TLR7/TLR9- and B Cell Receptor-Signaling Crosstalk: Promotion of Potentially Dangerous B Cells

Abstract

B cells are capable of receptor-mediated responses to foreign antigens. Recognition of microbial-derived nucleic acid (NA) by toll-like receptors (TLRs) 7 and 9 in B cells has been substantiated. Endogenous NA released from damaged or dying cells can also be immunogenic in certain contexts and can incite aberrant activation of B cells. When TLR-driven B cell receptor (BCR)-activated B cells are not properly constrained, pathologic autoantibodies are produced. It is also clear that endosomal TLR7/TLR9 can operate in conjunction with BCR. In addition to BCR signaling, a balance between TLR7 and TLR9 is pivotal in the development of B cell autoreactivity. While TLR9 is important in normal memory B cell responses through BCR, TLR9 activation has been implicated in autoantibody production. Paradoxically, TLR9 also plays known protective roles against autoimmunity by directly and indirectly inhibiting TLR7-mediated autoantibody production. Herein, we summarize literature supporting mechanisms underpinning the promotion of pathological BCR-activated B cells by TLR7 and TLR9. We focus on the literature regarding known points of TLR7/TLR9 and BCR crosstalk. Data also suggest that the degree of TLR responsiveness relies on alterations of certain intrinsic B-cell signaling molecules and is also context specific. Because allogeneic hematopoietic stem cell transplantation is a high NA and B cell-activating factor environment, we conclude that B cell studies of synergistic TLR–BCR signaling in human diseases like chronic graft-versus-host disease are warranted. Further understanding of the distinct molecular pathways mediating TLR–BCR synergy will lead to the development of therapeutic strategies in autoimmune disease states.

Cytokine‐Producing B Cells Promote Immune‐Mediated Bile Duct Injury in Murine Biliary Atresia

“…It was recently shown that TLR4 activation plays a key role in promoting the maturation of immature and transitional B cells . Recognition of nucleic acids (NAs) by TLRs 7 and 9 on B cells results in aberrant B‐cell activation, with subsequent production of proinflammatory cytokines . Potential NAs stimulating B cells in murine BA may include microbially derived NAs (i.e., RRV) or endogenous NAs from damaged bile duct epithelial cells.…”

“…(44) Recognition of nucleic acids (NAs) by TLRs 7 and 9 on B cells results in aberrant B-cell activation, with subsequent production of proinflammatory cytokines. (21,45) Potential NAs stimulating B cells in murine BA may include microbially derived NAs (i.e., RRV) or endogenous NAs from damaged bile duct epithelial cells. There is a paucity of data on the role of the B cell in innate immune activation, and this area warrants further investigation in BA.…”

B Cell Responses: Cell Interaction Dynamics and Decisions

“…Most complex antigens will engage other receptors on the B cell in addition to the BCR. The ligation of some co-receptors, such as toll-like receptors (TLRs) or complement receptors (CR2), leads to amplification and possibly qualitative modification in the BCR signal (Carroll and Isenman, 2012;Suthers and Sarantopoulos, 2017). Co-receptor engagement may also reduce the threshold of antigen needed to activate B cells.…”

Autoreactive B cells in SLE, villains or innocent bystanders?

“…9 Understanding the sequence of events that leads to the breakdown of follicular exclusion barrier provides insights into the chain of events that can lead to follicular translocation of B cells and autoantigens in SLE. [156][157][158][159][160] Secondary events of this process are twofold. 2,140,143,152 Related to this is the well-established interaction of such apoptotic cell debris with disposal mechanisms including uptake by DCs including plasmacytoid dendritic cells (pDCs), and with B-cells through their BCR antigen receptor.…”

“…20,61,78,80,81,[155][156][157] In SLE, such clearance mechanisms can lead to the localization of apoptotic cell debris in the endosome and induction of type l interferons via stimulation through the endosomal TLRs including TLR7 and TLR9. [156][157][158][159][160] Secondary events of this process are twofold. First, there is increased production of type l interferon, which is well-established as being associated with SLE.…”