Hypersensitivity reactions
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Hypersensitivity reactions. Prof . Mohamed Osman Gad El Rab. College of Medicine & KKUH. Introduction: Immune reactions leading to pathological tissue damage. - Occur as :

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Hypersensitivity reactions

Hypersensitivityreactions.

Prof . Mohamed Osman Gad El Rab.

College of Medicine & KKUH.


Hypersensitivity reactions

  • Introduction:

    Immune reactions leading to pathological

    tissue damage.

    - Occur as :

    1.Secondary heightened (increased) immune

    responses .

    OR

    2.Secndary inappropriate (abnormal ) immune

    responses.


Hypersensitivity reactions

  • Four major categories according toCoombs and Gell classification :

  • Type I : Immediate H/S.

  • Type II : Cytotoxic H/S.

  • Type III : Immune – complex H/S.

  • Type IV : Delayed H/S.


Hypersensitivity reactions

  • Types I , II and III :

    are mediated by antibodies .

  • Type IV :

    Is generated by cell-mediated immune responses.


Hypersensitivity reactions

Hypersensitivity reactions differ inthe rate at which they occur :

  • Type I : Can occur within minutes afterexposure to antigen.

  • Type II and III : time course , (4-8) hours todays .

  • Type IV : require 2 - 4 days.


Hypersensitivity reactions

  • Hypersensitivity reactions :

    - can occur as isolated reactions,

    OR

    - more than one reaction can occur

    in the same patient.

    e.g. : Type I and Type III.


Type i hypersensitivity

Type I Hypersensitivity.

  • Also termed :

    *Immediate H/S ( can literally occur within minutes to hours ).

    * Anaphylactic reactions .

    OR

    * Allergic reactions.


Features

Features :

  • Antibody isotype : IgE .

    - Cellular components:

    Mast cells , basophiles & eosinophils.

    - Antigens :

    termed allergens ( antigens with low

    molecular weight & highly soluble.


Type i h s

Type I H/S :

* Evolved as a defense against parasitic infections.

* However , many reactions in some

predisposed individuals are directed towards harmless molecules (allergens) and these are said to be :

“atopic.”


Atopy

Atopy.

  • Occur in certain genetically predisposed

    individuals .

  • They comprise approx. 15 – 20 % of the

    population .

  • Atopy tend to run in families .


Hypersensitivity reactions

  • The likelihood to generate a strong IgE response is determined by :

    - genetic factors .

    - environmental factors.

    these factors

    depend on exposure to allergens of

    diverse nature ( pollens , foods , drugs

    fungal spores , bee - sting venoms ,

    house dust mites and animal dander.


Type i reaction occur in 2 phases

Type I Reaction occur in 2 phases:

  • Phase I :

    - Sensitization phase .

    Allergen enter tissues , induce an

    immune response . B – cells transform

    to plasma cells & produce IgE.

    - IgE bind to receptors on Mast cells and

    basophiles ( FcЄRI - high affinity receptors).

    individuals become :

    “ Sensitized . “


Hypersensitivity reactions

  • Phase II :

    Challenge phase .

    -Subsequent encounter with same allergen cross – link IgE on Mast cells .

    -This generate an intracellular signal that prompts the Mast cells to:

    “ Degranulate”


Hypersensitivity reactions

Development of Allergy Requires

Sensitization , Re - exposure & Degranulation

Naive Mast Cell

Sensitized Mast Cell

Degranulated Mast Cell


Degranulation

Degranulation :

  • The release of a wide variety of mediators of inflammation .

  • These exert effects on surrounding target tissues.

  • There are 2 types :

    1. primary mediators.

    2. secondary mediators.


Primary mediators

Primary mediators.

  • 1. Histamine ,heparin.

  • 2. Serotonin .

  • 3. Eosinophil chemotactic factor (ECF).

  • 4. Neutrophil chemotactic factor (NCF ).

  • 5. Proteases .


