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- Ringh, MV, et al.
(författare)
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Methylome and transcriptome signature of bronchoalveolar cells from multiple sclerosis patients in relation to smoking
- 2021
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Ingår i: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1477-0970 .- 1352-4585. ; 27:7, s. 1014-1026
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Tidskriftsartikel (refereegranskat)abstract
- Despite compelling evidence that cigarette smoking impacts the risk of developing multiple sclerosis (MS), little is known about smoking-associated changes in the primary exposed lung cells of patients. Objectives: We aimed to examine molecular changes occurring in bronchoalveolar lavage (BAL) cells from MS patients in relation to smoking and in comparison to healthy controls (HCs). Methods: We profiled DNA methylation in BAL cells from female MS ( n = 17) and HC ( n = 22) individuals, using Illumina Infinium EPIC and performed RNA-sequencing in non-smokers. Results: The most prominent changes were found in relation to smoking, with 1376 CpG sites (adjusted P < 0.05) differing between MS smokers and non-smokers. Approximately 30% of the affected genes overlapped with smoking-associated changes in HC, leading to a strong common smoking signature in both MS and HC after gene ontology analysis. Smoking in MS patients resulted in additional discrete changes related to neuronal processes. Methylome and transcriptome analyses in non-smokers suggest that BAL cells from MS patients display very subtle (not reaching adjusted P < 0.05) but concordant changes in genes connected to reduced transcriptional/translational processes and enhanced cellular motility. Conclusions: Our study provides insights into the impact of smoking on lung inflammation and immunopathogenesis of MS.
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- Notarnicola, A., et al.
(författare)
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Serum and balf-derived anti-JO1 autoantibodies exhibit high reactivity to distinct HISRS domains and associate with lung and joint involvement in patients with IIM/ASS
- 2020
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ Publishing Group. - 0003-4967 .- 1468-2060. ; 79, s. 1109-1110
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Autoantibodies that target aminoacyl transfer(t) RNA synthetases (aaRS) represent the serological marker of the anti-synthetase syndrome (ASS), a major subgroup of the idiopathic inflammatory myopathies (IIM) (1). Among the anti-aaRS, anti-histidyl tRNA synthetase (HisRS) autoantibodies (anti-Jo1) are the most common. Up to 90% of IIM/ASS patients diagnosed with interstitial lung disease (ILD) harbor anti-Jo1 autoantibodies (2).Objectives:Reactivity and affinity of anti-Jo1 autoantibodies from serum and broncheoalveolar lavage fluid (BALF) were investigated against HisRS autoantigen. Associations with clinical data from patients IIM/ASS were addressed.Methods:Total IgGs were purified by affinity chromatography. Samples and clinical data were obtained from: i) 26 anti-Jo1+patients (19 at diagnosis, 16/19 at follow-up, 7 BALF/matching serum at baseline; ii) 29 anti-Jo1-(25 serum at diagnosis, 4 BALF/matching serum at baseline); iii) 24 age/gender matched healthy controls. Anti-Jo1 IgG and IgA response against HisRS was evaluated by ELISA and western blot. Affinity was measured by surface plasmon resonance. HisRS full-length (HisRS-FL), two HisRS domains (ABD and CD), and two HisRS splice variants (WHEP and WHEP + ABD splice variant (SV)) were tested. Correlations between autoantibody reactivity and clinical data, at baseline and over disease course, were evaluated.Results:Anti-Jo1 autoantibodies from serum and lung bound HisRS-FL, WHEP and SV with high reactivity and affinity already at diagnosis and recognized both conformational and linear HisRS epitopes (Fig. 1). Levels of autoantibodies (against HisRS-FL, -domains and -splice variants) varied among patients and overtime. Patients with ILD, arthritis and less skin involvement presented higher anti-Jo1 titers compared to those with lower anti-Jo1 titers and to the anti-Jo1 negative group (Fig. 2). Anti-WHEP reactivity in BALF strongly correlated with poor pulmonary function.Conclusion:High reactivity and affinity at time of diagnosis indicates that autoimmunity against HisRS is most likely initiated before IIM/ASS diagnosis. Reactivity to specific splice variants of HisRS may be employed as diagnostic and prognostic markers.References:[1]Marguerie C, Bunn CC, Beynon HL, Bernstein RM, Hughes JM, So AK, Walport MJ: Polymyositis, pulmonary fibrosis and autoantibodies to aminoacyl-tRNA synthetase enzymes. Q J Med 1990, 77(282):1019-1038[2]Richards TJ, Eggebeen A, Gibson K, Yousem S, Fuhrman C, Gochuico BR, Fertig N, Oddis CV, Kaminski N, Rosas IO et al: Characterization and peripheral blood biomarker assessment of anti-Jo-1 antibody-positive interstitial lung disease. Arthritis Rheum 2009, 60(7):2183-2192.Fig. 1.Anti-Jo1 reactivity in total IgG purified from the first available serum sampleFig. 2.Reactivity of total anti-Jo1+ IgG purified from the first available serum close to IIM/ASS diagnosis in relation to clinical dataDisclosure of Interests:Antonella Notarnicola: None declared, Charlotta Preger: None declared, Susanna Lundström: None declared, Nuria Renard: None declared, Edvard Wigren: None declared, Eveline Van Gompel: None declared, Angeles Shunashy Galindo-Feria: None declared, Helena Persson: None declared, Maryam Fathi: None declared, Johan Grunewald: None declared, Per-Johan Jakobsson Shareholder of: Gesynta Pharma, Grant/research support from: Gesynta Pharma, AstraZeneca,, Susanne Gräslund: None declared, Ingrid E. Lundberg Grant/research support from: Bristol Meyer Squibb, Corbus Pharmaceuticals, Inc and Astra Zeneca, Catia Cerqueira: None declared
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- Rossides, M, et al.
