_HYPERSENSITIVITY
_ Hypersensitivity
reactions are inappropriate or exaggerated
immune reactions harmful to the host. Hypersensitivity
occurs in individuals previously sensitized to an antigen with
further contact with the same antigen. The first contact with the
antigen induces immune response and sensitizes the individual, and the
subsequent contacts elicit hypersensitivity.
These are tissue damaging immune responses.
Hypersensitivity reaction occurs by the interaction of an antigen with its corresponding antibody or sensitized T cell. The antigen may be exogenous to the individual or autoantigen. Autoantigens can lead to autoimmune disease.
Allergy.
The term allergy is usually used to express certain hypersensitivity reactions.
Classification: Coombs and Gell's classification:
Four types: Type I to IV. Types I, II and III hypersensitivity are antibody-mediated. Type IV hypersensitivity is T cell-mediated.
Type I hypersensitivity: IgE-mediated hypersensitivity. Type II hypersensitivity: Antibody-mediated cytotoxicity.
Type ill hypersensitivity: Immune complex-mediatedhypersensitivity.
Type IV hypersensitivity: Cell-mediated hypersensitivity.
TYPE I - HYPERSENSITIVITY, IMMEDIATE
HYPERSENSITIVITY, ANAPHYLACTIC HYPERSENSITIVITY,
Immediate hypersensitivity is mediated by IgE antibodies produced in response to an antigen and bound to mast cells in individuals previously sensitized to the same antigen. These reactions are usually called allergy and the antigens that elicit them are allergens. Tissue reactions occur within minutes of antigen binding with the corresponding IgE antibodies on mast cells.
Symptoms such as erythema and oedema ("flare and wheal"), and itching appear.
There is accumulation of inflammatory cells, particularly eosinophils.
Sensitized sites are lungs, gastrointestinal tract and skin.
Hypersensitivity reaction occurs by the interaction of an antigen with its corresponding antibody or sensitized T cell. The antigen may be exogenous to the individual or autoantigen. Autoantigens can lead to autoimmune disease.
Allergy.
The term allergy is usually used to express certain hypersensitivity reactions.
Classification: Coombs and Gell's classification:
Four types: Type I to IV. Types I, II and III hypersensitivity are antibody-mediated. Type IV hypersensitivity is T cell-mediated.
Type I hypersensitivity: IgE-mediated hypersensitivity. Type II hypersensitivity: Antibody-mediated cytotoxicity.
Type ill hypersensitivity: Immune complex-mediatedhypersensitivity.
Type IV hypersensitivity: Cell-mediated hypersensitivity.
TYPE I - HYPERSENSITIVITY, IMMEDIATE
HYPERSENSITIVITY, ANAPHYLACTIC HYPERSENSITIVITY,
Immediate hypersensitivity is mediated by IgE antibodies produced in response to an antigen and bound to mast cells in individuals previously sensitized to the same antigen. These reactions are usually called allergy and the antigens that elicit them are allergens. Tissue reactions occur within minutes of antigen binding with the corresponding IgE antibodies on mast cells.
Symptoms such as erythema and oedema ("flare and wheal"), and itching appear.
There is accumulation of inflammatory cells, particularly eosinophils.
Sensitized sites are lungs, gastrointestinal tract and skin.
_
Mechanism
Steps :
1. First exposure to an antigen (allergen). The antigen induces the production of IgE antibody in about 1 to 3 weeks time. The antigen stimulates B lymphocyte with production of IgE mainly at mucosal site of entry of the antigen and in the draining lymph nodes. Th2 cells activated by the antigen help this process. Th2 cells are of importance in the pathogenesis of type I hypersensitivity. IL-4 produced by Th2 cells controls switching from IgM to IgE production. IgE antibody binds firmly by the Fc region to mast cells and basophils. The individual is now sensitized to the particular antigen,
2. Re-exposure of the sensitized individual with the same antigen results in binding of the antigen to IgE antibodies previously attached to the mast cells, and cause cross-linkage of adjacent IgE antibodies. It activates signal transduction pathways and leads to activation of mast cells which release their chemical mediators.
Mediators are preformed (primary mediators), and newly synthesized (secondary mediators).
I. Preformed or Primary Mediators. These are contained within mast cell granules. Signals for degranulation leads to release of preformed mediators by degranulation.
1.Histamine.It is released within 5 minutes and has effect for about an hour. It causes vasodilatation, increased vascular permeability, bronchial smooth muscle contraction, and secretion of nasal, bronchial and gastric glands.
2. Adenosine. It increases release of mediators from mast cells, causes bronchoconstriction, and inhibits platelet aggregation.
