Tuesday, December 11, 2012

What is Hypersensitivity ?


HYPERSENSITIVITY

1. Basic concepts

Definition:
Hypersensitivity (HS) reactions are  harmful antigen-specific immune responses  which produce tissue injury and dysfunction.

Allergen:the antigens that give rise to immediate HS.

Fig. Allergy
Atopy:

Familial tendency to make IgE more frequently against the common environmental substances to which most of the population is not reactive.
 
Fig. Types of Hypersensitivity

































Type I  hypersensitivity

Characteristics:

• Occur and resolve quickly
• Mediated by serum IgE
• Systemic and regional tissue dysfunction
• Genetic predisposition

Components and cells:

  1. Allergen :
    • pollen, dust mite, insects etc
    • selectively activate CD4+Th2 cells and B cell
  2. IgE and its production
    • IgE: mainly produced by mucosal B cells in the lamina propria 
    • IL-4 is essential to switch B cells to IgE production  
  3. High affinity receptor of the IgE on mast cell and basophi
  4. Eosinophil
Factors which stimulate Mast cells
• Cross linking of IgE by Allergen
• C3a, C4a, C5a receptor present in mast cell
• Drugs like Codeine and Morphine
• Venon (Snake bite- Mellitin), Bee sting, Ant Sting
• Physical agents like cold, heat, physical trauma
• Strong sun light







 Production of IgE Ab

  • In individuals who are prone to allergies (Atopic persons) encounter with some Ag activation of TH2 cells--->production of IgE Ab
  • IL-4 and IL-13 stimulate B lymphocytes specific for the foreign Ags to switch to IgE producing  plasma cells.
  • Strong genetic basis
Both Genetics and the Environment play a significant roles in determining who has allergies and which kind of allergy.

Certain allergies and autoimmunity can be mapped to specific gene loci.

Activation of mast cells and secretion of mediators


  1. Priming stage/Sensitizing
    • IgE Ab produced in response to an allergen binds to high affinity Fc receptors specific for the ε heavy chain on mast cell
  2. Activating stage
    • When mast cells sensitized by IgE are exposed to the allergen, the cells are activated to secrete their mediators 
  3. Effect stage:
    • Vasoactive amines and proteases—from granules, products of arachidonic acid metabolism, and cytokines. (Immediate and late phase) 
Immediate/early phase : mediated by histamine, start within seconds, last several hours.
Late phase: Mediated by new-synthesized lipid mediators, take up 8-12 hours to develop, last several days 

Sequence of events in immediate HS:

  • Intitiated by the introduction of an allergen, which stimulates Th2 reactions and IgE production. 
  • IgE binds to Fc receptors (FCERI) on mast cells, and subsequent exposure to the allergen activates the mast cells to secret the mediators that are responsible for the pathologic reactions of immediate HS.


















Schematic diagrams of the high-affinity FcRI and low-affinity FcRII receptors that bind the Fc region of IgE.

Each gamma-chain of the high-affinity receptor contains an ITAM, a motif also present in the Ig-/Ig- heterodimer of the B-cell receptor and in the CD3 complex of the T-cell receptor.






The low-affinity receptor is unusual because it is oriented in the membrane with its NH -terminus
directed toward the cell interior and its COOH-terminus directed toward the extracellular space.















Mast cell activation:


 Biochemical events in mast cell activation:
 

  • Cross linking of IgE on a mast cell by an allergen stimulates phosphorylation of ITAM (Immunoreceptor tyrosine based activation motifs) in the signalling chains of the IgE Fc receptor, which then initiates multiple signaling pathways. These signaling pathways stimulate the release of mast cell granule contents (amines, proteases). 
  • The synthesis of arachidonic acid metabolites (PG, LTs) and the synthesis of various cytokines. These mast cell mediators stimulate the various reactions of immediate HS.   

Clinical Syndrome:

 Diagnosis

  • Skin prick test
  • RAST (Radio allergo Immuno sorbent test)
    • Used to detect specific IgE against a particular Ag



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