Functional interplay between intrinsic B and T cell defects leads to amplification of autoimmune disease in New Zealand black chromosome 1 congenic mice

被引:12
作者
Cheung, YH
Chang, NH
Cai, YC
Bonventi, G
MacLeod, R
Wither, JE
机构
[1] Toronto Western Res Inst, Arthritis Ctr Excellence, Toronto, ON, Canada
[2] Univ Toronto, Dept Immunol, Toronto, ON, Canada
[3] Univ Hlth Network, Dept Med, Toronto, ON, Canada
关键词
D O I
10.4049/jimmunol.175.12.8154
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Genetic loci on New Zealand Black (NZB) chromosome I play an important role in the development of lupus-like autoimmune disease. We have shown previously that C57BL/6 mice with an introgressed NZB chromosome I interval extending from similar to 35 to 106 cM have significantly more severe autoimmunity than mice with a shorter interval extending from similar to 82 to 106 cM. Comparison of the cellular phenotype in these mice revealed that both mouse strains had evidence of increased T cell activation; however, activation was more pronounced in mice with the longer interval. Mice with the longer interval also had increased B cell activation, leading us to hypothesize that there were at least two independent lupus susceptibility loci on chromosome 1. In this study, we have used mixed hemopoietic radiation chimeras to demonstrate that autoimmunity in these mice arises from intrinsic B and T cell functional defects. We further show that a T cell defect, localized to the shorter interval, leads to spontaneous activation of T cells specific for nucleosome histone components. Despite activation of self-reactive T cells in mixed chimeric mice, only chromosome I congenic B cells produce anti-nuclear Abs and undergo class switching, indicating impaired B cell tolerance mechanisms. In mice with the longer chromosome I interval, an additional susceptibility locus exacerbates autoimmune disease by producing a positive feedback loop between T and B cell activation. Thus, T and B cell defects act in concert to produce and amplify the autoimmune phenotype.
引用
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页码:8154 / 8164
页数:11
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