Secondary mediators

Secondary mediators :

  • 1. Platelet activating factor .

  • 2. Leukotriens ( slow reacting substance of anaphylaxis).

  • 3. Prostaglandins .

  • 4. Bradykinin.

  • 5. Cytokines .( IL-1,TNF-a , IL-2 , 3, 4, 5, 6, )


Hypersensitivity reactions

Some effects of mediators :

  • Amines & active peptides

    - Histamine ( increase vascular permeab.).

    (constriction of vasc. smooth muscle).

    - Heparin ( counters coagulation ).

  • Cytokines & chemokines :

    -IL – 5 (eosinophils).

    -IL – 8 (neutrophils).

    - IL – 4. ( IgE)

  • Enzymes – Elastase : ( reconstruction of connective tissues).


Type 1 h s immediate hypersensitivity

Type 1 H/S. ( immediate hypersensitivity ).


Some effects of secondary mediators

Some effects of secondary mediators :

Prostaglandins :vasodilatation, contraction of

pulmonary smooth muscle

.

Leukotrienes :increased vascular permeab.

contraction of smooth muscle.

Platelet-activating factor: platelet aggregation,

contraction of smooth muscle .


Eosinophils

Eosinophils:-

  • Major basic protein (MBP) activate mast cells and basophiles.

  • Eosinophil Cationic protein (ECP) toxic to parasites.

  • Mast cells and Basophiles interact with Eosinophils (can bind IgE).

  • Eosinophils release:-

    - Enzymes.

    - Cytokines.

    - Chemokines.

  • Therefore, contribute to the inflammatory

    reaction.


Hypersensitivity reactions

  • Elevated IgE.

  • Blood eosinophilia.

    are clinical signs of Type I reactions.


Type 1 reactions result in

Type 1 reactions result in :

* Vasodilatation and increased capillary

permeability .

* Edema.

* Vasoconstriction ( arteries and arterioles )

* Bronchoconstriction.

* Increased mucus secretion.


Symptoms of an allergic type i reaction are determined by location of allergens

Symptoms of an allergic (Type I) reaction are determined by location of allergens:-

  • Inhaled allergenswhen deposit in nasopharyngeal

    and bronchial tissues result in :

    - Allergic rhinitis.

    - Allergic asthma.

  • Ingested allergens : food allergy (G.I.T symptoms)


Pathogenesis of allergic rhinitis

Pathogenesis of allergic rhinitis


Hypersensitivity reactions

  • Bee sting allergens Injected into the blood.

     Systemic inflammation.

     Anaphylactic shock.

    (life - threatening).

  • Anaphylactoid reactions:-

    are non - IgE mediated.

    may result from contrast media or

    local anesthetics.


Diagnosis

Diagnosis:-

1. Skin prick test (SPT).

2. Intradermal test.

3. Specific IgE measurement (RAST).

4. Challenge test ( Nasal , Bronchial).

4. Elimination / Provocation test (Food allergy).


Skin prick test diagnosis of type 1 hypersensitivity

Skin prick test ( diagnosis of type 1 hypersensitivity ).


Type ii hypersensitivity cytotoxic h s

Type II Hypersensitivity.(Cytotoxic H/S).

  • Features:-

    - IgG.

    - Antigens ( Bound to cell membranes

    or extra cellular matrix).

    - Self - antigens.

    - Exogenous antigens. (microbial )

    - Complement activation (Invariable).


Mechanisms of tissue damage in type 11

Mechanisms of tissue damage in type 11:-

  • IgG (from blood) fix to bound antigen.

    - Activate complement.

    - Complement generate

    chemotactic agents (C5a).

    - Attract neutrophils and other

    inflammatory cells.


Neutrophils bind to target through

Neutrophils bind to target through:-

A. Complement receptors -(immune -adherence).

B. Antibody receptors - (Opsonic -adherence).

- They secrete their enzymes to the

outside (Exocytosis).

