Discussed immunology of hypersensitivity reactions

1. HYPERSENSITIVITY REACTIONS
DR SB ZAILANI
PROFESSOR /CHIEF CONSULTANT
CLINICAL MICROBIOLOGIST

2. FORMAT
• INTRODUCTION
• CLASSIFICATION
• PATHOGENIC MECHANISMS
• CLINICAL SITUATIONS
• MANAGEMENT

3. INTRODUCTION
• Exaggerated immune response may lead to
different forms of tissue damage
1) An overactive immune response:
produce more damage than it prevents
e.g. hypersensitivity reactions and graft rejection
2 ) Failure of appropriate recognition:
as in autoimmune diseases

4. INTRO.
Hypersensitivity or allergy
* An immune response results in exaggerated reactions
harmful to the host
* There are four types of hypersensitivity reactions:
Type I, Type II, Type III, Type IV
* Types I, II and III are antibody mediated
* Type IV is cell mediated

5. CLASSIFICATION(Coomb’s & Gell)
• Type I- immediate type of hypersensitivity rxn
• Type II-Antibody mediated cytotoxic(AMC) rxn
• Type III-Immune complex mediated rxn
• Type IV-Cell mediated reaction

6. TYPE I
* An antigen reacts with cell fixed antibody (Ig E)
leading to release of soluble molecules
An antigen (allergen)
soluble molecules (mediators)
* Soluble molecules cause the manifestation of disease:
A) Systemic life threatening; anaphylactic shock
B) Local atopic allergies; bronchial asthma, hay fever
and food allergies

7. Pathogenic mechanism

9. Pathogenic mechanism
* Three classes of mediators derived from mast cells:
!) Preformed mediators stored in granules (histamine)
2) Newly sensitized mediators:
leukotrienes, prostaglandins, platelets activating factor
3) Cytokines produced by activated mast cells, basophils
e.g. TNF, IL3, IL-4, IL-5 IL-13, chemokines
* These mediators cause: smooth muscle contraction,
mucous secretion and bronchial spasm, vasodilatation,
vascular permeability and edema

10. Atopy
* Local form of type I hypersensitivity
* Exposure to certain allergens that induce production of
specific Ig E
* Allergens :
Inhalants:dust mite faeces, tree or pollens, mould spor.
Ingestants: milk, egg, fish, choclate
Contactants: wool, nylon, animal fur
Drugs: penicillin, salicylates, anesthesia, insect venom
* There is a strong familial predisposition to atopic allergy
* The predisposition is genetically determined

11. Anaphylactic shock
Systemic form of Type I hypersensitivity
* Exposure to allergen to which a person is previously sensitized
* Allergens:
Drugs: penicillin
Serum injection : anti-diphtheritic or ant-tetanus serum
anesthesia or insect venom
* Clinical picture:
Shock due to sudden decrease of blood pressure, respiratory
distress due to bronhospasm, cyanosis, edema, urticaria

13. Management
• 1. Avoidance of implicating allergens
• 2.Hyposensitisation (Desensitization)
• Drugs: i. Cromolyn sodium
ii. Antihistamin
iii. Cortocosteroid
iv. Epinephrine

14. TYPE II(Cyotoxic or cytolytic rxns)
* An antibody (Ig G or Ig M) reacts with
antigen on the cell surface
* This antigen may be part of cell membrane
or circulating antigen (or hapten) that
attaches to cell membrane

15. Pathogenic mechanism
• A. Cytotoxic reactions are initiated by
antibody
• B. Cell damage is occur in the presence of
complement or mononuclear cells

16. • Either mechanism may lead to cell destruction
via:
1. Lysis via activation of complement
2. Lysis via ADCC through the action of
NK cells and lymphocyte
3. Phagocytosis of target cells

17. 1) Complement mediated lysis: The binding of
cytotoxic antibody to antigens expressed on a
cell surface or basement membrane activates
complement which destroys or damages the
antibody coated structure.

18. Cell lysis via complement (MAC)

19. 2) Antibody depended cellular cytotoxicity (ADCC):
- Antibody coated cells
e.g. tumour cells, graft cells or infected cells can
be killed by cells possess Fc receptors
- The process different from phagocytosis and
independent of complement
- Cells most active in ADCC are:
NK, macrophages, neutrophils and eosinophils

20. 3) Phagocytosis is enhanced by the antibody
(opsonin) bound to cell antigen leading to
opsonization of the target cell

21. opsonization of the host cells
whereby phagocytes stick to host cells by way of IgG,
C3b, or C4b and discharge their lysosomes

22. Clinical situation
• RBC lysis:
a) ABO incompatibility
b) Rh incompatibility
- Blood transfusion reaction
- Haemolytic disease of new born
(Erythroblastosis fetalis)

23. • Autoimmune haemolytic disease
i) autoimmune haemolytic anaemia
ii)Platelets – are destroyed by autoimmune
antibody leading to thrombocytopenic
purpura
iii)SLE- autoimmune dx, can be considered a
mixed dx both type ii &iii. There is
autoantibody against DNA,RBC, &lymphocyte

24. iv) Thyroid – Hashimoto thyroiditis due to
antibodies to thyroid cells
v)Kidneys and Lungs- Good pasture’s syndrome.
The kidney is destroy by auto antibody to
glomerular membrane.

