Laboratory for Lymphocyte Biology, Department of Biomedicine, Aarhus University, Aarhus C, Denmark.
Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, CA, USA.
Nat Commun. 2023 Oct 31;14(1):6941. doi: 10.1038/s41467-023-42541-7.
Circumstantial evidence suggests that B cells may instruct T cells to break tolerance. Here, to test this hypothesis, we used a murine model in which a single B cell clone precipitates an autoreactive response resembling systemic lupus erythematosus (SLE). The initiating clone did not need to enter germinal centers to precipitate epitope spreading. Rather, it localized to extrafollicular splenic bridging channels early in the response. Autoantibody produced by the initiating clone was not sufficient to drive the autoreactive response. Subsequent epitope spreading depended on antigen presentation and was compartmentalized by major histocompatibility complex (MHC). B cells carrying two MHC haplotypes could bridge the MHC barrier between B cells that did not share MHC. Thus, B cells directly relay autoreactivity between two separate compartments of MHC-restricted T cells, leading to inclusion of distinct B cell populations in germinal centers. Our findings demonstrate that B cells initiate and propagate the autoimmune response.
间接证据表明，B 细胞可能指示 T 细胞打破耐受。在这里，为了验证这一假说，我们使用了一种小鼠模型，其中一个 B 细胞克隆引发类似于系统性红斑狼疮（SLE）的自身反应性应答。起始克隆不需要进入生发中心就可以引发表位扩展。相反，它在应答早期定位于滤泡外的脾脏桥接通道。起始克隆产生的自身抗体不足以驱动自身反应性应答。随后的表位扩展取决于抗原呈递，并受到主要组织相容性复合体（MHC）的分隔。携带两种 MHC 单倍型的 B 细胞可以在不共享 MHC 的 B 细胞之间架起 MHC 障碍的桥梁。因此，B 细胞直接在 MHC 受限的 T 细胞的两个独立隔室之间传递自身反应性，导致不同的 B 细胞群体进入生发中心。我们的研究结果表明，B 细胞启动并传播自身免疫反应。
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