Pathogenesis of Psoriasis and Current Challenges Aditya K. Gupta, Richard Langley, Yves Poulin, Harvey Lui, Gordon Searles, Wayne Carey, John Toole, and Kimberly Inniss Journal of Cutaneous Medicine and Surgery Incorporating Medical and Surgical Dermatology DOl: 10.1007/510227-004-2002-7 J Cutan Med Surg 2004; 3-7 Etiology of Psoriasis Etiology up to 2.5% world's population 1 WIth approximately one million Canadians affect- ed. 2 The onset is usually between the ages of 10 and 40 years, and approximately one-third of patients have an immediate family member with the disease. Psoriasis tends to be more prevalent at higher latitudes and in Caucasians than in any other race.' The susceptibility to psoriasis is inherited, but environmental factors, stress, and infections may determine disease onset and severity." Approximately 1.5 million adults in the United States are diagnosed as having moderate to severe psoriasis; one- third of those with psoriasis overall.i Psoriasis has a va- riety of clinical presentations, with the plaque type oc- curring in more than 80% of cases, 3 and may involve nails and joints. Immunology and T-Cell Involvement The pathogenesis of psoriasis is the result of the activa- tion of several types of leukocytes that control cellular immunity, and T-cell-dependent inflammatory processes in skin that accelerate the growth of epidermal and vas- cular cells in psoriasis lesions.? The process can be bro- ken down into three steps: initial activation of T -cells in the lymph nodes draining the skin in response to an an- tigen, migration of effector T -cells into the skin har- boring the activatin9" antigen, and the effector function of T -cells in the skin. In the course of a normal immune response, T -cell-stimulated pathways in the skin are able to eliminate the antigen with termination of the immune response; however, in a psoriatic, the T-cell infiltration and effector responses in reaction to an antigen continue to persist. 7 Initial T-cell activation requires two signals (Fig. 1). The primary signal originates with the binding of an antigen to an antigen-presenting cell (APC). Protein complexes on the APC surface include human leukocyte antigen (HLA) and major histocompatibility complex (MHC). MHC class I present the antigen to CD8+, while MHC class II present the antigen to CD4+. A Mediprobe Research Inc., London, Ontario, Canada Online publication: 3 August 2004 FIGURE 1 T-cell activation requires two signals. APC (Antigen Presenting Cell) T Cell downstream cascade is initiated as a result of the eros- slinkinf" between the T-cell receptor and MHC com- plexes. The second, costimulatory signal for activation involves a number of ligand pair interactions between the T-cell and the APe. These ligand pairs, expressed on the T-cell surface and the APC, respectively, include lymphocyte function-associated antigen (LFA)-lIinter- cellular adhesion molecule (ICAM)-l, CD28/B7, CD2I LFA-3. 8 Recent studies suggest that LFA-l/ICAM-l interactions may be more important in anchoring the immunological synapse between the T -cells and the APC than in providing a second activating signal to T- cells. 9 Once activated, T -cells travel out of the lymph nodes and into circulation where they are slowed down before migrating to the skin. T-cells engage with additional secondary receptors which form high-affinity bonds that stop the T-cell and assist in the flattening of the T-cell for migration through the vascular endothelium. 1 The T- cells in psoriasis lesions are mainly activated type-l helper T -cells (Thl) (CD4+) and type 1 cytotoxic T -cells (Tel) (CD8+).10 Thl and Tel lymphocytes have the ability to produce the inflammatory cytokines interferon (INF)-y and tumor necrosis factor (TNF)-<l upon acti- vation." TNF-<l increases the synthesis of proinflamma- tory cytokines and activates nuclear transcription factors such as NF6B. 11 Proinflammatory cytokines, such as interleukin (IL)-2, TNF-<l, lymphotoxin, IL-12, IL-18, and INF-y secreted byTl cells (CD4+ and CD8+) in the 3