Fatigue in primary Sjögren’s syndrome: A proteomic pilot study of cerebrospinal fluid

Larssen, Eivind; Brede, Cato; Hjelle, Anne; Tjensvoll, Anne Bolette; Norheim, Katrine Brække; Bårdsen, Kjetil; Jónsdóttir, Kristín; Ruoff, Peter; Omdal, Roald; Nilsen, Mari Mæland

doi:10.1177/2050312119850390

Cited by 18 publications

(13 citation statements)

References 53 publications

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“…There were five upregulated DEGs in our results, as shown in Figure 3 ( CFB, CFI, C2, C4A/B, and SERPING1) . CFB, a component of the alternative pathway of complement, is also increased in cerebrospinal fluid of patients with SS and fatigue ( 41 ). Both C2, C4A, and C4B proteins are known to participate in the generation of the classical complement pathway.…”

Section: Resultsmentioning

confidence: 99%

Differentially Expressed Gene Pathways in the Conjunctiva of Sjögren Syndrome Keratoconjunctivitis Sicca

et al. 2021

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Sjögren syndrome (SS) is an autoimmune condition that targets the salivary and lacrimal glands, with cardinal clinical signs of dry eye (keratoconjunctivitis sicca, KCS) and dry mouth. The conjunctiva of SS patients is often infiltrated by immune cells that participate in the induction and maintenance of local inflammation. The purpose of this study was to investigate immune-related molecular pathways activated in the conjunctiva of SS patients. Female SS patients (n=7) and controls (n=19) completed a series of oral, ocular surface exams. Symptom severity scores were evaluated using validated questionnaires (OSDI and SANDE). All patients fulfilled the ACR/EULAR criteria for SS and the criteria for KCS. Fluorescein and lissamine green dye staining evaluated tear-break-up time (TBUT), corneal and conjunctival disease, respectively. Impression cytology of the temporal bulbar conjunctiva was performed to collect cells lysed and subjected to gene expression analysis using the NanoString Immunology Panel. 53/594 differentially expressed genes (DEGs) were observed between SS and healthy controls; 49 DEGs were upregulated, and 4 were downregulated (TRAF5, TGFBI, KLRAP1, and CMKLRI). The top 10 DEGs in descending order were BST2, IFITM1, LAMP3, CXCL1, IL19, CFB, LY96, MX1, IL4R, CDKN1A. Twenty pathways had a global significance score greater or equal to 2. Spearman correlations showed that 29/49 upregulated DEGs correlated with either TBUT (inverse) or OSDI or conjunctival staining score (positive correlations). Venn diagrams identified that 26/29 DEGs correlated with TBUT, 5/26 DEGs correlated with OSDI, and 16/26 correlated with conjunctival staining scores. Five upregulated DEGs (CFB, CFI, IL1R1, IL2RG, IL4R) were uniquely negatively correlated with TBUT. These data indicate that the conjunctiva of SS patients exhibits a phenotype of immune activation, although some genes could be inhibitory. Some of the DEGs and pathways overlap with previous DEGs in salivary gland biopsies, but new DEGs were identified, and some of these correlated with symptoms and signs of dry eye. Our results indicate that gene analysis of conjunctiva imprints is a powerful tool to understand the pathogenesis of SS and develop new therapeutic targets.

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Section: Resultsmentioning

confidence: 99%

Differentially Expressed Gene Pathways in the Conjunctiva of Sjögren Syndrome Keratoconjunctivitis Sicca

et al. 2021

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“…The biological mechanisms involved in pSS fatigue are still not fully understood. Recent studies using proteomic analysis have shown the expression of proteins in the blood (SNAP-25, ENO1, UCHL1, IL-36a and complement factors) and in the CSF (apolipoprotein-A4, hemopexin, pigment epithelium-derived factor, secretogranin-1, secretogranin-3, selenium-binding protein-1, and complement factor B) in fatigued compared to non-fatigued pSS (13,26). 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.…”

