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- Björk, Albin, et al.
(författare)
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Protein and DNA methylation-based scores as surrogate markers for interferon system activation in patients with primary Sjögren's syndrome
- 2020
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Ingår i: RMD Open. - : BMJ PUBLISHING GROUP. - 2056-5933. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Standard assessment of interferon (IFN) system activity in systemic rheumatic diseases depends on the availability of RNA samples. In this study, we describe and evaluate alternative methods using plasma, serum and DNA samples, exemplified in the IFN-driven disease primary Sjogren's syndrome (pSS).Methods: Patients with pSS seropositive or negative for anti-SSA/SSB and controls were included. Protein-based IFN (pIFN) scores were calculated from levels of PD-1, CXCL9 and CXCL10. DNA methylation-based (DNAm) IFN scores were calculated from DNAm levels at RSAD2, IFIT1 and IFI44L. Scores were compared with mRNA-based IFN scores measured by quantitative PCR (qPCR), Nanostring or RNA sequencing (RNAseq).Results: mRNA-based IFN scores displayed strong correlations between B cells and monocytes (r=0.93 and 0.95, p<0.0001) and between qPCR and Nanostring measurements (r=0.92 and 0.92, p<0.0001). The pIFN score in plasma and serum was higher in patients compared with controls (p<0.0001) and correlated well with mRNA-based IFN scores (r=0.62-0.79, p<0.0001), as well as with each other (r=0.94, p<0.0001). Concordance of classification as 'high' or 'low' IFN signature between the pIFN score and mRNA-based IFN scores ranged from 79.5% to 88.6%, and the pIFN score was effective at classifying patients and controls (area under the curve, AUC=0.89-0.93, p<0.0001). The DNAm IFN score showed strong correlation to the RNAseq IFN score (r=0.84, p<0.0001) and performed well in classifying patients and controls (AUC=0.96, p<0.0001).Conclusions: We describe novel methods of assessing IFN system activity in plasma, serum or DNA samples, which may prove particularly valuable in studies where RNA samples are not available.
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- Brauner, Susanna, et al.
(författare)
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H1N1 vaccination in Sjogren's syndrome triggers polyclonal B cell activation and promotes autoantibody production
- 2017
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 76:10, s. 1755-1763
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesVaccination of patients with rheumatic disease has been reported to result in lower antibody titres than in healthy individuals. However, studies primarily include patients on immunosuppressive therapy. Here, we investigated the immune response of treatment-naive patients diagnosed with primary Sjogren's syndrome (pSS) to an H1N1 influenza vaccine.Methods Patients with Sjogren's syndrome without immunomodulatory treatment and age-matched and gender-matched healthy controls were immunised with an H1N1 influenza vaccine and monitored for serological and cellular immune responses. Clinical symptoms were monitored with a standardised form. IgG class switch and plasma cell differentiation were induced in vitro in purified naive B cells of untreated and hydroxychloroquine-treated patients and healthy controls. Gene expression was assessed by NanoString technology.ResultsSurprisingly, treatment-naive patients with Sjogren's syndrome developed higher H1N1 IgG titres of greater avidity than healthy controls on vaccination. Notably, off-target B cells were also triggered resulting in increased anti-EBV and autoantibody titres. Endosomal toll-like receptor activation of naive B cells in vitro revealed a greater propensity of patient-derived cells to differentiate into plasmablasts and higher production of class switched IgG. The amplified plasma cell differentiation and class switch could be induced in cells from healthy donors by preincubation with type 1 interferon, but was abolished in hydroxychloroquine-treated patients and after in vitro exposure of naive B cells to chloroquine.ConclusionsThis comprehensive analysis of the immune response in autoimmune patients to exogenous stimulation identifies a mechanistic basis for the B cell hyperactivity in Sjogren's syndrome, and suggests that caution is warranted when considering vaccination in non-treated autoimmune patients.
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- Mofors, Johannes, et al.
