B cell subsets with phenotypes characteristic of naive, non-isotype-switched, memory (B_mem) cells 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) to 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 antibody (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 the notion 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 and protective local Ab within the CNS following JHMV encephalomyelitis.

IMPORTANCE CD19 activation is known to promote GC formation and to 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 nonspecific 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.

具有幼稚的，非同种型转换的记忆（B _mem）细胞和抗体分泌细胞（ASC）的表型特征的B细胞亚群在各种模型的中枢神经系统（CNS）炎症（包括病毒性脑脊髓炎）中蓄积。在嗜神经性冠状病毒JHMV感染期间，保护性ASC的浸润在T细胞介导的病毒控制后发生，并且先于非同种型转换的IgD ⁺和IgM ⁺积累B细胞。但是，在宫颈淋巴结（CLN）周围激活事件对驱动感染的CNS中的体液免疫反应的贡献尚不明确。CD19是B细胞受体复合物的信号传导成分，是通过降低抗原驱动的激活阈值来驱动B细胞分化和生发中心（GC）形成的多种调节剂之一。因此，将JHMV感染的CD19 ^-/-小鼠用于确定CD19如何影响CNS募集B细胞亚群。CD19 ^-/-的CLN均显着损害了早期的多克隆ASC扩增，GC形成和病毒特异性ASC ^。小鼠与野生型（WT）小鼠相比，与较低且未维持的病毒特异性血清抗体（Ab）一致。中枢神经系统中的ASC也显着降低，导致持续性感染性病毒增加。然而，CD19缺乏症并不影响中枢神经系统IgD ⁺ B细胞早期积累。该结果支持以下观点：CD19依赖性因子可驱动早期B细胞动员并招募至受感染的CNS，而病毒特异性，同种型转换的ASC的延迟积累需要CLN中CD19依赖性GC的形成。因此，CD19对于JHMV脑脊髓炎后中枢神经系统内持续的血清Ab和保护性局部Ab都是必不可少的。

重要信息已知在抗原免疫和病毒感染后，CD19激活可促进GC的形成并维持血清Ab应答。但是，尚未评估CD19在中枢神经系统感染中的作用。这项研究表明，中枢神经系统中的抗病毒保护性ASC依赖于CD19激活和外周血GC的形成，而早期招募的IgD ⁺ B细胞的积累与CD19无关。这表示IgD ⁺通常在中枢神经系统中较早发现的B细胞不会引起局部ASC分化，只有抗原引发的，外周GC衍生的ASC才能渗入中枢神经系统，从而限制了潜在有害的非特异性Ab分泌。扩大我们对在神经炎性损伤期间驱动中枢神经系统迁移不同B细胞亚群的激活信号的理解，对于预防和管理急性脑炎感染以及在针对多发性硬化症（MS）中针对B细胞的免疫抑制疗法中避免持久性病毒的重新激活至关重要，如利妥昔单抗和奥珠单抗。