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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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| 2. |
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| 3. |
- Hedlund, Malin, et al.
(författare)
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Type I IFN system activation in newborns exposed to Ro/SSA and La/SSB autoantibodies in utero
- 2020
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Ingår i: RMD Open. - : BMJ. - 2056-5933. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: In utero exposure of the fetus to Ro/La autoantibodies may lead to congenital heart block (CHB). In the mother, these autoantibodies are associated with activation of the type I interferon (IFN)-system. As maternal autoantibodies are transferred to the fetus during pregnancy, we investigated whether the type I IFN-system is activated also in newborns of anti-Ro/La positive mothers, and whether fetal IFN activation is affected by maternal immunomodulatory treatment.METHODS: Blood drawn at birth from anti-Ro/La positive mothers, their newborns and healthy control pairs was separated into plasma and peripheral blood mononuclear cells (PBMC). PBMC were analysed directly or cultured. mRNA expression was analysed by microarrays, cell surface markers by flow cytometry, and IFNα levels by immunoassays.RESULTS: We observed increased expression of IFN-regulated genes and elevated plasma IFNα levels not only in anti-Ro/La positive women, but also in their newborns. CD14+ monocytes of both anti-Ro/La positive mothers and their neonates showed increased expression of Sialic acid-binding Ig-like lectin-1, indicating cellular activation. Notably, the IFN score of neonates born to mothers receiving immunomodulatory treatment was similar to that of controls, despite persistent IFN activation in the mothers. In both maternal and neonatal PBMC, IFNα production was induced when cells were cultured with anti-Ro/La positive plasma.CONCLUSIONS: Ro/La autoantibody-exposed neonates at risk of CHB have signs of an activated immune system with an IFN signature. This study further demonstrates that neonatal cells can produce IFNα when exposed to autoantibody-containing plasma, and that maternal immunomodulatory treatment may diminish the expression of IFN-regulated genes in the fetus.
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| 4. |
- Thorlacius, Gudny Ella, et al.
(författare)
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An update on the role of type I interferons in systemic lupus erythematosus and Sjogren's syndrome
- 2018
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Ingår i: Current Opinion in Rheumatology. - : LIPPINCOTT WILLIAMS & WILKINS. - 1040-8711 .- 1531-6963. ; 30:5, s. 471-481
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Forskningsöversikt (refereegranskat)abstract
- Purpose of review Systemic lupus erythematosus (SLE) and primary Sjogren's syndrome (pSS) share several clinical and laboratory features, including an overexpression of type I interferon (IFN) regulated genes. The genetic background to this IFN signature and the role of the type I IFN system in the disease process have been partly clarified. Here, we summarize the latest information concerning the type I IFN system in both diseases. Recent findings A number of gene variants in the type I IFN signalling pathways associate with an increased risk for both SLE and pSS in several ethnicities. The function of some risk gene variants has been elucidated, as well as the importance of epigenetic changes in type I IFN regulated genes. MicroRNA-451 and miR-302d have been shown to target IFN regulatory factor 8 and 9, suggesting that noncoding RNAs can control the IFN system. A prominent type I IFN activation is related to several disease manifestations, and in SLE to a more severe disease phenotype. Phase II studies in SLE suggest beneficial effects of blocking the type I IFN receptor. Summary The activated type I IFN system in SLE and pSS has a strong genetic component, is important in the disease etiopathogenesis and can be targeted.
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| 6. |
- Thorlacius, Guðný Ella, et al.
(författare)
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Genetic and clinical basis for two distinct subtypes of primary Sjögren's syndrome
- 2021
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Ingår i: Rheumatology. - : Oxford University Press. - 1462-0324 .- 1462-0332. ; 60:2, s. 837-848
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesClinical presentation of primary Sjögren’s syndrome (pSS) varies considerably. A shortage of evidence-based objective markers hinders efficient drug development and most clinical trials have failed to reach primary endpoints.MethodsWe performed a multicentre study to identify patient subgroups based on clinical, immunological and genetic features. Targeted DNA sequencing of 1853 autoimmune-related loci was performed. After quality control, 918 patients with pSS, 1264 controls and 107 045 single nucleotide variants remained for analysis. Replication was performed in 177 patients with pSS and 7672 controls.ResultsWe found strong signals of association with pSS in the HLA region. Principal component analysis of clinical data distinguished two patient subgroups defined by the presence of SSA/SSB antibodies. We observed an unprecedented high risk of pSS for an association in the HLA-DQA1 locus of odds ratio 6.10 (95% CI: 4.93, 7.54, P=2.2×10−62) in the SSA/SSB-positive subgroup, while absent in the antibody negative group. Three independent signals within the MHC were observed. The two most significant variants in MHC class I and II respectively, identified patients with a higher risk of hypergammaglobulinaemia, leukopenia, anaemia, purpura, major salivary gland swelling and lymphadenopathy. Replication confirmed the association with both MHC class I and II signals confined to SSA/SSB antibody positive pSS.ConclusionTwo subgroups of patients with pSS with distinct clinical manifestations can be defined by the presence or absence of SSA/SSB antibodies and genetic markers in the HLA locus. These subgroups should be considered in clinical follow-up, drug development and trial outcomes, for the benefit of both subgroups.
