HypersensitivityHypersensitivityreactions.reactions.

Prof . Mohamed Osman Gad El Rab.Prof . Mohamed Osman Gad El Rab.

College of Medicine & KKUH.College of Medicine & KKUH.

Introduction:Introduction:

Immune reactions leading to pathologicalImmune reactions leading to pathological

tissue damage.tissue damage.

- Occur as :- Occur as :

1.Secondary heightened (increased) immune1.Secondary heightened (increased) immune

responses .responses .

OROR

2.Secndary inappropriate (abnormal ) immune2.Secndary inappropriate (abnormal ) immune

responses.responses.

Four major categories according toFour major categories according to Coombs and Gell classificationCoombs and Gell classification : :

Type I :Type I : Immediate H/S. Immediate H/S.

Type II :Type II : Cytotoxic H/S. Cytotoxic H/S.

Type III :Type III : Immune – complex H/S. Immune – complex H/S.

Type IV :Type IV : Delayed H/S. Delayed H/S.

Types I , II and III :Types I , II and III :

are mediated by antibodies .are mediated by antibodies .

Type IV :Type IV :

Is generated by cell-mediated Is generated by cell-mediated immune responses. immune responses.

Hypersensitivity reactions differ inHypersensitivity reactions differ in the rate at the rate at which they occur :which they occur :

Type I :Type I : Can occur within minutes after Can occur within minutes after exposure to antigen.exposure to antigen.

Type II and III :Type II and III : time course , (4-8) hours time course , (4-8) hours toto days .days .

Type IV : Type IV : require 2 - 4 days. require 2 - 4 days.

Hypersensitivity reactions :Hypersensitivity reactions :

- can occur as isolated reactions,- can occur as isolated reactions,

OROR

- more than one reaction can occur- more than one reaction can occur

in the same patient. in the same patient.

e.g. :e.g. : Type I and Type III. Type I and Type III.

Type I Type I HypersensitivityHypersensitivity.. Also termed :Also termed : *Immediate H/S*Immediate H/S ( can literally occur ( can literally occur

within minutes to hours ).within minutes to hours ).

* * Anaphylactic reactionsAnaphylactic reactions . . OROR * * Allergic reactions.Allergic reactions.

FeaturesFeatures: : - Antibody isotype :Antibody isotype : IgE . IgE .

- Cellular components:- Cellular components:

Mast cells , basophiles & eosinophils.Mast cells , basophiles & eosinophils.

- Antigens :- Antigens :

termed allergens ( antigens with lowtermed allergens ( antigens with low

molecular weight & highly soluble. molecular weight & highly soluble.

Type I H/SType I H/S: : * Evolved as a defense against * Evolved as a defense against

parasitic infections.parasitic infections. * However , many reactions in some* However , many reactions in some predisposed individualspredisposed individuals are are

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

““atopic.”atopic.”

AtopyAtopy..

Occur in certain genetically predisposedOccur in certain genetically predisposed

individuals . individuals .

They comprise approx. 15 – 20 % of theThey comprise approx. 15 – 20 % of the

population . population .

Atopy tend to run in families . Atopy tend to run in families .

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

- genetic factors .- genetic factors .

- environmental factors.- environmental factors.

these factorsthese factors

depend on exposure to allergens of depend on exposure to allergens of

diverse nature ( pollens , foods , drugsdiverse nature ( pollens , foods , drugs

fungal spores , bee - sting venoms , fungal spores , bee - sting venoms ,

house dust mites and animal dander. house dust mites and animal dander.

Type I Reaction occur in 2 phasesType I Reaction occur in 2 phases:: Phase I :Phase I : - - Sensitization phase .Sensitization phase . Allergen enter tissues , induce anAllergen enter tissues , induce an immune response . B – cells transformimmune response . B – cells transform to plasma cells & produce IgE.to plasma cells & produce IgE. - IgE bind to receptors on Mast cells and- IgE bind to receptors on Mast cells and

basophiles ( Fcbasophiles ( FcЄЄRI - high affinity receptors).RI - high affinity receptors).

individuals become :individuals become :

“ “ Sensitized . “Sensitized . “

Phase II :Phase II :

Challenge phaseChallenge phase . .

