Drake C G, Rozzo S J, Hirschfeld H F, Smarnworawong N P, Palmer E, Kotzin B L
Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO 80206.
J Immunol. 1995 Mar 1;154(5):2441-7.
F1 progeny of New Zealand Black (NZB) and New Zealand White (NZW) mice spontaneously develop an autoimmune process remarkably similar to human systemic lupus erythematosus. Previous studies have implicated major genetic contributions from the NZW MHC and from a dominant NZB gene on chromosome 4. To identify additional NZB contributions to lupus-like disease, (NZB x SM/J)F1 x NZW backcross mice were followed for the development of severe renal disease and were comprehensively genotyped. Despite a 50% incidence of disease, significant associations between the presence of the NZB genotype and disease were noted on chromosomes 1, 4, 7, 10, 13, and 19. The data indicated that multiple NZB genes, in different combinations, contribute to severe renal disease, and that no single gene is required. To further investigate this NZB contribution, NZB x SM/J (NXSM) recombinant inbred (RI) strains were crossed with NZW mice, and F1 progeny were analyzed for the presence of lupus-like renal disease. Interestingly, nearly all of the (RI x NZW)F1 cohorts studied expressed some level of disease. Five RI strains generated a high incidence of disease, similar to (NZB x NZW)F1 mice, and nearly one-half of the cohorts developed disease at intermediate levels. Only two cohorts demonstrated very little disease, supporting the conclusion that multiple genes are capable of disease induction. Experiments correlating the genotypes of these RI strains with their ability to generate disease revealed that none of the disease-associated loci defined by the backcross analysis were present in all five RI strains that generated disease at high levels. Overall, both the backcross data and RI analysis provide additional support for the genetic complexity of lupus nephritis and uphold the conclusion that heterogeneous combinations of contributing NZB genes seem to operate in a threshold manner to generate the disease phenotype.
新西兰黑鼠（NZB）和新西兰白鼠（NZW）的F1代后代会自发出现一种自身免疫过程，与人类系统性红斑狼疮极为相似。先前的研究表明，NZW主要组织相容性复合体（MHC）以及NZB 4号染色体上的一个显性基因在其中起到了主要的遗传作用。为了确定NZB对狼疮样疾病的其他贡献，对（NZB×SM/J）F1×NZW回交小鼠进行了跟踪观察，以了解严重肾脏疾病的发展情况，并对其进行了全面的基因分型。尽管疾病发生率为50%，但在1、4、7、10、13和19号染色体上发现NZB基因型的存在与疾病之间存在显著关联。数据表明，多个NZB基因以不同组合形式导致严重肾脏疾病，且并非单个基因起作用。为了进一步研究NZB的这种贡献，将NZB×SM/J（NXSM）重组近交（RI）品系与NZW小鼠杂交，并对F1代后代进行狼疮样肾脏疾病检测。有趣的是，几乎所有研究的（RI×NZW）F1群体都表现出一定程度的疾病。五个RI品系疾病发生率较高，与（NZB×NZW）F1小鼠相似，近一半的群体疾病处于中等水平。只有两个群体疾病表现极少，这支持了多个基因能够诱发疾病的结论。将这些RI品系的基因型与其诱发疾病的能力进行关联实验发现，在所有五个疾病发生率高的RI品系中，均不存在回交分析所确定的与疾病相关的位点。总体而言，回交数据和RI分析都为狼疮性肾炎的遗传复杂性提供了更多支持，并支持这样的结论：NZB致病基因的异质组合似乎以阈值方式起作用，从而产生疾病表型。
