Strain, Gender and Age Differences in Autoimmune Disease in Murine Models of Sjogren’s Syndrome

Abstract

Abstract: : Purpose: To define in quantitative terms the development of the autoimmune state in genetic mouse models of Sjogren’s syndrome (SS) and to determine the initial time of lacrimal dysfunction in these animals. Methods: Lacrimal glands were obtained from male and female NOD, NZB/WF1, and BALB/c mice at 1-7mo. Paraffin sections were stained with hematoxylin and eosin, imaged with an RT Spot digital camera and quantitatively analyzed with RT Spot Advanced imaging software (Diagnostic Instruments, Inc; Sterling Heights, MI). In separate experiments, lacrimal acini were obtained from NOD, NZB/WF1 and BALB/c males and females using 10 animals per group and cultured for three days. The secretory response of the cultured acini was measured in response to vehicle, 100µM carbachol or 100nM vasoactive intestinal peptide (VIP). Results: Lacrimal glands from 5-9 animals for each strain at each of the seven ages were analyzed (total n = 244). The initial occurrence of lymphocytic foci, average size of foci, and fraction of the gland infiltrated were recorded. Lymphocytic infiltrates first appeared in: NOD ♂’s at 2mo, (7/7); NOD ♀’s at 3mo, (1/6); NZB/WF1 ♂’s at 5mo, (1/6); NZB/WF1 ♀’s at 4mo, (1/7); and BALB/c ♀’s at 6mo, (1/8). No infiltrates occurred in BALB/c ♂’s at any age studied. The animals with infiltrates remained at 100% for NOD ♂’s until 7mo. The maximum percent affected in the remaining groups were: NOD ♀’s, 88% at 7mo; NZB/WF1 ♂’s, 83% at 6mo; NZB/WF1 ♀’s, 71% at 7mo; and BALB/c ♀’s, 16% at 6mo. The extent of disease at the end of the study (7mo) was greatest in NOD ♂’s. The average size of foci and percent section occupied by lymphocytes were: NOD ♂’s, 0.28mm² and 27.1%; NOD ♀’s, 0.03mm² and 0.61%; NZB/WF1 ♂’s, 0.03mm² and 0.91%; NZB/WF1 ♀’s, 0.07mm² and 6.9%; BALB/c ♀’s, 0.003 mm² and 0.20%. Physiologic assessment of lacrimal function by measurement of the secretory response to cholinergic or peptidergic agonists revealed no difference in response to 100µM carbachol or 100nM VIP in 1 or 3mo female NOD and NZB/WF1 mice compared to BALB/c controls. There was a significant (p < .001) difference in the secretory response of acini from 1mo NOD ♂’s as compared to BALB/c ♂ controls in response to carbachol (8.25 ± 0.74µg/ml vs 23.34 ± 1.45µg/ml) but not to VIP. Conclusions: The time course and extent of the development of SS-like disease is strain, gender and age dependent. These differences may provide an important paradigm for the dissection of individual factors that may contribute to the development of autoimmune disease. C.R.:none Support: NIH EY07380

Keywords: animal model • autoimmune disease • lacrimal gland