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

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

“ “ Degranulate”Degranulate”

BOMB BOMB

Naive Mast Cell Sensitized Mast Cell Degranulated Mast Cell

Development of Allergy Requires Sensitization , Re - exposure & Degranulation

DegranulationDegranulation : :

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

These exert effects on surrounding These exert effects on surrounding target tissues.target tissues.

There are 2 types :There are 2 types :

1. primary mediators.1. primary mediators.

2. secondary mediators.2. secondary mediators.

Primary mediatorsPrimary mediators..11 . .Histamine ,heparinHistamine ,heparin..

22 . .SerotoninSerotonin. .

33 . .Eosinophil chemotactic factor (ECF)Eosinophil chemotactic factor (ECF)..

44 . .Neutrophil chemotactic factor Neutrophil chemotactic factor (NCF )(NCF )..

55 . .ProteasesProteases. .

Secondary mediatorsSecondary mediators: :

11 . .Platelet activating factorPlatelet activating factor. .

22 . .Leukotriens ( slow reacting substance of Leukotriens ( slow reacting substance of anaphylaxis)anaphylaxis) . .

33 . .ProstaglandinsProstaglandins. .

44 . .BradykininBradykinin..

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

Some effects of mediators :Some effects of mediators :

Amines & active peptidesAmines & active peptides - Histamine ( increase vascular permeab.).- Histamine ( increase vascular permeab.). (constriction of vasc. smooth muscle).(constriction of vasc. smooth muscle). - Heparin ( counters coagulation ).- Heparin ( counters coagulation ).

Cytokines & chemokines :Cytokines & chemokines : -IL – 5 (eosinophils).-IL – 5 (eosinophils). -IL – 8 (neutrophils).-IL – 8 (neutrophils). - IL – 4. ( IgE) - IL – 4. ( IgE)

Enzymes – Elastase : Enzymes – Elastase : ( ( reconstruction of reconstruction of

connective tissues).connective tissues).

Type 1 H/S. Type 1 H/S. ( immediate hypersensitivity )( immediate hypersensitivity )..

Some effects of secondary mediators :Some effects of secondary mediators :

Prostaglandins :Prostaglandins : vasodilatation, contraction of vasodilatation, contraction of

pulmonary smooth musclepulmonary smooth muscle.. Leukotrienes :Leukotrienes : increased vascular permeab.increased vascular permeab. contraction of smooth muscle.contraction of smooth muscle.

Platelet-activating factor: Platelet-activating factor: platelet platelet aggregation, aggregation, contraction of smooth contraction of smooth

muscle .muscle .

Eosinophils:-Eosinophils:-

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

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

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

Eosinophils release:-Eosinophils release:- - Enzymes.- Enzymes. - Cytokines.- Cytokines. - Chemokines.- Chemokines. Therefore, contribute to the inflammatoryTherefore, contribute to the inflammatory reaction.reaction.

Elevated IgE.Elevated IgE.

Blood eosinophilia.Blood eosinophilia.

are clinical signs of Type I reactions.are clinical signs of Type I reactions.

Type 1 reactions result in :Type 1 reactions result in :

* Vasodilatation and increased capillary * Vasodilatation and increased capillary

permeability . permeability .

* Edema.* Edema.

* Vasoconstriction ( arteries and arterioles )* Vasoconstriction ( arteries and arterioles )

* Bronchoconstriction.* Bronchoconstriction.

* Increased mucus secretion.* Increased mucus secretion.

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

Inhaled allergensInhaled allergens when deposit in nasopharyngeal when deposit in nasopharyngeal

and bronchial tissues result in :and bronchial tissues result in :

- - Allergic rhinitis.Allergic rhinitis.

- Allergic asthma.- Allergic asthma.

