II类MHC分子对于针对病原体的适当免疫应答是必需的,但也涉及自身免疫疾病和移植排斥的病理应答。先前的研究已经阐明了MHC单倍型对自身免疫性疾病的发展和严重程度的系统性贡献。在这项研究中,我们讨论了B细胞内在MHC单倍型对卵泡包涵体的影响,系统性红斑狼疮(SLE)背景下的生发中心(GC)参与和浆细胞(PC)分化。
■我们利用了564Igi小鼠模型,该模型具有来自识别细胞核成分的自反应性B细胞克隆的B细胞受体敲入,包括双链DNA(dsDNA)。该模型概括了SLE早期阶段的中心标志。我们比较了H2b/b上的564Igi杂合后代,H2b/d,或H2d/d背景。
这揭示了与H2d/d(p<0.0001)小鼠相比,H2b/b和H2b/d的脾中生发中心(GC)B细胞水平显著更高。同意这一点,抗dsDNA抗体水平在H2b/b和H2b/d高于H2d/d(p<0.0001),H2b/b也高于H2b/d(p<0.01)。具体来说,这些差异适用于来自敲入克隆和野生型(WT)克隆的自身抗体.在混合嵌合体中,564IgiH2b/b,H2b/d和H2d/d细胞在相同的环境中竞争对头,我们观察到H2b/b细胞在GC和PC区室中相对于它们在B细胞库中的代表性显著更高。与H2b/d和H2d/d细胞相比。此外,在混合嵌合体中,WTH2b/b和WTH2d/d细胞竞争包含在与表位扩散过程相关的GC中,H2b/b细胞参与程度更大,对PC隔室的贡献更强劲。最后,未成熟的WTH2b/b细胞具有较高的具有自身反应性独特型的BCR基线,并且在过渡阶段接受更严格的阴性选择。
■放在一起,我们的研究结果表明,B细胞内在MHC单倍型控制其参与多个水平的自身反应反应的能力:卵泡包涵体,GC参与,和PC输出。这些发现指出B细胞是自身免疫沉淀的主要贡献者。
MHC class II molecules are essential for appropriate immune responses against pathogens but are also implicated in pathological responses in autoimmune diseases and transplant rejection. Previous studies have shed light on the systemic contributions of MHC haplotypes to the development and severity of autoimmune diseases. In this study, we addressed the B cell intrinsic MHC haplotype impact on follicular inclusion, germinal center (GC) participation and plasma cell (PC) differentiation in the context of systemic lupus erythematosus (SLE).
We leveraged the 564Igi mouse model which harbors a B cell receptor knock-in from an autoreactive B cell clone recognizing ribonuclear components, including double-stranded DNA (dsDNA). This model recapitulates the central hallmarks of the early stages of SLE. We compared 564Igi heterozygous offspring on either H2b/b, H2b/d, or H2d/d background.
This revealed significantly higher germinal center (GC) B cell levels in the spleens of H2b/b and H2b/d as compared to H2d/d (p<0.0001) mice. In agreement with this, anti-dsDNA-antibody levels were higher in H2b/b and H2b/d than in H2d/d (p<0.0001), with H2b/b also being higher compared to H2b/d (p<0.01). Specifically, these differences held true both for autoantibodies derived from the knock-in clone and from wild-type (WT) derived clones. In mixed chimeras where 564Igi H2b/b, H2b/d and H2d/d cells competed head-to-head in the same environment, we observed a significantly higher inclusion of H2b/b cells in GC and PC compartments relative to their representation in the B cell repertoire, compared to H2b/d and H2d/d cells. Furthermore, in mixed chimeras in which WT H2b/b and WT H2d/d cells competed for inclusion in GCs associated with an epitope spreading process, H2b/b cells participated to a greater extent and contributed more robustly to the PC compartment. Finally, immature WT H2b/b cells had a higher baseline of BCRs with an autoreactive idiotype and were subject to more stringent negative selection at the transitional stage.
Taken together, our findings demonstrate that B cell intrinsic MHC haplotype governs their capacity for participation in the autoreactive response at multiple levels: follicular inclusion, GC participation, and PC output. These findings pinpoint B cells as central contributors to precipitation of autoimmunity.