T helper type 2-like cells and therapeutic effects of interferon-γ in combined immunodeficiency with hypereosinophilia (Omenn's syndrome). Familial reticuloendotheliosis with eosinophilia. The clinical impact of deficiency in DNA non-homologous end-joining. The scid mutation in mice causes a general defect in DNA repair. A severe combined immunodeficiency mutation in the mouse. A human severe combined immunodeficiency (SCID) condition with increased sensitivity to ionizing radiations and impaired V(D)J rearrangements defines a new DNA recombination/repair deficiency. Transplantation outcomes for severe combined immunodeficiency, 2000–2009.

Severe combined immunodeficiencies and related disorders. This report shows by cryo-electron microscopy how the RAG complex interacts with RSSs according to the 12–23 rule.įischer, A., Notarangelo, L. Molecular mechanism of V(D)J recombination from synaptic RAG1-RAG2 complex structures. This study investigates the specific requirement of RSS substrates with 12–23 spacers for optimal recognition and binding by RAG1. Recruitment of RAG1 and RAG2 to chromatinized DNA during V(D)J recombination. This study describes the crystal structure of the heterotetrameric complex of RAG1 and RAG2 core domains, offering important insights into RAG complex function and into mechanisms of disease in patients with RAG mutations. Crystal structure of the V(D)J recombinase RAG1–RAG2. By identifying patients with delayed-onset disease characterized by granulomas and autoimmunity, this manuscript has broadened the spectrum of human RAG deficiency. An immunodeficiency disease with RAG mutations and granulomas. Highly restricted human T cell repertoire in peripheral blood and tissue-infiltrating lymphocytes in Omenn's syndrome. Restricted heterogeneity of T lymphocytes in combined immunodeficiency with hypereosinophilia (Omenn's syndrome). This is the first demonstration that hypomorphic RAG mutations are a cause of Omenn syndrome.ĭe Saint-Basile, G. Partial V(D)J recombination activity leads to Omenn syndrome. This is the first study to report that RAG mutations in humans cause SCID. RAG mutations in human B cell-negative SCID. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. RAG-1-deficient mice have no mature B and T lymphocytes. RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. The V(D)J recombination activating gene, RAG-1. If confirmed in humans, these data may account for the high rate of graft rejection observed after unconditioned haematopoietic stem cell transplantation in patients with RAG deficiency. NK cells from Rag −/− mice have an activated phenotype and increased cytotoxicity. Recent data indicate that RAG expression during the early stages of lymphoid development selects cells with improved fitness. Neutralizing antibodies specific for interferon-α (IFNα) and IFNω have been documented particularly in patients with a history of severe viral infections. Studies in patients and in mice have demonstrated that RAG mutations affect central and peripheral T cell and B cell tolerance, including defective expression of autoimmune regulator (AIRE), reduced number and function of regulatory T cells, impaired receptor editing and increased levels of B cell-activating factor (BAFF), allowing the rescue of self-reactive B cells.Ī broad range of autoantibodies has been demonstrated in patients with RAG mutations presenting with inflammation and autoimmunity. Fine definition of this structure has also offered important insights into the disease-causing effects of naturally occurring RAG mutations. However, environmental factors may also contribute to determining the disease phenotype.Ĭrystal structure and cryo-electron microscopy studies have revealed the structure of the heterotetrameric RAG complex bound to DNA. There is a correlation between the severity of the clinical and immunological phenotypes and the recombination activity of the mutant RAG protein, and hypomorphic mutations that severely affect recombination activity are associated with restriction of the T cell and B cell repertoires. Recombination-activating gene (RAG) mutations in humans are associated with a broad spectrum of clinical phenotypes, ranging from severe, early-onset infections to inflammation and autoimmunity.

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