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.

Public Health Relevance

To define the role of B-cell immunity in regulating the vaginal microenvironment we will compare vaginal microbiota, cervical immune cell populations, vaginal fluid immunoglobulins and soluble markers of inflammation between women receiving rituximab (anti-CD20) therapy and healthy controls. We will collect longitudinal samples from women starting, stopping and on stable rituximab treatment to confirm the causality of identified associations.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Cellular and Molecular Immunology - B Study Section (CMIB)
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Hiltke, Thomas J
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Massachusetts General Hospital
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