B Cell Activation and Escape of Tolerance Checkpoints: Recent Insights from Studying Autoreactive B Cells

Abstract

Autoreactive B cells are key drivers of pathogenic processes in autoimmune diseases by the production of autoantibodies, secretion of cytokines, and presentation of autoantigens to T cells. However, the mechanisms that underlie the development of autoreactive B cells are not well understood. Here, we review recent studies leveraging novel techniques to identify and characterize (auto)antigen-specific B cells. The insights gained from such studies pertaining to the mechanisms involved in the escape of tolerance checkpoints and the activation of autoreactive B cells are discussed. In addition, we briefly highlight potential therapeutic strategies to target and eliminate autoreactive B cells in autoimmune diseases.

Keywords: B cells; autoimmune diseases; autoreactive B cells; tolerance.

Figure 1

Elimination of autoreactive B cells by central tolerance mechanisms. The development of immature B cells from hematopoietic stem cells is accompanied by the generation of autoreactivity as the result of random variable (V), diversity (D), and joining (J) recombination. In the bone marrow, a significant proportion of autoreactive immature B cells is reduced at the central tolerance checkpoint. Central tolerance mechanisms include clonal deletion, anergy, and receptor editing. Central tolerance mechanisms are induced dependent on the binding strength between the BCR of immature B cells and self-antigens present in the bone marrow. Immature B cells that have escaped central tolerance mechanisms migrate into the periphery as transitional B cells. Figure was created with BioRender.

Figure 2

Elimination of autoreactive B cells by peripheral tolerance mechanisms at various checkpoints. (A) Maturation of transitional B cells takes place in the spleen. Transitional B cells that strongly bind self-antigens present in the spleen undergo clonal deletion or anergy, which reduces the frequency of autoreactive B cells. The transitional B cells that moderately bind self-antigens mature into naive B cells. Naive B cells predominantly encounter antigens within lymph nodes and the spleen. Activation of naive B cells is dependent on the binding of antigens and interaction with CD4⁺ T helper (T_H) cells with the same antigen specificity in which B cells receive costimulatory signals. Naive B cells that do not have interaction with T_H cells undergo clonal deletion or anergy, which further reduces the frequency of autoreactive B cells. (B) Activated B cells enter germinal centers within lymph nodes and the spleen, undergo somatic hypermution (SHM) and isotype switching, and ultimately mature into memory B cells and long-lived plasma cells. These maturation processes are dependent on costimulatory signals from CD4⁺ follicular T helper (T_FH) cells with the same antigen specificity. Clonal deletion is induced in B cells that do not receive costimulatory signals from T_FH cells, resulting in the removal of autoreactive B cells from the B cell pool. Figure was created with BioRender.

Figure 3

Overview of potential therapeutic approaches for targeting autoreactive B cells. Stimulatory and inhibitory checkpoints of B cells such as CD40, Toll-like receptors (TLRs), B cell-activating factor receptor (BAFFR), programmed cell death 1 (PD1), low-affinity immunoglobulin-γ Fc region receptor IIb (FcγRIIb), and CD22; Bruton’s tyrosine kinase (BTK); glycosylation patterns of the variable (Fab) region of the B cell receptor (BCR); targets based on the unique gene expression profiles of autoreactive B cells compared to autologous non-autoreactive B cells; and the autoantigen-specific BCR of autoreactive B cells. Figure was created with BioRender.