Maternal B cells in health and disease.

PROJECT SUMMARY A detailed understanding of B cell and antibody responses to placental versus foreign antigen will illuminate how dysregulated responses contribute to pregnancy complications and inform the design of vaccines to best protect mothers and children from infection. Our published work and new preliminary data highlight two

checkpoints that restrain harmful B cell and antibody responses to the placenta. Checkpoint 1 involves how antigen interacts with B cells. Placental antigen is modified with sialic acid sugar-carrying glycans (sialoglycans) and activation of placental-specific B cells is suppressed in a mechanism that is at least partially

dependent upon recognition of sialoglycans by inhibitory receptors on the B cell surface. Checkpoint 2 is a fail- safe mechanism that protects the conceptus from antibody-mediated attack. This “effector phase” checkpoint is illustrated by our observation that pregnancy remains unaffected even when high titers of anti-placental

antibodies, experimentally introduced before mating, are present. Notably, both checkpoints are specific to placental antigen itself. Checkpoint 1 appears to be driven by immunosuppressive sialoglycans that coat placental antigen. For Checkpoint 2, our data and the literature support the hypothesis that anti-placental

antibodies become modified with suppressive glycans that diminish their function. Because the checkpoints are placental antigen-specific, maternal B cell responses to foreign antigen remain intact. Our data show that to foreign antigen, pregnant mice generate B cell and antibody responses commensurate with non-pregnant

mice. However, to our surprise, humoral responses during pregnancy occur seemingly independent of robust follicular helper T cells (Tfh). Since humoral immunity in non-pregnant hosts is well documented to be regulated by Tfh, discovery of a Tfh-independent mechanism that enhances humoral immunity during

pregnancy is warranted. We propose to study B cell and antibody responses to placental versus foreign antigen. Project hypothesis: Sialoglycan modification of placental antigen, suppressed effector capacity of anti- placental antibodies, and alteration in Tfh-B cell dynamics lead to protection of the conceptus while preserving

immunity to foreign antigen. We submit this application in response to RFA-AI-23-027. Aim 1. Define mechanisms of placental antigen-specific B cell suppression (Checkpoint 1). Aim 2. Characterize the non- pathogenic nature of anti-placental antibodies (Checkpoint 2). Aim 3. Evaluate maternal B cell and follicular

helper T cell dynamics in response to foreign antigen. Identifying molecular mechanisms suppressing B cell activation (Aim 1) and mapping out tolerance pathways that protect the conceptus from antibody-mediated damage (Aim 2) are the first steps in evaluating how alterations affect pregnancy outcomes. Identification of a

pregnancy factor capable of boosting humoral immunity (Aim 3) would be a significant divergence from the textbook paradigm and could become clinically useful to boost responses to vaccines and fight infections.