Protective Humoral Immunity in the CNS Requires Peripheral CD19-Dependent Germinal Center Formation Following Coronavirus Encephalomyelitis.

5 years ago

Protective Humoral Immunity in the CNS Requires Peripheral CD19-Dependent Germinal Center Formation Following Coronavirus Encephalomyelitis.

Atkinson JR, Bergmann CC

B cell subsets with phenotypes characteristic of naïve, non-isotype-switched, memory (B_mem), and antibody-secreting cells (ASC) accumulate in various models of central nervous system (CNS) inflammation, including viral encephalomyelitis. During neurotropic coronavirus JHMV infection infiltration of protective ASC occurs after T cell mediated viral control, and is preceded by accumulation of non-isotype switched IgD⁺ and IgM⁺ B cells. However, the contribution of peripheral activation events in cervical lymph nodes (CLN) in driving humoral immune responses in the infected CNS is poorly defined. CD19, a signaling component of the B cell receptor complex, is one of multiple regulators driving B cell differentiation and germinal center (GC) formation by lowering the threshold of antigen-driven activation. JHMV infected CD19^-/- mice were thus used to determine how CD19 affects CNS recruitment of B cell subsets. Early polyclonal ASC expansion, GC formation, and virus-specific ASC were all significantly impaired in CLN of CD19^-/- mice compared to wild type (wt) mice, consistent with lower and unsustained virus-specific serum Ab. ASC were also significantly reduced in the CNS resulting in increased infectious virus during persistence. Nevertheless, CD19 deficiency did not affect early CNS IgD⁺ B cell accumulation. The results support that CD19 independent factors drive early B cell mobilization and recruitment to the infected CNS, while delayed accumulation of virus-specific, isotype switched ASC requires CD19 dependent GC formation in CLN. CD19 is thus essential for both sustained serum Ab as well as protective local Ab within the CNS following JHMV encephalomyelitis.IMPORTANCE CD19 activation is known to promote GC formation and sustain serum Ab responses following antigen immunization and viral infections. However, the contribution of CD19 in the context of CNS infections has not been evaluated. This study demonstrates that antiviral protective ASC in the CNS are dependent on CD19 activation and peripheral GC formation, while accumulation of early-recruited IgD⁺ B cells is CD19-independent. This indicates that IgD⁺ B cells commonly found early in the CNS do not give rise to local ASC differentiation and that only antigen-primed, peripheral GC-derived ASC infiltrate the CNS, thereby limiting potentially harmful non-specific Ab secretion. Expanding our understanding of activation signals driving CNS migration of distinct B cell subsets during neuroinflammatory insults is critical for preventing and managing acute encephalitic infections, as well as preempting reactivation of persistent viruses during immune suppressive therapies targeting B cells in multiple sclerosis (MS), such as Rituximab and Ocrelizumab.

Publisher URL: https://www.ncbi.nlm.nih.gov/pubmed/28931676

DOI: PubMed:28931676