Rudofsky U H, Evans B D, Balaban S L, Mottironi V D, Gabrielsen A E
Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany.
Lab Invest. 1993 Apr;68(4):419-26.
F1 hybrids of New Zealand Black (NZB) and New Zealand White (NZW) mice develop autoimmune glomerulonephritis resembling human lupus nephritis. Susceptibility to this complex autoimmune syndrome in humans and mice has been linked to genes mapping in or near the major histocompatibility complex that govern immune responses and levels of certain complement components. Previous studies showed that both parental strains contribute major histocompatibility complex-linked genes that are important for disease of the F1 hybrid.
New inbred strains of New Zealand Mixed (NZM) mice were derived by selective inbreeding of progeny of a cross between NZB and NZW mice. Twelve of the 27 new NZM strains were selected for analysis. Mice were observed for up to 10 months of age to document the occurrence of nephritis and strain-specific differences in disease expression. H-2, Hc, and coat color loci were determined for each strain to establish homozygosity of NZB and NZW polymorphic markers. Strains were screened for the presence of anti-dsDNA autoantibodies.
In some NZM strains early onset of lupus nephritis in females resembled the (NZB x NZW)F1 model, whereas in other strains early disease also occurred in males. Age at death and severity of nephritis vary among the lines; a few strains remain relatively free of glomerular lesions. Histocompatibility (H-2) typing showed that all strains are homozygous for the NZW haplotype (Ku, Au, Sz, Dz). Coat color analysis for four loci on chromosomes 2, 4, and 7 was consistent with specific reassortments and recombinations to explain the grey, tan, and white mice with red/pink eyes and the presence or absence of the fifth component of serum complement (C5) (Hc, chromosome 2). Anti-dsDNA autoantibodies were found in all but one of the NZM strains reported here.
The NZM strains of mice are a unique set of inbred strains that have inherited various genomic segments of the two parental strains that lead to phenotypic differences in disease expression. These results indicate that the previously proposed strict requirement for H-2 heterozygosity for the development of nephritis in the (NZB x NZW)F1 hybrid mice may not be valid. It is assumed that both the Lpn-1 locus of NZB and the Lpn-2 locus of NZW and a sufficient number of other disease-associated genes of both ancestral strains have been recombined in these new strains to produce the various patterns of renal disease.
新西兰黑（NZB）鼠和新西兰白（NZW）鼠的F1杂种会发生类似于人类狼疮性肾炎的自身免疫性肾小球肾炎。人类和小鼠对这种复杂自身免疫综合征的易感性与位于主要组织相容性复合体中或其附近的基因有关，这些基因控制免疫反应和某些补体成分的水平。先前的研究表明，两个亲本品系都贡献了与主要组织相容性复合体相关的基因，这些基因对F1杂种的疾病很重要。
通过对NZB和NZW小鼠杂交后代进行选择性近亲繁殖，培育出了新的新西兰混合（NZM）近交系小鼠。从27个新的NZM品系中选择了12个进行分析。观察小鼠至10月龄，记录肾炎的发生情况以及疾病表达的品系特异性差异。确定每个品系的H-2、Hc和毛色基因座，以确定NZB和NZW多态性标记的纯合性。筛选品系中抗双链DNA自身抗体的存在情况。
在一些NZM品系中，雌性狼疮性肾炎早发类似于（NZB×NZW）F1模型，而在其他品系中，雄性也会出现早期疾病。不同品系的死亡年龄和肾炎严重程度各不相同；少数品系相对没有肾小球病变。组织相容性（H-2）分型显示，所有品系均为NZW单倍型（Ku、Au、Sz、Dz）的纯合子。对2号、4号和7号染色体上四个基因座的毛色分析与特定的重排和重组一致，以解释灰、棕褐色和红眼白小鼠以及血清补体第五成分（C5）（Hc，2号染色体）的有无。在本文报道的所有NZM品系中，除一个品系外，均发现了抗双链DNA自身抗体。
NZM品系小鼠是一组独特近交系，继承了两个亲本品系的各种基因组片段，导致疾病表达出现表型差异。这些结果表明，先前提出的（NZB×NZW）F1杂种小鼠肾炎发生对H-2杂合性的严格要求可能不成立。据推测NZB的Lpn-1基因座和NZW的Lpn-2基因座以及两个祖先品系中足够数量的其他疾病相关基因已在这些新品系中重组，从而产生了各种肾脏疾病模式。
