1. Hypersensitivity reactions.
Prof . Mohamed Osman Gad El Rab.
College of Medicine & KKUH.

2. Introduction:
Immune reactions leading to pathological
tissue damage.
- Occur as :
1.Secondary heightened (increased) immune
responses . OR
2.Secndary inappropriate (abnormal ) immune
responses.

3. Type III : Immune – complex H/S. Type IV : Delayed H/S.
Four major categories according to Coombs and Gell classification :
Type I : Immediate H/S.
Type II : Cytotoxic H/S.
Type III : Immune – complex H/S.
Type IV : Delayed H/S.

4. are mediated by antibodies .
Types I , II and III :
are mediated by antibodies .
Type IV :
Is generated by cell-mediated immune responses.

5. Hypersensitivity reactions differ in the rate at which they occur :
Type I : Can occur within minutes after exposure to antigen.
Type II and III : time course , (4-8) hours to days .
Type IV : require days.

6. 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.

7. Type I Hypersensitivity.
Also termed :
*Immediate H/S ( can literally occur within minutes to hours ).
* Anaphylactic reactions . OR
* Allergic reactions.

8. Features : Antibody isotype : IgE . - Cellular components:
Mast cells , basophiles & eosinophils.
- Antigens :
termed allergens ( antigens with low
molecular weight & highly soluble.

9. 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.”

10. Atopy. Occur in certain genetically predisposed individuals .
They comprise approx. 15 – 20 % of the
population .
Atopy tend to run in families .

11. 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.

12. 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 . “

13. “ Degranulate” 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”

14. Development of Allergy Requires
Sensitization , Re - exposure & Degranulation
Naive Mast Cell
Sensitized Mast Cell
Degranulated Mast Cell

16. 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.

17. Primary mediators.
1. Histamine ,heparin.
2. Serotonin .
3. Eosinophil chemotactic factor (ECF).
4. Neutrophil chemotactic factor (NCF ).
5. Proteases .

18. 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, )

19. 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 – ( IgE)
Enzymes – Elastase : ( reconstruction of connective tissues).

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

21. 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 .

22. 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.

23. Elevated IgE.
Blood eosinophilia.
are clinical signs of Type I reactions.

24. Type 1 reactions result in :
* Vasodilatation and increased capillary
permeability .
* Edema.
* Vasoconstriction ( arteries and arterioles )
* Bronchoconstriction.
* Increased mucus secretion.

25. 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)

26. Pathogenesis of allergic rhinitis

27. 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.

28. 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).

29. Skin prick test ( diagnosis of type 1 hypersensitivity ).

30. 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).

31. 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.

32. 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.

33. Complement - mediated damage (type11):-
Activation of complement  C8 , C9.
- Membrane attack complex
(MAC).
- Direct lytic damage on target
tissues.

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

37. 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.

38. 4. Autoimmune diseases (Self-antigens).
5. Graft rejection (Hyper - acute).
- Preformed antibodies in the recipient .
Diagnosis:-
- Detection of antibodies and antigens by immunofluorecence. (Biopsy).

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

40. Type III Hypersensitvity (Immune - complex H/S ):-
Features:-
- IgG or IgM.
- Soluble antigens.
- Immune – Complex formation.
- Complement activation.
(invariable).

41. 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.

42. 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.

43. 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.

44. 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).

45. Type 111 H/S . ( arthus reaction )

46. 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 .

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

48. 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 .

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

50. Clinical examples (type 111) :
1. Autoimmune disease ,(self – antigens ).
2. Chronic infections ,(microbial antigens) .
3. Cancer , (tumor antigens).
4. Drug reactions , (chemical haptens ).

51. Diagnosis (type 111) :
Demonstration of specific immune complexes in the blood or tissues by
immunofluorescence .

52. 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 .

53. 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 .

54. 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 .

55. 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 .

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

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

58. DTH reaction.
Double- edged sword
Fine line between:
protective response.
tissue damaging response .

59. Clinical examples( type 1v ):
1. Chronic infections :
- T.B.
- leprosy .
- fungal infections .
-parasitic infections.
2. Contact dermatitis .

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

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

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

63. Diagnosis (type 1v ):
1. Delayed skin test .
2. Patch test.
3. Lymphocyte transformation test.
( detection of activation markers by flow cytometry ).

64. 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 minutes.
Positive reaction : wheal (swelling ) & flare (redness).

65. Skin prick test (SPT ).

66. 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 hours .
* Positive reaction : indurations .

67. Patch test .

68. Immunology Quiz no.2

69. 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)

70. 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 ?