Dissimilar background genes control susceptibility to autoimmune disease in the context of different MHC haplotypes: NOD.H‐2s congenic mice are relatively resistant to both experimental autoimmune encephalomyelitis and type I diabetes

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Abstract
Nonobese diabetic (NOD) mice develop multi‐organ autoimmune diseases, including type 1 diabetes. We hypothesized that backcrossing the MHC region from SJL (H‐2s) mice, which have an endogenous PLP139–151‐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 PLP139–151 repertoire in the NOD.S mice, they did not develop spontaneous EAE and were relatively resistant to PLP139–151‐induced EAE when compared to SJL mice. This resistance was associated with lower production of proinflammatory cytokines and a decreased expansion of PLP139–151‐specific CD4+ T cells after immunization and restimulation with PLP peptide in vitro. Vβ chain usage among PLP139–151‐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‐As. 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.

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