Effect of B-cell depletion on vaginal microbiota and mucosal immunity

B 细胞耗竭对阴道微生物群和粘膜免疫的影响

• 批准号: 10374759
• 负责人: Caroline M Mitchell
• 金额: $ 25.2万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-19 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10374759
• 关键词: Age; Animals; Antibodies; Area; Atopobium vaginae; Autoantibodies; Autoimmune Diseases; B-Lymphocytes; Bacteria; Binding; Biological; Biology; Caring; Cell Count; Cells; Cervical; Clinical; Communities; Data; Diagnosis; Drops; Enrollment; Environment; Epithelial Cells; Epitopes; Escherichia coli; Etiology; Experimental Models; Female genitalia; Gardnerella vaginalis; Grant; Homeostasis; Human; Immune; Immunity; Immunoglobulin A; Immunoglobulin G; Immunoglobulin-Secreting Cells; Immunoglobulins; Immunologic Markers; Infection Control; Inflammation; Inflammatory; Intravenous Immunoglobulins; Knowledge; Lactobacillus; Lead; Low Birth Weight Infant; MS4A1 gene; Measurement; Measures; Monoclonal Antibodies; Morbidity - disease rate; Mucosal Immune Responses; Mucosal Immunity; Mucositis; Mucous Membrane; Mus; Observational Study; Outcome; Pain; Plasma Cells; Play; Population; Pregnancy; Premature Birth; Regulation; Reproductive Health; Risk; Role; Sampling; Secretory Immunoglobulin A; Sexually Transmitted Diseases; Spontaneous abortion; Streptococcus; Streptococcus Group B; Surface; Symptoms; Testing; Time; Vagina; Vaginal Discharge; Vaginitis; Woman; anti-CD20; chemokine; cohort; cytokine; density; design; dysbiosis; experience; experimental study; gut microbiota; high risk; host-microbe interactions; immunoregulation; implantation; in vivo; ineffective therapies; inflammatory marker; microbial community; microbiome; microbiota; novel; novel strategies; pathobiont; reproductive outcome; reproductive tract; restoration; rituximab; tositumomab; vaginal fluid; vaginal lactobacilli; vaginal microbiome; vaginal microbiota; vaginal mucosa

PROJECT SUMMARY The vaginal microbiome plays a significant role in reproductive health outcomes, influencing a woman’s chances of pregnancy implantation, miscarriage, low birth weight, preterm delivery, and acquisition of sexually transmitted infections. While many studies have shown that changes in the female genital tract (FGT) microbiota drive changes in the mucosal immune environment, there are few studies that have explored the alternate possibility: that changes in host mucosal immunity determine the composition of the vaginal microbial community. We have described a Lactobacillus-deficient, inflammatory vaginitis in women treated with rituximab, an anti-CD20 antibody which leads to systemic B-cell depletion. This observation led us to hypothesize that B-cells and vaginal fluid antibodies regulate the composition of the vaginal microbiota, controlling levels of pathobionts such as E. coli and Group B streptococcus and facilitating Lactobacillus dominance. Although associations between B-cells, antibodies and microbiota have been described in the gut, this is an unexplored area in the female genital tract. Our proposed project is novel in both exploring the role of B-cells and antibodies in regulation of vaginal microbiota, but also in using clinical rituximab treatment as an in vivo experimental model. This exploratory grant has potential to identify highly significant biologic mechanisms for regulation of FGT microbiota and mucosal inflammation, both of which are associated with adverse reproductive health outcomes. To test our hypothesis, we propose an observational study comparing women treated with rituximab to healthy controls to identify the role of B-cells in determining the composition of the vaginal microbiota. In Aim 1 we will compare the vaginal microbiota, cervical immune cells, vaginal fluid immunoglobulins and soluble markers of inflammation between 40 women being treated with rituximab to 40 healthy controls. We will also compare these markers between women being treated with rituximab with inflammatory vaginitis and those without. In Aim 2, we will assess the causal relationship with B-cell depletion by comparing changes in our measured analytes over time in women who are 1) starting, 2) stopping and 3) stable on treatment with rituximab (n = 10 in each group). Our local vaginal measurements of immune cell populations and soluble markers will be compared with systemic measurements of B-cell numbers and IgG levels. Using rituximab treatment as an in vivo experimental model will provide a novel opportunity to examine the role of systemic immunity in regulating the vaginal microbiota and mucosal immune responses, which will lead to broader understanding of both vaginal and systemic mucosal immunity.

项目总结