Two NOD Idd-associated intervals contribute synergistically to the development of autoimmune exocrinopathy (Sjögren's syndrome) on a healthy murine background

Abstract

Objective: The NOD mouse is genetically predisposed to the development of at least 2 autoimmune diseases, autoimmune diabetes and autoimmune exocrinopathy (AEC). More than 19 chromosomal intervals (referred to as Idd regions) that contribute to diabetes susceptibility in the NOD mouse model have been identified, but only 2 chromosomal intervals (associated with Idd3 and Idd5) have been shown to control sialadenitis. In the present study, we bred the Idd3 and Idd5 chromosomal intervals from NOD mice into non-autoimmune C57BL/6 mice to determine if these intervals recreate a Sjögren's syndrome (SS)-like phenotype.

Methods: C57BL/6.NODc3 mice carrying Idd3 and C57BL/6.NODc1t mice carrying Idd5 were crossed and intercrossed to generate a C57BL/6.NODc3.NODc1t mouse line homozygous for the Idd3 and Idd5 chromosomal intervals on an otherwise disease-resistant genetic background. C57BL/6.NODc3.NODc1t mice were evaluated for biochemical, pathophysiologic, and immunologic markers characteristic of the SS-like phenotype present in the NOD mouse.

Results: C57BL/6.NODc3.NODc1t mice fully manifested the SS-like phenotype of the NOD mouse, including decreased salivary and lacrimal gland secretory flow rates, increased salivary protein content due in part to less fluid, aberrant proteolytic enzyme activity, decline in amylase activity, appearance of autoantibodies to exocrine gland proteins, and glandular lymphocytic focal infiltrates. Loss of secretory function occurred more rapidly in C57BL/6.NODc3.NODc1t mice (by 12 weeks of age) than in NOD mice (by 16 weeks of age). No signs of insulitis or autoimmune (type 1) diabetes were observed in the C57BL/6.NODc3.NODc1t mice.

Conclusion: Genes located within the 2 chromosomal intervals Idd3 and Idd5 appear necessary and sufficient for manifestation of AEC. We propose that this murine model of SS-like disease be designated C57BL/6.NOD-Aec1Aec2. Identification of specific genes within the Aec1 and Aec2 genetic regions should help elucidate the mechanism(s) underlying SS-like disease.