Bacterial translocation to mesenteric adipose tissue drives pathogenic stromal-B cell interactions leading to inflammatory IgG

细菌易位至肠系膜脂肪组织驱动致病性基质 B 细胞相互作用，导致炎症 IgG

• 批准号: 10593509
• 负责人: Emilie Kristina Grasset
• 金额: $ 25.43万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-03 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593509
• 关键词: Adipocytes; Adipose tissue; Affect; Antibodies; Antigen Receptors; Antigens; Automobile Driving; B-Cell Activation; B-Lymphocytes; Bacteria; Bacterial Antigens; Bacterial Translocation; Biopsy; Cell Communication; Cell physiology; Cells; Chronic; Collection; Crohn' s disease; Data; Development; Diagnosis; Disease; Etiology; Excision; Fatty acid glycerol esters; Flow Cytometry; Genes; Genetic Transcription; Germ-Free; Gnotobiotic; Gut Mucosa; Human; IgA Deficiency; Immune system; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin M; Immunology; Impairment; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestines; Lead; Left; Leptin; Ligation; Lymphoid; Mesentery; Microbe; Modeling; Mucous Membrane; Mus; Operative Surgical Procedures; Pathogenicity; Pathologic; Pathology; Patients; Phenotype; Plasma Cells; Production; Proliferating; Property; Proteins; Serum; Signal Transduction; Stromal Cells; Tissue Expansion; Tissues; Toll-like receptors; adipokines; antimicrobial; comparison control; cytokine; disease diagnosis; genetic signature; gut inflammation; in vivo; microbiota; murine colitis; new therapeutic target; reconstitution; recruit; response; therapeutic target; transcriptome sequencing

Project Summary Anti-microbial antibodies are predictive of Crohn’s disease (CD) diagnosis and are present in patients’ serum up to 5 years before diagnosis, and their accumulation is associated with complications, often requiring bowel resection surgery. In patients with CD, more bacteria translocate to the mesenteric adipose tissue (MAT) compared to controls and a subset of bacteria are exclusive to CD MAT. This coincides with the expansion of the MAT and its wrapping around the intestine, or “creeping fat”, a hallmark of inflamed CD-affected tissue, which also correlates with complications. The etiology of anti-microbial antibodies and creeping fat are unknown. Although B cells and stromal cells co-localize within fat-associated lymphoid clusters in creeping fat, and B and plasma cell signatures are among the most highly upregulated genes in creeping fat compared to healthy MAT, B cell function in this tissue is unknown. We hypothesize that the translocation of microbes to MAT prompts stromal cells in fat-associated lymphoid clusters to recruit B cells, which differentiate into protective IgM-secreting plasma cells, inhibiting systemic dissemination of bacterial antigens. Sustained CD-specific bacterial translocation to the MAT leads to chronic inflammation activating stromal cells to secrete cytokines driving IgG class-switch and differentiation to inflammatory anti-microbial IgG-secreting plasma cells. Adipocyte-derived leptin is elevated in MAT of CD patients and drives inflammation in mouse colitis models. As leptin activates B cells, we posit leptin further drives preferential class-switch to IgG. We will address this hypothesis in germfree mice reconstituted with cultured collections of bacteria isolated from CD or healthy donors, as well as in human MAT associated or not with inflamed intestine from patients with CD undergoing bowel resection surgery at Mount Sinai. In these models, we will evaluate which bacteria translocate to the MAT, how they activate stromal cells by deep characterization at the transcriptional and protein level and how they drive leptin production by adipocytes in biopsy cultures (Aim 1). Next, we will investigate direct and indirect effects of CD microbiota on MAT B cells and their shift from protective IgM to inflammatory IgG. To do so we will characterize CD microbiota- driven changes in B cell activation, proliferation, class-switching and differentiation to plasma cells. We will also determine the IgG-inducing properties of MAT and stromal cells exposed in vivo to CD or healthy donor microbiota. Finally, we will investigate how CD microbiota perturbs stromal-B cell cross-talk within fat-associated lymphoid clusters (Aim 2). By showing that MAT is able to mount microbiota-specific B cell responses, this proposal will expand the study of mucosal immunology to mucosa-associated adipose tissues. Since creeping fat and anti-microbial IgG correlate with complications in CD, these studies have the potential to uncover mechanisms underlying CD pathology and identify needed therapeutic targets.

项目总结