Homeostatically proliferating CD4+ T cells are involved in the pathogenesis of an Omenn syndrome murine model

被引:62
作者
Khiong, Khie
Murakami, Masaaki
Kitabayashi, Chika
Ueda, Naoko
Sawa, Shin-ichiro
Sakamoto, Akemi
Kotzin, Brian L.
Rozzo, Stephen J.
Ishihara, Katsuhiko
Verella-Garcia, Marileila
Kappler, John
Marrack, Philippa
Hirano, Toshio
机构
[1] Osaka Univ, Grad Sch Med, Dept Dev Immunol, Suita, Osaka 5650871, Japan
[2] Osaka Univ, Grad Sch Frontier Biosci, Suita, Osaka, Japan
[3] Univ Colorado, Hlth Sci Ctr, Integrated Dept Immunol, Howard Hughes Med Inst, Denver, CO 80202 USA
[4] Natl Jewish Med & Res Ctr, Denver, CO USA
[5] Univ Colorado, Hlth Sci Ctr, Div Clin Immunol, Denver, CO 80202 USA
[6] Univ Colorado, Ctr Canc, Dept Med, Lung Canc Program, Denver, CO 80202 USA
[7] RIKEN, Res Ctr Allergy & Immunol, Lab Cytokine Signaling, Yokohama, Kanagawa, Japan
关键词
D O I
10.1172/JCI30513
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Patients with Omenn syndrome (OS) have hypomorphic RAG mutations and develop varying manifestations of severe combined immunodeficiency. It is not known which symptoms are caused directly by the RAG mutations and which depend on other polymorphic genes. Our current understanding of OS is limited by the lack of an animal model. In the present study, we identified a C57BL/10 mouse with a spontaneous mutation in, and reduced activity of, RAG1. Mice bred from this animal contained high numbers of memory-phenotype T cells and experienced hepatosplenomegaly and eosinophilia, had oligoclonal T cells, and demonstrated elevated levels of IgE, major symptoms of OS. Depletion of CD4(+) T cells in the mice caused a reduction in their IgE levels. Hence these "memory mutant" mice are a model for human OS; many symptoms of their disease were direct results of the Rag hypomorphism and some were caused by malfunctions of their CD4(+) T cells.
引用
收藏
页码:1270 / 1281
页数:12
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