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 aTlr7transgenic (tg) mouse model to investigate the cellular and molecular events required to induce spontaneous autoimmunity through increased TLR7 activity. We determined thatTlr7exerts 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/kprotectedTlr7tg mice from spontaneous lymphocyte activation and autoantibody production. Inflammatory myeloid cell expansion and autoimmunity did not develop inTlr7tgIgH^−/−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 inTlr7tg 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.

Uncontrolled secretion of type I IFN, as the result of endosomal TLR (i.e., TLR7 and TLR9) signaling in plasmacytoid DCs (pDCs), and abnormal production of autoantibodies by B cells are critical for systemic lupus erythematosus (SLE) pathogenesis. The importance of galectin-9 (Gal-9) in regulating various autoimmune diseases, including lupus, has been demonstrated. However, the precise mechanism by which Gal-9 mediates this effect remains unclear. Here, using spontaneous murine models of lupus (i.e., BXSB/MpJ and NZB/W F1 mice), we demonstrate that administration of Gal-9 results in reduced TLR7-mediated autoimmune manifestations. While investigating the mechanism underlying this phenomenon, we observed that Gal-9 inhibits the phenotypic maturation of pDCs and B cells and abrogates their ability to mount cytokine responses to TLR7/TLR9 ligands. Importantly, immunocomplex-mediated (IC-mediated) and neutrophil extracellular trap–mediated (NET-mediated) pDC activation was inhibited by Gal-9. Additionally, the mTOR/p70S6K pathway, which is recruited by both pDCs and B cells for TLR-mediated IFN secretion and autoantibody generation, respectively, was attenuated. Gal-9 was found to exert its inhibitory effect on both the cells by interacting with CD44.

IgG molecules are exposed on a regular basis to acidic conditions during immunoaffinity purification procedures, as well as during the production of some therapeutic immunoglobulin preparations. This exposure is known to induce in them an antigen‐binding polyreactivity. The molecular mechanisms and the possible biological significance of this phenomenon remain, however, poorly understood. In addition to the previously reported ability of these modified IgG antibodies to interact with a large panel of self‐antigens, enhanced binding to non‐self‐antigens (bacterial), an increased ability to engage in F(ab′)₂/F(ab′)₂(idiotype/anti‐idiotype) interactions and an increased functional antigen‐binding affinity are reported here. The newly acquired ‘induced polyreactivity’ of low‐pH buffer‐exposed IgG is related to structural changes in the immunoglobulin molecules, and is at least partly attributable to the enhanced role of the hydrophobic effect in their interactions with antigen. Our results suggest that data from many previous studies on monoclonal and polyclonal IgG antibodies purified by low‐pH buffer elution from protein A or protein G immunoaffinity columns should be reconsidered, as the procedure itself may have dramatically affected their antigen‐binding behavior and biological activity. Low‐pH buffer‐treated pooled therapeutic immunoglobulins acquire novel beneficial properties, as passive immunotherapy with the pH 4.0 buffer‐exposed, but not with the native therapeutic intravenous immunoglobulin preparation, improves the survival of mice with bacterial lipopolysaccharide‐induced septic shock.

The pathological DNA‐specific B lymphocytes in lupus are logical targets for a selected therapeutic intervention. We have hypothesized that it should be possible to suppress selectively the activity of these B cells in lupus mice by administering to them an artificial molecule that cross‐links their surface immunoglobulins with the inhibitory FcγIIb surface receptors. A hybrid molecule was constructed by coupling the DNA‐mimicking DWEYSVWLSN peptide to a monoclonal anti‐mouse FcγRIIb antibody. This chimeric antibody was added to cultured spleen cells from sick MRL/lpr mice, immunized with diphtheria toxoid, resulting in reduction of the numbers of anti‐DNA but not of anti‐diphtheria IgG antibody‐producing cells. Intravenous infusions with the DNA‐peptide antibody chimera to 7‐wk‐old animals prevented the appearance of IgG anti‐DNA antibodies and of albuminuria in the next 2 months. The administration of the DNA‐peptide chimeric antibody to 18 wk‐old mice with full‐blown disease resulted in the maintenance of a flat level of IgG anti‐DNA antibodies and in delay of the aggravation of the lupus glomerulonephritis. The use of chimeric antibodies targeting inhibitory B lymphocyte receptors represents a novel approach for the selective suppression of autoreactive disease‐associated B cells in autoimmune diseases.