Friday, May 9, 2025
5/9/2025
Maternal B cells enforce fetal tolerance - PROJECT SUMMARY TITLE: Maternal B cells enforce fetal tolerance GOALS/OBJECTIVES: The overall goal of this five-year proposal for a Mentored Clinical Scientist Research Career Development Award (K08) is for me to develop into a productive, independent academic investigator in the field of reproductive immunology. My prior training has provided me expertise regarding T cell and antibody mediated host defense. Through this proposal I will gain additional experience in B cell biology, glycoimmunology and fetal tolerance. The long-term goal of this research is to improve pregnancy outcomes, which will lead to healthier pregnancies and neonates. I graduated from the American Board of Pediatrics Accelerated Research Pathway for Residency in General, and I completed my Fellowship in Neonatal- Perinatal Medicine at Cincinnati Children’s Hospital (CCHMC). I joined the faculty of CCHMC and the University of Cincinnati as an Attending Physician and Research Assistant Professor in the Division of Neonatology. My mentor for this award, Dr. Sing Sing Way, is a physician-scientist with a longstanding track record of scientific innovation and providing exceptional training to mentees at all levels. As an internationally recognized expert in the immunology of pregnancy, microchimerism, commensalism and neonatal sepsis, Dr. Way’s work highly complements my own. My mentorship committee brings needed expertise to the areas of antigen-specific B cell responses (Dr. Justin Taylor), B cell interactions with N-linked glycans (Dr. Shiv Pillai), placental immunology (Dr. Tamara Tilburgs), transgenic lymphocytes (Dr. Koichi Araki) and maternal-fetal immunology (Dr. Hitesh Deshmukh). I am also extremely fortunate to have the unfettered support of CCHMC and the Perinatal Institute, whose combined resources are unmatched. Scientifically, this proposal focuses on deepening our understanding of mechanisms of fetal tolerance. The field currently focuses on immune suppressive CD4+ Foxp3+ regulatory T cells (Treg) as the key mediators of tolerance. This is based on observations that maternal Treg expand throughout pregnancy and are blunted in pregnancy complications associated with fetal intolerance (e.g., preeclampsia, stillbirth). However, there is growing appreciation that Treg do not work in isolation, and often require support from other cell types, including regulatory B cells (Breg). Activation of B cells is tightly regulated by the inhibitory receptor CD22, which binds to sialic acid present at the terminal position of certain glycoproteins. There remain numerous gaps in knowledge regarding the role of maternal B cells in mediating fetal tolerance, factors affecting their activation, and modification of fetal antigens. Additionally, whether these maternal B cells work independently or synergistically with maternal Treg remains to be determined. My central hypothesis is that CD22 impairs maternal B cell immune regulatory functions, preventing B cells from upholding fetal tolerance. This is based on very interesting preliminary data showing that CD22 blockade reverses pregnancy complications and fetal loss when maternal Treg are depleted or functionally impaired by infection. The aims of this proposal will establish: 1) how maternal B cell immune suppression is counter-regulated though antigen recognition and CD22, as well as 2) how maternal B cells enforce fetal tolerance through IL10-mediated inhibition of maternal T cells with fetal-specificity. The scientific rigor of this proposal is supported by numerous career development objectives that will help enable a transition to a successful independent research program. I will work closely with my mentor, Sing Sing Way, and mentoring committee to gain expertise in reproductive immunology, fetal tolerance, spectral flow cytometry, characterization of rare antigen-specific B cells, placental immunology, glycobiology and genetic manipulation of antigen-specific B cells. Coursework, seminars, scientific confer
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