Transcript hypersensitivity A

Hypersensitivity reactions
The immune system is concerned with
protection of the host against foreign antigens,
particularly infectious agents.
Inappropriate immune response may be:
1. Allergy: exaggerated immune response
against environmental antigens.
2. Autoimmunity: misdirected immune
response against the host’s own cells.
3. Alloimmunity: immune response
directed against beneficial foreign tissues
e.g. blood transfusion or organ
transplantation.
4. Immune deficiency: inability of the
immune system to protect the host.
Hypersensitivity
Is an altered immunologic
response to an antigen that
results in tissue damage.
Hypersensitivity reactions
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Type I: immediate (Ig E mediated) hypersensitivity
Type II: Tissue specific (cytotoxic) hypersensitivity
Type III: immune-complex mediated hypersensitivity
Type IV: cell mediated or delayed hypersensitivity
Type I hypersensitivity
1). Characteristics
2). Components and cells
3). Mechanism
4). Clinical examples of type I Hypersensitivity
5). Therapy for type I Hypersensitivity
Type I hypersensitivity reactions are the most
common forms of allergic reactions especially
against environmental agents.
1) Characteristics
Occur and resolve quickly
Mediated by serum IgE
Systemic and regional tissue dysfuntion
Genetic predisposition (atopy)
2) Components and cells in Type I hypersensitivity
 (Antigen) Allergen：
pollen、dust mite、insects etc
selectively activate CD4+Th2 cells and B cells
 Antibody:（IgE):
IgE： mainly produced by mucosal B cells in the lamina prapria.
IL-4 is essential to switch B cells to IgE production
 Mast cell and basophil
 Eosinophil
3). Mechanism:
* First exposure to allergen
Allergen stimulates B lymphocytes to form antibody (IgE type).
IgE fixes, by its Fc portion to mast cells and basophils.
* Second exposure to the same allergen
The antigen fixes directly to IgE (which is already fixed to mast cell)
leading to activation and degranulation of mast cells and release of
mediators
The biological mediators are:
1. Histamine:
Vasodilatation and increased vascular permeability.
2. Leukotrienes:
Bronchial smooth muscles contraction
3. Prostaglandin D2:
Causes bronchospasm and increased mucin secretion.
4. Platelet activating factor (PAF) :
platelet aggregation, release of histamine, bronchospasm,
increased vascular permeability, and vasodilation
5. Eosinophil chemotactic factor（ECF-A:
6. Bradykinin:
Vasodilation
Immediate Phase Allergic Reaction:
• Occurs within seconds to minutes of IgE receptor
activation (mast cell mediator release) and resolving
within an hour
• Intense pruritus, edema, erythema
Late Phase Allergic Reaction:
• A delayed inflammatory response (peaking at 4-8 hrs and
persisting up to 24 hrs) following an intense acute phase
reaction
– Skin: erythema, induration, burning
– Lungs: airway obstruction poorly responsive to bronchodilators
– Nose/eyes: erythema, congestion, burning
• Histology: infiltration of tissues with eosinophils, neutrophils, basophils,
monocytes, and CD4+ T cells as well as tissue destruction, typically in the
form of mucosal epithelial cell damage.
Clinical examples of type I hypersensitivity
1.
Systemic anaphylaxis: a very dangerous condition
Allergic reactions after injection of drugs (penicllin)or serum
2. Respiratory allergic diseases :
1) Allergic asthma：acute response, chronic response
2) Allergic rhinitis, Allergic rhinoconjunctivitis (hay
fever
3. Gastrointestinal allergic disease:
4. Skin allergy: Eczema (atopic dermatitis), Acute
urticaria
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-tetanic serum
anesthesia or insect venom
* Clinical picture:
Shock due to sudden decrease of blood pressure, respiratory distress due to
bronchospasm, cyanosis, edema, urticaria
* Treatment: corticosteroids injection, epinephrine, antihistamines
Atopy
* There is a strong familial predisposition to type I hypersensitvity
reaction.
* The predisposition is genetically determined
* Atopic individuals have higher quantities of IgE antibodies and higher
concentration of Fc receptors on mast cells.
* The airways and skin are commonly affected.
* Allergens :
Inhalants: dust mite, pollens, mould spores.
Ingestants: milk, egg, fish, chocolate
contactants: wool, nylon, animal fur.
Methods of diagnosis
1) History taking for determining the allergen involved
2) Skin tests:
Intradermal injection of battery of different allergens
A wheal and flare (erythema) develop at the site of
allergen to which the person is allergic
3) Determination of total serum IgE levelRadioimmunosorbent test (RIST)
4) Determination of specific IgE levels to the different allergensRadioallergosorbent test (RAST)
Skin test
Management
1) Avoidance of specific allergen.
2) Hyposensitization:
Minute quantities of the responsible allergen is injected in increasing
doses over a long peroid.
3) Drug Therapy:
corticosteroids injection, epinephrine, antihistamines
2. Type II Hypersensitivity
(Cytotoxic or Cytolytic Reactions)
1. Characteristic features
2. Mechanism of Type II Hypersensitivity
3. Common diseases of Type II Hypersensitivity
1. Characteristic features
Primed IgG or IgM
+
Antigen or hapten on membrane
Injury and dysfunction of target cells
Type II Hypersensitivity Reactions:
Mechanisms of Tissue Damage
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
* Mechanisms of type II hypersensitivity
reactions:
• Complement-mediated cell lysis.
Complement fixation to antigen antibody complex on
cell surface. The activated complement will lead to cell
lysis.
• Phagocytosis mediated cell lysis.
