Human RAG mutations: biochemistry and clinical implications

Key Points 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. 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. However, environmental factors may also contribute to determining the disease phenotype. Crystal structure and cryo-electron microscopy studies have revealed the structure of the heterotetrameric RAG complex bound to DNA. Fine definition of this structure has also offered important insights into the disease-causing effects of naturally occurring RAG mutations. 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. A broad range of autoantibodies has been demonstrated in patients with RAG mutations presenting with inflammation and autoimmunity. Neutralizing antibodies specific for interferon-α (IFNα) and IFNω have been documented particularly in patients with a history of severe viral infections. Recent data indicate that RAG expression during the early stages of lymphoid development selects cells with improved fitness. NK cells from Rag −/− mice have an activated phenotype and increased cytotoxicity. 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.