Genetic Analysis of Autoimmune Sialadenitis in Nonobese Diabetic Mice: A Major Susceptibility Region on Chromosome 1

The nonobese diabetic (NOD) mouse strain provides a good study model for Sjogren’s syndrome (SS). The genetic control of SS was investigated in this model using different matings, including a (NOD × C57BL/6 (B6))F 2 cross, a (NOD × NZW)F 2 cross, and ((NOD × B6) × NOD) backcross. Multiple and different loci were detected depending on parent strain combination and sex. Despite significant complexity, two main features were prominent. First, the middle region of chromosome 1 (chr.1) was detected in all crosses. Its effect was most visible in the (NOD × B6)F 2 cross and dominated over that of other loci, including those mapping on chr.8, 9, 10, and 16; the effect of these minor loci was observed only in the absence of the NOD haplotype on chr.1. Most critically, the chr.1 region was sufficient to trigger an SS-like inflammatory infiltrate of salivary glands as shown by the study of a new C57BL/6 congenic strain carrying a restricted segment derived from NOD chr.1. Second, several chromosomal regions were previously associated with NOD autoimmune phenotypes, including Iddm (chr.1, 2, 3, 9, and 17, corresponding to Idd5 , Idd13 , Idd3 , Idd2 , and Idd1 , respectively), accounting for the strong linkage previously reported between insulitis and sialitis, and autoantibody production (chr.10 and 16, corresponding to Bana2 and Bah2 , respectively). Interestingly, only two loci were detected in the (NOD × NZW)F 2 cross, on chr.1 in females and on chr.7 in males, probably because of the latent autoimmune predisposition of the NZW strain. Altogether these findings reflect the complexity and heterogeneity of human SS.