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）是一种破坏性的多系统自身免疫性疾病，影响结缔组织。皮肤纤维化是SSc最典型的特征，并且被认为是由真皮纤维化的不适当激活引起的。 成纤维细胞通过由浸润的炎性细胞（主要是T细胞）产生的免疫介质和其他生长因子而生长。在以前的研究中，我们发现外周血效应CD 8 + T细胞产生促纤维化细胞因子IL-13的失调与纤维化程度相关。 与IL-13产生的分子控制缺陷有关，如转录因子加塔-3的表达增加。以下是我们最新的结果。首先，我们发现IL-13和CD 8 + T细胞在早期SSc患者的皮肤病变中高度表达。其次，我们确定，与正常对照相比，在SSc患者的外周血中发现表达皮肤归巢受体和产生IL-13的CD 8 + T细胞的数量增加。最后，我们证明了来自SSc患者的CD 8 + T细胞上清液诱导正常皮肤成纤维细胞产生胶原蛋白，并且这通过添加抗IL-13抗体来抑制。我们的初步结果表明，SSc患者皮肤中的CD 8 + T细胞表达细胞毒性标记物，如颗粒酶B，因此具有潜在的细胞毒性。此外，我们还发现加塔-3也被表皮中的炎性细胞高度表达，这可能与IL-13的过度产生有关。该证据支持该提议的中心假设，即CD 8 + T细胞通过异常产生促纤维化IL-13和细胞毒性损伤参与皮肤系统性硬化症的发作。特定目的旨在确定CD 8 + T细胞在SSc发病机制中的独特作用，阐明导致SSc组织损伤和纤维化的细胞和分子机制（目的1），并靶向可能预防或逆转该过程的分子途径（目的2）。由于目前还没有减缓或逆转这种致残且通常致命的疾病的自然进展的疗法，因此在分子水平上了解SSc的致病机制将揭示新的治疗靶点，以开发更特异性的诊断和治疗。1

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