(författare)
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Cigarette smoking patterns preceding primary Sjögren's syndrome
- 2020
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Ingår i: RMD Open. - : BMJ Publishing Group Ltd. - 2056-5933. ; 6:3
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cigarette smoking is a well-established risk factor for several autoimmune diseases, but its role in primary Sjogren's syndrome (pSS) remains unclear. Here, we investigated the association between cigarette smoking and subsequent development of pSS.Methods: Information on smoking habits was collected from lifestyle habit questionnaires of patients with pSS (n=815) and a matched control group (n=4425) for a case-control study. Differences in smoking exposure were analysed by conditional logistic regression. Potential interactions between smoking and risk-associated human leucocyte antigens (HLA) were assessed by multivariate regression.Results: The fraction of patients with pSS having ever smoked prior to diagnosis was lower than in controls (OR 0.67, 95% CI 0.55 to 0.81). Current smoking at diagnosis was also less prevalent in cases (OR 0.37, 95% CI 0.26 to 0.53). However, period prevalence of smoking during early adulthood was not statistically different from controls (OR 0.89, 95% CI 0.66 to 1.22) but markedly decreased over time. This was partly due to patients being more prone to stop smoking, starting already 30 years prior to diagnosis (OR 2.01, 95% CI 1.22 to 3.30). Smoking patterns were also stratified by autoantibody status, yielding similar estimates. No interaction effects between HLA-DRB1 haplotypes and smoking were observed.Conclusion: The observed smoking patterns indicate that individuals who develop pSS smoke equally much as the general population during early life but are then more prone to stop. The data can be interpreted as smoking conferring protective effects, or reflecting early symptoms of pSS that affect smoking habits, emphasising the slow, progressive development of the disease.
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| 9. |
- Mofors, Johannes
(författare)
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Risk factors and comorbidity in primary Sjögren’s syndrome
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Primary Sjögren’s syndrome is an autoimmune disease, in which the immune system targets the exocrine glands. The disease is characterized by inflammation and dysfunction of the salivary and lacrimal glands, leading to dry eyes and mouth. The etiopathogenesis of autoimmune diseases is not entirely known. Genetic factors, primarily relating to the immune system, are central in the development of disease. In Sjögren’s syndrome, such genetic variations are associated with the production of autoantibodies to the Ro/SSA and La/SSB autoantigens and a more aggressive course of the disease. However, environmental factors are also involved in the development of autoimmunity. Viruses, smoking, alcohol and radiation include some of the more frequently proposed risk factors, although a causal relationship remains to be been proven. To expand the current understanding of environmental risk factors, the relationship between exposure to infections and smoking and the development of Sjögren’s syndrome were investigated in Study I and Study II, respectively. A clear association between infections and subsequent development of Sjögren’s syndrome was observed, as a history of infections was significantly more prevalent in individuals with Sjögren’s syndrome compared to controls from the general population. Notably, this association was even more prominent in patients who developed Ro/SSA and La/SSB autoantibodies. Exposure to smoking could however not be linked to an increased risk of the disease, despite the wellknown association with development of other rheumatic diseases. Rather, we observed that individuals who developed Sjögren's syndrome were more prone to stop smoking during the decades preceding diagnosis. This finding may indicate that the appearance of very early symptoms of the disease leads to the discontinuation of smoking. Sjögren’s syndrome is a systemic disease, and may cause adverse events in various organ systems. The risk of cardiovascular and hematological disease in patients with Sjögren’s syndrome was analyzed using the Swedish national health-care registers in Study III and Study IV, respectively. Compared to the general population, individuals with Sjögren’s syndrome had a significantly increased risk of myocardial infarction, cerebral infarction, and venous thromboembolism. Moreover, the results indicate that Ro/SSA and La/SSB autoantibodies demark the subgroup of patients with the highest risk of cardiovascular comorbidity. Similarly, an increased risk of multiple myeloma was observed in patients with Sjögren’s syndrome, which was confined to individuals with Ro/SSA and La/SSB autoantibodies. Long-term outcomes for individuals with congenital heart block, which may develop in fetuses whose mothers carry Ro/SSA autoantibodies, were analyzed in Study V. The results indicate that these individuals have an increased risk of cardiovascular complications, and also illnesses related to infections and chronic inflammation, suggesting that a systematic follow-up would benefit these patients. In conclusion, the findings indicate that infections contribute to the development of Sjögren’s syndrome. Furthermore, the presence or absence of Ro/SSA and La/SSB autoantibodies discriminate between two distinct patient subgroups, and is a useful parameter for predicting the risk of comorbidity. Lastly, the findings reveal the risk of longterm complications in patients with congenital heart block
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