Dissimilar background genes control susceptibility to autoimmune disease in the context of different MHC haplotypes: NOD.H-2(s) congenic mice are relatively resistant to both experimental autoimmune encephalomyelitis and type I diabetes.
Nonobese diabetic (NOD) mice develop multi-organ autoimmune diseases, including type 1 diabetes. We hypothesized that backcrossing the MHC region from SJL (H-2(s)) mice, which have an endogenous PLP(139-151)-reactive repertoire, onto the background of autoimmune-prone NOD mice would result in a mouse strain that is highly susceptible to experimental autoimmune encephalomyelitis (EAE). Unexpectedly, although we detected an endogenous PLP(139-151) repertoire in the NOD.S mice, they did not develop spontaneous EAE and were relatively resistant to PLP(139-151)-induced EAE when compared to SJL mice. This resistance was associated with lower production of proinflammatory cytokines and a decreased expansion of PLP(139-151)-specific CD4(+) T cells after immunization and restimulation with PLP peptide in vitro. V(beta) chain usage among PLP(139-151)-reactive T cells differed between SJL and NOD.S mice. Furthermore, NOD.S mice were resistant to the development of insulitis and cyclophosphamide-induced diabetes, but not sialadenitis. Altogether, even though NOD mice develop spontaneous autoimmune diseases, they become relatively resistant to induction of EAE even when they express the EAE-permissive class II molecule I-A(s). Our data show that certain combinations of otherwise susceptibility-conferring MHC and non-MHC genes can mediate autoimmune-disease resistance when they are paired together. These findings do not support the "shared autoimmune gene" hypothesis.
Greve
Bernhard
B
Center for Neurologic Diseases, Harvard Institutes of Medicine, Brigham and Women's Hospital, Boston, MA 02120, USA.
Reddy
Jayagopala
J
Waldner
Hans-Peter
HP
Sobel
Raymond A
RA
Kuchroo
Vijay K
VK
D000818:Animals; D020296:Animals, Congenic; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D003520:Cyclophosphamide / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics*; D006649:Histocompatibility Antigens / Q000235:genetics / Q000378:metabolism; D007114:Immunization; D008285:Major Histocompatibility Complex / Q000235:genetics*; D051379:Mice; D016688:Mice, Inbred NOD; D018991:Myelin Proteolipid Protein / Q000737:chemistry / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
D016207:Cytokines; D006649:Histocompatibility Antigens; D018991:Myelin Proteolipid Protein; D003520:Cyclophosphamide