A hypomorphic R229Q Rag2 mouse mutant recapitulates human Omenn syndrome

Veronica Marrella, Pietro Luigi Poliani, Anna Casati, Francesca Rucci, Laura Frascoli, Marie Lise Gougeon, Brigitte Lemercier, Marita Bosticardo, Maria Ravanini, Manuela Battaglia, Maria Grazia Roncarolo, Marina Cavazzana-Calvo, Fabio Facchetti, Luigi D. Notarangelo, Paolo Vezzoni, Fabio Grassi, Anna Villa

Research output: Contribution to journalArticle

Abstract

Rag enzymes are the main players in V(D)J recombination, the process responsible for rearrangement of TCR and Ig genes. Hypomorphic Rag mutations in humans, which maintain partial V(D)J activity, cause a peculiar SCID associated with autoimmune-like manifestations, Omenn syndrome (OS). Although a deficient ability to sustain thymopoiesis and to produce a diverse T and B cell repertoire explains the increased susceptibility to severe infections, the molecular and cellular mechanisms underlying the spectrum of clinical and immunological features of OS remain poorly defined. In order to better define the molecular and cellular pathophysiology of OS, we generated a knockin murine model carrying the Rag2 R229Q mutation previously described in several patients with OS and leaky forms of SCID. These Rag2 R229Q/R229Q mice showed oligoclonal T cells, absence of circulating B cells, and peripheral eosinophilia. In addition, activated T cells infiltrated gut and skin, causing diarrhea, alopecia, and, in some cases, severe erythrodermia. These findings were associated with reduced thymic expression of Aire and markedly reduced numbers of naturally occurring Tregs and NKT lymphocytes. In conclusion, Rag2 R229Q/R229Q mice mimicked most symptoms of human OS; our findings support the notion that impaired immune tolerance and defective immune regulation are involved in the pathophysiology of OS.

Original languageEnglish
Pages (from-to)1260-1269
Number of pages10
JournalJournal of Clinical Investigation
Volume117
Issue number5
DOIs
Publication statusPublished - May 1 2007

ASJC Scopus subject areas

  • Medicine(all)

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    Marrella, V., Poliani, P. L., Casati, A., Rucci, F., Frascoli, L., Gougeon, M. L., Lemercier, B., Bosticardo, M., Ravanini, M., Battaglia, M., Roncarolo, M. G., Cavazzana-Calvo, M., Facchetti, F., Notarangelo, L. D., Vezzoni, P., Grassi, F., & Villa, A. (2007). A hypomorphic R229Q Rag2 mouse mutant recapitulates human Omenn syndrome. Journal of Clinical Investigation, 117(5), 1260-1269. https://doi.org/10.1172/JCI30928