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Science 312 (5780): 1665-1669

Copyright © 2006 by the American Association for the Advancement of Science

Regulation of B Cell Tolerance by the Lupus Susceptibility Gene Ly108

Kirthi Raman Kumar,1 Liunan Li,1 Mei Yan,1 Madhavi Bhaskarabhatla,1 Angela B. Mobley,2 Charles Nguyen,2 Jill M. Mooney,3 John D. Schatzle,2,3 Edward K. Wakeland,2 Chandra Mohan1,2*

Abstract: The susceptibility locus for the autoimmune disease lupus on murine chromosome 1, Sle1z/Sle1bz, and the orthologous human locus 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 costimulatory molecule family constitute prime candidates for Sle1bz, among which the Ly108.1 isoform of the Ly108 gene was most highly expressed in immature B cells from lupus-prone B6.Sle1z mice. The normal Ly108.2 allele, but not the lupus-associated Ly108.1 allele, was found to sensitize immature B cells to deletion and RAG reexpression. As a potential regulator of tolerance checkpoints, Ly108 may censor self-reactive B cells, hence safeguarding against 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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