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Articles by J Chinen
Total Records ( 1 ) for J Chinen
  J. E Walter , F Rucci , L Patrizi , M Recher , S Regenass , T Paganini , M Keszei , I Pessach , P. A Lang , P. L Poliani , S Giliani , W Al Herz , M. J Cowan , J. M Puck , J Bleesing , T Niehues , C Schuetz , H Malech , S. S DeRavin , F Facchetti , A. R Gennery , E Andersson , N. R Kamani , J Sekiguchi , H. M Alenezi , J Chinen , G Dbaibo , G ElGhazali , A Fontana , S Pasic , C Detre , C Terhorst , F. W Alt and L. D. Notarangelo
 

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.

 
 
 
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