(författare)
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Are infectious diseases risk factors for sarcoidosis or a result of reverse causation? Findings from a population-based nested case-control study
- 2020
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Ingår i: European journal of epidemiology. - : Springer Science and Business Media LLC. - 1573-7284 .- 0393-2990. ; 35:11, s. 1087-1097
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Tidskriftsartikel (refereegranskat)abstract
- Findings from molecular studies suggesting that several infectious agents cause sarcoidosis are intriguing yet conflicting and likely biased due to their cross-sectional design. As done in other inflammatory diseases to overcome this issue, prospectively-collected register data could be used, but reverse causation is a threat when the onset of disease is difficult to establish. We investigated the association between infectious diseases and sarcoidosis to understand if they are etiologically related. We conducted a nested case–control study (2009–2013) using incident sarcoidosis cases from the Swedish National Patient Register (n = 4075) and matched general population controls (n = 40,688). Infectious disease was defined using inpatient/outpatient visits and/or antimicrobial dispensations starting 3 years before diagnosis/matching. Adjusted odds ratios (aOR) of sarcoidosis were estimated using conditional logistic regression and tested for robustness assuming the presence of reverse causation bias. The aOR of sarcoidosis associated with history of infectious disease was 1.19 (95% confidence interval [CI] 1.09, 1.29; 21% vs. 16% exposed cases and controls, respectively). Upper respiratory and ocular infections conferred the highest OR. Findings were similar when we altered the infection definition or varied the infection-sarcoidosis latency period (1–7 years). In bias analyses assuming one in 10 infections occurred because of preclinical sarcoidosis, the observed association was completely attenuated (aOR 1.02; 95% CI 0.90, 1.15). Our findings, likely induced by reverse causation due to preclinical sarcoidosis, do not support the hypothesis that common symptomatic infectious diseases are etiologically linked to sarcoidosis. Caution for reverse causation bias is required when the real disease onset is unknown.
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| 9. |
- Rossides, M, et al.
(författare)
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Risk of first and recurrent serious infection in sarcoidosis: a Swedish register-based cohort study
- 2020
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Ingår i: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 56:3
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Tidskriftsartikel (refereegranskat)abstract
- Serious infections impair quality of life and increase costs. Our aim was to determine if sarcoidosis is associated with a higher rate of serious infection and whether this varies by age, sex, time since diagnosis or treatment status around diagnosis.We compared individuals with sarcoidosis (at least two International Classification of Diseases codes in the Swedish National Patient Register 2003–2013; n=8737) and general population comparators matched 10:1 on age, sex and residential location (n=86 376). Patients diagnosed in 2006–2013 who were dispensed at least one immunosuppressant ±3 months from diagnosis (Swedish Prescribed Drug Register) were identified. Cases and comparators were followed in the National Patient Register for hospitalisations for infection. Using Cox and flexible parametric models, we estimated adjusted hazard ratios (aHR) and 95% confidence intervals for first and recurrent serious infections (new serious infection >30 days after previous).We identified 895 first serious infections in sarcoidosis patients and 3881 in comparators. The rate of serious infection was increased 1.8-fold in sarcoidosis compared to the general population (aHR 1.81, 95% CI 1.65–1.98). The aHR was higher in females than males and during the first 2 years of follow-up. Sarcoidosis cases treated with immunosuppressants around diagnosis had a three-fold increased risk, whereas nontreated patients had a 50% increased risk. The rate of serious infection recurrence was 2.8-fold higher in cases than in comparators.Serious infections are more common in sarcoidosis than in the general population, particularly during the first few years after diagnosis. Patients who need immunosuppressant treatment around diagnosis are twice as likely to develop a serious infection than those who do not.
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