A growing body of evidence suggests that when B cells are chronically stimulated, a phenotypically unique subset expands. Data suggest that this atypical population contains B cell receptor (BCR) specificities capable of binding the antigen, or sets of antigens that initiated the expansion of these cells. These B cells have been given various names, including double negative B cells, atypical memory B cells, tissue-like memory B cells, or age associated B cells (ABCs). However, on close inspection these reports described B cell subsets that closely resemble B cells we refer to as CD11c B cells that often express T-bet. Here we will review the human studies that describe atypical memory B cells and compare and contrast their phenotype and suggested function in health and disease.

Toll-like receptor 7 (Tlr7) has been linked to systemic lupus disease incidence in humans and mice, but how TLR7 potentiates autoimmunity is unclear. We used a Tlr7 transgenic (tg) mouse model to investigate the cellular and molecular events required to induce spontaneous autoimmunity through increased TLR7 activity. We determined that Tlr7 exerts B-cell-intrinsic effects in promoting spontaneous germinal center (GC) and plasmablast B-cell development, and that these B-cell subsets are dependent on T-cell-derived signals through CD40L and SLAM-associated protein (SAP), but not IL-17. Antigen specificity also factored into TLR7-induced disease, as both a restricted T cell receptor (TCR) specificity and MHC haplotype H2 k/k protected Tlr7tg mice from spontaneous lymphocyte activation and autoantibody production. Inflammatory myeloid cell expansion and autoimmunity did not develop in Tlr7tgIgH −/− mice, suggesting either that spontaneous TLR7 activation does not occur in dendritic cells, or, if it does occur, cannot drive these events in the absence of B-cell aid. These data indicate that autoimmune disease in Tlr7tg mice is contingent upon B cells receiving stimulation both through innate pathways and T-cell-derived signals and suggest a codependent relationship between B cells and T cells in the development of autoimmunity.inflammation | SLE | T follicular helper cells

B cells represent an important link between the adaptive and innate immune systems, as they express both antigen-specific B cell receptors (BCRs) as well as various toll-like receptors (TLRs). Several checkpoints in B cell development ensure that self-specific cells are eliminated from the mature B cell repertoire to avoid harmful autoreactive responses. These checkpoints are controlled by BCR-mediated events, but are also influenced by TLR-dependent signals from the innate immune system. Additionally, B cell-intrinsic and extrinsic TLR signaling are critical for inflammatory events required for the clearance of microbial infections. Factors secreted by TLR-activated macrophages or dendritic cells directly influence the fate of protective and autoreactive B cells. Additionally, naïve and memory B cells respond differentially to TLR ligands, as do different B cell subsets. We review here recent literature describing intrinsic and extrinsic effects of TLR stimulation on the fate of B cells, with particular attention to autoimmune diseases.