3. Eosinophil chemotactic factor (ECF).
4. Neutrophil chemotactic factor (NCF).
5. Enzymes. Proteases are present in granule matrix.
6. Heparin, an anticoagulant.
II. Newly Synthesized or Secondary Mediators.
A. Lipid mediators. Signals for activation of phospholipase A2 leads to synthesis and release of leukotrienes, prostaglandin D2 and PAF.
1. Leukotrienes: (a) Leukotriene B4 (LTB4). It is highly chemotactic for neutrophils, eosinophils and monocytes, (b) Slow reacting substance of anaphylaxis (SRS-A) consists of leukotrienes C4, D4 and E4. These increase vascular permeability and cause bronchial smooth muscle contraction.
2. Prostaglandin D2. It causes intense bronchospasm and increased mucus secretion.
3. Platelet Activating Factor (PAF). It causes platelet activation, histamine release, vasodilatation, increased vascular permeability and bronchospasm. It is chemotactic for neutrophils and eosinophils. It plays role in the late-phase response of local anaphylaxis.
B. Cytokines. There are signals for cytokine gene activation.
(a) Mast cells play an important role in the late phase reaction of immediate hypersensitivity by recruiting and activating inflammatory cells. Mast cells produce TNF, IL-1, IL-3, IL-4, IL-5, IL-6, GM-CSF, MIP-1a, and MIP-1p, eotaxin. IL-3, IL-5 and GM-CSF promote the survival of eosinophils.
(b) Th2 cells secrete IL-4, IL-5 and IL-13 which are needed for IgE synthesis.
Actions of mast cell mediators in type I disorder:
1. Vasodilatation and increased vascular permeability. Vasoactive mediators are histamine, leukotrines (C4, D4, E4), prostaglandin D2, PAF and neutral proteases, that activate complement and kinins.
2. Inflammatory cell infiltration. chemotactic agents are eosinophil chemotactic factor, neutrophil chemotactic factor, leukotriene B4, TNF, eotaxin and PAF. Eosinophils and neutrophils are accumulated. TNF can attract eosinophils and neutrophils. Eotaxin recruits eosinophils. IL-5 is needed for production of eosinophils and their activation. Inflammatory cells release mediators and also damage epithelial cells. Recruited cells amplify and sustain the inflammatory response without additional exposure to the triggering antigen.
3. Smooth muscle spasm. Spasmogenic mediators are histamine, leukotrines (C4, D4, E4), PGD2, PAF.
Steps :
1. First exposure to an antigen (allergen). The antigen induces the production of IgE antibody in about 1 to 3 weeks time. The antigen stimulates B lymphocyte with production of IgE mainly at mucosal site of entry of the antigen and in the draining lymph nodes. Th2 cells activated by the antigen help this process. Th2 cells are of importance in the pathogenesis of type I hypersensitivity. IL-4 produced by Th2 cells controls switching from IgM to IgE production. IgE antibody binds firmly by the Fc region to mast cells and basophils. The individual is now sensitized to the particular antigen,
2. Re-exposure of the sensitized individual with the same antigen results in binding of the antigen to IgE antibodies previously attached to the mast cells, and cause cross-linkage of adjacent IgE antibodies. It activates signal transduction pathways and leads to activation of mast cells which release their chemical mediators.
Mediators are preformed (primary mediators), and newly synthesized (secondary mediators).
I. Preformed or Primary Mediators. These are contained within mast cell granules. Signals for degranulation leads to release of preformed mediators by degranulation.
1.Histamine.It is released within 5 minutes and has effect for about an hour. It causes vasodilatation, increased vascular permeability, bronchial smooth muscle contraction, and secretion of nasal, bronchial and gastric glands.
2. Adenosine. It increases release of mediators from mast cells, causes bronchoconstriction, and inhibits platelet aggregation.
3. Eosinophil chemotactic factor (ECF).
4. Neutrophil chemotactic factor (NCF).
5. Enzymes. Proteases are present in granule matrix.
6. Heparin, an anticoagulant.
II. Newly Synthesized or Secondary Mediators.
A. Lipid mediators. Signals for activation of phospholipase A2 leads to synthesis and release of leukotrienes, prostaglandin D2 and PAF.
1. Leukotrienes: (a) Leukotriene B4 (LTB4). It is highly chemotactic for neutrophils, eosinophils and monocytes, (b) Slow reacting substance of anaphylaxis (SRS-A) consists of leukotrienes C4, D4 and E4. These increase vascular permeability and cause bronchial smooth muscle contraction.
2. Prostaglandin D2. It causes intense bronchospasm and increased mucus secretion.
3. Platelet Activating Factor (PAF). It causes platelet activation, histamine release, vasodilatation, increased vascular permeability and bronchospasm. It is chemotactic for neutrophils and eosinophils. It plays role in the late-phase response of local anaphylaxis.