25. TYPE III(Immume complex mediated)
*When antibodies (Ig G or Ig M) and antigen coexist
immune complexes are formed
*Immune complexes are removed by reticuloendoth.
syst.
*Some immune complexes escape phagocytosis
*Immune complexes deposited in tissues on the
basement membrane of blood vessels and cause tissue
injury

26. Pathogenic mechanisms
Immune complexes trigger inflammatory processes:
activate release
1) Immune complexes → the complement → anaphylatoxins C3a, C5a
stimulate release
degranulation of basophiles and mast cells histamine
Histamine vascular permeability and help deposition of immune complexes
2) Neutrophils are attracted to the site by immune complexes and release
lysosomal enzymes which damage tissues and intensify the inflammat. fru.

27. 3) Platelets are aggregated with two
consequences
a- release of vasoactive amines (histamine)
b- form of microthrombi which lead to
ischemia

28.  Damage occurs due to:
Anaphylatoxin release due to complement activation (C3a,
C5a) which then attracts neutrophils, and causes mast cell
degranulation
Neutrophils have trouble phagocytosing “stuck” immune
complexes so they release their granule contents leading
to more inflammation
Platelet aggregation also results from complement
activation

29. Implicating agents
• 1. Endogenous antigen
• 2.Foreign serum
• 3.Exogenous antigen; Strep. ,EBV, HBV,
Aspergillus, M leprae, Rat, Pigeon
• 4. Food

30. Clinical situations
Diseases produced by immune complexes are those in
which antigens persists without being eliminated as:
a- Repeated exposure to extrinsic antigen
b- injection of large amounts of antigens
c- Persistent infections
d- Autoimmunity to self components

31. Arthus reaction(Antibody excess)
* This is a local immune complex deposition phenomenon
e.g. diabetic patients receiving insulin subcutaneously
• Local reactions in the form of
Oedema
erythema
necrosis
deposited
* Immune complexes → in small blood vessels →
leading to
→ Vasculitis
microthrombi formation
vascular occlusion
necrosis

32. Arthus reaction cont’d
Cutaneus Arthus reaction;
• Rheumatoid arthritis
• Erythema nodosum leprosum
Intrapulmunary Arthus reaction;
*Farmers lung
*Bronchpulmunary aspergillosis
*Pigeon fancies' disease
*Rat handlers’ disease

33. Serum Sickness (systemic, soluble)
due to Antigen excess
* A systemic immune complex phenomenon
* Injection of large doses of foreign serum
* Antigen is slowly cleared from circulation
* Immune complexes are deposited in various sites
* 10 days after injection of large dose foreign serum
fever
urticaria
arthralgia
lymphadenopathy
splenomegaly
glomerulonephritis

34. Other soluble(systemic) immune
complex reactions
• Post Strep. Glomerulonephritis
• Malaria nephropathy
• SLE
• SSPE

35. TYPE IV (DELAYED TYPE)
• It is a cell mediated type of HSR
• Non antibody, non complement dependent
reaction. The cell that is involve is T lymphocyte
(T dth, Tc cell)
• The reactions are detected in previously
sensitized individual

36. Characters
• i. Antigen stimulation is necessary
• ii. In sensitive individual, reaction occurs on
exposure to specific antigen e.g. tuberculin
protein
• iii. Induction period is 7-10 days
• iv. Delayed HSR is transferred by cells from
lymphoid tissue or blood lymphocytes

37. Pathogenic Mechanism
triggering DTH reactions by TH1
* T-cells cause tissue injury by ; or
directly killing target cells by CD8
* TH1 and CD8 T cells secrete cytokines (IFN-γ and TNF)
Cytokines
-attract lymphocyte
- activate macrophages
- induce inflammation
* Tissue damage results from products of activated macrophages

38. Clinical situations
• Classical type of type Iv HSR occur in infective
diseases(Bacterial,viral,parasitic&fungal)
1.Bacterial HS e.g Tuberculosis, Trachoma,
syphilis, Brucellosis, Psittacosis, LGV e.t.c
2. Viral HS e.g Mumps, Vaccinia virus, Herpes
3. Fungal HS e.g Histoplasmosis, Coccidioides etc
4. Parasitic HS e.g Schistosomiasis,Hadatid dx,
Leismaniasis, Filariasis.

39. Differences Between AMR/CMR
• Cell mediated reactions are delayed in time, in
contrast to antibody mediated immune cytotoxic
reactions
• AMR has more fluid & erythema (wheal/flare),
whereas CMR are xterised by significant
mononuclear cell infiltration with resultant
indurations
• Delayed HR is transferred by cells from lymphoid
tissue, peritoneal exudates and blood
lymphocytes

40. THANK YOU FOR YOUR ATTENTION