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Objective Bruton's tyrosine kinase (BTK) plays a critical role in B cell development and function. We recently described a selective BTK inhibitor, RN486, that blocks B cell receptor (BCR) and Fcγ receptor signaling and is efficacious in animal models of arthritis. The aim of this study was to examine the potential efficacy of BTK in systemic lupus erythematosus (SLE), using an NZB × NZW mouse model of spontaneous SLE. Methods Mice received RN486 or its vehicle (administered in chow) at a final concentration of 30 mg/kg for 8 weeks, starting at 32 weeks of age. Results The administration of RN486 completely stopped disease progression, as determined by histologic and functional analyses of glomerular nephritis. The efficacy was associated with striking inhibition of B cell activation, as demonstrated by a significant reduction in CD69 expression in response to BCR crosslinking. RN486 markedly reduced the secretion of IgG anti-double-stranded DNA (anti-dsDNA) secretion, as determined by enzyme-linked immunosorbent and enzyme-linked immunospot assays. Flow cytometric analysis demonstrated depletion of CD138highB220low plasma cells in the spleen. RN486 inhibited secretion of IgG anti-dsDNA but not IgM anti-dsDNA, suggesting that pharmacologic blockade of BTK resembles the reported transgenic expression of low levels of endogenous BTK in B cells. In addition, RN486 may also impact the effector function of autoantibodies, as evidenced by a significant reduction in immune complex-mediated activation of human monocytes in vitro and down-regulation of the expression of macrophage-related and interferon-inducible genes in both the kidneys and spleens of treated mice. Conclusion Collectively, our data suggest that BTK inhibitors may simultaneously target autoantibody-producing and effector cells in SLE, thus constituting a promising therapeutic alternative for this disease. [ABSTRACT FROM AUTHOR]

Cells of hematopoietic origin express high levels of the immunoproteasome, a cytokine‐inducible proteasome variant comprising the proteolytic subunits LMP2 (β1i), MECL‐1 (β2i), and LMP7 (β5i). Targeting the immunoproteasome in pre‐clinical models of autoimmune diseases with the epoxyketone inhibitor ONX 0914 has proven to be effective. ONX 0914 was previously described as a selective LMP7 inhibitor. Here, we show that PRN1126, developed as an exclusively LMP7‐specific inhibitor, has limited effects on IL‐6 secretion, experimental colitis, and experimental autoimmune encephalomyelitis (EAE). We demonstrate that prolonged exposure of cells with ONX 0914 leads to inhibition of both LMP7 and LMP2. Co‐inhibition of LMP7 and LMP2 with PRN1126 and LMP2 inhibitors LU‐001i or ML604440 impairs MHC class I cell surface expression, IL‐6 secretion, and differentiation of naïve T helper cells to T helper 17 cells, and strongly ameliorates disease in experimental colitis and EAE. Hence, co‐inhibition of LMP2 and LMP7 appears to be synergistic and advantageous for the treatment of autoimmune diseases. Synopsis: Simultaneous targeting of the immunoproteasome subunits LMP2 and LMP7 is required for optimal therapeutic efficacy in the treatment of autoimmunity. These findings will promote the design of novel immunoproteasome inhibitors with optimal therapeutic efficacy. Simultaneously targeting the immunoproteasome subunits LMP2 and LMP7 blocks autoimmunity.Co‐inhibition of LMP2 and LMP7 is required to reduce MHC‐I surface expression, IL‐ 6 production, and Th17 differentiation.Co‐inhibition strongly ameliorates disease phenotypes of experimental colitis and EAE. Simultaneous targeting of the immunoproteasome subunits LMP2 and LMP7 is required for optimal therapeutic efficacy in the treatment of autoimmunity. These findings will promote the design of novel immunoproteasome inhibitors with optimal therapeutic efficacy. [ABSTRACT FROM AUTHOR]