Allergic Response Pathway

Atopy or Allergic disease is a complex familial disorder with multiple manifestations, including allergic asthma, rhinitis, conjunctivitis, and dermatitis. Allergens are derived from different sources such as cockroaches, ragweed pollens, and house dust mites. The primary immune cell lineages involved in the initiation and progression of allergic inflammation include DCs (Dendritic Cells), mast cells, basophils, eosinophils, and Th2 (Type-2 Helper T) cells. The responses of these principal players in allergic reactions are influenced by the local environments in which they reside. When susceptible or atopic individuals are initially exposed or sensitized to allergens, Antigen-presenting cells capture, process, and present allergen as an allergen-derived peptide fragment in the contest of specific MHC II (HLA II) molecules this induces allergen-specific acquired immune responses, which are characterized by CD4+ T cells that produce a Th2 profile of cytokines for example, IL-4(Interleukin-4), IL-5, IL-9 and IL-13, IL-10 and the presence of allergen-specific IgE. Subsequent challenge with allergen causes the rapid activation of mast cells through allergen and IgE crosslinking, and the release of mediators such as histamine and leukotrienes causes increases in vascular permeability, smooth-muscle contraction and mucus secretion. Late-phase allergic responses are characterized by the additional recruitment and activation of eosinophils and Th2 cells at the site of allergen challenge (Ref.1, 2 & 3).

Mast-cell activation by IgE crosslinking with allergen requires access of allergen into the tissue and input from the adaptive immune system to be effective. Mast-cell activation requires not only the synthesis of specific IgE by B cells (regulated by interleukin-4 (IL-4) and IL-13 derived from Th2 cells and basophils), but also mast-cell priming by IL-4 for enhanced mediator release. The subsequent release of mast-cell mediators such as histamine, LTC4 (Leukotriene C4) and PGD2 (Prostaglandin D2) leads to an early reaction, consisting classically of a ‘wheal and flare’ reaction of the skin or the mucosa. These mediators affect the mucosa, the blood vessels and sensory nerves (pain). Other mast-cell mediators, such as IL-3, IL-5, IL-8,IL-33, TNF (Tumor-Necrosis Factor),NT3 (Neurotrophin 3) and proteases contribute to the initiation of a facultative latephase reaction by recruiting and activating eosinophils, neutrophils and Th2 cells, and by interaction with tissue cells such as nerve cells, smooth-muscle cells, endothelial cells and the epithelium. Ongoing dysregulation of such cell types not only causes symptoms of allergy, but also organ dysfunction, including loss of barrier function and, subsequently, increased bacterial translocation. This enables non-specific triggers to access mast cells, dendritic cells and other cells.Triggers such as bacterial products, or immunoglobulin such as monomeric IgE and light chains might perpetuate the inflammatory process, even in the absence of allergen (Ref.4 & 5). Eotaxin is mainly produced by epithelial cells, but in some conditions it is also produced by other cell types, such as mast cells and alveolar macrophages. Signals that trigger the production of eotaxin by epithelial cells come from lymphocytes, but possibly also mast cells and dendritic cells. Eotaxin recruits Th2 cells that in turn produce IL-4 and IL-5 and amplify all the effects on epithelial cells and mast cells, resulting in the production of more eotaxin. Significant levels of eotaxin result in eosinophil recruitment and degranulation, further Th2 recruitment, basophil degranulation and mast cell migration and differentiation. Antigen-activated basophils secrete soluble factors that stimulate tissue-resident nonhaematopoietic cells, such as fibroblasts, to produce various chemokines that in turn recruit inflammatory cells, including eosinophils and neutrophils, to the skin lesions. These results suggested that basophils have an important and nonredundant role in chronic allergic inflammation as initiators rather than effectors of the inflammatory response (Ref.6, 7 & 8).

Once attracted to the site of inflammation the eosinophil becomes activated and, as a result of this, secretes several tissue-toxic mediators. These are either basic or granule-stored proteins, ECP (Eosinophil Cationic Protein), EPO (Eosinophil Peroxidase), eosinophil protein/eosinophil-derived neurotoxin, and MBP (Major Basic Protein) or reactive oxygenfree radicals. The eosinophil also produces a wide array of different cytokines, leukotrienes, chemokines, and lipid mediators, granulocyte/macrophage colony-stimulating factor, and is therefore, in addition to being an effector cell, thought to play an immunoregulatory role in inflammatory processes as well as taking part in tissue remodeling. EDN (Eosinophil-derived neurotoxin), a member of the RNase A superfamily, is a mediator produced by human eosinophils and placental epithelial cells. In addition to its ribonuclease activity EDN reduces the infectivity of respiratory syncytial virus for target cells in vitro and is also responsible in part for the anti HIV-1 activity found in the supernatants of mixed lymphocyte cultures by identifying EDN (Ref.9, 10 & 11). TSLP emerged as a central player in the development of allergic symptoms, especially in the airways, and is a prime regulatory cytokine at the interface of virus- or antigen-exposed epithelial cells and DCs. DCs activated by epithelium-derived TSLP can promote naïve CD4+ T cells to adopt a Th2 phenotype, which in turn recruit eosinophilic and basophilic granulocytes as well as mast cells into the airway mucosa. These different cells secrete inflammatory cytokines and chemokines operative in inducing an allergic inflammation and atopic asthma. TSLP is, thus, involved in the control of both an innate and an adaptive immune response (Ref.12).