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.

项目摘要体液免疫缺陷是人类原发性免疫缺陷最常诊断的形式。常见的可变免疫缺陷（CVID）是临床上最严重的形式，慢性胃肠道并发症在CVID患者中既常见，也很常见，可以通过静脉注射治疗对治疗难治性。严重胃肠道被称为“ CVID肠病”；小肠（SI）特定的肠病，在临床上呈现为慢性腹泻和吸收不良。胆汁酸（BAS）是肝脏产生的乳化剂，并分泌到肠道促进饮食脂质和脂溶性维生素的溶解和吸收。他们也可以服务作为能够在组织居住的免疫细胞中诱导耐受性反应的信号分子。粘膜抗体缺乏改变微生物群的组成。鉴于微生物群会深刻影响腔体BA 生物化学，总的总体假设该R01提案将解决的是粘膜抗体 - 缺乏导致异常细菌BA代谢，从而废除了BA诱导的免疫学 Si的耐受性。在此提案中，我们提供了支持粘膜抗体缺陷结果的证据在异常的炎症免疫反应中，与SI肠病的发展有关；可能由升高的细菌胆汁盐水解酶（BSH）活性驱动，导致BA吸收不良（BAM）。我们还确定，BSH消融或口服BA补充减轻了BAM并抑制炎症疾病。特定目标＃1的目的是定义体液免疫如何影响BA体内平衡，并且这如何协调SI中的耐受性免疫表型。几种互补模型将用于解决这个基本问题，并将结合超纯度的先进技术液相色谱质谱法（UPLC-MS），以全面表征BA池组成，并配对高参数流式细胞仪和单细胞RNA测序以表征Si-enders Immune 细胞表型。特定目标＃2的目的是证明粘膜抗体缺乏症如何影响 Si-Resident微生物群落的组成和BA代谢能力。几本小说和互补的微生物定植模型，收养转移模型和下一代测序方法将用于解决这个问题。特定目标＃3的目的是测试两种候选方法的功效减轻炎症性SI肠病症并涉及口服BA补充或药理学敲低细菌BSH活性。这项研究的创新包括对体液免疫作用的首次分析在调节BA代谢方面的作用，对粘膜IgA和IgM抗体的作用进行了全面评估反应在SI稳态中发挥作用，营养不良驱动疾病的新机制的表征，以及角色的表征BSH消融和口服BA补充作用，以耐受性重新编程在慢性疾病的情况下，Si-Si-endent免疫细胞。除了CVID之外，这项工作的结果与其他人类中的其他SI肠病，包括克罗恩病，乳糜泻和热带泉水。