Recent studies have identified critical roles for B cells in triggering autoimmune germinal centers (GCs) in systemic lupus erythematosus (SLE) and other disorders. The mechanisms whereby B cells facilitate loss of T cell tolerance, however, remain incompletely defined. Activated B cells produce interleukin 6 (IL-6), a proinflammatory cytokine that promotes T follicular helper (T_FH) cell differentiation. Although B cell IL-6 production correlates with disease severity in humoral autoimmunity, whether B cell–derived IL-6 is required to trigger autoimmune GCs has not, to our knowledge, been addressed. Here, we report the unexpected finding that a lack of B cell–derived IL-6 abrogates spontaneous GC formation in mouse SLE, resulting in loss of class-switched autoantibodies and protection from systemic autoimmunity. Mechanistically, B cell IL-6 production was enhanced by IFN-γ, consistent with the critical roles for B cell–intrinsic IFN-γ receptor signals in driving autoimmune GC formation. Together, these findings identify a key mechanism whereby B cells drive autoimmunity via local IL-6 production required for T_FH differentiation and autoimmune GC formation.

最近的研究已经确定了B细胞在引发系统性红斑狼疮（SLE）和其他疾病的自身免疫生发中心（GC）中的关键作用。但是，B细胞促进T细胞耐受性丧失的机制尚不完全清楚。活化的B细胞产生白介素6（IL-6），这是一种促炎性细胞因子，可促进T卵泡辅助物（T _FH）细胞分化。尽管B细胞IL-6的产生与体液自身免疫疾病的严重程度相关，但据我们所知，是否需要B细胞衍生的IL-6触发自身免疫GC。在这里，我们报告了一个出乎意料的发现，即缺乏B细胞的IL-6消除了小鼠SLE中自发的GC形成，从而导致了类转换自身抗体的丧失和对系统自身免疫的保护。从机理上讲，IFN-γ增强了B细胞IL-6的产生，这与B细胞固有的IFN-γ受体信号在驱动自身免疫GC形成中的关键作用相一致。在一起，这些发现确定了一种关键机制，其中B细胞通过T _FH分化和自身免疫GC形成所需的局部IL-6产生来驱动自身免疫。