Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
Proc Natl Acad Sci U S A. 2020 Oct 6;117(40):24957-24963. doi: 10.1073/pnas.2015372117. Epub 2020 Sep 22.
B lymphocytes acquire self-reactivity as an unavoidable byproduct of antibody gene diversification in the bone marrow and in germinal centers (GCs). Autoreactive B cells emerging from the bone marrow are silenced in a series of well-defined checkpoints, but less is known about how self-reactivity that develops by somatic mutation in GCs is controlled. Here, we report the existence of an apoptosis-dependent tolerance checkpoint in post-GC B cells. Whereas defective GC B cell apoptosis has no measurable effect on autoantibody development, disruption of post-GC apoptosis results in accumulation of autoreactive memory B cells and plasma cells, antinuclear antibody production, and autoimmunity. The data presented shed light on mechanisms that regulate immune tolerance and the development of autoantibodies.
B 淋巴细胞在骨髓和生发中心（GC）中通过抗体基因多样化获得自身反应性，这是不可避免的副产物。从骨髓中出现的自身反应性 B 细胞在一系列明确的检查点中被沉默，但对于 GC 中体细胞突变产生的自身反应性如何受到控制知之甚少。在这里，我们报告了 GC 后 B 细胞中存在凋亡依赖性耐受检查点。虽然 GC B 细胞凋亡缺陷对自身抗体的产生没有可测量的影响，但 GC 后凋亡的破坏导致自身反应性记忆 B 细胞和浆细胞的积累、抗核抗体的产生和自身免疫。所提出的数据阐明了调节免疫耐受和自身抗体产生的机制。
