Thursday, November 21, 2024
11/21/2024
Project Summary Central nervous system (CNS) inflammation as a result of viral infection, tissue injury, or autoimmunity is associated with recruitment of various B cell subsets ranging from naïve, isotype class unswitched, isotype switched memory B cells (Bmem) and antibody secreting cells (ASC). ASC have been a major focus of research due to their reactivity to autoantigens in multiple sclerosis (MS), neuromyelitis optica and Ab encephalitic diseases. However, beyond Ab secretion B cells are important modulators of immune responses by serving as antigen presenting cells, producing pro- and anti-inflammatory cytokines, and participating in formation of tertiary lymphoid structures (TLS) in non-lymphoid organs. TLS exacerbate local immune responses during chronic inflammation. Their presence in the meninges correlates with subpial cortical demyelination and disability progression in MS. An underlying feature of TLS is the activation of meningeal stromal cells, including follicular reticular cells (FRC) which provide a structural network guiding leukocyte accumulation and orchestrating CNS immune responses. Activated FRC are marked by upregulation of the mucin-type transmembrane protein PDPN, lymphoid chemokines CXCL13, CCL19 and CCL21, extracellular matrix (ECM) and integrins, such ICAM-1, which together support immune cell interactions in stromal niches. While some chronic inflammatory diseases including MS are associated with sustained activated FRC dependent TLS formation, CNS viral infection elicits transient FRC activation with no evidence for TLS despite ongoing inflammation during viral RNA persistence. Context dependent plasticity and/or heterogeneity of FRC is supported by tissue and insult specific mediators of stromal network activation and stabilization to form chronic TLS in distinct models. The mechanisms underlying transient versus chronic meningeal FRC network activation and TLS during CNS infections remain unexplored. The goal of this proposal is to define how B cell/stromal cell interactions shape adaptive antiviral immune responses during acute and persistent infection established by neurotropic coronavirus. The Specific Aims are to determine 1) the role of early CNS accumulating B cells in promoting meningeal stromal cell activation and 2) signals sustaining CNS stromal cell activation and effects on local B cell differentiation and diversity as well as control of viral persistence. We will test the hypothesis that IgD+ B cells participate in LTβR dependent FRC activation by using select blocking approaches to define mediators activating stromal cells (anti- PDPN and -CD20 treatment, LTβR blockade and cell type specific LTβ ablation) during acute infection. Aim 2 tests the hypothesis that sustaining FRC activation with distinct immune modulators during viral control retains recruited B cells in stromal niches, thereby promoting local B cell maturation. A better understanding of reciprocal FRC/B cell interactions within defined microenvironments will impact strategies to remodel FRC networks to improve antimicrobial function, while minimizing pathological consequences.
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