Susceptibility gene loci to collagen disease in a murine model

包括SLE和RA的胶原病变病理表现为复杂的病变，如肾小球肾炎、血管炎、关节炎和/或涎腺炎，这导致胶原疾病难以明确分类。胶原蛋白疾病病理表现的这种多样性和相似性是由于诊断的模糊性还是胶原蛋白疾病本身的内在特性，目前还存在争议。在这项研究中，我们从遗传学的角度来关注这个问题，并研究了一个小鼠模型，一个MRL菌株的基因组学。携带Fas缺失突变基因lpr（MRL/lpr）的MRL/MpJ-lpr/lpr小鼠，在同一个体中自发发展各种形式的胶原蛋白疾病，包括肾小球肾炎、多动脉炎、关节炎和涎腺炎。这些疾病不是单基因疾病，涉及多效性等复杂的病理表现，需要特定的MRL背景基因来影响病变的发展。利用N2回交和F2杂交小鼠与C3H/lpr小鼠对每个病变与多态性微卫星标记的关联研究发现，每个病变的基因位点存在于不同的染色体位置，并且在一些病变的多基因遗传上具有加性和层次性。此外，一些对全身血管炎的易感位点对动脉的直径有特异性。每个基因座的候选基因包括血管炎和肾小球肾炎的CD72和肾小球肾炎的骨桥蛋白（OPN）。两种菌株间合成的OPN多态性蛋白诱导B细胞活化的能力不同^1。一些小鼠在与MSM/Msf野生近交系的回交后代中，与MRL菌株的遗传距离为100万年，在杂合遗传中受chr18上的一个易感位点控制，在足关节发生了一种新的关节病变，其特征是软骨增生。我们认为胶原蛋白疾病的复杂病理表现是由涉及等位基因多态性的多基因的不同组合控制的。少

The pathological findings in collagen disease involving SLE and RA show complex lesions such as glomerulonephritis, vasculitis, arthritis and/or sialoadenitis, which have resulted in confusion in distinctly categorizing collagen diseases. It is still controversial whether such diversity and similarity of pathological manifestations among the collagen disease depends on ambiguity in diagnosis or is an intrinsic quality of the collagen diseases themselves. In this research, we focused on this subject based on a genetic aspect and studied genomics of a murine model, an MRL strain.MRL/MpJ-lpr/lpr mice bearing a Fas deletion mutant gene lpr(MRL/lpr), spontaneously develop various forms of collagen disease in the same individuals, including glomerulonephritis, polyarteritis, arthritis and sialoadenitis. These diseases are not a single gene disease involving the complex pathological manifestations as pleiotropy, and particular gene(s)of MRL background are required for affecting the developmen … More t of each lesion. Association studies of each lesion with polymorphic microsatellite markers using N2 backcross and F2 intercross mice with C3H/lpr mice revealed that gene loci responsible for each lesion exists at different chromosomal positions and they have additive and hierarchical properties on polygenic inheritance for some of the lesions. Moreover, some of susceptibility loci to systemic vasculitis showed the specificity for the caliber of arteries. Candidate gegnes in each locus involved CD72 for vasculitis and glomerulonephritis, and osteopontin(OPN)for glomerulonephritis. Synthetic polymorphic proteins of OPN were different in the ability to induce B cells activation between both strains^1. Some mice in the backcross progeny with a wild inbred strain of mice MSM/Msf, which is genetically one million year distant from an MRL strain, developed a novel arthropathy in foot joints, characteristic of chondrohyperplasia, which was under the control of a susceptible locus on Chr.18 in a heterozygous inheritance.We conclude that the complex pathological manifestations of collagen disease are under the control of different combinations of polygenes involving allelic polymorphism. Less