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

描述(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的最大特征，被认为是由于皮肤的不适当激活所致 成纤维细胞由免疫介质和其他由炎症细胞(主要是T细胞)渗入产生的生长因子产生。在以前的研究中，我们发现外周血效应CD8+T细胞产生促纤维化细胞因子IL-13的失调与疾病的程度有关 与皮肤纤维化有关，并与IL-13产生的分子控制缺陷有关，如转录因子GATA-3表达增加。以下是我们的最新结果。首先，我们发现IL-13和CD8+T细胞在早期SSC患者皮损中高表达。其次，我们发现SSC患者外周血中表达皮肤归巢受体和产生IL-13的CD8+T细胞数量比正常对照组增加。最后，我们证明了来自SSC患者的CD8+T细胞上清液诱导正常皮肤成纤维细胞产生胶原，并且这一作用被添加抗IL-13抗体所抑制。我们的初步结果表明，SSC患者硬化皮肤中的CD8+T细胞表达细胞毒标志，如颗粒酶B，因此具有潜在的细胞毒作用。此外，我们还发现GATA-3在硬化皮肤中的炎性细胞中也有高表达，这可能与IL-13的过度产生有关。这一证据支持了这一建议的中心假设，即CD8+T细胞通过异常产生促纤维化的IL-13和细胞毒性损伤参与了皮肤系统性硬化症的发病。其目的是确定CD8+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(AIMS 1)，并针对可以阻止或逆转这一过程的分子途径(AIMS 2)。由于目前还没有治疗方法来减缓或逆转这种致残且往往是致命的疾病的自然发展，在分子水平上了解SSC的发病机制将为开发更具体的诊断和治疗提供新的治疗靶点。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