Omenn syndrome (OS) is a combined immunodeficiency characterized by severe tissue damage due to infiltrating, activated, oligoclonal and anergic T lymphocytes. Most patients with OS lack circulating B lymphocytes and show profound hypogammaglobulinemia, but normal or elevated serum IgE. We have found that most patients with OS carry hypomorphic mutations of the RAG genes that decrease but do not abolish V(D)J recombination. However, hypomorphic mutations in genes involved in V(D)J recombination may also cause leaky SCID, with accumulation of activated and anergic T cells, without tissue damage. We have found that the transcription factor Aire and tissue-specific transcripts are poorly expressed in the thymus of patients with OS, raising the possibility that negative selection of autoreactive T cells may not be properly in place. In addition, development of regulatory T cells (Tregs) is likely to be altered in OS, as the thymus of these patients lacks Hassall's corpuscles, which are involved in Tregs development. Finally, environmental factors may also be involved in the pathophysiology of OS, as it has been shown that the disease phenotype in infants with hypomorphic RAG mutations can be dramatically modified by exposure to pathogens. We will take advantage of three recently developed murine models of hypomorphic rag2, ragl, and Iig4 mutations to investigate the cellular and molecular mechanisms that underlie OS and leaky SCID. Our overall hypothesis is that the variable clinical and immunological phenotype associated with hypomorphic mutations in genes involved in V(D)J recombination reflects a different degree of impairment of V(D)J recombination that affects deletional and non deletional mechanisms of central tolerance, and that the resulting phenotype may be modified by environmental factors. To test this hypothesis,we will evaluate the V(D)J recombination activity of the mutants. We will analyze negative selection in these models, and use adoptive transfer to assess the role of impaired function of Tregs. Finally, we will challenge the mice with TLR agonists, MCMV and oxazolone to precipitate or accelerate the disease phenotype. We expect that detailed characterization of these unique animal models will provide critical information to understand the pathophysiology of OS and leaky SCID, but also of other, more common, disorders of immune regulation. The information that will be collected might be useful also for development of novel and more appropriate forms of treatment of these severe conditions of immune deficiency and dysreactivity.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Beth Israel Deaconess Medical Center
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Jabara, Haifa H; Boyden, Steven E; Chou, Janet et al. (2016) A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency. Nat Genet 48:74-8
Felgentreff, Kerstin; Lee, Yu Nee; Frugoni, Francesco et al. (2015) Functional analysis of naturally occurring DCLRE1C mutations and correlation with the clinical phenotype of ARTEMIS deficiency. J Allergy Clin Immunol 136:140-150.e7
Zhang, Xianqin; Bogunovic, Dusan; Payelle-Brogard, Béatrice et al. (2015) Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation. Nature 517:89-93
Boisson, Bertrand; Laplantine, Emmanuel; Dobbs, Kerry et al. (2015) Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia. J Exp Med 212:939-51
Frock, Richard L; Hu, Jiazhi; Meyers, Robin M et al. (2015) Genome-wide detection of DNA double-stranded breaks induced by engineered nucleases. Nat Biotechnol 33:179-86
Mooster, Jana L; Le Bras, Severine; Massaad, Michel J et al. (2015) Defective lymphoid organogenesis underlies the immune deficiency caused by a heterozygous S32I mutation in IκBα. J Exp Med 212:185-202
Chou, Janet; Massaad, Michel J; Cangemi, Brittney et al. (2015) A novel mutation in ICOS presenting as hypogammaglobulinemia with susceptibility to opportunistic pathogens. J Allergy Clin Immunol 136:794-797.e1
Chou, Janet; Badran, Yousef R; Yee, Christina S K et al. (2015) A novel mutation in ORAI1 presenting with combined immunodeficiency and residual T-cell function. J Allergy Clin Immunol 136:479-82.e1
van Driel, Boaz; Wang, Guoxing; Liao, Gongxian et al. (2015) The cell surface receptor Slamf6 modulates innate immune responses during Citrobacter rodentium-induced colitis. Int Immunol 27:447-57
Buchbinder, David; Baker, Rebecca; Lee, Yu Nee et al. (2015) Identification of patients with RAG mutations previously diagnosed with common variable immunodeficiency disorders. J Clin Immunol 35:119-24

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