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

Abstract

IntroductionTo 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.MethodsCD25/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.ResultsγDKO 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.ConclusionsThe 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.

Interferon gamma in autoimmunity: A complicated player on a complex stage

“…There is strong evidence for the involvement of both Type I and Type II interferons in SjS pathogenesis [165,166]. Further deficiency in IFNc ameliorates disease in SjS mouse models [167][168][169]. Interestingly, deficiency in IL-4 expression also ameliorates disease in one model, with the defect occurring at a later stage of disease [170].…”

Ageing and ocular surface immunity

“…19 Studies using human subjects as well as animal models suggest that these guardians of the ocular surface integrity are affected in the course of ageing; for example, the lacrimal gland is affected due to exposure to oxidative stress. [20][21][22][23][24][25][26][27] Age-related physiological changes of the ocular surface have been reported; [25][26][27][28] however, the effect of ageing on ocular surface immunity remains poorly understood. Immunological mechanisms play a pivotal role in regulating the ocular surface environment as well.…”

T helper cytokines in dry eye disease

“…IFN-γ has been proposed as a biomarker for dry eye disease and Sjögren syndrome (SS) because elevated IFN-γ, either protein and/or RNA, has been detected in tears, saliva, conjunctiva, submandibular glands and blood [tears (Boehm et al, 2011; Corrales et al, 2007; de Paiva et al, 2007a; Enriquez-de-Salamanca et al, 2010; Lam et al, 2008; Massingale et al, 2009; Mrugacz et al, 2006; Riemens et al, 2012), conjunctiva (Chen et al, 2011; Chen et al, 2006; Corrales et al, 2007; de Paiva et al, 2007a; Zhang et al, 2011b) , saliva (Kang et al, 2011; Pertovaara et al, 2006), lacrimal (de Paiva et al, 2010a; Hayashi et al, 2012; Jie et al, 2010; Ogawa et al, 2002; Pelegrino et al, 2012; Rahimy et al, 2010b; Viau et al, 2011) submandibular glands (Brookes et al, 1995; Hayashi et al, 2012; Koarada et al, 2006; Kohashi et al, 2008; Mrugacz et al, 2006), and blood (Hagiwara et al, 1998; Szodoray et al, 2008)] Evidence from mouse models and human SS patients indicate that IFN-γ is a relevant therapeutic target (de Paiva et al, 2007; de Paiva et al, 2011; Ogawa et al, 2002). …”

“…IFN-γ expression has been evaluated in minor salivary glands of human SS patients, as well as lacrimal and submandibular (SMG) gland biopsies in animal models. Virtually every mouse autoimmune model that mimics SS, or even environmentally-induced mouse dry eye models have shown increased expression of IFN-γ in submandibular and/or lacrimal glands (de Paiva et al, 2010a; Hayashi et al, 2012; Jie et al, 2010; Kohashi et al, 2008; Mitsias et al, 2002; Ogawa et al, 2002; Pelegrino et al, 2012; Rahimy et al, 2010b; Viau et al, 2011). In cultured labial salivary gland biopsies obtained from SS patients, the concentration of IFN-γ, but not IL-13, was associated with greater lymphocytic infiltration (Mitsias et al, 2002).…”