Abstract
BackgroundSystemic lupus erythematosus (SLE) is associated with B cell hyperactivity, and lupus nephritis (LN), in particular, is promoted by the production of autoantibodies and immune complex deposition. Bruton’s tyrosine kinase (BTK) plays critical roles in B cell receptor-related and Fc receptor-related signaling. We aimed to investigate the impact of therapeutic intervention with HM71224 (LY3337641), a selective BTK inhibitor, on the development of murine SLE-like disease features.MethodsWe examined the therapeutic effects of HM71224 on SLE-like disease features in MRL/lpr and NZB/W F1 mice. The disease-related skin lesion was macroscopically observed in MRL/lpr mice, and the impact on splenomegaly and lymphadenopathy was determined by the weight of the spleen and cervical lymph node. The renal function was evaluated by measuring blood urea nitrogen, serum creatinine, and urine protein, and the renal damage was assessed by histopathological grading. Survival rate was observed during the administration period. The impact of B cell inhibition was investigated in splenocytes from both mice using flow cytometry. Autoantibody was measured in serum by ELISA.ResultsHM71224 effectively suppressed splenic B220+GL7+, B220+CD138+, and B220+CD69+ B cell counts, and anti-dsDNA IgG and reduced splenomegaly and lymph node enlargement. The compound also prevented skin lesions caused by lupus development, ameliorated renal inflammation and damage with increased blood urea nitrogen and creatinine, and decreased proteinuria. Furthermore, HM71224 also decreased mortality from lupus development in both mouse models.ConclusionOur results indicate that inhibition of BTK by HM71224 effectively reduced B cell hyperactivity and significantly attenuated the development of SLE and LN in rodent SLE models.
Highlights
Systemic lupus erythematosus (SLE) is associated with B cell hyperactivity, and lupus nephritis (LN), in particular, is promoted by the production of autoantibodies and immune complex deposition
550 Dongtangiheung-Ro, Hwaseong-Si, Gyeonggi-Do 18469, Republic of Korea 1Host Defense Modulation Lab, College of Pharmacy, Chung-Ang University, 84 Heukseok-Ro, Dongjak-Gu, Seoul 06974, Republic of Korea (BCR) signaling that can lead to autoimmunity including autoantigen presentation to activate T cells and proinflammatory signaling by cytokines secretion and complement activation have been implicated in pathogenesis of SLE and LN [5, 6]
HM71224 regulates B cell receptor (BCR) signaling in B cells and FcγR signaling in monocytes To characterize the inhibitory effect of HM71224 on the BCR signaling pathway, the activation of Bruton’s tyrosine kinase (BTK) and PLCγ2, the physiological substrate of BTK, following stimulation with anti-Immunoglobulin M (IgM) was examined in human Ramos B lymphoma cells
Summary
Systemic lupus erythematosus (SLE) is associated with B cell hyperactivity, and lupus nephritis (LN), in particular, is promoted by the production of autoantibodies and immune complex deposition. Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease [1, 2], and lupus nephritis (LN) is one of the most severe SLE-associated organ complications [3, 4]. The etiology of SLE has been still unclear, abnormalities of genetic variants, that of molecular pathways, and dysregulation of several immune cells have been previously reported as disease pathogenesis in SLE. Several pathogenic autoantibodies secreted by abnormalities of B cells play crucial roles in pathogenesis of SLE. Given the crucial role of B cells in SLE pathogenesis, they have emerged as promising new targets for SLE and LN treatment in the last decade. Clinical trials of several B celltargeted biological treatments, such as the anti-CD20 antibody rituximab [10,11,12], B cell-activating factor
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