Peripheral Germinal Centers Regulate Virus-specific B Cell Accumulation in the CNS

Résumé du livre

Multiple B cell subsets with phenotypes characteristic of naive, non-isotype-switched, memory (Bmem), and antibody-secreting cells (ASC), accumulate in various models of central nervous system (CNS) inflammation. However, how peripheral activation events, including germinal center (GC) formation, contribute to the dynamics of humoral immune responses in the inflamed CNS is poorly delineated. To address the role of GC formation in driving CNS humoral responses we are using a well-established model of mouse hepatitis virus (MHV) encephalomyelitis. Following MHV-induced CNS infection, T and B cell responses are initiated in cervical lymph nodes and local CNS antibody (Ab) production is crucial for control of viral persistence following initial T cell-mediated immune control. Our overall hypothesis is that antigen (Ag)-driven, peripheral GC formation is critical for development of Ag-specific B cells, as well as accumulation and maintenance in the inflamed CNS following MHV-induced encephalomyelitis. The findings of this thesis strongly support that GC reactions are critical for imprinting migration of virus-specific B cells, particularly ASC, to the CNS. They further imply that accumulation of ASC and Bmem is differentially regulated, with early GC reactions supporting preferential Bmem egress and accumulation in the CNS, and late GC reactions preferentially mediating ASC migration to the CNS during viral persistence. Our studies also do not provide any evidence for local de novo synthesis of Ag-specific B cells in the CNS, or local conversion of Bmem to ASC. Moreover, the results demonstrate that the survival factor APRIL, which maintains long-lived ASC in the bone marrow, is also important in maintaining virus-specific ASC in the CNS during MHV infection.