Allergic Contact Dermatitis Pathophysiology

Allergic Contact Dermatitis Pathophysiology

Approximately 3000 chemicals are well documented as specific causes of allergic contact dermatitis.

Compounds must be less than 500 d for efficient penetration through the stratum corneum barrier, which is the water-impermeable outer layer of the skin. Small organic molecules that are chemically reactive (chemical sensitizers) bind with self-proteins to generate immunogenic neoantigens through a process termed haptenization. Although haptens can penetrate through intact skin, patients with certain disease states that impair barrier function (eg, leg ulcers, perianal dermatitis) have an increased risk of sensitization to topically applied medications and their vehicle components.

Many patients with atopic dermatitis or allergic contact dermatitis to nickel harbor a defective form of the filaggrin gene.^[1] Filaggrin helps aggregate cytoskeletal proteins that form the cornified cell envelope. In its absence, the barrier is defective.

Prehaptens are chemicals that are not activated by host proteins, but instead require chemical transformation by oxidative derivatization by ambient or air oxidation to form hydroperoxide. Examples include certain fragrance materials and dyes used in hair coloring, such as para-phenylenediamine.

Haptens activate Toll-like receptors (TLRs) and activate innate immunity. The importance of hapten-mediated activation of innate immunity is highlighted by the clinical observation that the irritancy of chemicals (ie, the ability of these chemicals to cause grossly visible skin inflammation upon primary exposure) correlates with their ability to act as contact sensitizers and to induce acute contact dermatitis.

Haptens or haptenated self-proteins are recognized by innate immune mechanisms in the skin, and this leads to the elaboration of a number of proinflammatory mediators, including interleukin (IL)–1β. As a result, skin-resident dendritic cells (DCs) become activated. There are several populations of DCs. Langerhans cells are the only DC subtype in the epidermis. Like all skin-resident DCs, Langerhans cells efficiently acquire antigen in the periphery and migrate to regional lymph nodes where they present antigen to naïve and memory T cells. These DCs, which may have been directly haptenated or could have acquired haptenated proteins from their surroundings, migrate to skin-draining lymph nodes where they present peptides from haptenated proteins to activate memory and naïve T cells.

In the final step, hapten-induced inflammation recruits activated effector T cells back to the initial site of antigen encounter in the skin. The effector T cells release proinflammatory cytokines, such as interferon-γ, and promote the killing of haptenated cells, resulting in the development of the classic inflammatory rash seen in allergic contact dermatitis.

Keratinocytes are crucial for the development of allergic contact dermatitis. They constitute the vast majority of cells in the epidermis and form the anatomic barrier of the skin. Keratinocytes express most TLRs, and this allows them to respond to TLR4-triggering haptens, such as nickel. Keratinocytes are also a source of IL-10, an immunosuppressive cytokine that limits the extent of contact hypersensitivity

The initial sensitization typically takes 10-14 days from initial exposure to a strong contact allergen such as poison ivy. Some individuals develop specific sensitivity to allergens following years of chronic low-grade exposure; for example, sensitivity to chromate in cement can eventually develop in individuals with chronic irritant contact dermatitis resulting from the alkaline nature of cement. Once an individual is sensitized to a chemical, allergic contact dermatitis develops within hours to several days of exposure.

CD4⁺ CCR10⁺ memory T cells persist in the dermis after clinical resolution of allergic contact dermatitis.

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