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

Pathogenesis of allergic rhinitisPathogenesis of allergic rhinitis

Cytokines, Leukotrienes (Chemotaxis)

Immediate Allergic Response Runny Nose, Sneezing, Nasal Congestion Symptoms: Acute, Responsive to antihistamines

Late Allergic Response Significant Nasal Congestion, Runny Nose Symptoms: Chronic, Less responsive to antihistamines

Histamine, Prostaglandins, Leukotrienes, Tryptase

Major Basic Protein, Eosinophil Cationic Protein, Lipid-derived Mediators of Inflammation

Bee sting allergensBee sting allergens Injected into the blood. Injected into the blood. Systemic inflammation.Systemic inflammation. Anaphylactic shock.Anaphylactic shock. (life - threatening).(life - threatening).

Anaphylactoid reactions:-Anaphylactoid reactions:- are non - IgE mediated.are non - IgE mediated. may result from contrast media ormay result from contrast media or local anesthetics.local anesthetics.

Diagnosis:-Diagnosis:-

1. Skin prick test (SPT).1. Skin prick test (SPT).

2. Intradermal test.2. Intradermal test.

3. Specific IgE measurement (RAST).3. Specific IgE measurement (RAST).

4. Challenge test ( Nasal , Bronchial).4. Challenge test ( Nasal , Bronchial).

4. Elimination / Provocation test (Food allergy).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.Type II Hypersensitivity. (Cytotoxic H/S).(Cytotoxic H/S).

Features:- Features:-

- IgG.- IgG.

- Antigens ( Bound to cell membranes- Antigens ( Bound to cell membranes

or extra cellular matrix).or extra cellular matrix).

- Self - antigens.- Self - antigens.

- Exogenous antigens. (microbial )- Exogenous antigens. (microbial )

- Complement activation (Invariable).- Complement activation (Invariable).

Mechanisms of tissue damage in type 11:-Mechanisms of tissue damage in type 11:-

IgG (from blood) fix to bound antigen.IgG (from blood) fix to bound antigen.

- Activate complement.- Activate complement.

- Complement generate - Complement generate

chemotactic agents (C5a).chemotactic agents (C5a).

- Attract neutrophils and other - Attract neutrophils and other

inflammatory cells.inflammatory cells.

Neutrophils bind to target throughNeutrophils bind to target through-:-:

A. Complement receptorsA. Complement receptors -(immune -adherence). -(immune -adherence).

B. Antibody receptorsB. Antibody receptors - (Opsonic -adherence). - (Opsonic -adherence).

- They secrete their enzymes to the- They secrete their enzymes to the

outside outside (Exocytosis).(Exocytosis).

- They cause direct damage.- They cause direct damage.

Complement - mediated damage (type11):-Complement - mediated damage (type11):-

Activation of complementActivation of complement C8 , C9. C8 , C9.

- Membrane attack complex - Membrane attack complex

(MAC).(MAC).

- Direct lytic damage on target- Direct lytic damage on target

tissues.tissues.

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

GBM )GBM )..

Clinical Examples ( type 11):-Clinical Examples ( type 11):-1, Incompatible blood transfusion (ABO).1, Incompatible blood transfusion (ABO).

-massive intravascular hemolysis of RBC.-massive intravascular hemolysis of RBC.

--Immediate reactions-IgMImmediate reactions-IgM mediated. mediated.

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

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

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

- Lead to:-- Lead to:-

- Hemolytic anemia.- Hemolytic anemia.

- Thrombocytopenia.- Thrombocytopenia.

- Leucopenia.- Leucopenia.

4. Autoimmune diseases (Self-antigens).4. Autoimmune diseases (Self-antigens).

5. Graft rejection (Hyper - acute).5. Graft rejection (Hyper - acute).

- Preformed antibodies in the recipient . - Preformed antibodies in the recipient .

Diagnosis:-Diagnosis:-

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

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

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

Features:-Features:-

- IgG or IgM.- IgG or IgM.

