity

Allergen- POLLEN GRAIN

STEP 1:EXPOSURE OF ANTIGEN TO ANTIGEN

PRESENTING CELL1.2- RECOGNITION BY T- HELPER CELLS

STEP 2:ACTIVATION OF B-CELLS INTO PLASMA AND MEMORY CELLS

AND

SECRETION OF ANTIBODIES (IgE)

STEP 3:IgE BINDS TO HIGH AFFINITY RECEPTORS

(FC EPSILONRI)ON THE SURFACE OF MAST CELLS

SUBSEQUENT EXPOSURESTEP 4:

SUBSEQUENT EXPOSURE OF ANTIGEN

ANTIGEN BINDS WITH IgE ON THE SURFACE OF MAST CELLS

STEP 5:RELEASE OF PRIMARY INFLAMMATORY METABOLTES

ACTIVATION OF SECONDARY METABOLITES

Typical responses to these chemicals:• Increased capillary permeability

Urticaria [hives]• Excessive mucus production

Allergic rhinitis [hay fever]Diarrhea or vomiting

Asthma

MECHANISM OF ACTIONMOLECULE EFFECTS

PRIMARY MEDIATORS

HISTAMINE VASCULAR PERMEABILITY, SMOOTH MUSCLE CONTRACTION

SEROTONIN VASCULAR PERMEABILITY, SMOOTH MUSCLE CONTRACTION

ECF-A EOSINOPHIL CHEMOTAXIS

NCF-A NEUTROPHIL CHEMOTAXIS

PROTEASES MUCUS SECRETION, CONNECTIVE TISSUE DEGRADATION

SECONDARY MEDIATORS

LEUKOTRIENES VASCULAR PERMEABILITY, SMOOTH MUSCLE CONTRACTION

PROSTAGLANDINS VASCULAR PERMEABILITY, SMOOTH MUSCLE CONTRACTIONAND PLATELET ACTIVATION

BRADYKININ VASCULAR PERMEABILITY, SMOOTH MUSCLE CONTRACTION

CYTOKINES NUMEROUS EFFECTS INC. ACTIVATION OF VASCULAR ENDOTHELIUM, EOSINOPHIL RECRUITMENT AND ACTIVATION

SPECIAL NOTES

The reactions, mediated by agents without IgE-allergen interaction, are not hypersensitivity

reactions although they produce the same symptoms.

.Corticosteroids and other immunosuppressive agentsANTI-INFLAMMATORY DRUGS

Epinephrine (pen-injection)

THERAPY

Hypo sensitization2X weekly, for 20 weeks

Highest dosage-Every 4 weeks for 5 years

THERAPY

DIAGNOSTICS

Type II

• Type II Hypersensitivity• Type II hypersensitivity is also known as

cytotoxic hypersensitivity and may affect a variety of organs and tissues. The antigens are normally endogenous, although exogenous chemicals (haptens) which can attach to cell membranes can also lead to type II hypersensitivity.

Type II

• A hypersensitivity resulting from antibodies mistakenly reacting with normal self antigens on body cells. Binding of the antibodies to these normal cells results in immune destruction

• Drug-induced haemolytic anaemia, granulocytopenia and thrombocytopenia are such examples. The reaction time is minutes to hours. Type II hypersensitivity is primarily mediated by antibodies of the IgM or IgG classes and complement (Figure 2). Phagocytes and K cells may also play a role (ADCC)

Type II• small molecules bound to cells and make a structure perceived as

foreign by immune cells [ blood transfusion reactions. Erythroblastolysis foetalysis]

• Allergens create a situation that induces cytolysis or cytotoxicity. • Antibodies involved are

IgG OR IgMIN THIS CASE1. MADE AGAINST SELF ANTIGENS

2. ATTACH TO THE SURFACES OF CELLS HAVING SELF EPITOPS

SELF ANTIGEN=Any constituent of the body's own tissues capable of stimulating autoimmunity

Complement (are also involved)

• Blood proteins – initiate a series of enzymatic reactions leading to the ‘fixing’ of complement fragments to the pathogen’s surface – tagging it for destruction

• Allergens trigger the classical complement pathway: antibody binds to specific antigen recruitment of inflammatory cells, opsonization facilitating phagocytosis

OPSONIZATION

MECHANISMTHE OPSONIZATION IS OF THE HOST CELL

PHAGOCYTES STICK TO MEMBRANES OF HOST CELL

VIA IgG, C3B, C4B

PHAGOCYTES DISCHARGE THEIR LYSOSOMES

OPSONIZATION

RESULT:LYSIS OF HOST CELL

MAC LYSIS

MECHANISM

Type III Hypersensitivity

• Type III hypersensitivity is also known as immune complex hypersensitivity.

