Regulatory mechanisms of B cell responses and the implication in B cell-related diseases

Abstract

Terminally differentiated B cell, the plasma cell, is the sole cell type capable of producing antibodies in our body. Over the past 30 years, the identification of many key molecules controlling B cell activation and differentiation has elucidated the molecular pathways for generating antibody-producing plasma cells. Several types of regulation modulating the functions of the important key molecules in B cell activation and differentiation add other layers of complexity in shaping B cell responses following antigen exposure in the absence or presence of T cell help. Further understanding of the mechanisms contributing to the proper activation and differentiation of B cells into antibody-secreting plasma cells may enable us to develop new strategies for managing antibody humoral responses during health and disease. Herein, we reviewed the effect of different types of regulation, including transcriptional regulation, post-transcriptional regulation and epigenetic regulation, on B cell activation, and on mounting memory B cell and antibody responses. We also discussed the link between the dysregulation of the abovementioned regulatory mechanisms and B cell-related disorders.

Keywords: Antibody; Autoimmune disease; B cell; B cell malignancy; Epigenetic regulation; Plasma cell; Transcription factor; microRNA.

Fig. 1

The action of miRNAs and key transcription factors in coordinately directing plasma cell differentiation. Several factors are involved in the negative regulation of PRDM1 in mature B cells, including BCL6/BACH2/FOXP1 and the miR-101-3p, miR-125b-5p, miR-223-3p miRNA hub. During B cell activation, NF-κB induces not only PRDM1 for the initiation of plasma cell differentiation, but also the miR-34a-5p, miR-148a-3p, miR-183-5p and miR-365a-5p hub. The induced miRNA hub including miR-34a-5p, miR-148a-3p, miR-183-5p and miR-365a-5p downregulates BCL6/BACH2/FOXP1, thereby establishing elevated levels of PRDM1 for driving plasma cell differentiation. Induced PRDM1 in turn suppresses the expression of the miR-101-3p, miR-222-3p and miR-223-3p hub, and BCL6/BACH2/FOXP1, resulting in commitment to the plasma cell fate. Lines with arrow and bars indicate upregulation and downregulation, respectively. miRNAs in a red or green box represent upregulated or downregulated expression, respectively

Fig. 2

Proposed model of the role of KDM4A and KDM4C in B cell activation. During activation by Tfh cell-mimicking signals, the induced demethylases, KDM4A and KDM4C, cooperate with NF-κB to upregulate the expression of Wdr5 by removing H3K9me3/me2. WDR5, a core subunit of the COMPASS histone H3K4 methyltransferase complex, in turn facilitates the transcription of Cdkn2a and Cdkn3 by elevating H3K4me3/me2. Both CDKN2A and CDKN3 are involved in the regulation of stimulated B cell proliferation