- Soluble antigens.- Soluble antigens.

- Immune – Complex formation.- Immune – Complex formation.

- Complement activation.- Complement activation.

(invariable). (invariable).

Mechanism of tissue damage (type 111):-Mechanism of tissue damage (type 111):-

Immune - Complexes are continuously Immune - Complexes are continuously forming.forming.

- Depend on the nature and conc. of - Depend on the nature and conc. of

antigens and antibodies.antigens and antibodies.

- As long as they are not :-- As long as they are not :-

- Extremely large.- Extremely large.

- Numerous.- Numerous.

they are readily cleared.they are readily cleared.

Immune complex clearance :Immune complex clearance :

1.1. The mononuclear- Phagocyte system. The mononuclear- Phagocyte system.

- Macrophages and dendritic cells - Macrophages and dendritic cells

degrade particles and debris.degrade particles and debris.

2.2. Erythrocytes bind complexes via FcR1 Erythrocytes bind complexes via FcR1

receptors and release them in the liver.receptors and release them in the liver.

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

1.1. Complexes accumulate and deposit in Complexes accumulate and deposit in

blood vessels and tissues.blood vessels and tissues.

2.2. They activate complement. They activate complement.

Therefore : induce immune - complexTherefore : induce immune - complex

disease. disease.

Mechanism of tissue damage (type 111)Mechanism of tissue damage (type 111)::

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

.. Two main types :Two main types :

1.1. Complexes with antibody excess , Complexes with antibody excess , are termed are termed Arthus – type reactionsArthus – type reactions

(localized ).(localized ).

2.2. Complexes with antigen excess , Complexes with antigen excess , are termed are termed serum – sickness reactionsserum – sickness reactions

(systemic). (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:

1.1. Glomeruli . Glomeruli . - high blood flow .- high blood flow . - filtration of the blood.- filtration of the blood. - complement receptors .- complement receptors . Lead to glomerulonephritisLead to glomerulonephritis . .

2.2. Blood vessel walls . Blood vessel walls .- complexes deposit on walls of veins - complexes deposit on walls of veins

and arteries . and arteries . Lead to vasculitisLead to vasculitis . .

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

DISEASE )DISEASE )

Type 111,contType 111,cont . .

3.3. Synovial membrane of joints . Synovial membrane of joints .

- immune- complexes.- immune- complexes.

deposition can damage bone anddeposition can damage bone and

cartilage .cartilage .

4.4. Skin . Skin .

- a common site for deposition of immune - a common site for deposition of immune

complexes manifest as rashes .complexes manifest as rashes .

Type 111 H/SType 111 H/S..( Glomerulonephritis )( Glomerulonephritis )..

Clinical examples (type 111)Clinical examples (type 111): :

1. Autoimmune disease ,(self – antigens ).1. Autoimmune disease ,(self – antigens ).

2. Chronic infections ,(microbial antigens)2. Chronic infections ,(microbial antigens)

..

3. Cancer , (tumor antigens).3. Cancer , (tumor antigens).

4. Drug reactions , (chemical haptens ).4. Drug reactions , (chemical haptens ).

Diagnosis (type 111)Diagnosis (type 111): :

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

immunofluorescenceimmunofluorescence . .

Type IV hypersensitivityType IV hypersensitivity ( delayed H/S )( delayed H/S )::

Features :Features : - cell-mediated (CD 4 T-cells).- cell-mediated (CD 4 T-cells). - activated macrophages .- activated macrophages . - delayed- onset (2 – 4 days).- delayed- onset (2 – 4 days). - secondary abnormal cellular- secondary abnormal cellular responses . responses .

- granuloma formation .- granuloma formation .

Type IV H/SType IV H/S . .

Four subtypes :Four subtypes :

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

2. Contact sensitivity ( chemical antigens )2. Contact sensitivity ( chemical antigens )

..

