The Genetics of Silica-Induced Autoimmunity

接触二氧化硅与各种疾病有关，包括肺矽肺和自身免疫性疾病。 如进行性系统性硬化症(PSS)、系统性红斑狼疮(SLE)、类风湿性关节炎(RA) 和皮肌炎(DM)。尽管一些研究已经注意到接触二氧化硅与 肾病，特别是在二氧化硅诱导的自身免疫的背景下，对肾病的遗传学一无所知 二氧化硅引起的肾脏疾病。这确定了理解二氧化硅暴露如何取得进展的关键障碍 会导致自身免疫病理。肾脏疾病是自身免疫的共同特征，特别是在SLE中 30-60%的成年人可能患有狼疮性肾炎。一些特征似乎与此有关，包括炎症。 由含有免疫复合体的自身抗体的沉积引发，导致炎症的产生 涉及先天和获得性免疫反应的介体，导致细胞渗透，特别是 巨噬细胞，进展为组织损伤，异常组织修复和纤维化。研究，主要是在 动物模型，已经确定了许多影响肾小球肾炎(GN)的分子介质。然而， 大多数在先天免疫和/或获得性免疫中发挥作用，并不主要决定肾脏疾病。此外，基因 对小鼠的研究已经确定了一些GN易感基因，但其中许多也与 自身抗体的产生反对在肾炎中起主要作用。二氧化硅诱导的自身免疫和免疫反应的研究 相关的病理学由于缺乏合适的动物模型而受到阻碍。为了解决这一不足，我们 已经开始描述导致自身免疫多样性的免疫反应的光谱 繁殖(繁殖)小鼠。我们已经检查了对二氧化硅的免疫反应，包括炎症反应 肺反应和BAL液中相关蛋白生物标志物、血清自身抗体谱 以及肾脏的组织病理学。这些发现揭示了矽肺的显著发展， 自身免疫与肾小球肾炎(GN)。数量性状基因座(QTL)分析确定了后者是 与15号染色体上的一个区域连锁。值得注意的是，该基因座(称为Smgn1)与易感性有关 和对二氧化硅诱导的GN的抗性。在该基因座携带A/J等位基因的DO小鼠中没有一只发生GN 暗示了显性遗传特征。我们提出了两个截然不同但相互关联的目标，以进一步描述 参与肾小球肾炎发生发展的遗传因素。 目的1：鉴定对二氧化硅肾炎的抵抗模式。 目的2：明确二氧化硅肾小球肾炎的易感模式。 这些研究具有相当重要的意义，因为它们将使人们能够深入了解分子和细胞 接触二氧化硅后导致肾小球肾炎的途径。这类信息将对 确定潜在的治疗靶点以及提高我们对肾脏疾病的了解 自身免疫的背景。

Silica exposure is associated with different disorders including pulmonary silicosis and autoimmune diseases such as progressive systemic sclerosis (Pss), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and dermatomyositis (DM). Although a number of studies have noted the association of silica exposure with nephropathy, particularly in the setting of silica-induced autoimmunity, nothing is known about the genetics of silica-induced renal disease. This identifies a critical barrier to progress in understanding how silica exposure leads to autoimmune pathology. Kidney disease is a common feature in autoimmunity particularly in SLE where 30–60% of adults may have lupus nephritis. A number of features appear to be implicated including inflammation initiated by deposition of autoantibody containing immune complexes, leading to production of inflammatory mediators involving the innate and adaptive immune responses which results in cellular infiltrates, particularly of macrophages, progression to tissue damage, aberrant tissue repair and fibrosis. Studies, predominantly in animal models, have identified numerous molecular mediators that affect glomerulonephritis (GN). However, most play roles in innate and/or adaptive immunity and do not primarily dictate renal disease. Moreover, genetic studies in mice have identified a number of GN susceptibility loci, but many of these also associate with autoantibody production arguing against a primary role in nephritis. Studies of silica-induced autoimmunity and related pathology have been hampered by the lack of suitable animal models. To address this deficiency, we have begun to characterize the spectrum of immunological responses leading to autoimmunity in Diversity Outbred (DO) mice. We have examined the immunological responses to silica including the inflammatory response in the lung and associated protein biomarkers in the BAL fluid, the spectrum of serum autoantibodies and tissue pathology in the kidney. These findings have revealed significant development of silicosis, autoimmunity and glomerulonephritis (GN). Quantitative trait locus (QTL) analysis determined the latter to be linked with a region on chromosome 15. Significantly, this locus (called Smgn1) is associated with susceptibility and resistance to silica-induced GN. None of the DO mice carrying the A/J allele at the locus developed GN suggesting a dominant inheritance trait. We proposed two distinct but interrelated aims to further characterize the genetic elements involved in the development of GN. Aim 1: Identification of the mode of resistance to silica-induced glomerulonephritis. Aim 2: Identification of the mode of susceptibility to silica-induced glomerulonephritis. These studies are of considerable importance because they will allow insight into the molecular and cellular pathways leading to glomerulonephritis following silica exposure. Such information will be essential for identification of potential therapeutic targets as well as improving our understanding of kidney disease within the context of autoimmunity.