B cell autonomous TLR signaling and autoimmunity

Abstract

B cells play a central role in the pathogenesis of multiple autoimmune diseases and the recognition of importance of B cells in these disorders has grown dramatically in association with the remarkable success of B-cell depletion as a treatment for autoimmunity. The precise mechanisms that promote alterations in B cell tolerance remain incompletely defined. There is increasing evidence, however, that TLRs play a major role in these events. Stimulation of B cells via the TLR pathway not only leads to an increase in antibody production but also promotes additional changes including cytokine production and upregulation of activation markers increasing the effectiveness of B cells as APCs. Understanding the role of TLRs in systemic autoimmunity will not only provide insight into the disease pathogenesis but may also lead to the development of novel therapies. This article gives an overview of TLR signaling in B cells and the possible involvement of such signals in autoimmune diseases. Keywords B cells; Toll-like receptors; TLR signaling; autoimmunity Take home message• TLRs can be stimulated by exogenous and endogenous TLR ligands• Stimulation of B cells via TLRs leads to proliferation, up-regulation of co-stimulatory signals, immunoglobulin production, and cytokine secretion.• TLRs are also involved in class switching.• TLR signals can break tolerance in B cells.• Signaling via TLR7 and TLR9 seems to be predominantly involved in breaking tolerance.• TLRs are a potential target for therapeutic intervention in autoimmune diseases.

Prolonged infection byFonsecaea pedrosoiafter antigenic co-stimulation at different sites in experimental murine chromoblastomycosis

“…23 Despite the professional antigen-presenting macrophages and dendritic cells, mature B lymphocytes play a pivotal role in autoimmunity as antigen-presenting cells (APCs) as well as in cellular responses to self-antigens. 24 Furthermore, the possible presence of B cells may also be important for the host "peripheral intolerant" response to non-self-antigens.…”

Toll-like receptor signaling pathway in chronic lymphocytic leukemia: distinct gene expression profiles of potential pathogenic significance in specific subsets of patients

“…10,[18][19][20] The activation of B cells by TLR engagement may lead to a more efficient interaction with T cells and dendritic cells due to up-regulation of the co-stimulatory CD80 and MHCII molecules. 21,22 Finally, TLR-dependent signals may be implicated in the regulation of B-cell immune responses, either by inducing TLR tolerance or by subverting the mechanisms that ensure the silencing of autoreactive B cells, thus promoting autoreactivity. 23 Several TLR agonists have been used in clinical trials of CLL patients as adjuvants to improve the efficacy of chemotherapy.…”

Suppression of innate and adaptive B cell activation pathways by antibody coengagement of FcγRIIb and CD19

“…Indeed, signaling through the TLR pathway has been implicated in the pathogenesis of autoimmune diseases including RA and SLE. 31 Therefore it is crucial to examine if XmAb5871 influences TLR9-mediated signals in B cells. Our goal here was to study the effect of XmAb5871 on B cell functions mediated by the synergistic action of BCR and TLR9.…”

“…29,30 TLR9 and BCR act synergistically in human B cells, inducing enhanced proliferation, cytokine, and antibody production; thus, TLR9 plays a crucial role in breaking tolerance and developing autoimmunity. 31,32 We show here that XmAb5871 inhibits proliferation and cytokine secretion of B cells induced by TLR9 and by synergistic stimulation via both BCR and TLR9. Additionally, XmAb5871 reduced citrullinated peptide-specific IgG production by B cells of RA patients, suggesting that it has potential to suppress autoantibody production in this and other immune-mediated diseases.…”