Deletion of interferon-γ delays onset and severity of dacryoadenitis in CD25KO mice

INTRODUCTION: To investigate the role of interferon-gamma (IFN-γ) in the onset and severity of dacryoadenitis in the CD25 knockout (KO) mouse model of Sjögren Syndrome. METHODS: CD25/IFN-γ double KO (γDKO) mice were created by crossbreeding CD25KO and IFN-γKO mice. Mice were used at 8, 12, and 16 weeks. Lacrimal gland (LG) infiltrating lymphocytes were characterized with flow cytometry. Tear epidermal growth factor (EGF) concentration was measured with enzyme-linked immunosorbent assay (ELISA). Quantitative polymerase chain reaction (PCR) evaluated T-cell-related cytokines in LGs. Serum autoantibodies against M3R in LG lysates were detected with Western blot. RESULTS: γDKO LG showed lower lymphocytic infiltration at 8 weeks than in the CD25KO parental strain (˜20% versus ˜60%, respectively), which increased to CD25KO levels at 16 weeks. Flow-cytometry analysis showed an increase in CD4(+ )and CD8(+ )T cells with aging in γDKO LG, similar to that in CD25KO. γDKO had lower levels of interleukin (IL)-17A, transforming growth-factor (TGF)-β1, IL-21, and CCL20, and higher IL-1β and IL-13 mRNA transcripts in the LG than in the parental CD25KO strain. Autoantibodies to M3R were observed in both strains and significantly increased with aging in both strains. CD25KO mice had very low tear EGF concentrations at all ages, whereas the ear EGF concentration in γDKO mice significantly decreased with aging and inversely correlated with the presence of M3R autoantibodies and the degree of LG CD4 and CD8(+ )T-cell infiltration. CONCLUSIONS: The deletion of IFN-γ in the CD25KO mice strain delays glandular destruction and preserves glandular function. M3R autoantibodies increased with aging in both the γDKO and the CD25KO strains. The decrease in LG function in γDKO correlated with the degree of T-cell infiltration and the presence of M3R autoantibodies.