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.

项目摘要 阴道微生物组在生殖健康结果中起着重要作用，影响着女性的机会 怀孕植入，流产，低出生体重，早产，和获得性传播疾病 感染.虽然许多研究表明，女性生殖道（FGT）微生物群的变化 粘膜免疫环境的变化，很少有研究探索了替代的可能性： 宿主粘膜免疫力的变化决定了阴道微生物群落的组成。我们有 描述了一种使用利妥昔单抗（一种抗CD20抗体）治疗的女性乳杆菌缺陷性炎症性阴道炎， 抗体导致全身性B细胞耗竭。这一观察使我们假设B细胞和 阴道液抗体调节阴道微生物群的组成，控制 致病菌如E.大肠杆菌和B群链球菌，促进乳酸杆菌优势。 尽管已经描述了肠道中B细胞、抗体和微生物群之间的联系，但这是一个不确定因素。 女性生殖道中未被探索的区域。我们提出的项目在探索B细胞的作用和 和抗体调节阴道微生物群，而且在使用临床利妥昔单抗治疗作为体内 实验模型这项探索性资助有可能确定高度重要的生物学机制， FGT微生物群和粘膜炎症的调节，两者都与不良生殖 健康成果。为了验证我们的假设，我们提出了一项观察性研究， 利妥昔单抗与健康对照组比较，以确定B细胞在确定阴道微生物群组成中的作用。 在目标1中，我们将比较阴道微生物群、宫颈免疫细胞、阴道液免疫球蛋白和阴道分泌物免疫球蛋白。 用利妥昔单抗治疗的40名妇女与40名健康对照之间的可溶性炎症标志物。我们将 我还比较了用利妥昔单抗治疗的炎症性阴道炎妇女和 没有.在目标2中，我们将通过比较我们的 在1）开始、2）停止和3）稳定接受利妥昔单抗治疗的女性中随时间推移测量的分析物 （每组n = 10）。我们对免疫细胞群和可溶性标记物的局部阴道测量将是 与B细胞数量和IgG水平的系统测量相比。使用利妥昔单抗治疗作为 体内实验模型将提供一个新的机会，检查系统免疫的作用，在调节 阴道微生物群和粘膜免疫反应，这将导致更广泛的理解，阴道和粘膜的免疫反应。 和全身粘膜免疫。