The pathogenesis of psoriasis has undergone several revisions over the past several decades. The most recent evidence has suggested that psoriasis is due to activated T cells present in the psoriatic plaques that produce proinflammatory cytokines and mediators that produce the changes seen in psoriasis (Fig. 9.2). Today's newest therapies for psoriasis target specific steps in this cascade of events to specifically inhibit the reactions necessary for the inflammation changes seen in psoriasis.
There are two subsets of T cells that are differentiated by the type of cytokines they release: T1 (type 1) and T2 (type 2). T1 cells produce interleukin (IL)-2 and IFN-y, are in part responsible for cell-mediated immunity and are inflammatory in nature. T2 cells release IL-4, IL-5, and IL-10, which enhance the humoral immune system and are anti-inflammatory in nature. It is believed that psoriasis is a T1 mediated process, as suggested by the increased levels of IFN- in psoriatic skin, lesional and non-lesional. IFN- also induces macrophages to secrete high levels of inflammatory cytokines such as TNF-a, which is present in high levels of psoriatic plaques and synovium of patients with psoriatic arthritis. T2 cytokines levels, on the other hand, have been shown to be low in psoriatic patients.
There are many steps required before the phenotyp-ic production of psoriasis is expressed. Mehlis and Gordon break this process down into three steps: (1) the activation of T cells, (2) the migration of T cells into the skin, (3), and the effector function of T cells or the induction of T cells by the secretions of inflammatory cells. The newer biologic therapies have targeted these specific steps in order to provide specific and less toxic therapy for psoriasis.
Fig. 9.2. Putative T-cell responses in the pathogenesis of a psoriatic lesion. To generate a cutaneous T-cell response, antigen-presenting cells take up and process antigens and migrate to the regional lymph nodes. There, they come in contact with nai've T cells. Within an immunologic synapse (inset), molecular interactions result in T-cell activation. Following the activation signals, T cells differentiate into memory T-cells and re-enter the circulation, where they extravasate at sites of cutaneous inflammation. In the skin, on encountering the respective antigen, T cells exert their effector functions, which include the secretion of pro-inflammatory cytokines. Psoriasis is characterized by a chronically persisting response in effector T-cells. (Reproduced with permission from: N Engl J Med 2005: 352:1905)
T-cell activation is a multi-step process that begins with binding to an antigen-presenting cell (APC) through interactions between LFA-1 (leukocyte function associated antigen), ICAM-1 (intercellular adhesion molecule), and LFA-3. Once bound, the T cell becomes activated by two signals, antigen (it is currently not known which antigen is responsible) bound to class I or II MHC on the APC, and another signal supplied by a number of different cell surface molecules including LFA-1, ICAM-1, CD-2, and LFA-3 (Gottlieb 2003). Alefacept is a fusion protein that consists of the extracellular domain of LFA-3 fused to hinge sequences of IgG1. This biologic binds CD-2 on T cells, which results in the inhibition of T-cell costimulation and a reduction in memory effector cells. By binding CD-2 on memory effector T cells, alefacept facilitates apoptosis of the cell.
T cells must also be present in the skin to produce the inflammatory changes, and therefore must migrate from the circulation. The activated T cell must slow and then bind the endothelium before it can enter the affected tissue. Several surface molecules are responsible for this process including CLA (cutaneous lymphocyte antigen) on the T cell and E selectin on the endo-thelium. This interaction slows the cell along the endo-thelial surface. The interaction between LFA-1 and ICAM and VLA and VCAM allows the T cell to bind to the endothelium. Once bound, the cell can cross the endothelium. Efalizumab is a monoclonal antibody that binds LFA-1 and blocks its interaction with ICAM, and inhibits migration and possibly activation.
Once in the skin, T cells and the inflammatory changes they can induce, alter keratinocytes. As previously mentioned, the cytokines released in psoriatic plaques are primarily T1, and include TNF-a, which in turn increases the production of other inflammatory cytokines such as IL-1, IL-6, and IL-8. Therapies such as etanercept, infliximab, and adalimumab work to block the effects of TNF- and therefore its actions including the increased production of pro-inflammatory cytokines, adhesion molecules, vascular endothelial growth factor, and keratinocyte hyperproliferation.
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