Hypersensitivity reactions

Hypersensitivity Reactions

1. Dr. PULIPATI SOWJANYA
Professor & Head
Dept. of Pharmaceutical Biotechnology
Vignan Pharmacy College
Vadlamudi, Guntur (Dt)

2. Immunopathology
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

3. Hypersensitivity Reaction
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

4. Classification
•Based on time required for a sensitized host to
develop clinical reactions on re –exposure
➢Immediate
➢Delayed
•Based on different mechanisms of pathogenesis
➢Type 1 ( IgEmediated)
➢Type 2 (cytotoxicor cell stimulating)
➢Type 3 (immune complex)
➢Type 4 ( cell mediated)

5. Immediate hypersensitivity
Appears and recedes
rapidly
Induced by antigens by
any route
B cell or Antibody
mediated
Delayed hypersensitivity
Appears slowly, lasts longer
Induced by antigens
intradermallyor skin contact
T cell mediated

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

7. Pathogenic mechanisms
* First exposure to allergen
Allergen stimulates formation of antibody (IgE type)
IgE fixes, by its Fcportion to mast cells and basophils
* Second exposure to the same allergen
It bridges between Ig E molecules fixed to mast cells
leading to activation and degranulation of mast cells
and release of mediators

8. Pathogenic mechanisms
•Three classes of mediators derived from mast cells:
1) 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, chemotacticfactors
* These mediators cause:smooth muscle contraction,
mucous secretion and bronchial spasm, vasodilatation,
vascular permeability and edema

9. Anaphylaxis
* Systemic form of Type I hypersensitivity
* Exposure to allergen to which a person is previously sensitized
* Allergens:
Drugs: penicillin
Serum injection : anti-diphtheritic or anti-tetanicserum
anesthesia or insect venom
* Clinical manifestations:
Shock due to sudden decrease of blood pressure, respiratory distress
due to bronchospasm, cyanosis, edema, urticaria
* Treatment: corticosteroids injection, epinephrine, antihistamines

10. Mechanism of anaphylaxis
IgEmolecules bind to the surface
receptors of mast cells and
basophils
Shocking dose
Antigen combines with cell bound
IgE
Cross linking between adjacent
antibody molecules
Increased permeability of cells to
calcium ions
Degranulation
Release of inflammatory
mediators

11. Atopy
•Local form of type I hypersensitivity
•Exposure to certain allergensthat induce production of specific Ig E
* Allergens :
Inhalants: dust, tree or pollens, mould spur.
Ingestants:milk, egg, fish, chocolate
Contactants:wool, nylon, animal fur
Drugs:penicillin, salicylates, anaesthesia, insect venom
•There is a strong familial predispositionto atopic allergy
•The predisposition is genetically determined

12. 4. Skin allergy:
4. Common disease of type I hypersensitivity
1. Systemic anaphylaxis: a very dangerous syndrome
1) Anaphylactic drug allergy ：penicillin
2) Anaphylactic serum allergy ：
2. Respiratory allergic diseases :
1) Allergic asthma：acute response, chronic response
2)Allergic rhinitis
3. Gastrointestinal allergic diseases :
The lack of SIgA protein
hydrolase
Undigested
protein
Allergen

13. Type II Hypersensitivity
Primed IgGor IgM+Antigen or haptenon membrane
Injury and dysfunction of target cells

14. Type 2 Reaction: cytolyticand cytotoxic
IgG and rarely IgM antibodies
Bind to antigenic cell
Lysisof cell
➢Cell surface antigens
(autoimmune anaemia's)
➢Adsorption of antigens on
cell surface (drugs)
➢Cell surface receptor and
disrupts normal function
(Graves disease)

15. Allergen
Stimulate
Antibody
A. Opsonicphagocytosis
D. ADCC of NK
C. Effect of complement
Combined opsonicactivities
Cell injury ways of type II hypersensitivity
Cell

16. 2. Mechanism of Type II hypersentivity
1. Surface antigen on target cells
Target cells: Normal tissue cell, changed or modified self tissue cells
2. Antibody, complement and modified self-cell
Antigen :Blood group antigen,Common antigen,
Self-antigen modified by physical factors or infection
Drug antigen,
Antigen-antibody complex
Activate complementLyses target cells
Opsonic phagocytosis Destroy target cells
Stimulating or blocking effectPromote /suppress the target cell function

17. Antigen or haptenon cell
Antibody (IgG, IgM)
Activate complement
Lysetarget cell
OpsonicphagocytosisNK , phagocyte Stimulate / block
Destroy target cell ADCC
Target cell injuryChange the function of Target cell
Mechanism of Type II hypersensitivity

18. Free Ag + Primed Ab Larger immune complex
Deposit in tissue or blood vessel wall
Inflammation
Type IIIhypersensitivity

19. Type 3 reactions –immune complex diseases
Antigen –antibody complexes
Complement activation
Release of inflammatory
mediators
Increased vascular
permeability
Infiltration with neutrophils

