HYPERSENSITIVITY DEFINATION - PowerPoint Presentation

Slide1

HYPERSENSITIVITY

Slide2

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.

Slide3

CLASSIFICATION

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

Slide4

Slide5

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

Slide6

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.

Slide7

Demonstration of type I hypersensitivity reactions

P-K reaction

Schultz Dale phenomenon

Theobald Smith Phenomenon

Slide8

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)

Slide9

Antigenic peptides are presented to the CD4 helper T cells.

Activated T

H

cells differentiated into T

H

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.

Slide10

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.

Slide11

Slide12

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

Slide13

Manifestations

Immediate

Late

Slide14

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

Slide15

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

Slide16

LATE MANIFESTATIONS

Immediate response followed 4-6 hrs later by inflammatory response which leads to tissue damage

Slide17

Factors influencing type I HS reactions

Genetic make up

Allergen dose

Th1 vs Th2 response

Slide18

Detection of type I HS response

Skin prick test

Radioimmunosorbent

test (RIST)

Radioallergosorbent

test (RAST)

Slide19

Treatment

Avoiding contact with

knowm

allergen

Hyposensitization

Monoclonal anti

IgE

Drugs like antihistamines, epinephrine, cortisone, theophylline.

Slide20

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.

Slide21

Ag-Ab bind, Fc region of antibody initiates the reaction by the following 3 broad mechanisms:

Complement dependent reactions

Antibody dependent cellular cytotoxicity (ADCC)

Autoantibody mediated OR Antibody dependent cellular dysfunction

Slide22

COMPLEMENT DEPENDENT REACTIONS

The Fc region of bound antibody activates classical complement pathway and leads to host cell injury mediated by following mechanisms:

Complement dependent cytolysis- MAC(C5-C9) formed during activation of classical pathway, produces pores which lead to lysis of target cells.

Complement dependent inflammation-

Byproducts

of complement pathway like C3a & C5a which act as

chemoattractants

, induces inflammatory response leading to tissue injury.

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.

Slide23

Clinical conditions in which type II hypersensitivity:

ABO incompatibility/ Transfusion reaction

Erythroblastosis

fetalis

/ Rh incompatibility

Autoimmune haemolytic anaemia- due to production of autoantibodies to individuals own membrane antigens of RBC’s/granulocytes/platelets.

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.

Pemphigus vulgaris- autoantibodies against

desmosomal

protein result in disruption of epidermal intracellular junction.

Slide24

Slide25

Slide26

Antibody against

rbc

antigen binds and

mediates killing of

rbcs

via

C’or

ADCC

causes systemic inflammation.

ABO Blood Groups

Slide27

Slide28

ERYTHROBLASTOSIS FETALIS

Slide29

Slide30

Slide31

Slide32

Autoimmune

Hemolytic

Anemia

Slide33

DRUG INDUCED HEMOLYTIC ANAEMIA

Slide34

Slide35

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.

Slide36

Slide37

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.

Slide38

Autoantibody mediated cellular dysfunction

Slide39

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.

Slide40

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

Slide41

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

Slide42

Generalised reaction

Occurs in 2 phases: formation of small sized soluble IC and induction of inflammatory immune response.

Prototype is serum sickness

Slide43

Disease associated with generalised type III reactions

SLE

RA

PAN

Parasitic diseases

PSGN

M.

leprae

HBV, HCV, IM, Dengue

Graft rejection

Slide44

TYPE IV HYPERSENSITIVITY REACTIONS

Also k/as “Delayed Hypersensitivity type of reaction

” occurs

48-72 hrs after Ag

exposure

Its

cell mediated

:

T

DTH

(delayed type hypersensitivity cells) are the main mediators

Tissue

injury predominantly due to

activated Macrophages

Slide45

Mechanisms of Type IV reactions

2 phases

Sensitization phase

:

Slide46

Effector

phase:

Slide47

Slide48

Examples of DTH

Intracellular pathogens inducing DTH

Intracellular bacteria:

M.Leprae

M.Tuberculosis

Listeria

monocytogenes

Brucella

abortus

Intracellular fungi:

Pneumocystis

jerovecii

Candida

albicans

Histoplasma

capsulatum

Crytococcus

neoformans

Intracellular viruses

HSV, Smallpox virus

Measles virus

Other examples of DTH

Multiple sclerosis

Hashimotos

thyroiditis

Chronic transplant rejection

Contact dermatitis:

following exposure to nickel, poison ivy

Slide49

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

Slide50

Pathology of DTH reaction:

Granuloma formation

Continuous DTH response

for killing

persistent

/non

degradable

Ags

leads to granuloma formation (TB, Leprosy)

Slide51

Clinically important Delayed Hypersensitivity reactions

-

A.

C

ontact 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.

Slide52

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

Slide53

Slide54

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

.

Slide55

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.

Slide56

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

.

Slide57

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.