Schell Stephanie L, Chodisetti Sathi Babu, Fike Adam J, Choi Nicholas M, Bricker Kristen N, Rahman Ziaur S M
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033.
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033
Immunohorizons. 2019 Oct 8;3(10):463-477. doi: 10.4049/immunohorizons.1900048.
Germinal centers (GCs) are essential for the production of somatically hypermutated, class-switched Abs that are protective against infection, but they also form in the absence of purposeful immunization or infection, and are termed spontaneous GCs (Spt-GCs). Although Spt-GCs can arise in nonautoimmune-prone mice, aberrant regulation of Spt-GCs in autoimmune-prone mice is strongly associated with the development of autoimmune diseases like systemic lupus erythematosus. The formation of Spt-GCs is crucially driven by TLR7-mediated RNA sensing. However, the impact of MAVS-dependent, Rig-like receptor-mediated RNA sensing on the Spt-GC response remains unknown. In this study, we assessed the Spt-GC response and splenic B cell development in two MAVS-deficient mice with distinct genetic backgrounds. Importantly, we found that MAVS differentially controls Spt-GC responses and B cell development, depending on genetic background. B6/129 mixed background MAVSKO mice had nearly absent Spt-GC responses in the spleen and cervical lymph nodes, which were associated with impaired splenic B cell development, in addition to impaired B cell activation and TLR7 expression. Interestingly, treatment of mice with TLR7 agonist could partially rescue GC responses by overcoming follicular B cell activation deficits. Contrastingly, the absence of MAVS on a B6 background resulted in normal B cell development and Spt-GC formation. Our results highlight important differences in the contribution of MAVS to B cell development and Spt-GC function, depending on the genetic background, warranting greater regard for the impact of genetic background in further studies using these mice for the study of autoimmunity.
生发中心（GCs）对于产生体细胞高频突变、类别转换的抗体至关重要，这些抗体可抵御感染，但它们也会在没有刻意免疫或感染的情况下形成，被称为自发性生发中心（Spt-GCs）。尽管Spt-GCs可在非自身免疫易感性小鼠中出现，但自身免疫易感性小鼠中Spt-GCs的异常调节与系统性红斑狼疮等自身免疫性疾病的发展密切相关。Spt-GCs的形成关键由TLR7介导的RNA感知驱动。然而，MAVS依赖性、视黄酸诱导基因样受体介导的RNA感知对Spt-GC反应的影响仍不清楚。在本研究中，我们评估了两种具有不同遗传背景的MAVS缺陷小鼠的Spt-GC反应和脾脏B细胞发育。重要的是，我们发现MAVS根据遗传背景差异控制Spt-GC反应和B细胞发育。B6/129混合背景的MAVS敲除（MAVSKO）小鼠在脾脏和颈部淋巴结中几乎没有Spt-GC反应，这与脾脏B细胞发育受损有关，此外还伴有B细胞活化和TLR7表达受损。有趣的是，用TLR7激动剂治疗小鼠可通过克服滤泡B细胞活化缺陷部分挽救生发中心反应。相比之下，B6背景下MAVS的缺失导致B细胞发育和Spt-GC形成正常。我们的结果突出了MAVS对B细胞发育和Spt-GC功能贡献的重要差异，这取决于遗传背景，在使用这些小鼠进行自身免疫研究的进一步研究中，需要更重视遗传背景的影响。
