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

系统性硬化症的发病机制：皮肤驻留 CD8 T 细胞的作用

• 批准号: 8769486
• 负责人: PATRIZIA FUSCHIOTTI
• 金额: $ 7.7万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8769486
• 关键词: Activated Lymphocyte; Affect; Antibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Autologous; Biological Assay; Biological Response Modifiers; Biopsy Specimen; Blood; Blood Vessels; CD8B1 gene; Case Fatality Rates; Cells; Characteristics; Clinical; Collagen; Complex; Confocal Microscopy; Connective Tissue; Connective Tissue Diseases; Cutaneous; Defect; Deposition; Dermal; Development; Diagnosis; Diagnostic; Disease; Drug or chemical Tissue Distribution; Event; Fibroblasts; Fibrosis; Granzyme; Growth; Growth Factor; Homing; Immunologics; Infiltration; Inflammatory; Inflammatory Infiltrate; Injury; Innovative Therapy; Interleukin-13; Lead; Light; Molecular; Molecular Target; Organ; Pathogenesis; Pathway interactions; Patients; Phase; Phenotype; Process; Production; Research Priority; Role; Scleroderma; Severities; Skin; Small Interfering RNA; Systemic Scleroderma; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; Vascular Diseases; cytokine; cytotoxic; cytotoxicity; design; granzyme B; inhibiting antibody; inhibitor/antagonist; insight; macrophage; new therapeutic target; novel; novel therapeutics; peripheral blood; prevent; public health relevance; receptor; skin disorder; skin lesion; transcription factor

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

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，被认为是由于真皮层不适当的激活造成的。 成纤维细胞由免疫介质和浸润性炎症细胞（主要是 T 细胞）产生的其他生长因子产生。在之前的研究中，我们发现外周血效应 CD8+ T 细胞促纤维化细胞因子 IL-13 的产生失调与纤维化程度相关。 皮肤纤维化的发生，并与 IL-13 产生的分子控制缺陷有关，例如转录因子 GATA-3 表达的增加。以下是我们的最新结果。首先，我们发现早期SSc患者皮损中IL-13和CD8+ T细胞高表达。其次，我们确定，与正常对照相比，SSc 患者外周血中表达皮肤归巢受体并产生 IL-13 的 CD8+ T 细胞数量增加。最后，我们证明来自 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蛋白，并且添加抗 IL-13 抗体可以抑制这种情况。我们的初步结果表明，SSc 患者硬化皮肤中的 CD8+ T 细胞表达细胞毒性标记物，例如颗粒酶 B，因此具有潜在的细胞毒性。此外，我们发现硬化皮肤中的炎症细胞也高度表达 GATA-3，这可能与 IL-13 的过量产生有关。这一证据支持了该提议的中心假设，即 CD8+ T 细胞通过促纤维化 IL-13 的异常产生和细胞毒性损伤参与皮肤系统性硬化症的发生。具体目标旨在确定 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（目标 1），并确定可以预防或逆转该过程的分子途径（目标 2）。由于目前尚无疗法可以减缓或逆转这种致残且往往致命的疾病的自然进展，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，以开发更具体的诊断和治疗。 1