Pathophysiology of allergic skin disease

Whilst classical allergy usually involves type 1 (immediate and late phase – see figures 1 and 2) or type 1V (cell mediated) hypersensitivity reactions this is a gross oversimplification. Dysfunction of the epidermal barrier may increase permeability to allergens, irritants and microbes. Decreased production of antimicrobial proteins can increase susceptibility to pyoderma, and environmental factors may modify allergic responses in genetically predisposed individuals.

T helper 2 lymphocytes drive humoral immunity and result in IgE production. Studies have detected Th2 polarisation in the skin of human atopics and IL-4 expression is thought to be a hallmark of human AD. The importance of IL-4 in canine and feline atopic disease is less consistent. IL-5 expression may be more common in atopic compared to healthy canine skin. Many other cytokines have been associated with atopic dermatitis including the newly described IL-31, also produced (not exclusively) by sensitised Th2 cells.

Binding of IL-31 to its receptor triggers the Janus kinase/signal tranducer and activator of transcription (JAK/STAT) pathway, resulting in an unrelenting cycle of pruritus and neuroimmune stimulation. The ability to block JAK/STAT could act at many levels of the itch-scratch cycle to block the pruritic response.

Antigen (allergen) is presented by dendritic antigen presenting cells, to Th2 lymphocytes (see fig 1).

Figure 1: Pathogenesis of Type 1 Hypersensitivity

Th2 cells produce a variety of cytokines including

IL-3, IL-4, IL-5 and GM-CSF. IL-4 is instrumental in “turning on” IgE- producing B cells, sustaining development of Th2 cells and triggering IgE synthesis. IL-3, IL-5 and GM-CSF (also produced by activated mast cells) promote survival of eosinophilis, important effectors of type 1 hypersensitivity. Activated B lymphocytes develop into plasma cells and up-regulate IgE production.

IgE is present in serum in minute quantities compared to other immunoglobulins. Most is bound irreversibly to mast cells or basophils, via the high-affinity receptor (see fig 2).

Figure 2: IgE/Mast Cell Receptor Complex

IgE binding results in mast cell sensitisation. If specific antigen subsequently cross-links two mast-cell-bound IgE molecules, a message is transmitted into the cell (signal transduction) initiating a series of reactions which ultimately lead to both mast cell degranulation, with discharge of potent pre-formed inflammatory mediators (histamine, heparin, tryptase, chemotactic factors, TNF) and de novo synthesis of secondary mediators (prostaglandins, leukotrienes, cytokines, PAF). These mediators are responsible for initial (immediate) signs of type1 hypersensitivity and initiate events leading to the late-phase response.

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