20. •The reaction may be general (e.g., serum sickness) or
may involve individual organs including skin (e.g.,
systemic lupus erythematosus, Arthusreaction), kidneys
(e.g., lupus nephritis), lungs (e.g.,aspergillosis), joints
(e.g., rheumatoid arthritis) or other organs.
•This reaction may be the pathogenic mechanism of
diseases caused by many microorganisms.
Type IIIhypersensitivity

21. •The reaction may take 3 -10 hours after exposure to the
antigen .
•It is mediated by soluble immune complexes.
•They are mostly of the IgGclass, although IgMmay also
be involved.
•The antigen may be exogenous (chronic bacterial, viral
or parasitic infections), or endogenous (non-organ
specific autoimmunity:e.g., systemic lupus
erythematosus, SLE).
•The antigen is soluble and not attached to the organ
involved
Type IIIhypersensitivity

22. •PMNs and macrophages bind to immune
complexes via FcRand phagocytosethe
complexes.
BUT
•If unable to phagocytosethe immune
complexes can cause inflammation via C’
activation ---> C3a C4a, C5a and "frustrated
phagocytes".
Type IIIhypersensitivity

23. Arthus Reaction

24. Mechanism of type III hypersensitivity
Formation of the intermediateimmune complex
Deposition of the intermediate immune complex
Tissue injury by the immune complex

25. CommondiseasesoftypeIIIhypersensitivity
1.Localimmunecomplexdisease
Arthusreaction ：Experimental local reaction,
Necrotic vasculitis, Ulcer
Human local reaction: Insulin-dependent diabetes mellitus (IDDM)
2. Acute systemic immune complex disease
serum sickness
Anti-serum Ab+Ag systemic tissue injury, fever, arthritis, skin rash
Penicillin, Sulfanilamide
Acute immune complex glomerulonephritis:Streptococcus
infection
3. Chronic immune complex disease
Rheumatoid arthritis

26. InteractionofprimedTcellsandassociatedantigen
Infiltration of Mononuclear Cells, Inflammatory response
Type IV hypersensitivity (Delayed)

27. Type 4 –Delayed hypersensitivity
Sensitized T cells
Contact with specific
antigen
Release cytokines
Effects on leucocytes,
macrophages and tissue
cells

28. MechanismoftypeIVhypersensitivity
Formation of effectorand memory T cells
Inflammation and cytotoxicitycaused by effectorT cells
1) Inflammation and tissue injury mediated by CD4+Th1
Release chemokinesand cytokines
Immune injury mainly caused by infiltration of mononuclear cells and
lymphocytes
2) Cytotoxicityof CD8+CTL

29. Antigen T cell
(CD4
+
,CD8
+
)
Secondary
contact
Induce
Primed T cell
CD4
+
T cell
CD8
+
T cell
Release
Cytokines
IL-2
TNF-b
INF-g
TF
MCF
MIF
MAF
SRF
Directly kill target cells
Infiltration of
monocyte and Mf
Proliferation of T cell
Exudation and edema
Cytotoxicity
Inflammation characterized by infiltration of Mf, monocyte,
and tissue injury
Mechanism of type IV hypersensitivity

30. Delayed hypersensitivity reactions
Type Reaction time
Clinical
appearance
Histology
Antigen and
site
Contact
dermatitis
48-72 hr eczema
lymphocytes,
followed by
macrophages;
edema of
epidermis
epidermal
(organic
chemicals,
poison ivy,
heavy
metals,etc.)
tuberculin 48-72 hr
local
induration
lymphocytes,
monocytes,
macrophages
intradermal
(tuberculin,
lepromin,etc.)
granuloma 21-28 days hardening
macrophages,
epitheloidand
giant cells,
fibrosis
persistent
antigen or
foreign body
presence
(tuberculosis,
leprosy,etc.)

31. DIAGNOSIS AND TREATMENT
•Diagnostic testsin vivoinclude delayed cutaneous
reaction (e.g.Mantouxtest and patch test (for contact
dermatitis).
•In vitro tests for delayed hypersensitivity include
mitogenicresponse, lympho-cytotoxicityand IL-2
production.
•Corticosteroids and other immunosuppressive agents
are used in treatment.

32. Common disease of type IV hypersensitivity
1) Infectious delayed type hypersensitivity
OT( Old Tuberculin ) test
2) Contact dermatitis :
Paint, drugs, water blister, dermatitis

33. Comparison of Different Types of hypersensitivity
characteris
tics
type-I
anaphylactic
type-II
(cytotoxic)
type-III
(immune
complex)
type-IV
(delayed type)
antibody IgE IgG, IgM IgG, IgM None
antigen exogenous cell surface soluble tissues & organs
response
time
15-30 minutesminutes-hours 3-8 hours 48-72 hours
appearancewheal & flare
lysis and
necrosis
erythema and
edema, necrosis
erythema and
induration
histology
basophils and
eosinophil
antibody and
complement
complement and
neutrophils
monocytes and
lymphocytes
transferred
with
antibody antibody antibody T-cells
examples
allergic asthma,
hay fever
erythroblastosis
fetalis,
Goodpasture's
nephritis
Arthusreaction,
serum sickness,
farmer's lung
disease
tuberculin test,
poison ivy,
granuloma