MAIT cells in lupus skin disease and photosensitivity

MAIT 细胞在狼疮皮肤病和光敏性中的作用

• 批准号: 10556664
• 负责人: Sladjana Skopelja-Gardner
• 金额: $ 38.7万
• 依托单位: DARTMOUTH-HITCHCOCK CLINIC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10556664
• 关键词: 16S ribosomal RNA sequencing; Acceleration; Address; Affect; Area; Autoimmune Diseases; Bacteria; Biology; Blood; CD8B1 gene; Cause of Death; Cell physiology; Cells; Cellular biology; Circulation; Clonal Expansion; Coupled; Cutaneous; Data; Dermal; Development; Disease; Frequencies; Funding Opportunities; Gene Expression; Genus staphylococcus; Goals; Health; Heterogeneity; Human; IL17 gene; Immune; Immune response; Immunologics; Inbred MRL lpr Mice; Inflammatory; Investigation; Kidney; Knowledge; Ligands; Lupus; Lymphocyte; Mediating; Mission; Mucous Membrane; Mus; National Institute of Arthritis, and Musculoskeletal, and Skin Diseases; Organ; Outcome; Participant; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Phenotype; Photosensitivity; Population; Property; Proteomics; Reaction; Reporting; Research; Research Personnel; Resources; Riboflavin; Role; Sampling; Shapes; Signal Transduction; Skin; Skin colonization; Skin injury; Staphylococcaceae; Sunlight; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Therapeutic; Tissues; Translational Research; Ultraviolet Rays; United States; United States National Institutes of Health; burden of illness; commensal bacteria; cytokine; cytotoxic; direct application; experience; immune activation; in vivo; inhibitor; innovation; lupus cutaneous; microbial community; microbiome; microbiome alteration; migration; mortality; mouse model; novel; prevent; programs; recruit; response; single-cell RNA sequencing; skin disorder; skin lesion; skin microbiome; skin microbiota; skin organogenesis; stem; tissue injury; transcriptomics; ultraviolet; young woman

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.

项目摘要 /摘要 全身性红斑狼疮（SLE，狼疮）是一种多器官自身免疫性疾病，有5-10％ 10年内的死亡率。皮肤受到这种疾病的严重影响和对紫外线（UV）的敏感性 阳光射线最多影响80％的患者。皮肤涉及的免疫机制 狼疮（CLE）仍然很了解。特别是，不同类型的T细胞的作用高度 CLE皮肤中流行的淋巴细胞尚不清楚。该提案中的总体目标是：（i） 并确定与皮肤微生物组相关的Mait细胞在CLE中的功能和（ii） 定义Mait细胞在狼疮皮肤病和体内光敏反应中的作用。这 中心假设是Mait细胞的激活，受到优先膨胀的影响 产生核黄素的细菌，介导CLE中的皮肤发病机理。这个项目的理由 源于了解狼疮皮肤中微生物组如何影响免疫的差距 激活，特别是MAIT细胞，并导致组织损伤。中心假设将是 通过追求两个具体目标测试：1定义皮肤微生物组如何形成Mait细胞功能 CLE患者和2）确定皮肤微生物群和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，来自狼疮皮肤的Mait细胞（病变 将评估不受影响的）数量，异质性，转录组特征和TCR 用法（相对于健康皮肤），这些发现与丰度分析 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 在缺乏MAIT细胞的MRL-LPR小鼠中，将评估狼疮皮肤病的发育 （mrl.lprmr1 - / - ）。这种新的鼠菌株将用于研究皮肤如何与 核黄素或葡萄球菌细菌会影响自发和紫外线的MAIT细胞功能 在体内加速CLE。本应用程序中提出的研究具有创新性，因为它将 产生一种新型的狼疮皮肤疾病机制，并询问据报道的T细胞种群 在其他皮肤疾病中具有炎症特性，但尚未在CLE中进行研究。这 拟议的研究很重要，因为有望为其提供强大的科学原理 解决狼疮皮肤微生物组和/或调节MAIT细胞的不平衡治疗 狼疮皮肤病的目的。