3. Tuberculin reactions ( mantoux test )3. Tuberculin reactions ( mantoux test )

4. Granuloma formation . 4. Granuloma formation .

Mechanism of tissue Mechanism of tissue damage (typedamage (type 1v ): 1v ):

Sensitized CD 4 Th1-cells recognize antigen.Sensitized CD 4 Th1-cells recognize antigen. Become activated and secrete cytokines .Become activated and secrete cytokines . Attract and activate macrophages .Attract and activate macrophages .

This lead to intense inflammation that This lead to intense inflammation that

cause permanent damage .cause permanent damage .

DTH responses to persistent antigenDTH responses to persistent antigen: :

Lead to formation of a granuloma .Lead to formation of a granuloma .

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

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

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

Type 1V H/SType 1V H/S. (granuloma. (granuloma .) .)

DTH reactionDTH reaction..

Double- edged swordDouble- edged sword

Fine line betweenFine line between : :

11 . .protective responseprotective response . .

22 . .tissue damaging tissue damaging responseresponse . .

Clinical examples( type 1v )Clinical examples( type 1v )::

1. Chronic infections :1. Chronic infections :

- T.B.- T.B.

- leprosy .- leprosy .

- fungal infections .- fungal infections .

-parasitic infections.-parasitic infections.

2.2. Contact dermatitis Contact dermatitis ..

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

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

Contact dermatitis .(Type 1V hypersensitivity )Contact dermatitis .(Type 1V hypersensitivity )..

Diagnosis (type 1v )Diagnosis (type 1v )::

1. Delayed skin test .1. Delayed skin test .

2. Patch test.2. Patch test.

3. Lymphocyte transformation test.3. Lymphocyte transformation test.

( detection of activation markers by ( detection of activation markers by flow cytometry ). flow cytometry ).

Practical pointsPractical points: :

11..Allergen extracts for the skin prick testAllergen extracts for the skin prick test . .))SPTSPT .( .( * * This test is used to diagnose type 1This test is used to diagnose type 1 HypersensitivityHypersensitivity . .

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

The reaction is read The reaction is read after 15 minutesafter 15 minutes . .

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

Skin prick test (SPT )Skin prick test (SPT )..

22 . .The RAST testThe RAST test. . The RAST test measures specific IgE (toThe RAST test measures specific IgE (to different allergens ) in the patients serumdifferent allergens ) in the patients serum. .

* * used to confirm the skin prick testused to confirm the skin prick test. . * * also used when the skin test is not possiblealso used when the skin test is not possible. .

) ) patient taking anti-histaminespatient taking anti-histamines( (

33 . .The patch testThe patch test.. * * used to test for contact dermatitis ( delayed H/S .)used to test for contact dermatitis ( delayed H/S .)

* * allergens are applied on the back under coverallergens are applied on the back under cover * * the reaction is read after 48- hoursthe reaction is read after 48- hours. .

* * Positive reaction :Positive reaction : indurations indurations . .

Patch testPatch test. .

Immunology Quiz no.2Immunology Quiz no.2

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

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

throatthroat . . . . After a short time he had wateryAfter a short time he had watery

nasal discharge & congestion (nasal block)nasal discharge & congestion (nasal block)..

Examination of a nasal smear showed Examination of a nasal smear showed

high level of granulocytes high level of granulocytes . .

The patient was given a drug to control theThe patient was given a drug to control the symptoms but the tablets were not effective & he was symptoms but the tablets were not effective & he was

given a topical steroid (nasal spray)given a topical steroid (nasal spray)

11 . .What is the type of reaction underlying What is the type of reaction underlying this conditionthis condition? ?

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

33..Explain the underlying immunopathology Explain the underlying immunopathology of all the symptoms & signs mentioned of all the symptoms & signs mentioned

in this conditionin this condition? ? 44..What type of drug was given to control the What type of drug was given to control the

symptomssymptoms ? ? 55 . .What is the mechanism by which What is the mechanism by which

cortisone help in control of symptoms in cortisone help in control of symptoms in this conditionthis condition ? ?