The Journal of immunology : official journal of the American Association of Immunologists
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Comparative Study
Protective and pathogenic roles for B cells during systemic autoimmunity in NZB/W F1 mice.
Delineating the relative contributions of B lymphocytes during the course of autoimmune disease has been difficult. Therefore, the effects of depleting all mature B cells using a potent CD20 mAb, or of depleting circulating and marginal zone B cells using a ligand-blocking CD22 mAb, were compared in NZB/W F(1) mice, a model for human systemic lupus erythematosus. Single low-dose mAb treatments depleted B cells efficiently in both NZB/W F(1) and C57BL/6 mice. ⋯ B10 cells were phenotypically similar in NZB/W F(1) and C57BL/6 mice, but were expanded significantly in young NZB/W F(1) mice. Thus, B cell depletion had significant effects on NZB/W F(1) mouse survival that were dependent on the timing of treatment initiation. Therefore, distinct B cell populations can have opposing protective and pathogenic roles during lupus progression.
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Previous findings suggest that 17beta-estradiol (estradiol) has a suppressive effect on TNF-alpha, but the mechanism by which estradiol regulates TNF-alpha expression in primary human macrophages is unknown. In this article, we demonstrate that pretreatment of human macrophages with estradiol attenuates LPS-induced TNF-alpha expression through the suppression of NF-kappaB activation. Furthermore, we show that activation of macrophages with LPS decreases the expression of kappaB-Ras2, an inhibitor of NF-kappaB signaling. ⋯ Our data suggest that pretreatment with estradiol reverses this effect. We propose a novel mechanism for estradiol inhibition of LPS-induced NF-kappaB signaling in which kappaB-Ras2 expression is induced by estradiol via regulation of let-7a and miR-125b. These findings are significant in that they are the first to demonstrate that estradiol represses NF-kappaB activation through the induction of kappaB-Ras2, a key inhibitor of NF-kappaB signaling.
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Inhibiting signal transduction induced by inflammatory cytokines offers a new approach for the treatment of autoimmune diseases such as rheumatoid arthritis. Kinase inhibitors have shown promising oral disease-modifying antirheumatic drug potential with efficacy similar to anti-TNF biologics. Direct and indirect inhibition of the JAKs, with small molecule inhibitors like CP-690,550 and INCB018424 or neutralizing Abs, such as the anti-IL6 receptor Ab tocilizumab, have demonstrated rapid and sustained improvement in clinical measures of disease, consistent with their respective preclinical experiments. ⋯ INCB028050 was also effective in multiple murine models of arthritis, with no evidence of suppression of humoral immunity or adverse hematologic effects. These data suggest that fractional inhibition of JAK1 and JAK2 is sufficient for significant activity in autoimmune disease models. Clinical evaluation of INCB028050 in RA is ongoing.