Genetics and epigenetics of primary Sjögren syndrome: implications for future therapies

Abstract

In primary Sjögren syndrome (pSS), chronic inflammation of exocrine glands results in tissue destruction and sicca symptoms, primarily of the mouth and eyes. Fatigue, arthralgia and myalgia are also common symptoms, whereas extraglandular manifestations that involve the respiratory, nervous and vascular systems occur in a subset of patients. The disease predominantly affects women, with an estimated female to male ratio of 14 to 1. The aetiology of pSS, however, remains incompletely understood, and effective treatment is lacking. Largescale genetic and epigenetic investigations have revealed associations between pSS and genes in both innate and adaptive immune pathways. The genetic variants mediate context-dependent effects, and both sex and environmental factors can influence the outcome. As such, genetic and epigenetic studies can provide insight into the dysregulated molecular mechanisms, which in turn might reveal new therapeutic possibilities. This Review discusses the genetic and epigenetic features that have been robustly connected with pSS, putting them into the context of cellular function, carrier sex and environmental challenges. In all, the observations point to several novel opportunities for early detection, treatment development and the pathway towards personalized medicine. Key points• Advances in the past few years provide new insight into the genetic and epigenetic basis of primary Sjögren syndrome (pSS), and how environmental factors and carrier sex might interact with risk-associated loci.• Immunomodulatory treatments that affect disease progression and activity have not been identified for pSS and remain unmet clinical needs.• Data from genetic and epigenetic studies point to Toll-like receptor and interferon signalling, lymphocyte regulation, antigen presentation and target tissue maintenance as the most relevant processes for therapeutic targeting.• Of the implicated pathogenic processes, Toll-like receptor and interferon signalling, as well as lymphocyte regulation, contain targets of various treatments in development or in clinical trials.• Novel treatment approaches for pSS could include modification of epigenetic signatures, interference with antigen presentation pathways and antigen-specific immunotherapy.Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author selfarchiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Variants in theDDX6-CXCR5autoimmune disease risk locus influence the regulatory network in immune cells and salivary gland

“…To further evaluate the co-inheritance of the index SNP and other possible functional variants within the region, the haplotype structure was examined. Co-inheritance in European ancestry ( D’ ≥ 0.89) and LD ( r 2 =0.64-0.99) between several shared SNPs were observed ( Supplemental Figure 2A-C ) with the exception of rs480958 ( D’ ≤0.81; r 2 ≤11), which was previously associated with SLE of East Asian ancestry ( Supplemental Figure 2D-F ) 22 . Strong co-inheritance of SNPs spanning the risk locus may explain why the Bayesian analyses were unable to sufficiently refine the association and predict likely functional SNPs.…”

“…from mean) and relatedness determined by identity-by-descent (IBD) >0.4 using PLINK (v1.9) 61 were excluded. EIGENSTRAT 62 was used to identify population substructure using independent genetic markers ( r 2 <0.2 between variants).…”

“…CXCR5 (C-X-C chemokine receptor type 5) is an important modulator of B and T follicular cell trafficking to peripheral lymphoid organs 26 . Loss of CXCR5 expression has been reported in purified circulating CD19 + B cells isolated from SjD patients homozygous for the risk allele (T) of rs4938573 27 ; a proxy in strong linkage disequilibrium (LD; r 2 =0.865) with the top associated SNP, rs7119038, of the DDX6-CXCR5 SjD risk interval 21 . Loss of CXCR5 was inversely correlated with increased homing of CXCR5 + cells to the salivary gland 27 , suggesting a potential SjD-specific role for this risk interval.…”

Diagnostic value of the saliva immunoglobulin free light chains concentrations measured in primary Sjцgren's syndrome

“…2 1 Almazov National Medical Research Centre, Ministry of Health of Russia, St. Petersburg; 2 розом, ревматоидным артритом [6]. В то же время они отсутствуют у 27% пациентов с ПСШ [4,7]. Биопсия МСЖ и получение периферической кровиинвазивные процедуры.…”

“…Гистологическое и лабораторное исследования обладают наибольшим диагностическим удельным весом, но имеют недостатки. Изменения в биоптатах МСЖ у 23,3-30,1% больных с ПСШ не соответствуют установленным гистологическим критериям, и патоморфологический диагноз во многом зависит от опыта морфолога [3][4][5]. После проведения биопсии МСЖ возможны осложнения в месте выполнения вмешательства [3].…”