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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.


  • Introduction:

    Immune reactions leading to pathological

    tissue damage.

    - Occur as :

    1.Secondary heightened (increased) immune

    responses .

    OR

    2.Secndary inappropriate (abnormal ) immune

    responses.


  • 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.


  • Types I , II and III :

    are mediated by antibodies .

  • Type IV :

    Is generated by cell-mediated immune responses.


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 :

    - 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 .


  • 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: response is determined by :

  • 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 . “


  • Phase II : response is determined by :

    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”


Development of Allergy Requires response is determined by :

Sensitization , Re - exposure & Degranulation

Naive Mast Cell

Sensitized Mast Cell

Degranulated Mast Cell


Degranulation
Degranulation : response is determined by :

  • 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. response is determined by :

  • 1. Histamine ,heparin.

  • 2. Serotonin .

  • 3. Eosinophil chemotactic factor (ECF).

  • 4. Neutrophil chemotactic factor (NCF ).

  • 5. Proteases .


Secondary mediators
Secondary mediators : response is determined by :

  • 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, )


Some effects of mediators : response is determined by :

  • 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. response is determined by :( immediate hypersensitivity ).


Some effects of secondary mediators
Some effects of secondary mediators : response is determined by :

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:- response is determined by :

  • 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.


  • Elevated IgE. response is determined by :

  • Blood eosinophilia.

    are clinical signs of Type I reactions.


Type 1 reactions result in
Type 1 reactions result in : response is determined by :

* 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 determined by location of allergens:-


  • Bee sting allergens determined by location of 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:- determined by location of allergens:-

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 ). determined by location of allergens:-


Type ii hypersensitivity cytotoxic h s
Type II Hypersensitivity. determined by location of allergens:-(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:- determined by location of allergens:-

  • 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:- determined by location of allergens:-

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):- determined by location of allergens:-

  • 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. determined by location of allergens:-( Glomerulonephritis anti-GBM ).


Clinical examples type 11
Clinical Examples ( type 11):- determined by location of allergens:-

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.


4. Autoimmune diseases (Self-antigens). determined by location of allergens:-

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) determined by location of allergens:-


Type iii hypersensitvity immune complex h s
Type III Hypersensitvity determined by location of allergens:-(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):- determined by location of allergens:-

  • 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.


  • Immune complex clearance : determined by location of allergens:-

    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.



Mechanism of tissue damage type 1111
Mechanism of tissue damage (type 111): clearance mechanism:-

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).



Sites susceptible to type iii h s
Sites susceptible to type III H/S: clearance mechanism:-

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. clearance mechanism:- ( 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 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 ).



Diagnosis type 1v
Diagnosis (type 1v ):

1. Delayed skin test .

2. Patch test.

3. Lymphocyte transformation test.

( detection of activation markers by flow cytometry ).


  • 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).



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 .




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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