Humoral immunodeficiency disrupts bile-acid-induced immune tolerance in the small intestine

体液免疫缺陷破坏胆汁酸诱导的小肠免疫耐受

基本信息

批准号：
10664252
负责人：
Jason L Kubinak
金额：
$ 24.65万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10664252
关键词：
Ablation Address Adoptive Transfer Amino Acids Antibodies Antibody Response B-Lymphocytes Bacteria Bile Acids Bile Acids and Salts Binding Biochemistry CD19 gene Celiac Disease Cell Maturation Cells Chronic Chronic Disease Chronic diarrhea Clinical Colon Common Variable Immunodeficiency Complication Crohn&apos s disease Defect Development Diagnosis Diarrhea Dietary Fats Disease Enzymes Flow Cytometry Heritability Homeostasis Human Humoral Immunities Hydrolase IgA Deficiency Immune Immune Tolerance Immune response Immunoglobulin A Immunoglobulin M Immunologic Deficiency Syndromes Inflammatory Intestinal Content Intravenous Immunoglobulins Lead Link Lipids Liver Malabsorption Syndromes Metabolic Metabolic Biotransformation Metabolic Diseases Metabolism Modeling Mucous Membrane Oral Patients Performance Pharmacology Phenotype Play Population Production Publishing Reaction Recurrence Refractory Research Risk Factors Role Serum Signaling Molecule Small Intestines Supplementation Techniques Testing Therapeutic Intervention Tissues Treatment Efficacy Tropical sprue Vitamins Work absorption bile acid metabolism bile salts clinically relevant commensal bacteria congenital immunodeficiency dysbiosis efficacy testing experimental study gastrointestinal gastrointestinal symptom human disease immunoregulation innovation intestinal homeostasis knock-down liquid chromatography mass spectrometry metatranscriptomics microbial colonization microbial community microbiome microbiome composition microbiota mouse model next generation sequencing novel oral supplementation programs response single-cell RNA sequencing tauroursodeoxycholic acid

项目摘要

Project Summary Humoral immunodeficiency is the most frequently diagnosed form of primary immunodeficiency in humans. Common variable immunodeficiency (CVID) is the most clinically severe form, and chronic gastrointestinal complications are both common in CVID patients and refractory to treatment by intravenous Ig therapy. A severe GI disorder is termed 'CVID enteropathy'; a small intestine (SI)-specific enteropathy that presents clinically as chronic diarrhea and malabsorption. Bile acids (BAs) are emulsifiers produced by the liver and secreted into the gut that promote the solubilization and absorption of dietary lipids and lipid-soluble vitamins. They may also serve as signaling molecules capable of inducing tolerogenic responses in tissue-resident immune cells. Mucosal antibody deficiency alters microbiota composition. Given that the microbiota profoundly influence luminal BA biochemistry, the overarching hypothesis this R01 proposal will address is that mucosal antibody- deficiency results in aberrant bacterial BA metabolism that abolishes BA-induced immunological tolerance in the SI. In this proposal, we provide evidence supporting that mucosal antibody-deficiency results in aberrant inflammatory immune responses that are associated with the development of SI enteropathy; potentially driven by elevated bacterial bile salt hydrolase (bsh) activity that causes BA malabsorption (BAM). We also identify that bsh ablation or oral BA supplementation alleviates BAM and suppresses inflammatory disease. The objective of Specific Aim #1 is to define how humoral immunity influences BA homeostasis, and how this coordinates establishment of a tolerogenic immune phenotype in the SI. Several complementary models will be utilized to address this fundamental question and will incorporate the advanced techniques of ultra-purity liquid chromatography mass spectrometry (UPLC-MS) to comprehensively characterize BA pool composition, and paired high-parameter flow cytometry and single cell RNA sequencing to characterize SI-resident immune cell phenotypes. The objective of Specific Aim #2 is to demonstrate how mucosal antibody deficiency influences the composition and BA-metabolizing capacity of the SI-resident microbial community. Several novel and complementary microbial colonization models, adoptive transfer models, and next-gen sequencing approaches will be utilized to address this. The objective of Specific Aim #3 is to test the efficacy of two candidate approaches to alleviate inflammatory SI enteropathies and involve oral BA supplementation or pharmacological knockdown of bacterial bsh activity. Innovations from this research include the first analysis of the role of humoral immunity plays in regulating BA metabolism, a comprehensive assessment of the role mucosal IgA and IgM antibody responses play in SI homeostasis, characterization of a novel mechanism by which dysbiosis drives disease, and characterization of the role bsh ablation and oral BA supplementation play in tolerogenic re-programming of SI-resident immune cells in the setting of chronic disease. Beyond, CVID, results of this work are relevant to other SI enteropathies in humans including Crohn's disease, celiac disease, and tropical sprue.

项目概要体液免疫缺陷是人类原发性免疫缺陷最常见的诊断形式。常见变异型免疫缺陷（CVID）是临床上最严重的形式，慢性胃肠道疾病并发症在 CVID 患者中很常见，并且静脉注射 Ig 疗法难以治疗。严重的胃肠道疾病被称为“CVID 肠病”；一种小肠 (SI) 特异性肠病，临床表现为慢性腹泻和吸收不良。胆汁酸 (BA) 是由肝脏产生并分泌到体内的乳化剂肠道促进膳食脂质和脂溶性维生素的溶解和吸收。他们也可能服务作为能够在组织驻留免疫细胞中诱导耐受性反应的信号分子。粘膜抗体缺乏会改变微生物群组成。鉴于微生物群深刻影响管腔 BA 生物化学，该 R01 提案将解决的首要假设是粘膜抗体- 缺乏会导致细菌 BA 代谢异常，从而消除 BA 诱导的免疫功能 SI 中的公差。在本提案中，我们提供证据支持粘膜抗体缺乏导致与 SI 肠病的发展相关的异常炎症免疫反应；可能是由于细菌胆盐水解酶 (bsh) 活性升高导致 BA 吸收不良 (BAM)。我们还发现 bsh 消融或口服 BA 补充剂可减轻 BAM 并抑制炎症疾病。具体目标 #1 的目标是定义体液免疫如何影响 BA 稳态，以及这如何协调 SI 中耐受性免疫表型的建立。多种互补型号将用于解决这一基本问题，并将结合先进的超纯技术液相色谱质谱法 (UPLC-MS) 全面表征 BA 池的组成，并配对高参数流式细胞术和单细胞 RNA 测序来表征 SI 驻留免疫细胞表型。具体目标 #2 的目的是证明粘膜抗体缺乏如何影响 SI 驻留微生物群落的组成和 BA 代谢能力。几部小说和互补微生物定植模型、过继转移模型和下一代测序方法将用于解决这个问题。具体目标#3 的目标是测试两种候选方法的有效性缓解炎症性 SI 肠病并涉及口服 BA 补充剂或药物抑制细菌 bsh 活性。这项研究的创新包括首次分析体液免疫的作用调节BA代谢，综合评估粘膜IgA和IgM抗体的作用反应在 SI 稳态中发挥作用，是生态失调驱动疾病的新机制的特征， bsh 消融和口服 BA 补充在耐受性重编程中的作用和表征慢性疾病中的 SI 驻留免疫细胞。除此之外，CVID，这项工作的结果与其他人类 SI 肠病，包括克罗恩病、乳糜泻和热带口炎性腹泻。