Downregulation of select splenic genes related to B cell differentiation, in particular Blimp1, have previously been noted in the spontaneous NZB/W_F1 model with RN486 (24), indicating that the transcriptional program related to B cell terminal differentiation may not be highly controlled by IFN. essential for splenic B cell terminal differentiation, particularly the secretory Cobimetinib hemifumarate pathway, as well as renal transcriptional profiles coupled with myeloid cellCmediated pathology and glomerular plus tubulointerstitial disease in human glomerulonephritis patients. These findings reveal the mechanism through which a selective Btk inhibitor blocks murine autoimmune kidney disease, highlighting pathway activity that may translate to human SLE. Introduction Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by breakdown of immune cell tolerance, activation of autoreactive T and B cells, production of antinuclear antibodies (ANA), and deposition of immune-complexes (IC) leading to recruitment of inflammatory cells (1). Alterations in both innate and adaptive arms of the immune system promote disease progression and organ damage. COL1A1 B cells play a central role in lupus pathogenesis through the production of autoantibodies that recognize nuclear components, by generation of proinflammatory cytokines, including IL-6 and IL-10, and through T cell activation (2). Myeloid cells and DCs also contribute to the breakdown in peripheral tolerance and, thus, disease progression (3). Lupus nephritis (LN) is a common and potentially devastating manifestation of lupus that occurs in more than half of SLE patients. Renal disease in lupus is associated with significant morbidity and mortality. LN is characterized by renal IC deposition and infiltration with mononuclear phagocytes that, in humans, correlate with poor disease outcome and are associated with glomerular cytokine/chemokine production, complement activation, and extensive proteinuria (4, 5). In NZB/W_F1 SLECprone mice, direct activation of Fc receptorCbearing (FcR-bearing) myeloid cells, including monocytes/macrophages, by glomerular ICs is sufficient to initiate inflammatory responses, resulting in tissue damage (6). The autoantibody IC also activate TLRs 7 and 9 in myeloid cells and plasmacytoid DCs, leading to the secretion of IFN that amplifies Cobimetinib hemifumarate immune responses and consequently worsens disease (7, 8). IFN augments B cell abnormalities in conjunction with TLR stimulation by lowering the activation threshold of autoreactive B cells, enhancing their survival and differentiation into plasmablasts and thereby triggering an excessive germinal center (GC) response (1, 2, 9, 10). In human SLE patients, enhanced IFN stimulation, demonstrated through an IFN gene signature in blood, correlates with disease severity and higher ANA levels (11). Studies in NZB/W_F1 mice have confirmed the enhancing function of type-I IFNs in lupus pathogenesis. NZB/W_F1 mice deficient in type-I IFN receptor show prolonged survival (12), and conversely, adenovirus-mediated delivery of IFN accelerates lupus manifestations, leading to severe glomerulonephritis (5, 13, 14). Current treatments for severe SLE or LN, such as mycophenolate mofetil or cyclophosphamide (CTX), are effective at reducing mortality but fail to provide a cure, and they are accompanied by severe adverse effects via their immunosuppressive or cytotoxic properties, respectively (15, 16). The only targeted immunotherapy approved for SLE is the anti-BAFF Ab belimumab that acts by reducing naive and transitional B cells (17). However, initial clinical trials were not designed to assess the efficacy of belimumab for the treatment of LN. B cell depletion through anti-CD20 treatment has been studied in lupus, substantiating pathogenic roles of B cells, but clinical trials of anti-CD20 in SLE and LN have not supported approval (2, 9). Therefore, there is a high unmet need for targeted therapy in SLE. Because of the complexity of B cell involvement in disease pathogenesis, a drug that antagonizes more than one effector pathway would hold Cobimetinib hemifumarate great therapeutic potential for more severe disease. Brutons tyrosine kinase (Btk) is a Tec-family kinase that is expressed in most hematopoietic cells but not T cells. Btk.