• Phagocytosis is enhanced by the antibody (opsinin) bound
to cell antigen leading to opsonization of the target cell
• Antibody-dependent cell-mediated
cytotoxicity (ADCC):
- Antibody coated cells e.g. tumor cells, graft cells or infected
cells can be killed by cells possess Fc receptors.
• Antibody mediated cellular dysfunction:
• The antibody does not destroy the cell but attach certain
receptor to either block them (myasthenia gravis) or stimulate
them (Grave’s disease).
Clinical examples of type II hypersensitivity
reaction:
1) Incompatible blood transfusion: due to ABO incompatibility
2) Rh-incompatability (Haemolytic disease of the newborn)
3) Autoimmune hemolytic anaemia.
4). Autoimmune thrombocytopenic purpura.
5). Myasthenia gravis.
6). Gravis disease.
7). Insulin-resistant diabetes mellitus.
8). Graft rejection cytotoxic reactions:
In hyperacute rejection the recipient already has performed antibody against the
graft
9). Drug reaction:
Penicillin may attach as haptens to RBCs and
induce antibodies which are cytotoxic for the
cell-drug complex leading to haemolysis
Quinine may attach to platelets and the antibodies
cause platelets destruction and thrombocytopenic
purpura
3. Type III (Immune complex-mediated
hypersensitivity reactions.
1. Characteristics
2. Mechanism of type III hypersensitivity
3. Clinical examples of type III hypersensitivity
1. characteristics
Free Ag + Primed Ab forming larger immune complexs
Deposit in tissue or blood vessel wall
complement activation and subsequent
Inflammation
2. Mechanism of type III hypersensitivity:
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Immune complex activate Complement system
Split products-C3a, C4a,C5a.
C3a, C4a, C5a are chemotactic for Neutrophils.
Neutrophils attempt to phagocytose the immune
complex which is often unsuccessful because the
complexes are bound to a large areas of tissue.
• During this attempts, release of large quantities of
lysosomal enzymes causing tissue damage and
inflammation.
3. Clinical examples of type III hypersensitivity
1. SLE.
2. Polyarteritis nodosa.
3. Post-streptococcal glomerulonephritis.
4. Serum sickness.
5. Arthus reaction.
Arthus reaction
• Caused by repeated local exposure to an antigen that reacts
with preformed antibody and forms immune complexes in the
walls of the local blood vessels.
• The symptoms appear within 1 hour after injection and the
peak 6-12 hours later.
• Lesions include; edema, hemorrhage, clotting and tissue
necrosis.
Serum sickness
 Is a protoype of systemic immune complex hypersensitivity
reaction.
 The immune complex circulate in the blood and deposit in blood
vessels (vascultitis), joint (arthritis) and kidney
(glomerulonephritis) associated with fever, rash and
lymphadenopathy.
 Serum sickness was initially described as a complication of
therapeutic administration of horse serum that contains antitetanic Abs.
 Serum sickness reactions can be caused by repeated intravenous
administration of other antigens such as drugs.
TYPE IV (cell mediated)
hypersensitivity
• Whereas types I, II and III mediated by antibody, type IV
mediated by T lymphocytes (cytotoxic T cells or cytokineproducing Th1 cells).
• Develops after 48-72 hrs of second exposure to antigen in a
sensitized individual.
• Some subpopulations of activated TH cells encounter certain
types of antigens, they secrete cytokines that induce a
localized inflammatory reaction- delayed-type hypersensitivity
(DTH).
• The reaction is characterized by large influxes of nonspecific
inflammatory cells, macrophages.
• A prolonged DTH response leads to
destructive inflammatory response with
development of granulomatous reaction.
• A granuloma develops by continuous
activation of macrophages.
• Giant cells displace the normal tissue cells,
forms palpable nodules, and release high
concentrations of lytic enzymes, which
destroy surrounding tissue.
PHASES of DTH response
• Sensitization phase
– Activation of TH cells by Antigen presenting cells
(APC) e.g Langerhans cells & Macrophages
– Proliferation TH 1 subtype occurs.
• Effector phase
– TH 1 secrete cytokines , IL2, TNFβ
– Recruitment & activation of Macrophages
3. Clinical examples of type IV hypersensitivity
1) Tuberculin test: a skin test for T.B
2) Contact dermatitis :
caused by Paint, drug leading to appearance of red rash, papula,
water blister, dermatitis
3) Graft rejection after organ transplantation
4) Immune response in local tumor mass
Summary
Gell and Coombs classification of hypersensitivity reaction
Type
Description
Time
Mechanism,
Typical manifestation
Type I IgE-mediated 2-3min Ag induce cross-linkage Systemic anaphylaxis
hypersensitivity
of IgE bound to mast cells Localized anaphylaxis:
or basophils with release -Hay fever, Asthma,
of vasoactive mediators
Hives, Food Allergy
Eczema.
Type II Ab-mediated 5-8h
Ab directed against cellBlood-transfusion
cytotoxic
surface Ags mediates cell reactions.
hypersensitivity
destruction via C activation Erythroblastosis
fetalis
Autoimmune
hemolytic anemia.
Gell and Coombs classification of hypersensitivity reaction
Type
Description
TypeIII Immune complex
-mediated
hypersensitivity
Time
Mechanism
Typical Manifestations
2-8h Ag-Ab complexes
Localized Arthus
deposited in various
reaction
tissues induce C acti- Generalized reactions:
vation and an ensuing Serum sickness,
inflammatory response Glomerulonephritis
Rheumatoid arthritis
SLE
Delayed reactions
Type IV cell-mediated 24-72h Sensitized TDTH cells
hypersensitivity
release cytokines that
activate Macrophages,
which mediate direct
cellular damage.
Contact dermatitis,
Tuberculous lesions,
Graft rejection.