Genetic modifiers of systemic lupus erythematosus in FcgammaRIIB(-/-) mice.
Genetic modifiers of systemic lupus erythematosus in FcgammaRIIB(-/-) mice.
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DOI：
10.1084/jem.20020165
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发表时间：
2002-05-06
影响因子：
15.3
通讯作者：
Ravetch, Jeffrey V
中科院分区：
文献类型：
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作者：
Bolland, Silvia;Yim, Young-Sun;Tus, Katalin;Wakeland, Edward K;Ravetch, Jeffrey V
FcγRIIB是一种有效的狼疮易感基因，在C57BL/6背景下，观察到该分子缺陷的小鼠发生自发性抗核抗体和致死性肾小球肾炎。为了确定该基因所表现出的上位性的机制，我们构建了Fc、γ、RIIB、−/−与系统性红斑狼疮修饰基因yaa和lpr以及易感基因Sle1的杂交。Sle1和B6RIIB−/−在物理和功能上都是偶联的；Sle1和B6的复合杂合子RIIB−/−会发生明显的疾病，而单一杂合子没有表现出自身免疫或疾病的证据，这表明这些基因位于同一遗传途径上，导致对核抗原的耐受性丧失。然而，ANA本身的产生不足以解释该模型中自身免疫性疾病的严重程度，正如对YAA和LPR杂交的分析所证明的那样。因此，B6.RIIB−/−/lpr小鼠受到保护，不受疾病进展的影响，尽管抗核抗体效价相当。相比之下，B6.RIIB−/−/yaa小鼠尽管抗核抗体滴度降低，但疾病显著增加。YaA改变了B6的特异性，从而改变了其致病性。RIIb−/−抗核抗体，通过将它们转化为抗核仁抗体。除了这些已知的修饰途径外，我们还发现了两个由C57BL/6基因组贡献的新的隐性基因座，这是ANA表型所必需的，进一步表明了这个SLE模型的上位性属性。
FcγRIIB is a potent lupus susceptibility gene as demonstrated by the observation that mice deficient in this molecule develop spontaneous antinuclear antibodies (ANA) and fatal glomerulonephritis when on the C57BL/6 background. To determine the mechanisms underlying the epistasis displayed by this gene we have constructed hybrids between FcγRIIB−/− and the systemic lupus erythematosus (SLE) modifiers yaa and lpr and the susceptibility locus Sle1. Sle1 and B6.RIIB−/− are both physically and functionally coupled; compound heterozygotes of Sle1 and B6.RIIB−/− develop significant disease, while single heterozygotes display no evidence of autoimmunity or disease, indicating that these genes lie on the same genetic pathway resulting in the loss of tolerance to nuclear antigens. However, the generation of ANA in itself is insufficient to account for the severity of autoimmune disease in this model, as demonstrated by analysis of yaa and lpr hybrids. Thus, B6.RIIB−/−/lpr mice are protected from disease progression, despite equivalent titers of ANA. In contrast, B6.RIIB−/−/yaa mice have significantly enhanced disease despite reduced ANA titers. Yaa modifies the specificity and thus the pathogenicity of the B6. RIIB−/− ANA, by converting them to antinucleolar antibodies. In addition to these known modifier pathways, we have discovered two novel, recessive loci contributed by the C57BL/6 genome that are required for the ANA phenotype, further indicating the epistatic properties of this SLE model.