Genetic control of autoimmunity: protection from diabetes, but spontaneous autoimmune biliary disease in a nonobese diabetic congenic strain.
At least 20 insulin-dependent diabetes (Idd) loci modify the progression of autoimmune diabetes in the NOD mouse, an animal model of human type 1 diabetes. The NOD.c3c4 congenic mouse, which has multiple B6- and B10-derived Idd-resistant alleles on chromosomes 3 and 4, respectively, is completely protected from autoimmune diabetes. We demonstrate in this study, however, that NOD.c3c4 mice develop a novel spontaneous and fatal autoimmune polycystic biliary tract disease, with lymphocytic peribiliary infiltrates and autoantibodies. Strains having a subset of the Idd-resistant alleles present in the NOD.c3c4 strain show component phenotypes of the liver disease: NOD mice with B6 resistance alleles only on chromosome 3 have lymphocytic liver infiltration without autoantibody formation, while NOD mice with B10 resistance alleles only on chromosome 4 show autoantibody formation without liver infiltration. The liver disease is transferable to naive NOD.c3c4 recipients using splenocytes from affected NOD.c3c4 mice, demonstrating an autoimmune etiology. Thus, substitution of non-NOD genetic intervals into the NOD strain can prevent diabetes, but in turn cause an entirely different autoimmune syndrome, a finding consistent with a generalized failure of self-tolerance in the NOD genetic background. The complex clinical phenotypes in human autoimmune conditions may be similarly resolved into largely overlapping biochemical pathways that are then modified, potentially by alleles at a few key chromosomal regions, to produce specific autoimmune syndromes.
Division of Rheumatology and Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Syuichi
S
Koarada
Yuehong
Y
Wu
Noreen
N
Fertig
David A
DA
Sass
Michael
M
Nalesnik
John A
JA
Todd
Paul A
PA
Lyons
Judith
J
Fenyk-Melody
Daniel B
DB
Rainbow
Linda S
LS
Wicker
Laurence B
LB
Peterson
William M
WM
Ridgway
D019264:Adoptive Transfer; D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics*; D001660:Biliary Tract Diseases / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D005838:Genotype; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D016688:Mice, Inbred NOD; D010641:Phenotype
D000974:Antibodies, Antinuclear