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Regulation of B Cell Tolerance by the Lupus Susceptibility Gene Ly108
Kirthi Raman Kumar,1Liunan Li,1Mei Yan,1Madhavi Bhaskarabhatla,1Angela B. Mobley,2Charles Nguyen,2Jill M. Mooney,3John D. Schatzle,2,3Edward K. Wakeland,2Chandra Mohan1,2*
The susceptibility locus for the autoimmune disease lupus onmurine chromosome 1, Sle1z/Sle1bz, and the orthologous humanlocus are associated with production of autoantibody to chromatin.We report that the presence of Sle1z/Sle1bz impairs B cell anergy,receptor revision, and deletion. Members of the SLAM costimulatorymolecule family constitute prime candidates for Sle1bz, amongwhich the Ly108.1 isoform of the Ly108 gene was most highlyexpressed in immature B cells from lupus-prone B6.Sle1z mice.The normal Ly108.2 allele, but not the lupus-associated Ly108.1allele, was found to sensitize immature B cells to deletionand RAG reexpression. As a potential regulator of tolerancecheckpoints, Ly108 may censor self-reactive B cells, hence safeguardingagainst autoimmunity.
1 Department of Internal Medicine (Rheumatology), University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. 2 Center for Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. 3 Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
* To whom correspondence should be addressed. E-mail: chandra.mohan{at}utsouthwestern.edu
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