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

Khie Khiong, Masaaki Murakami, Chika Kitabayashi, Naoko Ueda, Shin Ichiro Sawa, Akemi Sakamoto, Brian L. Kotzin, Stephen J. Rozzo, Katsuhiko Ishihara, Marileila Verella-Garcia, John Kappler, Philippa Marrack, Toshio Hirano

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55 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1270-1281
Number of pages12
JournalJournal of Clinical Investigation
Volume117
Issue number5
DOIs
Publication statusPublished - May 1 2007

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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    Khiong, K., Murakami, M., Kitabayashi, C., Ueda, N., Sawa, S. I., Sakamoto, A., Kotzin, B. L., Rozzo, S. J., Ishihara, K., Verella-Garcia, M., Kappler, J., Marrack, P., & Hirano, T. (2007). Homeostatically proliferating CD4+ T cells are involved in the pathogenesis of an Omenn syndrome murine model. Journal of Clinical Investigation, 117(5), 1270-1281. https://doi.org/10.1172/JCI30513