Experiment
Loci associated with susceptibility to sialitis were mapped in several crosses involving the autoimmune disease susceptible inbred strain NOD. This strain is a mouse model for insulin-dependent diabetes melitis but also exhibits a phenotype similar to Sjogren's syndrome, namely inflammatory infiltration and destruction of the salivary and lacrimal glands. In an (NOD x C57BL/6)F2 intercross, 156 markers at an average density of 10 cM mapped a major sialitis susceptibility locus, Ssial1, to central mouse Chromosome 1 with a LOD=4.8 at D1Mit11 (58.7 cM). Ssial1 spans 23.8 cM (D1Mit300) - 79 cM (D1Mit104) and colocalizes with Idd5 (~40 cM), a QTL associated with insulin dependent diabetes susceptibility. Bcl2 maps 1.1 cM from the peak linkage of Ssial1 and has previously been associated with sialitis. Bcl2 may be a possible candidate gene for Ssial1. NOD-derived alleles at Ssial1 confer recessive susceptibility to sialitis. The genotype NOD/NOD increases lymphocyte infiltration by 2X compared to F2 animals with a B6/B6 genotype. Ssial1 was also detected in the 2 crosses indicated below with LOD scores reaching suggestive linkage. The major effect of Ssial1 was confirmed in a congenic strain carrying an NOD-derived region centered on the Ssial1 locus from 29.7 cM (D1Mit18) - 62.1 cM (D1Mit26) on a C57BL/6 genetic background. This congenic recapitulates the sialitis phenotype seen in the NOD donor strain at 20 weeks of age. A second female-specific locus, Ssial4, mapped mouse Chromosome 17 in this cross. Ssial4 gives peak linkage to sialitis susceptibility with LOD=3.9 at Hsp70-1 (18.9 cM). NOD-derived alleles confer dominant susceptibility to sialitis at Ssial4. In an (NOD x C57BL/6)F1 x NOD backross population, a female-specific sialitis susceptibility locus, Ssial2, mapped to 19.2 cM on mouse Chromosome 3 with LOD=3.62 at Il2. This locus colocalized with Idd3 (19.2 cM) of which Il2 is a candidate gene. NOD-derived alleles confer sialitis susceptibility at Ssial2. Linkage analysis using an (NOD x NZW)F2 intercross and 87 markers mapped a male-specific sialitis susceptibility locus, Ssial3, to 58.7 cM on mouse Chromosome 7 with LOD=4.72 at D7Mit53. NOD-derived alleles confer recessive susceptibility to sialitis at Ssial3.
Analysis Tools