Department of Microbiology, Immunology & Molecular Genetics, University of Texas Long School of Medicine, UT Health Science Center, San Antonio, TX 78229, USA.
Department of Microbiology, Immunology & Molecular Genetics, University of Texas Long School of Medicine, UT Health Science Center, San Antonio, TX 78229, USA.
Curr Opin Immunol. 2020 Dec;67:75-86. doi: 10.1016/j.coi.2020.09.004. Epub 2020 Nov 8.
B cell differentiation driven by microbial antigens leads to production of anti-microbial antibodies, such as those neutralizing viruses, bacteria or bacterial toxin, that are class-switched (IgG and IgA) and somatically hypermutated (maturation of the antibody response) as well as secreted in large volume by plasma cells. Similar features characterize pathogenic antibodies to self-antigens in autoimmunity, reflecting the critical role of class switch DNA recombination (CSR), somatic hypermutation (SHM) and plasma cell differentiation in the generation of antibodies to not only foreign antigens but also self-antigens (autoantibodies). Central to CSR/SHM and plasma cell differentiation are AID, a potent DNA cytidine deaminase encoded by Aicda, and Blimp-1, a transcription factor encoded by Prdm1. B cell-intrinsic expression of Aicda and Prdm1 is regulated by epigenetic elements and processes, including DNA methylation, histone post-translational modifications and non-coding RNAs, particularly miRNAs. Here, we will discuss: B cell-intrinsic epigenetic processes that regulate antibody and autoantibody responses; how epigenetic dysregulation alters CSR/SHM and plasma cell differentiation, thereby leading to autoantibody responses, as in systemic lupus; and, how these can be modulated by nutrients, metabolites, and hormones through changes in B cell-intrinsic epigenetic mechanisms, which can provide therapeutic targets in autoimmunity.
B 细胞在微生物抗原的驱动下分化，导致产生抗微生物抗体，如中和病毒、细菌或细菌毒素的抗体，这些抗体发生类别转换（IgG 和 IgA）和体细胞高频突变（抗体反应的成熟），并由浆细胞大量分泌。自身免疫中针对自身抗原的致病性抗体也具有类似特征，反映了类别转换 DNA 重组（CSR）、体细胞高频突变（SHM）和浆细胞分化在产生不仅针对外来抗原，而且针对自身抗原（自身抗体）的抗体中的关键作用。CSR/SHM 和浆细胞分化的核心是 AID，它是由 Aicda 编码的一种有效的 DNA 胞嘧啶脱氨酶，以及由 Prdm1 编码的转录因子 Blimp-1。Aicda 和 Prdm1 的 B 细胞内在表达受表观遗传元件和过程的调节，包括 DNA 甲基化、组蛋白翻译后修饰和非编码 RNA，特别是 microRNA。在这里，我们将讨论：调节抗体和自身抗体反应的 B 细胞内在表观遗传过程；表观遗传失调如何改变 CSR/SHM 和浆细胞分化，从而导致自身抗体反应，如系统性红斑狼疮；以及这些如何通过改变 B 细胞内在的表观遗传机制来被营养物质、代谢物和激素调节，从而为自身免疫提供治疗靶点。
