Regulation of B cell tolerance by the lupus susceptibility gene Ly108.
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.
Kumar
Kirthi Raman
KR
Department of Internal Medicine (Rheumatology), University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Li
Liunan
L
Yan
Mei
M
Bhaskarabhatla
Madhavi
M
Mobley
Angela B
AB
Nguyen
Charles
C
Mooney
Jill M
JM
Schatzle
John D
JD
Wakeland
Edward K
EK
Mohan
Chandra
C
D000818:Animals; D000950:Antigens, Ly / Q000235:genetics*; D001324:Autoantigens / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D001854:Bone Marrow Cells / Q000276:immunology; D016923:Cell Death; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D017635:Clonal Anergy; D017637:Clonal Deletion; D020022:Genetic Predisposition to Disease; D007108:Immune Tolerance; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D020412:Multifactorial Inheritance; D009113:Muramidase / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D013154:Spleen / Q000276:immunology; D014162:Transfection; D000071176:Signaling Lymphocytic Activation Molecule Family
D000950:Antigens, Ly; D001324:Autoantigens; D009113:Muramidase; D011947:Receptors, Antigen, B-Cell; C421864:hen egg lysozyme; C000604063:Slamf6 protein, mouse; D000071176:Signaling Lymphocytic Activation Molecule Family