Genetic control of anti-Sm autoantibody production in NOD congenic mice narrowed to the Idd9.3 region.
Anti-Smith (anti-Sm) autoantibodies are directed to proteins in the small-nuclear ribonucleoprotein (snRNP) family and are considered specific for systemic lupus erythematosus (SLE) in both humans and mice. We previously established that NOD.c3c4 mice, carrying B6 and B10 congenic segments from chromosomes 3 to 4 on an nonobese diabetic (NOD) background, and NOD.Idd9R28 mice, carrying a B10 segment on c4 alone, developed significant penetrance of anti-Sm antibody production. Here we determine autoantibody incidence in additional NOD.Idd9 congenic strains and use a congenic mapping approach to narrow the interval necessary for enhanced autoantibody production to a approximately 5.6-Mb region containing insulin-dependent diabetes (Idd)9.3. The Idd9.3 interval contains the candidate molecule cluster of differentiation (CD)137, which is a member of the tumor necrosis factor (TNF) receptor superfamily, functions as an inducible costimulator of T cells, and controls T-B interactions. The NOD and B10 CD137 alleles have sequence polymorphisms and different functional effects on T cells; the NOD CD137 allele mediates weaker T cell proliferative responses and decreased interleukin (IL)-2 production after CD137-mediated costimulation. Our work establishes CD137 as a candidate gene for control of autoantibody production in NOD.Idd9.3 congenic mice.
Irie
Junichiro
J
Division of Rheumatology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Wu
Yuehong
Y
Sass
David A
DA
Ridgway
William M
WM
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis / Q000235:genetics*; D001324:Autoantigens / Q000276:immunology*; D002874:Chromosome Mapping; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005819:Genetic Markers; D014644:Genetic Variation; D006801:Humans; D020014:K562 Cells; D008180:Lupus Erythematosus, Systemic / Q000276:immunology; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000276:immunology; D017411:Ribonucleoproteins, Small Nuclear / Q000276:immunology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D055517:snRNP Core Proteins
D015703:Antigens, CD; D001323:Autoantibodies; D001324:Autoantigens; D005819:Genetic Markers; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D017411:Ribonucleoproteins, Small Nuclear; C505714:TNFRSF9 protein, human; C505715:Tnfrsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D055517:snRNP Core Proteins