Systemic manifestations of primary Sjögren's syndrome in the NOD.B10Sn-H2/J mouse model

Abstract

Animal models that recapitulate human disease are crucial for the study of Sjögren’s Syndrome (SS). While several SS mouse models exist, there are few primary SS (pSS) models that mimic systemic disease manifestations seen in humans. Similar to pSS patients, NOD.B10Sn-H2b/J (NOD.B10) mice develop exocrine gland disease and anti-nuclear autoantibodies. However, the disease kinetics and spectrum of extra-glandular disease remain poorly characterized in this model. Our objective was to characterize local and systemic SS manifestations in depth in NOD.B10 female mice at early and late disease time points. To this end, sera, exocrine tissue, lung, and kidney were analyzed. NOD.B10 mice have robust lymphocytic infiltration of salivary and lacrimal tissue. In addition, they exhibit significant renal and pulmonary inflammation. We identified numerous autoantibodies, including those directed against salivary proteins. In conclusion, the NOD.B10 model recapitulates both local and systemic pSS disease and represents an excellent model for translational studies.

Myd88 is required for disease development in a primary Sjögren's syndrome mouse model

“…We then assessed ANA levels by both ELISA and Hep-2 staining. ANA levels increase with clinical disease in NOD.B10 females [26,28]. ANA-specific IgM ELISA results revealed diminished titers in NOD.B10 Myd882/2 mice compared with NOD.B10 and NOD.B10 Myd88+/2 animals (trend test P value = 0.00008; Fig.…”

“…Exocrine gland inflammation is a hallmark of SS patients [1,33] and is seen in NOD.B10 females with clinical disease, which occurs spontaneously by 26 wk of age [27,28]. We sought to determine whether NOD.B10 Myd882/2 mice with clinical disease (n = 6) had reduced sialadenitis compared with age-and gendermatched NOD.B10 and NOD.B10 Myd88+/2 animals (n = 9 and 11, respectively).…”

“…NOD.B10 Myd882/2 mice exhibit diminished pulmonary and renal inflammation NOD.B10 mice display extraglandular disease manifestations, including lymphocytic infiltration of pulmonary and renal tissue that is also observed in a subset of pSS patients [2,28]. To determine whether Myd88 activation contributes to systemic inflammation in pSS, we harvested lung and kidney tissue from NOD.B10 (n = 12), NOD.B10 Myd88+/2 (n = 10), and NOD.B10 Myd882/2 females with clinical disease (n = 8).…”

“…To determine whether pSS mice deficient in Myd88 were protected from SS disease, we generated NOD.B10 mice that lacked this adaptor. We used the NOD.B10 strain because SS pathogenesis in this model closely recapitulates the human disease, as these animals have a female disease predilection and develop both local and systemic disease spontaneously by 26 wk of age [26][27][28]. We found that NOD.B10 Myd882/2 females had attenuated disease, as lymphocytic infiltration was reduced in exocrine tissue, as well as in the lung and kidney.…”

Salivary‐gland‐protective regulatory T‐cell dysfunction underlies female‐specific sialadenitis in the non‐obese diabetic mouse model of Sjögren syndrome

“…Collectively, these studies demonstrate that the effects of testosterone on salivary and lacrimal gland autoimmunity in NOD mice are opposite and that testosterone is a key factor that drives lacrimal gland autoimmunity while protecting from salivary gland autoimmunity. Interestingly, in NOD mice modified to express the C57BL/10 mouse‐derived MHC locus (H2 b haplotype) in place of the NOD H2 g7 haplotype, female mice develop both salivary and lacrimal gland inflammation . Hence, comparing disease mechanisms in these NOD.B10 mice and wild‐type NOD mice may provide insight into both hormonal and non‐hormonal factors driving salivary and lacrimal gland disease.…”