Epigenetic regulation in B-cell maturation and its dysregulation in autoimmunity

Abstract

B cells have a critical role in the initiation and acceleration of autoimmune diseases, especially those mediated by autoantibodies. In the peripheral lymphoid system, mature B cells are activated by self or/and foreign antigens and signals from helper T cells for differentiating into either memory B cells or antibody-producing plasma cells. Accumulating evidence has shown that epigenetic regulations modulate somatic hypermutation and class switch DNA recombination during B-cell activation and differentiation. Any abnormalities in these complex regulatory processes may contribute to aberrant antibody production, resulting in autoimmune pathogenesis such as systemic lupus erythematosus. Newly generated knowledge from advanced modern technologies such as next-generation sequencing, single-cell sequencing and DNA methylation sequencing has enabled us to better understand B-cell biology and its role in autoimmune development. Thus this review aims to summarize current research progress in epigenetic modifications contributing to B-cell activation and differentiation, especially under autoimmune conditions such as lupus, rheumatoid arthritis and type 1 diabetes.

Identifying novel B-cell targets for chronic inflammatory autoimmune disease by screening of chemical probes in a patient-derived cell assay

“…In this study, we intestigate the potential of novel chemical probes targeting epigenetic regualtors and thereby identify novel druggable tagets with the potential to modulate B-cell functionality also in B cells from autoimmune patients that may otherwise be more resistant to modulation. The differentiation of mature B cells into antibodysecreting cells occurs through genetic reprogramming [14] involving epigenetic mechanisms shown to be dysregulated in autoimmunity [15]. An abnormal DNA methylation status of SLE B cells points toward the opportunity to target epigenetic regulation for novel therapeutic approaches [16,17].…”

Epigenetic suppression of SLFN11 in germinal center B cells in the process of the dynamic expression change during B-cell development

“…As epigenetic modifications are profoundly involved in the GCB-specific gene regulation [39][40][41], we hypothesized that the expression of SLFN11 gene is also epigenetically downregulated in GCBs, like many other genes that are specifically repressed in GCBs. To explore the regulatory mechanisms of SLFN11 gene expression in GCBs, we selected two epigenetic modifiers, an EZH2 inhibitor tazemetostat (EPZ6438) and a histone deacetylase (HDAC) inhibitor panobinostat (LBH589), both of which have been reported to upregulate the expression of genes that are specifically suppressed in GCBs [42,43].…”

The development of rheumatology at the stage of formation of a new technological paradigm

“…Важное направление исследований с позиций ПМ представляет эпигеномика. Так, накопленные данные свидетельствуют о значении эпигенетической дисрегуляции (включая гипометилирование ДНК, ацетилирование гистонов, некодирующие РНК) в патогенезе РА, СКВ и других ИВРЗ [33][34][35].…”