Pathogenesis of systemic sclerosis: role of the skin-resident CD8+ T cells

描述（由申请人提供）：系统性硬化症（SSc）是一种影响结缔组织的破坏性多系统自身免疫性疾病。皮肤纤维化是SSc最典型的特征，被认为是真皮不适当激活的结果

DESCRIPTION (provided by applicant): Systemic sclerosis (SSc) is a devastating multisystem autoimmune disorder affecting the connective tissue. Cutaneous fibrosis is the most characteristic feature of SSc and is believed to result from the inappropriate activation of dermal fibroblasts by immune mediators and other growth factors produced by infiltrating inflammatory cells, predominantly T cells. In previous studies, we found that dysregulated production by peripheral blood effector CD8+ T cells of the profibrotic cytokine IL-13 correlates with the extent of skin fibrosis and is associated with defects in the molecular control of IL-13 production, such as increased expression of the transcription factor GATA-3. The following are our most recent results. Firstly, we found that IL-13 and CD8+ T cells are highly expressed in the skin lesions of early SSc patients. Secondly, we established that increased numbers of CD8+ T cells expressing skin homing receptors and producing IL-13 are found in the peripheral blood of SSc patients compared to normal controls. Finally, we demonstrated that CD8+ T-cell supernatants from SSc patients induce collagen production by normal skin fibroblasts and that this is inhibited by the addition of an anti-IL-13 antibody. Our preliminary results show that CD8+ T cells in the sclerotic skin of SSc patients express markers of cytotoxicity, such as Granzyme B, and are therefore potentially cytotoxic. Furthermore we show that GATA-3 is also highly expressed by inflammatory cells in the sclerotic skin where it may be associated with the overproduction of IL-13. This evidence supports the central hypothesis of this proposal, that CD8+ T cells are involved in the onset of cutaneous systemic sclerosis by aberrant production of pro-fibrotic IL-13 and cytotoxic damage. The Specific Aims are designed to establish the unique role of CD8+ T cells in the pathogenesis of SSc and to elucidate the cellular and molecular mechanisms leading to tissue damage and fibrosis in SSc (Aims 1) and to target molecular pathways that could prevent or reverse the process (Aim 2). Since currently there is no therapy that slows or reverses the natural progression of this disabling and often fatal disease, understanding the pathogenic mechanisms of SSc at a molecular level will reveal new therapeutic targets for developing more specific diagnosis and treatment. 1