B. Cytokines. There are signals for cytokine gene activation.
(a) Mast cells play an important role in the late phase reaction of immediate hypersensitivity by recruiting and activating inflammatory cells. Mast cells produce TNF, IL-1, IL-3, IL-4, IL-5, IL-6, GM-CSF, MIP-1a, and MIP-1p, eotaxin. IL-3, IL-5 and GM-CSF promote the survival of eosinophils.
(b) Th2 cells secrete IL-4, IL-5 and IL-13 which are needed for IgE synthesis.
Actions of mast cell mediators in type I disorder:
1. Vasodilatation and increased vascular permeability. Vasoactive mediators are histamine, leukotrines (C4, D4, E4), prostaglandin D2, PAF and neutral proteases, that activate complement and kinins.
2. Inflammatory cell infiltration. chemotactic agents are eosinophil chemotactic factor, neutrophil chemotactic factor, leukotriene B4, TNF, eotaxin and PAF. Eosinophils and neutrophils are accumulated. TNF can attract eosinophils and neutrophils. Eotaxin recruits eosinophils. IL-5 is needed for production of eosinophils and their activation. Inflammatory cells release mediators and also damage epithelial cells. Recruited cells amplify and sustain the inflammatory response without additional exposure to the triggering antigen.
3. Smooth muscle spasm. Spasmogenic mediators are histamine, leukotrines (C4, D4, E4), PGD2, PAF.
Types of Type I Hypersensitivity
1. Systemic anaphylaxis
2. Local Type I hypersensitivity (Local anaphylaxis)
Systemic Anaphylaxis
Systemic anaphylaxis may occur after administration of various drugs such as penicillin, antisera (heterologous protein), hormones and enzymes; or bite of honey bees. Shock dose of antigen may be exceedingly small. Within minutes after exposure there may be skin erythema, pruritic, urticaria, bronchospasm, laryngeal oedema, anaphylactic shock (hypotension) and life threatening and even death. May give a previous history of allergy.
Local Type I Hypersensitivity
Example of local type I hypersensitivity or allergic reactions is atopic allergy or atopic disorders. Atopy is a genetic predisposition to form excessive IgE. Family history of allergy is found in about 50% of the patients. Target tissues often contain large number of Th2 cells. IL-4 produced by Th-2 cells leads to increased synthesis of IgE. It is due to excessive IgE response to allergens (extrinsic antigens). IgE level is elevated. Several genes associated with atopy have been identified in atopic individuals. Mutations in genes eg. gene for IL-4 has been identified. It results in an increased amount of IgE synthesis by B cells. Atopic individuals manifest one or more of a group of atopic diseases that include asthma, hay fever, urticaria, eczema against various foods, various drugs and other allergens.
Man local type I hypersensitive reactions occur in two phases: (i) Immediate phase or initial response occurs within 5 to 30 minutes and may subside in an hour, Histamine is the mediator. (ii) Late-phase reaction. It occurs in 2 to 8 hours later without additional exposure to the antigen. It lasts for several days. Mediators are leukatriene C4, D4, E4, PAF and others. There is infiltration of tissues with eosinophils, neutrophils, basophils, monocytes and CD4 T cells. Damage of mucosal epithelial cells occurs_
1. Systemic anaphylaxis
2. Local Type I hypersensitivity (Local anaphylaxis)
Systemic Anaphylaxis
Systemic anaphylaxis may occur after administration of various drugs such as penicillin, antisera (heterologous protein), hormones and enzymes; or bite of honey bees. Shock dose of antigen may be exceedingly small. Within minutes after exposure there may be skin erythema, pruritic, urticaria, bronchospasm, laryngeal oedema, anaphylactic shock (hypotension) and life threatening and even death. May give a previous history of allergy.
Local Type I Hypersensitivity
Example of local type I hypersensitivity or allergic reactions is atopic allergy or atopic disorders. Atopy is a genetic predisposition to form excessive IgE. Family history of allergy is found in about 50% of the patients. Target tissues often contain large number of Th2 cells. IL-4 produced by Th-2 cells leads to increased synthesis of IgE. It is due to excessive IgE response to allergens (extrinsic antigens). IgE level is elevated. Several genes associated with atopy have been identified in atopic individuals. Mutations in genes eg. gene for IL-4 has been identified. It results in an increased amount of IgE synthesis by B cells. Atopic individuals manifest one or more of a group of atopic diseases that include asthma, hay fever, urticaria, eczema against various foods, various drugs and other allergens.
Man local type I hypersensitive reactions occur in two phases: (i) Immediate phase or initial response occurs within 5 to 30 minutes and may subside in an hour, Histamine is the mediator. (ii) Late-phase reaction. It occurs in 2 to 8 hours later without additional exposure to the antigen. It lasts for several days. Mediators are leukatriene C4, D4, E4, PAF and others. There is infiltration of tissues with eosinophils, neutrophils, basophils, monocytes and CD4 T cells. Damage of mucosal epithelial cells occurs_