Naiki M, Yoshida S H, Watanabe Y, Izui S, Ansari A A, Gershwin M E
Division of Rheumatology, Allergy and Clinical Immunology, University of California, School of Medicine, Davis 95616.
J Autoimmun. 1993 Apr;6(2):131-43. doi: 10.1006/jaut.1993.1011.
To further understand the contribution of I-A to the development of disease in murine lupus, we compared the incidence and/or titers of natural thymocytotoxic autoantibodies (NTAs), autoantibodies to red blood cells, gp70 immune complexes (gp70), antibodies to Sm, and rheumatoid factor in NZB (H-2d), NZB.H-2b and NZB.H-2bm12 mice. There were striking and significant differences among the three NZB strains in several of these parameters. NZB (H-2d) and NZB.H-2bm12 mice had a 100% incidence of NTA. In contrast, NZB.H-2b mice were found to have NTA in only 36% of animals at 8-10 months of age. Furthermore, the NTA titers of NZB.H-2bm12 mice were relatively low. There were also distinct differences between these strains with respect to the presence of antibodies to anti-erythrocytes (positive Coombs' test). NZB (H-2d) and NZB.H-2bm12 both had high titers of anti-erythrocyte autoantibodies (AEAs), whereas there was a delayed onset and lower titers in NZB.H-2b mice. Additionally, there was a dramatic increase in gp70 IC levels in NZB.H-2bm12 mice. In previous studies, NZB.H-2bm12 as well as NZB.H-2bm12 x NZB.H-2b F1 mice were found to produce high autoantibody titers to single-stranded (ss) and double-stranded (ds) DNA. Using unfractionated or fractionated splenic T cells (CD4+ CD8-, CD4- CD8+, or CD4-CD8-) from NZB.H-2b or NZB.H-2bm12 mice, we compared their relative abilities to cooperate with T-depleted splenocytes from NZB.H-2bm12 x NZB.H-2b F1 mice to produce antibodies to ss- and ds-DNA. Only T cells, including both CD4+ CD8- and CD4- CD8- populations, from NZB.H-2bm12 mice, were able to induce such autoantibody production among F1 splenocytes. Finally, marked alterations in splenic T cell subsets were found in NZB.H-2bm12 mice compared to NZB.H-2b mice, and to a lesser extent, in B6.C-H-2bm12 mice compared to C57BL/6 (H-2b) mice. These data further highlight the influence of I-A on autoimmunity and in particular the influence of the bm12 mutation on altering the natural history of disease expression in NZB mice.
为了进一步了解I-A在小鼠狼疮疾病发展中的作用，我们比较了NZB（H-2d）、NZB.H-2b和NZB.H-2bm12小鼠中自然胸腺细胞毒性自身抗体（NTA）、抗红细胞自身抗体、gp70免疫复合物（gp70）、抗Sm抗体和类风湿因子的发生率和/或滴度。在这些参数中的几个方面，这三种NZB品系之间存在显著差异。NZB（H-2d）和NZB.H-2bm12小鼠的NTA发生率为100%。相比之下，发现NZB.H-2b小鼠在8至10个月龄时只有36%的动物有NTA。此外，NZB.H-2bm12小鼠的NTA滴度相对较低。这些品系在抗红细胞抗体（阳性库姆斯试验）的存在方面也有明显差异。NZB（H-2d）和NZB.H-2bm12都有高滴度的抗红细胞自身抗体（AEA），而NZB.H-2b小鼠的发病较晚且滴度较低。此外，NZB.H-2bm12小鼠的gp70 IC水平有显著升高。在先前的研究中，发现NZB.H-2bm12以及NZB.H-2bm12×NZB.H-2b F1小鼠对单链（ss）和双链（ds）DNA产生高自身抗体滴度。使用来自NZB.H-2b或NZB.H-2bm12小鼠的未分级或分级脾T细胞（CD4+ CD8-、CD4- CD8+或CD4-CD8-），我们比较了它们与来自NZB.H-2bm12×NZB.H-2b F1小鼠的T细胞耗竭脾细胞合作产生抗ss-和ds-DNA抗体的相对能力。只有来自NZB.H-2bm12小鼠的T细胞，包括CD4+ CD8-和CD4- CD8-群体，能够在F1脾细胞中诱导这种自身抗体的产生。最后，与NZB.H-2b小鼠相比，在NZB.H-2bm12小鼠中发现脾T细胞亚群有明显改变，与C57BL/6（H-2b）小鼠相比，在B6.C-H-2bm12小鼠中改变程度较小。这些数据进一步突出了I-A对自身免疫的影响，特别是bm12突变对改变NZB小鼠疾病表达自然史的影响。