- They cause direct damage.


Complement mediated damage type11

Complement - mediated damage (type11):-

  • Activation of complement C8 , C9.

    - Membrane attack complex

    (MAC).

    - Direct lytic damage on target

    tissues.


Type 11 h s glomerulonephritis anti gbm

Type 11 H/S.( Glomerulonephritis anti-GBM ).


Clinical examples type 11

Clinical Examples ( type 11):-

1, Incompatible blood transfusion (ABO).

-massive intravascular hemolysis of RBC.

-Immediate reactions-IgM mediated.

-Delayed reactions-(2-6 days ),IgG mediated.

2. Hemolytic disease of the new -born (HDN).

3. Drug reactions (Drugs bind to R.B.C , W.B.C , platelets).

- Lead to:-

- Hemolytic anemia.

- Thrombocytopenia.

- Leucopenia.


Hypersensitivity reactions

4. Autoimmune diseases (Self-antigens).

5. Graft rejection (Hyper - acute).

- Preformed antibodies in the recipient .

Diagnosis:-

- Detection of antibodies and antigens by immunofluorecence. (Biopsy).


Type 11 h s hemolytic disease of the newborn

Type 11 H/S. (hemolytic disease of the newborn)


Type iii hypersensitvity immune complex h s

Type III Hypersensitvity(Immune - complex H/S ):-

  • Features:-

    - IgG or IgM.

    - Soluble antigens.

    - Immune – Complex formation.

    - Complement activation.

    (invariable).


Mechanism of tissue damage type 111

Mechanism of tissue damage (type 111):-

  • Immune - Complexes are continuously forming.

    - Depend on the nature and conc. of

    antigens and antibodies.

    - As long as they are not :-

    - Extremely large.

    - Numerous.

    they are readily cleared.


Hypersensitivity reactions

  • Immune complex clearance :

    1. The mononuclear- Phagocyte system.

    - Macrophages and dendritic cells

    degrade particles and debris.

    2. Erythrocytes bind complexes via FcR1

    receptors and release them in the liver.


Hypersensitivity reactions

  • When size and quantity over whelm the normal clearance mechanism:-

    1. Complexes accumulate and deposit in

    blood vessels and tissues.

    2. They activate complement.

    Therefore : induce immune - complex

    disease.


Mechanism of tissue damage type 1111

Mechanism of tissue damage (type 111):

Complexes deposit in blood vessels and tissues and result in vasculitis , arthritis …et

.

  • Two main types :

    1. Complexes with antibody excess ,

    are termed Arthus – type reactions (localized ).

    2. Complexes with antigen excess ,

    are termed serum – sickness reactions (systemic).


Type 111 h s arthus reaction

Type 111 H/S . ( arthus reaction )


Sites susceptible to type iii h s

Sites susceptible to type III H/S:

1. Glomeruli .

- high blood flow .

- filtration of the blood.

- complement receptors .

Lead to glomerulonephritis .

2. Blood vessel walls .

- complexes deposit on walls of veins and arteries .

  • Lead to vasculitis .


Type 111 h s immune complex disease

Type 111 H/S.( IMMUNE - COMPLEX DISEASE )


Type 111 cont

Type 111,cont.

3. Synovial membrane of joints .

- immune- complexes.

deposition can damage bone and

cartilage .

4. Skin .

- a common site for deposition of immune

complexes manifest as rashes .


Type 111 h s glomerulonephritis

Type 111 H/S.( Glomerulonephritis ).


Clinical examples type 111

Clinical examples (type 111) :

1. Autoimmune disease ,(self – antigens ).

2. Chronic infections ,(microbial antigens)

.

3. Cancer , (tumor antigens).

4. Drug reactions , (chemical haptens ).


Diagnosis type 111

Diagnosis (type 111) :

  • Demonstration of specific immune complexes in the blood or tissues by

    immunofluorescence .


