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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.
Insights
Removing interferon-gamma (IFN-γ) in CD25 knockout mice delays lacrimal gland damage and preserves function in a Sjögren syndrome model. Autoantibodies and T-cell infiltration still increased with age, impacting tear production.
Area of Science:
- Immunology
- Ophthalmology
- Autoimmune Diseases
Background:
- Sjögren Syndrome (SS) is an autoimmune disorder affecting exocrine glands.
- Dacryoadenitis, inflammation of the lacrimal gland, is a key feature of SS.
- The role of interferon-gamma (IFN-γ) in SS-related dacryoadenitis is not fully understood.
Purpose of the Study:
- To investigate the role of IFN-γ in the onset and severity of dacryoadenitis.
- To evaluate the impact of IFN-γ deletion on lacrimal gland function and immune cell infiltration in a CD25 knockout (KO) mouse model of SS.
Main Methods:
- Created CD25/IFN-γ double KO (γDKO) mice by crossbreeding CD25KO and IFN-γKO strains.
- Analyzed lacrimal gland (LG) infiltrating lymphocytes using flow cytometry at 8, 12, and 16 weeks.
- Measured tear epidermal growth factor (EGF) via ELISA, T-cell cytokines via PCR, and serum autoantibodies against M3R via Western blot.
Main Results:
- γDKO mice exhibited lower lymphocytic infiltration at 8 weeks compared to CD25KO mice (20% vs. 60%), which increased with age.
- γDKO mice showed altered T-cell cytokine profiles, with lower IL-17A, TGF-β1, IL-21, CCL20 and higher IL-1β, IL-13 mRNA.
- Tear EGF concentration decreased with age in γDKO mice, correlating inversely with M3R autoantibodies and T-cell infiltration.
Conclusions:
- IFN-γ deletion delays glandular destruction and preserves lacrimal gland function in the CD25KO mouse model.
- M3R autoantibodies increased with age in both γDKO and CD25KO strains.
- Reduced lacrimal gland function in γDKO mice correlated with T-cell infiltration and M3R autoantibodies.