The contribution of B cells to the pathology of Omenn syndrome and leaky severe combined immunodeficiency (SCID) has not been previously investigated. We have studied a mut/mut mouse model of leaky SCID with a homozygous Rag1 S723C mutation that impairs, but does not abrogate, V(D)J recombination activity. In spite of a severe block at the pro–B cell stage and profound B cell lymphopenia, significant serum levels of immunoglobulin (Ig) G, IgM, IgA, and IgE and a high proportion of Ig-secreting cells were detected in mut/mut mice. Antibody responses to trinitrophenyl (TNP)-Ficoll and production of high-affinity antibodies to TNP–keyhole limpet hemocyanin were severely impaired, even after adoptive transfer of wild-type CD4+ T cells. Mut/mut mice produced high amounts of low-affinity self-reactive antibodies and showed significant lymphocytic infiltrates in peripheral tissues. Autoantibody production was associated with impaired receptor editing and increased serum B cell–activating factor (BAFF) concentrations. Autoantibodies and elevated BAFF levels were also identified in patients with Omenn syndrome and leaky SCID as a result of hypomorphic RAG mutations. These data indicate that the stochastic generation of an autoreactive B cell repertoire, which is associated with defects in central and peripheral checkpoints of B cell tolerance, is an important, previously unrecognized, aspect of immunodeficiencies associated with hypomorphic RAG mutations.

Children with primary immunodeficiency disorders (PIDD) have an increased risk of suffering from physical, social, and psychological problems. The aim of this study was to evaluate the performance status and mortality of children with PIDD in Kuwait and to determine the variables and co-morbidities that may affect their performance and risk of death. The data for the children were obtained from Kuwait National Primary Immunodeficiency Disorders Registry describes the patients' characteristics, comorbidities and their treatment regimens. Each patient was scored using the Lansky Play Performance Scale (LPPS), and we evaluated the number of deaths among the children and the effects of different variables on their LPPS scores and mortality. We examined 98 pediatric patients with a mean delay in diagnosis of 21.2 months. Antimicrobial prophylaxis was administered to 57.2% of the patients, whereas intravenous immunoglobulin (IVIG) therapy was used in 44%. Eight patients underwent bone marrow transplants. The mean LPPS score for all the patients was 65.5, and there was a significant disparity in the mean LPPS scores across PIDD categories. Twenty-one patients died. The variables that were found to have a significant effect on both the LPPS score and the risk of death were an age of onset of less than 6 months, a history of CMV infection, parental consanguinity, the use of antimicrobial prophylaxis and IVIG therapy. In conclusion, patients with PIDD have a poor performance status and a high rate of mortality. Early diagnosis and aggressive therapeutic interventions directed at patients with early onset of symptoms and CMV infections can help improve the quality of life of patients with PIDD.