Development of novel Sjogren's Syndrome susceptible mouse lines expressing floxed COX-2 within the major Aec2 disease susceptibility region in chromosome 1 (P4016)

Abstract

Abstract SS patients exhibit impaired exocrine gland function and high risk for B cell lymphoma. IgG autoAbs to acetylcholine receptors, detectable in humans, impair salivation in SS-afflicted mice with NOD Aec2 and Aec1 susceptibility loci. COX-2 is a potential target for reducing SS pathogenic IgG Ab and B cell lymphoma, since (a) within in vitro cultures B cell-expressed COX-2 and PGE2 augment DNA-modifying AID and downstream IgG switching and (b) mice deficient in COX-2 have reduced IgG. If B cell specific COX-2 function is critical for SS disease, cell-targeted delivery of inhibitors might circumvent adverse side effects. With a downstream goal of examining whether B cell COX-2 contributes to autoimmunity, we introduced a floxed COX-2 gene and a CD19Cre gene independently onto the NOD.B10-H2b SS-susceptible background. To our surprise, early congenic lines HET for either CD19Cre or COX-2flox failed to show aging-related hyposalivation (xerostomia), in contrast to wild-type NOD.B10. Reduced disease in CD19cre HET mice might reflect haplodiploid CD19 or flanking non-NOD genes. Extended backcrossing of COX-2flox onto NOD.B10 yielded two congenic lines that are comparable to wild-type NOD.B10 in developing xerostomia upon aging. Fine genetic mapping of the chr 1 Aec2 region within the novel COX-2flox lines showed that (a) variations in COX-2 do not explain the observed diversity and (b) unidentified genes within a presently more narrowed Aec2 interval are important for xerostomia.