Both type I and II interferons (IFNs) have been implicated in the pathogenesis of Sjogren's syndrome (SS). We aimed to explore the contribution of type I and II IFN signatures in the generation of distinct SS clinical phenotypes including lymphoma development. Peripheral blood (PB) from SS patients (n=31), SS patients complicated by lymphoma (n=13) and healthy controls (HC, n=30) were subjected to real-time PCR for 3 interferon inducible genes (IFIGs) preferentially induced by type I IFN, 2 IFIGs preferentially induced by IFNγ as well as for IFNα and IFNγ genes. The same analysis was performed in minor salivary gland tissues (MSG) derived from 31 SS patients, 10 SS-lymphoma patients and 17 sicca controls (SC). In PB and MSG tissues, overexpression of both type I and type II IFIGs was observed in SS patients versus HC and SC, respectively, with a predominance of type I IFN signature in PB and a type II IFN signature in MSG tissues. In SS-lymphoma MSG tissues, lower IFNα, but higher IFNγ and type II IFIG transcripts compared to both SS and SC were observed. In receiver operating characteristic curve analysis, IFNγ/IFNα mRNA ratio in MSG tissues showed the best discrimination for lymphoma development. Discrete expression patterns of type I and II IFN signatures might be related to distinct SS clinical phenotypes. Additionally, IFNγ/IFNα mRNA ratio in diagnostic salivary gland biopsies is proposed as a novel histopathological biomarker for the prediction of in situ lymphoma development in the setting of SS.
Sjögren's syndrome (SS) is a chronic autoimmune disorder that typically affects exocrine glands--mainly labial and lacrimal--leading to complaints of dry mouth and eyes. Given that periepithelial mononuclear cell infiltrates, both in exocrine glands and in other parenchymal organs (kidney, lung, and liver), are the histopathological disease hallmark, the term autoimmune epithelitis has been proposed. B cell hyperactivity is another cardinal SS feature manifested by the presence of autoantibodies and hypergammaglobulinemia, as well as clinical/serological phenotypes mediated by immune complexes, such as peripheral neuropathy, vasculitic lesions, and hypocomplementemia. These have been designated adverse predictors for lymphoma development in approximately 5% to 10% of patients. Activation of the type I interferon/B cell-activating factor axis in SS has recently attracted particular attention. Inappropriate overexpression of endogenous nucleic acids in a genetically susceptible individual might provide a plausible scenario for the immune activation observed in SS.
Objective
Increased type I interferon (IFN-I) and a broad signature of IFN-I-induced gene transcripts are observed in patients with SLE and other systemic autoimmune diseases. To identify disease-relevant triggers of the IFN-I pathway we investigated whether endogenous virus-like genomic repeat elements, normally silent, might be expressed in patients with systemic autoimmune disease, activate an innate immune response and induce IFN-I.
Methods
Expression of IFN-I and long interspersed nuclear element-1 (LINE-1; L1) was studied in kidney tissue from lupus patients and minor salivary gland (MSG) tissue from patients with primary Sjogren’s syndrome (SS) by PCR, western blot and immunohistochemistry. Induction of IFN-I by L1 was investigated by transfection of plasmacytoid dendritic cells (pDCs) or monocytes with an L1-encoding plasmid or L1 RNA. Involvement of innate immune pathways and altered L1 methylation were assessed.
Results
L1 mRNA transcripts were increased in lupus nephritis kidneys and in MSG from SS patients and correlated with IFN-I expression and L1 DNA demethylation. L1 open reading frame 1/p40 protein and IFNβ were expressed in MSG ductal epithelial cells and in lupus kidneys, and IFNα was detected in infiltrating pDCs. Transfection of pDCs or monocytes with L1-encoding DNA or RNA induced IFN-I. Inhibition of TLR7/8 reduced L1 induction of IFNα in pDCs and an inhibitor of IKKε/TBK1 abrogated induction of IFN-I by L1 RNA in monocytes.
Conclusion
L1 genomic repeat elements represent endogenous nucleic acid triggers of the IFN-I pathway in SLE and SS and may contribute to initiation or amplification of autoimmune disease.
Objective. Recent clinical trials suggest that etanercept is ineffective in controlling Sjögren's syndrome (SS). To address the hypothesis that tumor necrosis factor blockade can result in increased levels of interferon-␣ (IFN␣) and BAFF, we quantified those mediators in plasma from etanercept-and placebotreated SS patients.Methods. We studied plasma samples from 20 patients with SS treated with etanercept (25 mg twice weekly) or placebo in a 12-week, randomized, doubleblind clinical trial. In addition, we studied plasma samples from 29 healthy controls. IFN␣ activity was determined by reporter cell assay, and BAFF levels were determined by enzyme-linked immunosorbent assay.Results. Baseline IFN␣ plasma activity and BAFF levels were increased in SS patients compared with healthy controls (mean ؎ SD IFN␣ plasma activity score 4.43 ؎ 2.60 versus 2.08 ؎ 0.91; P < 0.0001) (mean ؎ SD BAFF level 0.83 ؎ 0.27 ng/ml versus 0.60 ؎ 0.15 ng/ml; P ؍ 0.008). A significant increase in IFN␣ activity was detected after 12 weeks of treatment in the etanercept group, but not in the placebo group (P ؍ 0.04 and P ؍ 0.58, respectively). Furthermore, a statistically significant increase in BAFF levels was noted in patients receiving etanercept, but not in those receiving placebo (P ؍ 0.01 and P ؍ 0.56, respectively). In vitro culture of control peripheral blood mononuclear cells with etanercept resulted in a dose-dependent increase in the expression of IFN␣ and the IFN␣-inducible genes IFNinduced protein with tetratricopeptide repeats 1 and BAFF.Conclusion. IFN␣ activity and BAFF levels are elevated in the plasma of patients with SS compared with healthy controls. Etanercept treatment exacerbates IFN␣ and BAFF overexpression, providing a possible explanation for the lack of efficacy of this agent in SS.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.