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| 7. |
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| 8. |
- Thorlacius, Guðný Ella
(författare)
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Genetics of systemic autoimmunity and comorbidities
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Sjögren‘s syndrome (SS) is a systemic autoimmune disease that typically affects the salivary and lacrimal glands leading to dry eyes and dry mouth, but the patients may also have systemic involvement. Most patients with SS carry autoantibodies, most often to the Ro (SSA) and La (SSB) proteins. During pregnancy, these autoantibodies can pass over from affected mothers to the fetus, who is then at risk of developing a congenital heart block (CHB). There is a prominent gender bias in systemic autoimmunity overall, particularly in SS where the ratio of women to men is approximately 14:1. While some genetic susceptibility factors for SS have been identified, much about the interplay between genetics, sex and the varying clinical presentation of this disease needs further study. In order to identify genetic associations with SS, we performed targeted sequencing of 1853 immune-related loci in over a thousand clinically well characterized SS patients and population controls. After subgrouping the patients by clinical manifestations, we identified three independent genetic signals in the HLA locus for Ro/La autoantibody positive SS, that were absent in the antibody negative group. The two top associations further indicated higher risk of severe manifestations, including purpura, major salivary gland swelling and lymphadenopathy. Our findings demonstrate that two distinct subgroups of patients with SS can be defined by the presence or absence of Ro/La antibodies and genetic markers. We and others have identified genetic variants associated with SS and/or the partially overlapping disease systemic lupus erythematosus (SLE). The frequency of these variants is the same in women and men in the general population. However, as the vast majority of patients are women, the risk of developing SS or SLE is much higher if the carrier is female. Genetic variants may contribute to different phenotypes via differential gene regulation, so called expression quantitative trait loci (eQTL). We hypothesized that sex may influence the eQTL effects of SS/SLE-associated genetic variants differentially in women and men, and discovered several associated variants that had sex-specific effects on the expression of nearby genes in CD19+ B cells. We also specifically studied the SS/SLE-associated FAM167A-BLK locus on chromosome 8, since the associated variants in this locus have prominent eQTL effects on the unknown gene FAM167A. We found the gene to be evolutionarily conserved, with one additional family member, but no other homologies in the genome, and the proteins to have a high level of intrinsic disorder. The gene is expressed in B cells, and we further found high expression in the lung of both mice and humans. We named the FAM167 encoded proteins Disordered Autoimmunity 1 and 2 (DIORA1 and 2), and will continue our efforts to further characterize their function. CHB affects 1-3% of anti-Ro/La autoantibody exposed pregnancies, with a recurrence rate of approximately 12-16%. The relatively low recurrence rate, despite persistent maternal autoantibodies, suggests fetal susceptibility factors are important. We performed a genome-wide association study in patients with CHB and controls. We found genetic associations with variants in the HLA region, KCNT2 on chromosome 1, and several suggestive signals. Most women with Ro/La autoantibodies have a steady state interferon activation, and to study the interferon in anti-Ro/La autoantibody positive pregnancy, we sampled anti-Ro/La positive mothers and their neonates at the time of birth, as well as healthy control mother-child pairs, and analyzed cellular profiles and cytokine- and gene expression. We found that anti-Ro/La exposed neonates had measurable type I and II interferon in plasma, and increased NK cell frequencies. Intracellular interferon detected by flow cytometry in neonatal NK and T cells indicates the neonates may produce the interferon, and we confirmed neonatal cell ability for interferon production in vitro. Notably, the genes near the CHB-associated signals were enriched for interferon regulation, suggesting an interplay between interferon activation and fetal genetic susceptibility factors in the pathogenesis of CHB. In summary, this thesis presents novel insight into genetic associations with SS and CHB, and begins to delineate how genetic susceptibility interacts with biological context such as sex or intrauterine exposure to maternal immune factors to lead to disease. The results will be important in clinical practice for personalized treatment and follow-up strategies, and as a basis for future therapy development.
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