Mechanisms and New Strategies for Primary Sjögren's Syndrome

Primary Sjögren's syndrome (SS) is a common chronic autoimmune disease characterized by lymphocytic infiltration of exocrine glands, mainly salivary and lacrimal, resulting in oral and ocular dryness, although virtually any organ system can be affected. SS-related systemic manifestations are classified as either related to the presence of periepithelial infiltrates in exocrine and parenchymal organs or resulting from immunocomplex deposition due to B cell hyperactivity with increased risk for B cell lymphoma development. Activation of both innate and adaptive immune pathways contributes to disease pathogenesis, with prominent interferon (IFN) signatures identified in both peripheral blood and affected salivary gland tissues. Recently, LINE-1 genomic repeat elements have been proposed as potential triggers of type I IFN pathway activation in SS through activation of Toll-like receptor-dependent and -independent pathways. In view of the increasingly appreciated variability of SS, elucidation of distinct operating pathways in relation to diverse clinical phenotypes and selection of the optimal therapeutic intervention remain major challenges. Inhibition of cathepsin S molecules, blockade of costimulation through administration of abatacept and inhibitors of B7-related molecules and CD40, blockade of B cell function and B cell survival factors, and disruption of the formation of ectopic germinal centers are considered the main therapeutic targets. Well-controlled multicenter clinical trials are ongoing and data are awaited. © 2017 by Annual Reviews. All rights reserved

Activation of the type I interferon pathway in primary Sjogren's syndrome

Sjogren's syndrome (SS), a chronic autoimmune systemic disease affecting middle aged women, is characterized by lymphocytic infiltration of the salivary and lachrymal glands resulting in dry eyes and dry mouth. Recent advances have revealed a major role for activation of the type I interferon (IFN) pathway in the pathogenesis of the syndrome, as evidenced by the increased circulating type I IFN activity and an IFN "signature" in peripheral blood mononuclear cells (PBMC) and minor salivary gland (MSG) biopsies from these patients. Polymorphisms in genes involved in the IFNα pathway, such as IRF5 and STAT4, have been found to be associated with disease susceptibility. While the initial triggers of the innate immune response in SS remain elusive, preliminary evidence supports the role of inappropriately expressed endogenous LINE-1 (L1) retroelements as potential triggers of type I IFN activation in SS, possibly through Toll-like receptor (TLR) dependent or independent pathways. Proteins of the methylation machinery and the APOBEC family of cytidine deaminases are coordinately overexpressed, suggesting that those proteins might contribute to regulation of the inappropriately expressed L1 endogenous retroelements in SS. Given the apparent central role of IFNα in the pathogenesis of SS, blockade of this cytokine may be a rational therapeutic approach. In the current review we summarize the current evidence regarding the potential triggers of type I IFN activation as well as the data supporting genetic and epigenetic regulation of the type I IFN system in SS. © 2010 Elsevier Ltd

Activation of the type i interferon pathway in primary Sjögren's syndrome: An update

Purpose of Review: Recent advances suggest type I interferon (IFN) pathway as an emerging mediator of systemic autoimmunity. This review aims to summarize the latest developments in the biology of type I IFN pathway and its contributory role in the pathogenesis of autoimmune disorders with a particular focus on Sjögren's syndrome. Recent Findings: Increased circulating type I IFN levels along with upregulated type I IFN inducible genes in salivary gland tissues, peripheral blood and mononuclear cells suggest activation of type I IFN pathway in Sjögren's syndrome. Additional regulatory mechanisms and novel potential suppressors of type I IFN production provide new insights into disease pathogenesis, pointing to type I IFN system as a potential new therapeutic target. Summary: Compelling evidence suggests type I IFN as a key player in pathogenesis of Sjögren's syndrome and an attractive potential therapeutic target. Meticulous stratification of patient subgroups characterized by activation of type I IFN pathway should be performed in carefully designed translational studies. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins

Contribution of Genetic Factors to Sjögren's Syndrome and Sjögren's Syndrome Related Lymphomagenesis

We aimed to summarize the current evidence related to the contributory role of genetic factors in the pathogenesis of Sjögren's syndrome (SS) and SS-related lymphoma. Genes within the major histocompatibility complex (MHC) locus previously considered conferring increased susceptibility to SS development have been also revealed as important contributors in recent genome wide association studies. Moreover, genetic variations outside the MHC locus involving genes in type I interferon pathway, NF-B signaling, B- and T-cell function and methylation processes have been shown to be associated with both SS and SS-related lymphoma development. Appreciating the functional implications of SS-related genetic variants could provide further insights into our understanding of SS heterogeneity, allowing the design of tailored therapeutic interventions. © 2015 Adrianos Nezos and Clio P. Mavragani

A case of antisynthetase syndrome

Respiratory complaints alone or in association with musculoskeletal complaints can be the predominant presenting feature of antisynthetase syndrome. Therefore, antibodies to cellular antigens should be evaluated in such clinical settings. © 2020 The Authors. Clinical Case Reports published by John Wiley & Sons Lt

The geoepidemiology of Sjögren's syndrome

Sjogren's syndrome (SS) is a slowly progressing autoimmune disease, affecting predominantly middle-aged women, with a female to male ratio reaching 9:1. It is characterized by lymphocytic infiltration of the exocrine glands, mainly the lacrimal and salivary glands, resulting in reduced secretory functions and oral and ocular dryness. The syndrome can present alone as primary SS (pSS) or in the context of underlying connective tissue disease as secondary SS (sSS). While the pathogenesis of the disease remains elusive, environmental, genetic and hormonal contributors seem to be involved. Over the last years, compelling evidence has suggested a pivotal role of the epithelium in orchestrating the immune response in the histopathological lesion of Sjogren's syndrome and the term "autoimmune epithelitis" has been proposed as an etiological term. Although the clinical manifestations of pSS patients are mainly those of an autoimmune exocrinopathy, almost half of patients develop extraglandular disease, which may be manifested either by epithelial lymphocytic invasion of lung, liver, or kidney (resulting in interstitial nephritis) or by skin vasculitis, peripheral neuropathy, glomerulonephritis, and low C4 levels. The latter reflect immune-complex mediated disease and confer increased risk for lymphoma development. © 2009 Elsevier B.V. All rights reserved