Aberrant B Cell Signaling in Autoimmune Diseases

Abstract

Aberrant B cell signaling plays a critical in role in various systemic and organ-specific autoimmune diseases. This is supported by genetic evidence by many functional studies in B cells from patients or specific animal models and by the observed efficacy of small-molecule inhibitors. In this review, we first discuss key signal transduction pathways downstream of the B cell receptor (BCR) that ensure that autoreactive B cells are removed from the repertoire or functionally silenced. We provide an overview of aberrant BCR signaling that is associated with inappropriate B cell repertoire selection and activation or survival of peripheral B cell populations and plasma cells, finally leading to autoantibody formation. Next to BCR signaling, abnormalities in other signal transduction pathways have been implicated in autoimmune disease. These include reduced activity of several phosphates that are downstream of co-inhibitory receptors on B cells and increased levels of BAFF and APRIL, which support survival of B cells and plasma cells. Importantly, pathogenic synergy of the BCR and Toll-like receptors (TLR), which can be activated by endogenous ligands, such as self-nucleic acids, has been shown to enhance autoimmunity. Finally, we will briefly discuss therapeutic strategies for autoimmune disease based on interfering with signal transduction in B cells.

Keywords: B cell; B cell receptor; Toll-like receptor; autoimmunity; kinase; receptor; signal transduction; tolerance.

Figure 1

B cell selection is controlled by B cell receptor signals at several points during B cell development and activation. At several checkpoints during B cell development in the bone marrow (central tolerance) and B cell maturation and activation in the periphery (peripheral tolerance), autoreactive B cells can escape negative selection that is dependent on B cell receptor (BCR) signals. (A) (1) A functional pre-BCR will result in a positive selection and proliferation, whereas strong binding of self-antigens by the pre-BCR may induce apoptosis. At this stage, defective selection can result in the survival of B cells bearing a self-reactive BCR. (2) At the immature B cell stage, expression of a fully functional BCR, amongst other factors, results in the survival and positive selection of the B cell. However, expression of an autoreactive BCR should lead to either receptor editing or apoptosis. Defective selection at this stage can result in the escape of autoreactive B cells. (B) (3, 4) Transitional B cells emerging from the bone marrow are subject to the induction of apoptosis or anergy, when they recognize self-antigen. If defective, autoreactive B cells escape apoptosis or will not be constrained by anergy. (5) Germinal center B cells can undergo several rounds of selection and proliferation. During this process, somatic hypermutation generally increases affinity towards the antigen but can also generate B cells with self-reactive BCRs. Normally, such B cells undergo apoptosis, because essential survival signals, particularly those derived from activated T cells, are lacking. By contrast, in autoimmune disease, signals from the BCR may drive survival and differentiation of autoreactive B cells. (6) Various autoimmune diseases show an expansion of age-associated B cells that can be activated by TLR signaling and are prone to autoreactivity. See text for details. ABC: age-associated B cell; GC: germinal center; ASC: antibody secreting cell; MZ: marginal zone; Tfh: follicular T helper cell; Tfr: follicular regulatory T cell.

Figure 2

Signaling molecules downstream of the B cell receptor that are associated with autoimmunity. The signaling pathway downstream of the B cell receptor (BCR) contains signaling molecules that are partially shared with other pathways. In particular, the BAFF receptor provides essential survival signals and the CD19 co-receptor, which is intimately connected to the BCR. Inhibitory signals are provided by the kinase CSK and various phosphatases, including SHIP-1 and SHP-1, the activity of which is induced by Siglec-10, FcγRIIb, and CD22 surface receptors, as well as PTEN and PTPN22. Highlighted signaling molecules have been linked to an increased risk in the development of autoimmune disease (yellow), have crucial inhibitory function in BCR signaling by preventing autoimmunity (orange), or show increased expression and/or activity in B cells from autoimmune disease patients (red). Signaling molecule abbreviations are explained in the text.

Figure 3

The vicious cycle of autoreactive B cell activation and the interplay between BCR and TLR signaling. (A) 1, A viral infection induces inflammation and cellular apoptosis and necrosis. This can lead to the accumulation of debris, containing autoantigens and nucleic acids. 2, Plasmacytoid dendritic cells (pDCs) are activated during viral infections via Toll-like receptors (TLR) and produce vast amounts of interferon-α (IFN-α). 3, IFN-α stimulates autoreactive B cells via the IRFα receptor, causing upregulation of TLR7 expression. Meanwhile, the B cell is activated via the B cell receptor (BCR) by self-antigen and internalizes the antigen. 4, The autophagosome, containing self-antigen bound to the BCR, and the endosome, containing TLRs, fuse. Self-antigens, containing TLR ligands, stimulate both BCR and TLR in a synergistic manner. 5, Autoreactive B cells proliferate and differentiate into antibody-secreting cells (ASC). These produce high numbers of autoreactive antibodies. 6, Autoreactive antibodies recognizing self-antigen form immune complexes (IC). In turn, these can promote inflammation at the site of deposition and stimulate pDCs via fragment crystallizable region γ receptor (FcγR) to increase IFN-α production, completing the cycle. (B) Synergy of BCR and TLR signaling pathways leading to the activation of autoreactive B cells. Signaling molecule abbreviations are explained in the text.