Type iv hypersensitivity delayed h s

Type IV hypersensitivity( delayed H/S ):

  • Features :

    - cell-mediated (CD 4 T-cells).

    - activated macrophages .

    - delayed- onset (2 – 4 days).

    - secondary abnormal cellular

    responses .

    - granuloma formation .


Type iv h s

Type IV H/S.

  • Four subtypes :

    1. Basophil H/S ( Jones-mote reaction ).

    2. Contact sensitivity ( chemical antigens )

    .

    3. Tuberculin reactions ( mantoux test )

    4. Granuloma formation .


Mechanism of tissue damage type 1v

Mechanism of tissue damage (type 1v ):

  • Sensitized CD 4 Th1-cells recognize antigen.

  • Become activated and secrete cytokines .

  • Attract and activate macrophages .

    This lead to intense inflammation that

    cause permanent damage .


Dth responses to persistent antigen

DTH responses to persistent antigen :

  • Lead to formation of a granuloma .

  • This prevent spread of infection e.g. T.B. tubercle .

  • May cause local mechanical pressure on adjacent tissues e.g. leprosy .


Type 1v h s 2 phases

Type 1V H/S. ( 2 phases.)


Type 1v h s granuloma

Type 1V H/S. (granuloma .)


Dth reaction

DTH reaction.

  • Double- edged sword

  • Fine line between:

  • 1. protective response.

  • 2. tissue damaging response .


Clinical examples type 1v

Clinical examples( type 1v ):

1. Chronic infections :

- T.B.

- leprosy .

- fungal infections .

-parasitic infections.

2. Contact dermatitis.


Type 1v h s allergic contact dermatitis

Type 1V H/S.( ALLERGIC CONTACT DERMATITIS ).


Type 1v h s contact dermatitis

Type 1V H/S. ( CONTACT DERMATITIS ).


Contact dermatitis type 1v hypersensitivity

Contact dermatitis .(Type 1V hypersensitivity ).


Diagnosis type 1v

Diagnosis (type 1v ):

1. Delayed skin test .

2. Patch test.

3. Lymphocyte transformation test.

( detection of activation markers by flow cytometry ).


Hypersensitivity reactions

  • Practical points :

  • 1.Allergen extracts for the skin prick test.

  • (SPT ).

  • * This test is used to diagnose type 1

  • Hypersensitivity.

    A drop of the allergen is placed on the forearm & pricked through by a lancet.

    The reaction is read after 15 minutes.

  • Positive reaction : wheal (swelling ) & flare (redness).


Skin prick test spt

Skin prick test (SPT ).


2 the rast test

2. The RAST test .

  • The RAST test measures specific IgE (to

  • different allergens ) in the patients serum .

  • * used to confirm the skin prick test .

  • * also used when the skin test is not possible .

  • ( patient taking anti-histamines )

  • 3. The patch test.

  • * used to test for contact dermatitis ( delayed H/S .)

  • * allergens are applied on the back under cover

  • * the reaction is read after 48- hours .

  • * Positive reaction : indurations .


Patch test

Patch test .


Hypersensitivity reactions

  • Immunology Quiz no.2


A35 years old man suddenly developed severe nasal symptoms on entering an old store room

A35-years old man suddenly developed severe nasal symptoms on entering an old store room.

The symptoms included severe bouts of sneezing, itching in the nose, eyes ,ears & throat. .

After a short time he had watery

nasal discharge & congestion (nasal block).

Examination of a nasal smear showed high level of granulocytes .

The patient was given a drug to control the

symptoms but the tablets were not effective & he was given a topical steroid (nasal spray)


1 what is the type of reaction underlying this condition

1. What is the type of reaction underlying this condition ?

2.What is the type of granulocytes detected in the nasal smear ?

3.Explain the underlying immunopathology of all the symptoms & signs mentioned in this condition ?

4.What type of drug was given to control the symptoms ?

5. What is the mechanism by which cortisone help in control of symptoms in this condition ?


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