MAIT cells in lupus skin disease and photosensitivity

项目概要/摘要 系统性红斑狼疮（SLE，lupus）是一种多器官自身免疫性疾病， 十年内死亡率皮肤受到这种疾病的严重影响，对紫外线（UV）敏感 80%的患者会受到阳光的影响。皮肤癌的免疫机制 狼疮（CLE）仍然知之甚少。特别是，不同类型的T细胞的作用， CLE皮肤中普遍存在的淋巴细胞是未知的。本建议的总体目标是： 分析并确定CLE中MAIT细胞与皮肤微生物组相关的功能，以及（ii） 确定MAIT细胞在狼疮皮肤病和体内光敏反应中的作用。的 中心假设是MAIT细胞的激活，受细胞的优先扩增的影响， 产生核黄素的细菌介导CLE中的皮肤发病机制。该项目的基本原理 源于对狼疮皮肤中改变的微生物组如何影响免疫系统的知识的差距。 激活，特别是MAIT细胞，并导致组织损伤。核心假设是 通过追求两个具体目标进行测试：1定义皮肤微生物组如何在皮肤中塑造MAIT细胞功能， CLE患者和2）建立皮肤微生物群和MAIT之间的狼疮特异性相互作用 细胞在体内介导皮肤狼疮。在第一个目标下，来自狼疮皮肤（病变）的MAIT细胞 和未受影响）的数量、异质性、转录组特征和TCR 使用（相对于健康皮肤），这些研究结果分析了与丰富的 微生物群落和核黄素基因表达。对于第二个目标，MAIT细胞的作用 将在MAIT细胞缺陷的Mrl-lpr小鼠中评价 （Mrl.lprMR1-/-）。这种新的小鼠品系将用于研究皮肤如何与 核黄素或葡萄球菌影响MAIT细胞在自发和紫外线下的功能- 体内加速CLE。本申请中提出的研究是创新的，因为它将 产生狼疮皮肤病的新机制，并询问T细胞群， 在其他皮肤病中具有炎症特性，但尚未在CLE中进行研究。的 拟议的研究是重要的，因为它预计将提供一个强有力的科学依据， 解决狼疮皮肤微生物组的不平衡和/或调节MAIT细胞以用于治疗 狼疮性皮肤病

Project Summary / Abstract Systemic lupus erythematosus (SLE, lupus) is a multi-organ autoimmune disease with 5-10% mortality in 10 years. Skin is severely affected by this disease and sensitivity to ultraviolet (UV) sunlight rays affects up to 80% of patients. The immunologic mechanisms involved in cutaneous lupus (CLE) remain poorly understood. In particular, the role of different types of T cells, highly prevalent lymphocytes in CLE skin, is unknown. The overall objectives in this proposal are: (i) to profile and determine the function of MAIT cells in CLE in relation to the skin microbiome and (ii) to define the role of MAIT cells in lupus skin disease and photosensitive responses in vivo. The central hypothesis is that activation of MAIT cells, influenced by preferential expansion of riboflavin-producing bacteria, mediates skin pathogenesis in CLE. The rationale for this project stems from the gap in the knowledge of how the altered microbiome in lupus skin impacts immune activation, and specifically MAIT cells, and leads to tissue damage. The central hypothesis will be tested by pursuing two specific aims: 1 Define how skin microbiome shapes MAIT cell function in CLE patients and 2) Establish how lupus-specific interactions between skin microbiota and MAIT cells mediate cutaneous lupus in vivo. Under the first aim, MAIT cells from lupus skin (lesional and unaffected) will be evaluated for quantity, heterogeneity, transcriptomic signatures, and TCR usage (relative to healthy skin) and these findings analyzed in relation to the abundance of microbial communities and riboflavin gene expression. For the second aim, the role of MAIT cells in the development of lupus skin disease will be evaluated in Mrl-lpr mice deficient in MAIT cells (Mrl.lprMR1-/-). This new murine strain will be used to investigate how dermal association with riboflavin or Staphylococcus bacteria influences MAIT cell function in spontaneous and UV light- accelerated CLE in vivo. The research proposed in this application is innovative because it will generate a novel mechanism of lupus skin disease and interrogate a T cell population reported to have inflammatory properties in other skin disease but has not yet been studied in CLE. The proposed research is significant because it is expected to provide a strong scientific rationale to address the imbalance in lupus skin microbiome and/or modulate MAIT cells for therapeutic purposes in lupus skin disease.