Asthma

Pathogenesis

Immediate (type I) Hypersensitivity is a complex disorder resulting from an IgE-mediated triggering mast
cells aand subsequent accumulation of inflammatory cells at site of antigen deposition. These events are
regualted mainly by the inductinon of TH2 Helper T cell that stimulate production of IgE (which
promotes Mast cell activation), causes accumulation of inflammatory cells (particulary Eosinophils), and
trigger secretion of mucus. The clinical feature result from release of Mast cell mediators as well as
esosinphil-rich inflammation.

There are 2 phases of Immediate (Type I) Hypersensitivity

1. Immediate or initial reaction (Minutes after exposure)

Upon exposure to antigen (allergen) of your antigen to T cell via antigen presenting cells
(APC) , T helper cell differentiates into subsets which will stimulate secretion of different
Cytokines (Interleukins) to activates the B cells which in turn the B cells produces IgE
Antibodies.

Subset TH1 secretes the cytokine IFN-Y which results in the induction of microbicidal
activity of the macrophages.

Subset TH2 produces Il-4 which stimulates B cells to differentiate into IgE secreting
palsma cells; IL-5 activates eosinophils ; IL-13 enhances IgE production and acts on
epithelial cells to stimulate mucus secretion.

The formed IgE expresses a high affinity receptor to circulating Mast cells and Basophils,
therefore IgE and mast cells avidly binds together. When a Mast cell together with IgE
antibodies is exposed to a specific allergen, a sereis of reaction takes place and will
cause Mast cell degranulation, leading to the release of powerful mediators responsible
for the clinical manifestations of Type 1 Immediate Hypersensitivity reaction. Mediators
responsible for the initial reaction are divided into Preformed, Lipid, and Cytokine.

Preformed mediators are Vasoactive amine (Histamine); Enzymes (Proteases and acid
hydrolases); and Proteoglycans (Heparin) which causes intense smooth muscle
contraction, increased vascular permeability, and increase mucus secretion causing
tissue damage, generation of kinins, and coagulation.

Lipid mediators such as Leukotrines C4 and D4 are the most potent vasoactive and
spasmogenic agents known; Leukotrine B4 attracts other lymphocytes; Prostaglandin
D2 is the most abundant mediator which causes intense bronchospasm as wel las
increased mucus secretion; Platelet-activating factor (PAF) causes platelt aggregation,
release of histamines, bronchospasm, increased vascular permeability and vasodilation.
2. Late Phase Reaction (2-24 hours after exposure)
Mast cells also produces cytokines such as TNF, IL-1, and chemokines which promote
leukocyte recriutment and produces additional wave of mediators.
Eosinophils activated by your IL-5 in the initial reaction produces proteolytic enzymes
which are toxic to epithelial cells, it also produce Leukotrines C4 and PAF and directly
activates mast cells to release mediators. Thus, the recruited cells amplify and sustain
the inflammatory response without additional exposure to antigen.