Rabbit Anti-Mouse CD40 Polyclonal antibody

B lymphocyte hyperactivity plays a pathogenic role in systemic lupus erythematosus (SLE), and spliced X box-binding protein 1 (XBP1s) has been implicated in B cell maturation and differentiation. We hypothesized that blockade of the XBP1s pathway inhibits the B cell hyperactivity underlying SLE, and lupus nephritis (LN) development. In the present study, we systematically evaluated the changes in B cell activation induced by the Xbp1 splicing inhibitor STF083010 in a pristane-induced lupus mouse model. The lupus mouse model was successfully established, as indicated by the presence of LN with markedly increased urine protein levels, renal deposition of Ig, and mesangial cell proliferation. In lupus mice, B cell hyperactivity was confirmed by increased CD40 and B cell-activating factor levels. B cell activation and plasma cell overproduction were determined by increases in CD40-positive and CD138-positive cells in the spleens of lupus mice by flow cytometry and further confirmed by CD45R and Ig light chain staining in the splenic tissues of lupus mice. mRNA and protein expression of XBP1s in B cells was assessed by real-time PCR, Western blot analysis, and immunofluorescence analysis and was increased in lupus mice. In addition, almost all changes were reversed by STF083010 treatment. However, the expression of XBP1s in the kidneys did not change when mice were exposed to pristane and STF083010. Taken together, these findings suggest that expression of XBP1s in B cells plays key roles in SLE and LN development. Blockade of the XBP1s pathway may be a potential strategy for SLE and LN treatment.

IgG4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory disorder that results from massive expansion of polyclonal IgG4-switched B and/or plasma cells. It can virtually affect all organs and its diagnosis relies on clinical, serological and histopathological criteria. The role of autoimmunity and adaptive immune system in IgG4-RD is reflected in plasmablast differentiation, germinal center formation and IgG4 production induced by CD4+ cells expressing CD40 ligand. IgG4-RD has been considered to be a Th2/Treg-driven disorder, but follicular helper T cells are important in driving the IgG subclass switch. Prompt clinical responses to rituximab, human leukocyte antigen (HLA) associations and the presence of autoantibodies also point to the importance of adaptive immune system. However, innate immunity may induce storiform fibrosis through T-cell independent responses as a consequence of toll-like receptors activation by microbe-and damage-associated molecular patterns, while macrophages and basophils also appear to have a significant role in IgG4-RD pathogenesis. Allergic mechanisms may drive IgG4-RD, but only a subgroup has elevated IgE serum levels and peripheral eosinophilia. Finally, the 2012 revised Chapel Hill Consensus Conference nomenclature pointed IgG4-RD as a cause of large-vessel vasculitis. This review aims to discuss how to place IgG4-RD in the spectrum of immune-mediated and rheumatologic disorders.