Vyse T J, Morel L, Tanner F J, Wakeland E K, Kotzin B L
Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO 80206, USA.
J Immunol. 1996 Sep 15;157(6):2719-27.
F1 hybrids of New Zealand Black (NZB) and New Zealand White (NZW) mice are genetically predisposed to develop a lupus-like autoimmune disease characterized by IgG autoantibody production and an immune complex glomerulonephritis. Genes from both parental strains contribute to autoimmunity in the F1 animal. NZW mice produce mostly non-pathogenic autoantibodies to ssDNA and histones as their major autoimmune trait. We studied the genetics of this trait in order to gain insight into the NZW contribution to F1 disease. Genome-wide mapping of (NZW x BALB/c)F1 x NZW backcross mice showed that four NZW non-MHC loci on chromosomes 1, 11, 16, and 19 were linked with IgG autoantibody production. Another NZW locus on chromosome 14 appeared to be selectively linked with IgG anti-histone Abs. In this backcross, contributions from the nonautoimmune BALB/c strain were also apparent. Heterozygosity for the BALB/c MHC (H2d) was linked with IgG autoantibody production. This influence of H2d is therefore similar to that seen in (NZW x NZB)F1 mice, in which heterozygosity for H2d enhances autoantibody production and disease. Surprisingly, two non-MHC BALB/c loci were linked with IgM autoantibody levels, whereas no NZW loci had such an effect. Neither of these two loci have been previously linked with autoimmunity in lupus-prone mice. These data show that autoantibody production in NZW mice is a polygenic trait that is influenced by contributions from MHC and non-MHC genes. The results also support the hypothesis that NZW genes act to class-switch the autoantibody response, an effect that appears to contribute to disease in (NZB x NZW)F1 mice.
新西兰黑（NZB）小鼠和新西兰白（NZW）小鼠的F1杂交后代具有发生狼疮样自身免疫性疾病的遗传倾向，其特征为产生IgG自身抗体和免疫复合物性肾小球肾炎。两个亲本品系的基因均对F1动物的自身免疫起作用。NZW小鼠主要产生针对单链DNA和组蛋白的非致病性自身抗体，这是它们主要的自身免疫特征。我们研究了这一特征的遗传学，以便深入了解NZW对F1疾病的影响。对（NZW×BALB/c）F1×NZW回交小鼠进行全基因组定位分析表明，位于1号、11号、16号和19号染色体上的4个NZW非MHC基因座与IgG自身抗体产生相关。位于14号染色体上的另一个NZW基因座似乎与IgG抗组蛋白抗体选择性相关。在这次回交中，非自身免疫性BALB/c品系的作用也很明显。BALB/c MHC（H2d）的杂合性与IgG自身抗体产生相关。因此，H2d的这种影响与在（NZW×NZB）F1小鼠中观察到的情况相似，在（NZW×NZB）F1小鼠中，H2d的杂合性会增强自身抗体产生和疾病发生。令人惊讶的是，两个非MHC BALB/c基因座与IgM自身抗体水平相关，而没有NZW基因座有这样的作用。这两个基因座以前都未与易患狼疮小鼠的自身免疫相关联。这些数据表明，NZW小鼠中自身抗体的产生是一个多基因性状，受到MHC和非MHC基因的影响。结果还支持这样的假说，即NZW基因作用于自身抗体反应的类别转换，这种效应似乎在（NZB×NZW）F1小鼠的疾病发生中起作用。
