Th17 Trafficking Cells in Behcet's Disease Skin Lesions

Abstract

Behcet's disease (BD) is a vasculitis characterized by oral, genital ulcers and uveitis with varying other manifestations associated with vascular inflammation. Additional target organ, including vascular, neurological, and gastrointestinal manifestations, were added to the disease spectrum [Yazici et al., 2003]. The etiology of BD is considered to be a complex systemic vasculitis, caused by T-helper-1 (Th1) cytokine skewed neutrophilic and lymphohistiocytic inflammation [Suzuki et al., 2006; Kulaber et al., 2007; Koarada et al., 2004; Keller et al., 2005]. The pathogenesis of BD is still unclear, but immune dysfunction, viral and bacterial agents, such as Staphylococcus spp. and herpes simplex virus, have been postulated [Onder et al., 2001]. Cytokines play crucial roles in the inflammatory responses in BD [Hamzaoui et al., 2002; Direskeneli et al., 2003]. BD as many autoimmune diseases are considered to be T cellregulated diseases, further classified as Th1-mediated diseases, with Th1-like diseases featuring a high production of IFN-. However, this classification fails to explain the involvement of inflammatory cells as seen in many autoimmune/inflammatory diseases. A unifying feature of the inflammation observed in BD is the nonspecific hyperreactivity of tissue to minor trauma, termed the skin pathergy reaction (SPR), which remains the most diagnostically relevant lesion in BD patients, where an exaggerated inflammatory response develops in the skin of BD patients that is characterized by dermal infiltration of activated dentritic cells (DCs) and the presence of a Th1-type immunological cascade [Melikoglu et al., 2006]. The immunohistochemistry of patients with sterile, pustular skin eruptions in the context of a systemic autoinflammatory disease revealed a substantially denser, lymphocyte rich cell infiltrate (mainly CD4+ and some CD8+ T cells than in normal skin). The majority of T cells detected were immigrating, inflammatory T cells, as they expressed CCR6, the receptor for CCL20 (MIP-3) [Keller et al., 2005]. Studies show that CD4+ IL-17+ and CD8+ IL-17+ T cells (Th17) play an active role in inflammation and autoimmune diseases in murine systems [Komiyama et al., 2006; Bettelli et al., 2007; Kryczek et al. 2007], and have never been studied in skin lesions from BD patients. The question addressed in this study is why Th1 and Th17 cells often colocalized in