The Renal Pathogenicity of Anti-DNA Antibodies

抗双链DNA抗体不仅对系统性红斑狼疮具有高度特异性 (SLE)，但也直接参与狼疮性肾炎(LN)的发病机制，LN是一种主要疾病 显化。然而，尽管抗dsDNA抗体与肾炎之间存在明显的联系，但 抗dna抗体导致肾损害的机制尚不明确。 下定决心。LN可能是通过与抗DNA结合，在原位形成免疫复合体而启动的 核小体抗原抗体沉积于肾小球基底膜(GBM)。 或者，抗DNA抗体可能不是通过与核抗原结合而致病的，而是 而是通过与交叉反应的肾脏靶点结合。在这笔资金的最初阶段，我们发现 致病性小鼠抗DNA抗体与系膜细胞(MC)α-肌动蛋白结合，高滴度抗-α-肌动蛋白 狼疮小鼠的血清和肾洗脱液中均存在肌动蛋白抗体。此外，我们还报道了 在人类SLE血清中，与MC结合的抗α-Actinin抗体也存在高滴度，并且 与LN的存在和活动密切相关。最后，与MC结合的致病抗体 α-肌动蛋白直接调节炎性基因表达，包括细胞因子和中性粒细胞明胶酶 相关的Lipocalin(NGAL，Lipocalin)，通过Fc依赖和独立的机制。我们假设 肾脏细胞中致肾病抗体诱导的基因调控是导致肾小球疾病的重要因素 LN的发病机制--通过与细胞表面受体的结合和额外的 Toll样受体(TLR)家族的受体，血和/或尿NGAL水平可能反映 肾炎抗体对肾脏的损伤程度。我们打算继续我们的研究，以 了解抗DNA抗体对肾脏的致病性。具体来说，我们会： I)研究α-肌动蛋白的特异性在确定抗体的肾原性方面的重要性及其影响 致病抗体与α-肌动蛋白结构和功能的结合； Ii)研究肾脏细胞的直接基因调控机制，包括Fc受体和TLR 信号通路；以及 三)确定NGAL是否是肾炎抗体对肾脏细胞损伤的可靠标志 上调在SLE肾病发病机制中的作用以及血清和/或尿液水平 NGAL可作为狼疮性肾炎的生物标志物。

Antibodies to double stranded (ds) DNA are not only highly specific for systemic lupus erythematosus (SLE), but are also directly involved in the pathogenesis of lupus nephritis (LN), a major disease manifestation. However, despite the clear association between anti-dsDNA antibodies and nephritis, the mechanisms by which anti-DNA antibodies contribute to renal damage have yet to be conclusively determined. LN may be initiated by formation of immune complexes in situ, via binding of anti-DNA antibodies to nucleosomal antigens deposited on the glomerular basement membrane (GBM). Alternatively, anti-DNA antibodies may be pathogenic not by virtue of binding to nuclear antigens, but rather via binding to cross reactive renal targets. In the initial period of funding for this grant, we found that pathogenic murine anti-DNA antibodies bind to mesangial cell (MC) a-actinin, and that high titers of anti-a- actinin antibodies were present in the serum and kidney eluates of lupus mice. Furthermore, we reported that in human SLE serum anti-a-actinin antibodies that bound to MC were present in high titers as well, and were closely associated with the presence and activity of LN. Finally, pathogenic antibodies binding to MC a-actinin directly modulated inflammatory gene expression including cytokines and neutrophil gelatinase associated lipocalin (NGAL, lipocalin), via Fc-dependent and independent mechanisms. We hypothesize that gene regulation induced by nephritogenic antibodies in kidney cells is an important contributor to the pathogenesis of LN, mediated by binding to cell surface receptors and engagement of an additional receptor from the Toll-like receptor (TLR) family, and that serum and/or urinary levels of NGAL may reflect the degree of renal injury induced by nephritogenic antibodies. We propose to continue our studies to understand the renal pathogenicity of anti-DNA antibodies. Specifically we will: I) Study the importance of specificity for a-actinin in determining antibody nephritogenicity and the effects of binding by pathogenic antibodies on a-actinin structure and function; II) Investigate the mechanisms of direct gene modulation in kidney cells, including Fc receptor and TLR signaling pathways; and III) Determine if NGAL is a reliable marker for injury of kidney cells by nephritogenic antibodies, is NGAL upregulation instrumental in the pathogenesis of SLE renal disease, and whether serum and/or urine levels of NGAL may be useful as a biomarker for lupus nephritis.