Section: Discussionmentioning

confidence: 99%

“…Among these were apolipoprotein-A4, hemopexin, pigment epithelium-derived factor, secretogranin-1, secretogranin-3, selenium-binding protein-1, and complement factor B, with important roles in regulation of innate immunity, cellular stress defense, and/or functions in the central nervous system, and some downregulate inflammation. An important sleep regulator, Hypocretin-1, was also increased in pSS and can influence fatigue by an IL-1b independent mechanism (26).…”

Section: Biomarkers To Understand Fatiguementioning

confidence: 99%

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

et al. 2021

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Sjögren’s syndrome (SS) is an autoimmune disease affecting the salivary and lacrimal glands. Symptoms range from dryness to severe extra-glandular disease involving manifestations in the skin, lungs, nervous system, and kidney. Fatigue occurs in 70% of patients, characterizing primary SS (pSS) and significantly impacting the patient’s quality of life. There are some generic and specific instruments used to measure fatigue in SS. The mechanisms involved with fatigue in SS are still poorly understood, but it appears fatigue signaling pathways are more associated with cell protection and defense than with pro-inflammatory pathways. There are no established pharmacological treatment options for fatigue in pSS. So far, exercise and neuromodulation techniques have shown positive effects on fatigue in pSS. This study briefly reviews fatigue in pSS, with special attention to outcome measures, biomarkers, and possible treatment options.

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“… 32 34 38–42 There were no direct associations with SNPs in genes coding for cytokines in our data, but as discussed above the pathways of the immune system are complex and it is difficult to pinpoint one specific cytokine or molecule, rather a number of signalling pathways interact and generate fatigue. 32 …”

Section: Discussionmentioning

confidence: 58%

“…Complement factor B has been associated with fatigue in a proteomics study of cerebrospinal fluid (CSF) in pSS. 32 To further characterise a possible functional impact of genetic variants in pSS-related fatigue, we assessed gene and protein expression levels of RTP4 in pSS patients. Increased mRNA expression of RTP4 in patients compared with controls was found in peripheral B cells, supporting the hypothesis of a putative functional role for RTP4 in fatigue.…”

Section: Discussionmentioning

confidence: 99%

Genetic variants at the RTP4/MASP1 locus are associated with fatigue in Scandinavian patients with primary Sjögren’s syndrome

et al. 2021

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ObjectivesFatigue is common and severe in primary Sjögren’s syndrome (pSS). The aim of this study was to identify genetic determinants of fatigue in pSS through a genome-wide association study.MethodsPatients with pSS from Norway, Sweden, UK and USA with fatigue and genotype data available were included. After genotype imputation and quality control, 682 patients and 4 966 157 genetic markers were available. Association analysis in each cohort using linear regression with fatigue as a continuous variable and meta-analyses between the cohorts were performed.ResultsMeta-analysis of the Norwegian and Swedish cohorts identified five polymorphisms within the same linkage disequilibrium block at the receptor transporter protein 4 (RTP4)/MASP1 locus associated with fatigue with genome-wide significance (GWS) (p<5×10−8). Patients homozygous for the major allele scored 25 mm higher on the fatigue Visual Analogue Scale than patients homozygous for the minor allele. There were no variants associated with fatigue with GWS in meta-analyses of the US/UK cohorts, or all four cohorts. RTP4 expression in pSS B cells was upregulated and positively correlated with the type I interferon score. Expression quantitative trait loci effects in whole blood for fatigue-associated variants at RTP4/MASP1 and levels of RTP4 and MASP1 expression were identified.ConclusionGenetic variations at RTP4/MASP1 are associated with fatigue in Scandinavian pSS patients. RTP4 encodes a Golgi chaperone that influences opioid pain receptor function and MASP1 is involved in complement activation. These results add evidence for genetic influence over fatigue in pSS.

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Fatigue in primary Sjögren’s syndrome: A proteomic pilot study of cerebrospinal fluid

Cited by 18 publications

References 53 publications

Differentially Expressed Gene Pathways in the Conjunctiva of Sjögren Syndrome Keratoconjunctivitis Sicca

Differentially Expressed Gene Pathways in the Conjunctiva of Sjögren Syndrome Keratoconjunctivitis Sicca

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

Genetic variants at the RTP4/MASP1 locus are associated with fatigue in Scandinavian patients with primary Sjögren’s syndrome

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