Ontogenetic niche of B cells at the CNS borders in homeostasis, aging and autoimmunity

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PROJECT SUMMARY B cells have an important pathogenic role in neurological autoimmune disorders, such as multiple sclerosis (MS) and neuropsychiatric systemic lupus erythematosus (NP-SLE), one of the most disabling manifestations of SLE. The relevance of B cells in central nervous system (CNS) autoimmunity is underscored by the therapeutic efficacy of mAb-mediated B cell depletion in MS. How autoreactive B cells are generated and infiltrate the CNS remains enigmatical. The CNS is enclosed within three membranes: pia, arachnoid, and dura. Between the arachnoid and pia lies the subarachnoid space, which contains cerebrospinal fluid that harbors assorted immune cells, including B cells. During neuroinflammation, blood lymphocytes infiltrate the meninges to mount local humoral and/or cellular responses. Thus, meningeal B cells are thought to exclusively derive from the systemic circulation. However, we recently showed that in young adult mice meningeal B cells mainly derive from the bone marrow of cranial flat bones, known as calvaria, through special vascular channels. During aging, in contrast, age-associated-B cells (ABC) migrate from the periphery into the dura, where they may differentiate into Ig- secreting plasma cells. We hypothesize that meningeal B cells that derive from calvaria and differentiate locally are tolerant to CNS-Ag. By contrast, B cells that originate from the periphery and hence are not educated by the local antigenic milieu, may differentiate into autoreactive plasma cells upon CNS-Ag encounter. In Aim 1, we will investigate mechanisms of meningeal B cell tolerance to local antigens under steady-state. Preliminary data suggest that self-Ag experience during B cell development induces meningeal B cell depletion. Alongside, we will examine meningeal B cell activation upon foreign Ag encounter. Finally, we will investigate the impact of the microenvironment in dura B cell development, focusing on CXCL12 produced by dura fibroblasts. In Aim 2, we will investigate autoreactivity of meningeal B cells and plasma cells in the SWAP-70/DEF6 double knock-out (DKO) model of lupus. Preliminary data show accumulation of plasmablasts in the meninges of DKO mice. We will compare the transcriptional profiles and B cell receptor (BCR) repertoires of B cells and plasma cells from the dura and spleen to determine whether systemic B cells clones disseminate equally in lymphoid organs and meninges, or whether the CNS environment recruits specific clones that further differentiate into plasma cells. In parallel, DKO mice will be examined for behavioral alterations and CNS pathology. We will also identify the utmost expanded BCR clones in the dura of DKO mice and generate monoclonal antibodies to ascertain specificity for autoantigens. In Aim 3, we will obtain a single-cell transcriptomic profile of human dura immune cells isolated from autoptic specimens, filling a critical gap in our knowledge of human meninges. Overall, this proposal will advance our understanding of B cells in the CNS and mechanisms that promote neuroinflammation. To achieve this, we will leverage the complementary expertise of the Colonna lab, which studies neuroinflammation, and the Pernis lab, which studies autoimmunity in both humans and mouse models.