Irie Junichiro, Wu Yuehong, Sass David A, Ridgway William M
Division of Rheumatology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Immunogenetics. 2006 Feb;58(1):9-14. doi: 10.1007/s00251-005-0066-1. Epub 2006 Jan 27.
Anti-Smith (anti-Sm) autoantibodies are directed to proteins in the small-nuclear ribonucleoprotein (snRNP) family and are considered specific for systemic lupus erythematosus (SLE) in both humans and mice. We previously established that NOD.c3c4 mice, carrying B6 and B10 congenic segments from chromosomes 3 to 4 on an nonobese diabetic (NOD) background, and NOD.Idd9R28 mice, carrying a B10 segment on c4 alone, developed significant penetrance of anti-Sm antibody production. Here we determine autoantibody incidence in additional NOD.Idd9 congenic strains and use a congenic mapping approach to narrow the interval necessary for enhanced autoantibody production to a approximately 5.6-Mb region containing insulin-dependent diabetes (Idd)9.3. The Idd9.3 interval contains the candidate molecule cluster of differentiation (CD)137, which is a member of the tumor necrosis factor (TNF) receptor superfamily, functions as an inducible costimulator of T cells, and controls T-B interactions. The NOD and B10 CD137 alleles have sequence polymorphisms and different functional effects on T cells; the NOD CD137 allele mediates weaker T cell proliferative responses and decreased interleukin (IL)-2 production after CD137-mediated costimulation. Our work establishes CD137 as a candidate gene for control of autoantibody production in NOD.Idd9.3 congenic mice.
抗史密斯（anti-Sm）自身抗体靶向小核核糖核蛋白（snRNP）家族中的蛋白质，在人类和小鼠中均被认为是系统性红斑狼疮（SLE）的特异性抗体。我们先前已证实，在非肥胖糖尿病（NOD）背景下携带来自3号至4号染色体的B6和B10同源片段的NOD.c3c4小鼠，以及仅在c4上携带B10片段的NOD.Idd9R28小鼠，出现了显著的抗Sm抗体产生。在此，我们确定了其他NOD.Idd9同源品系中的自身抗体发生率，并采用同源定位方法将增强自身抗体产生所需的区间缩小至一个约5.6兆碱基（Mb）的区域，该区域包含胰岛素依赖型糖尿病（Idd）9.3。Idd9.3区间包含分化簇（CD）137候选分子，它是肿瘤坏死因子（TNF）受体超家族的成员，作为T细胞的诱导性共刺激因子发挥作用，并控制T - B相互作用。NOD和B10的CD137等位基因存在序列多态性，对T细胞具有不同的功能影响；NOD CD137等位基因在CD137介导的共刺激后介导较弱的T细胞增殖反应并降低白细胞介素（IL）-2的产生。我们的研究确定CD137是NOD.Idd9.3同源小鼠中控制自身抗体产生的候选基因。