• The reaction may be general (e.g., serum sickness) or may involve individual organs including skin (e.g., systemic lupus erythematosus, Arthus reaction), kidneys (e.g., lupus nephritis), lungs (e.g., aspergillosis), blood vessels (e.g., polyarteritis), joints (e.g., rheumatoid arthritis) or other organs.

MECHANISM OF ACTION

STEP 1 Large quantities of soluble antigen-antibody complexes form

in the blood and are not completely removed by macrophages.

MECHANISM OF ACTION

STEP 2 These antigen-antibody complexes lodge in the blood vessels

between the endothelial cells and the basement membrane.

.

• The reaction may take 3 - 10 hours after exposure to the antigen

• It is mediated by soluble immune complexes. They are mostly of the IgG class, although IgM may also be involved.

Type III• soluble protein complexes found in blood

bound to IgG [ when non human proteins are given therapeutically – can be side effect]

• Cause acute inflammatory reactions• Immune complexes can become deposited

in walls of small blood vessels in alveoli ANAPHYLAXIS

Type IV Hypersensitivity

• Type IV hypersensitivity is also known as cell mediated or delayed type hypersensitivity (cytotoxic T-lymphocytes and cytokines)

• The classical example of this hypersensitivity is tuberculin reaction which peaks 48 hours after the injection of antigen (PPD or old tuberculin).

• The lesion is characterized by indurations and erythema.

MECHANISM OF ACTION T-H CELLS INDUCED

STEP 1ANTIGEN ENTERS THE BODY

ENGULFED BY MACROPHAGES

PRESENTED TO T-H CELLS

T-H CELLS BECOMES ACTIVATED AND INCREASED IN NUMBER

MECHANISM OF ACTION T-H CELLS INDUCED

STEP 2SECOND EXPOSURE

ENGULFED BY MACROPHAGES

PRESENTED TO T-H CELLS

T-H CELLS RELEASE CYTOKINES

MECHANISM OF ACTION T-H CELLS INDUCED

STEP 3 T-H 1 or TD CELLS RELEASE

CYTOKINES

ATTRACTION FOR MORE MACROPHAGES AT THE

SITE OF ATTACK

MORE INFLAMMATION

SKIN LESIONS

T-H 2 CELLS RELEASE

IL-4 AND IL-5

PROMOTE EXTRACELLULAR KILLING BY EOSINOPHILS

TISSUE DAMAGE

.

• Type IV hypersensitivity is involved in the pathogenesis of many autoimmune and infectious diseases (tuberculosis, leprosy, blastomycosis, histoplasmosis, toxoplasmosis, leishmaniasis, etc.)

Tuberculin Test

Measurement of Mx

SUMMARY

CHARACTERISTICS

type-I(anaphylactic)

type-II(cytotoxic)

type-III(immune complex)

type-IV(delayed type)

ANTIBODY IgE IgG, IgM IgG, IgM None

ANTIGEN exogenous cell surface soluble tissues & organs

RESPONSE TIME 15-30 minutes minutes-hours 3-8 hours 48-72 hours

APPEARANCE weal & flare lyses and necrosis

erythema and edema, necrosis

erythema and indurations

HISTOLOGY basophiles and eosinophil

antibody and complement

complement and neutrophils

monocytes and lymphocytes

TRANSFERRED WITH

antibody antibody antibody T-cells

EXAMPLES allergic asthma, hay fever

Erythro-blastosisfetalis,

Farmer's lung disease

tuberculin test, poison ivy, granuloma

THANK YOU