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