The Renal Pathogenicity of anti-DNA Antibodies

描述（由申请人提供）：双链DNA抗体不仅对系统性红斑狼疮（SLE）具有高度特异性，而且直接参与狼疮肾炎（LN）的发病机制，狼疮肾炎是一种主要的疾病表现。然而，尽管抗dsdna抗体与肾炎之间存在明确的关联，但抗dna抗体导致肾损害的机制尚未得到最终确定。LN可能由原位形成的免疫复合物引发，通过抗dna抗体结合沉积在肾小球基底膜（GBM）上的核小体抗原。另外，抗dna抗体可能不是通过与核抗原结合而致病，而是通过与交叉反应性肾靶点结合而致病。在这项资助的初始阶段，我们发现致病性小鼠抗dna抗体与系膜细胞(MC) -肌动蛋白结合，并且在狼疮小鼠的血清和肾脏洗脱液中存在高滴度的抗-肌动蛋白抗体。此外，我们报道了在人SLE血清中，与MC结合的抗-肌动蛋白抗体也以高滴度存在，并且与LN的存在和活性密切相关。最后，与MC （- actitin）结合的致病性抗体通过fc依赖和独立的机制直接调节炎症基因的表达，包括细胞因子和中性粒细胞明胶酶相关的脂钙蛋白（NGAL, lipocalin-2）。我们假设肾细胞中肾源性抗体诱导的基因调控是LN发病的重要因素，通过结合细胞表面受体和toll样受体（TLR）家族的另一个受体介导，血清和/或尿液中NGAL的水平可能反映肾源性抗体诱导的肾损伤程度。我们建议继续我们的研究，以了解抗dna抗体的肾致病性。具体来说，我们将：

DESCRIPTION (provided by applicant): 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) (-actinin, and that high titers of anti-(-actinin antibodies were present in the serum and kidney eluates of lupus mice. Furthermore, we reported that in human SLE serum anti-(-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 (-actinin directly modulated inflammatory gene expression including cytokines and neutrophil gelatinase associated lipocalin (NGAL, lipocalin-2), 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 (-actinin in determining antibody nephritogenicity and the effects of binding by pathogenic antibodies on (-actinin structure and cellular 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. Public Health Relevance: Inflammation of the kidney, or nephritis, is a common and dangerous manifestation of disease in patients with systemic lupus erythematosus. While it is known that in lupus patients antibodies against DNA contribute to nephritis, how they actually cause kidney damage is not yet clear. We propose to study how anti-DNA antibodies induce kidney injury in an attempt to identify new approaches for more effective treatment, and discover novel serum or urine diagnostic markers that will improve the clinical care of lupus patients.