The Role of Interferons in the Pathogenesis of Sjögren’s Syndrome and Future Therapeutic Perspectives

Abstract

There is a great deal of evidence pointing to interferons (IFNs) as being key cytokines in the pathogenesis of different systemic autoimmune diseases, including primary Sjögren’s syndrome (pSS). In this disease, a large number of studies have shown that an overexpression of type I IFN, the ‘so-called’ type I IFN signature, is present in peripheral blood mononuclear cells, and that this finding is associated with the development of systemic extra-glandular manifestations, and a substantial production of autoantibodies and inflammatory cytokines. In contrast, the absence or a milder expression of type I IFN signature and low level of inflammatory cytokines characterizes patients with a different clinical phenotype, where the disease is limited to glandular involvement and often marked by the presence of widespread pain and depression. The role of type II (IFNγ) in this subset of pSS patients, together with the potentially related activation of completely different immunological and metabolic pathways, are emerging issues. Expression of both types of IFNs has also been shown in target tissues, namely in minor salivary glands where a predominance of type II IFN signature appeared to have a certain association with the development of lymphoma. In view of the role played by IFN overexpression in the development and progression of pSS, inhibition or modulation of IFN signaling has been regarded as a potential target for the therapeutic approach. A number of therapeutic compounds with variable mechanisms of action have been tested or are under consideration for the treatment of patients with pSS.

Understanding Fatigue in Sjögren’s Syndrome: Outcome Measures, Biomarkers and Possible Interventions

“…With important roles in regulation of innate immunity, cellular stress defense, and/or functions in the central nervous system, supporting the hypothesis that fatigue signaling pathways appear to be more associated with cell protection and defense than with pro-inflammatory pathways and cytokines. Future studies should try to confirm this hypothesis and explore the role of type II (IFN-g) and Kynurinines pathway (27)(28)(29). In this review we focus on biomarkers of the immune system involved in fatigue in pSS.…”

“…The role of type II interferons (IFN-g) in pSS is emerging in a subset of patients characterized by widespread pain, fatigue, and depression (27). Interferon-g is a major inducer of indoleamine 2,3 dioxygenase (IDO) in many cell types, including fibroblasts, endothelial cells, tumor cells, monocyte-derived macrophages, mesenchymal stromal cells, and dendritic cells.…”

DNA Methylation-Based Interferon Scores Associate With Sub-Phenotypes in Primary Sjögren’s Syndrome

“…Chloroquine interferes with endosomal TLR-signaling and inhibits plasma cell differentiation and class switch, but had no effect on symptoms of dryness, pain and fatigue in a previous study (38,41). Potential therapeutics within the IFN system are antibodies against IFN-a, the IFNAR1 subunit (Anifrolumab) or molecules targeting JAK1, TLR7 or IRAK4 (42,43). Sub-classification of patients who present with a high IFN system activation score and therefore could benefit particularly from IFN inhibition may be essential for future clinical trial outcomes.…”

Sjögren syndrome: looking forward to the future

“…anti-blood dendritic cell antigen 2, BIIB059). 167 The new-generation microRNA therapeutic approach might also play a future role. 168 – 170 Moreover, the interest should be extended to the simultaneous intervention targeting different pathogenetic pathways with biologic and conventional synthetic disease-modifying antirheumatic drugs, as supported by belimumab/rituximab double therapeutic approach 158 – 160 and the leflunomide-hydroxychloroquine association.…”