High incidence of autoimmune dacryoadenitis in male non-obese diabetic (NOD) mice depending on sex steroid

Abstract

SUMMARYThe NOD mouse develops spontaneous autoimmune lesions in the lacrimal and salivary glands, besides a well characterized T cell-mediated autoimmune pancreatic b cell lesion. We report unique pathological findings developed in the lacrimal glands as an autoimmune dacryoadenitis of NOD mice in contrast to those found in the salivary glands and pancreas. A high incidence of autoimmune lesions in the lacrimal glands was observed exclusively in male NOD mice at any age. Histology of autoimmune dacryoadenitis in male NOD mice showed severe destructive changes compared with those observed previously as an autoimmune lesion in the lacrimal glands. Castration in male NOD mice significantly decreased the incidence of autoimmune dacryoadenitis, and testosterone treatment with castration also increased the incidence of autoimmune lesions. Oestrogen treatment with castration did not increase the incidence, but tamoxifen treatment without castration significantly increased the incidence of autoimmune dacryoadenitis in NOD mice. In addition, we detected up-regulation of local cytokine genes (IL-1b, tumour necrosis factor-alpha (TNF-a), IL-2, interferon-gamma (IFN-g), IL-6, IL-10, and IL-12 p40) during the course of autoimmune dacryoadenitis. These data suggest that in spontaneous autoimmune dacryoadenitis of male NOD mice there may be an intimate relationship with sex steroids, particularly testosterone, in the development and progression of autoimmune lesions, and autoreactive Th1 cells secrete up-regulated cytokine genes, including IL-10 and IL-12.

Pathogenesis of Sjögren's Syndrome: Characteristics of Different Mouse Models for Autoimmune Exocrinopathy

“…A predominance of CD4 ϩ T lymphocytes over CD8 ϩ T lymphocytes and B lymphocytes was demonstrated in lymphocytic infiltrates in SMG and lacrimal glands of NOD mice (12,23,24). We demonstrated the infiltrates in the SMG of the NOD mouse to gain structure in time, with separate T cell and B cell areas.…”

“…In addition to lymphocytic infiltrates that develop in the pancreas, the presence of lymphocytic infiltrates in the SMG was reported (11). Other organs of the NOD mouse in which lymphocytic infiltrates have been found include the lacrimal glands and the thyroid (12,13). The incidence of diabetes and sialoadenitis in NOD females is higher than that in males, whereas dacryoadenitis developed more frequently in male mice (14,15).…”

Genetic Lesions in Thymic T Cell Clonal Deletion and Thresholds for Autoimmunity

“…NOD mice exhibit spontaneous Type 1 diabetes, sialitis and dacryoadenitis, and are highly susceptible to autoimmune encephalitis, prostatitis, autoimmune haemolytic anemia or systemic lupus upon exposure to particular exogenous challenges (Baker et al 1995;Baxter et al 1994;Boulard et al 2002;Braley-Mullen et al 1999;Oldenborg et al 2002;Ridgway et al 1996;Rivero et al 1998;Takahashi et al 1997;Wicker et al 1995;Zaccone et al 2002). Over 20 loci have been linked to diabetes development in the NOD mouse (Idd loci), some of which appear to specifically cause susceptibility to diabetes (eg Idd1), while others are associated with enhanced susceptibility to a range of autoimmune diseases (eg Idd3, Idd5).…”

The role of MUC1 splice variants in dry eye and inflammation.

“…The nonobese diabetic (NOD) mouse model has been extensively used to study Sjogren's syndrome (30). These mice show infiltration of CD4+ Th1 cells in the lacrimal glands and submandibular glands.…”

“…Inflammation is one of the core mechanisms causing dry eye disease, and it possible that MUClIA and MUClIB can differentially regulate the inflammatory response. MUCI alleles can be divided into size classes that contain small (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45) or large numbers of repeats.…”