| 1. |
- Celik, Yeliz, et al.
(författare)
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Association of TNF-α (-308G/A) Gene Polymorphism with Changes in Circulating TNF-α Levels in Response to CPAP Treatment in Adults with Coronary Artery Disease and Obstructive Sleep Apnea
- 2023
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Ingår i: Journal of Clinical Medicine. - : MDPI. - 2077-0383. ; 12:16
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: We recently demonstrated that patients with coronary artery disease (CAD) and obstructive sleep apnea (OSA) carrying the tumor necrosis factor-alpha (TNF-α) A allele had increased circulating TNF-α levels compared with the ones carrying the TNF-α G allele. In the current study, we addressed the effect of TNF-α (-308G/A) gene polymorphism on circulating TNF-α levels following continuous positive airway pressure (CPAP) therapy. Methods: This study was a secondary analysis of the RICCADSA trial (NCT00519597) conducted in Sweden. CAD patients with OSA (apnea–hypopnea index) of ≥15 events/h and an Epworth Sleepiness Scale (ESS) score of <10 were randomized to CPAP or no-CPAP groups, and OSA patients with an ESS score of ≥10 were offered CPAP treatment. Blood samples were obtained at baseline and 12-month follow-up visits. TNF-α was measured by immunoassay (Luminex, R&D Systems). Genotyping of TNF-α-308G/A (single nucleotide polymorphism Rs1800629) was performed by polymerase chain reaction–restriction fragment length polymorphism. Results: In all, 239 participants (206 men and 33 women; mean age 64.9 (SD 7.7) years) with polymorphism data and circulating levels of TNF-α at baseline and 1-year follow-up visits were included. The median circulating TNF-α values fell in both groups between baseline and 12 months with no significant within- or between-group differences. In a multivariate linear regression model, a significant change in circulating TNF-α levels from baseline across the genotypes from GA to GA and GA to AA (standardized β-coefficient −0.129, 95% confidence interval (CI) −1.82; −0.12; p = 0.025) was observed in the entire cohort. The association was more pronounced among the individuals who were using the device for at least 4 h/night (n = 86; standardized β-coefficient −2.979 (95% CI −6.11; −1.21); p = 0.004)), whereas no significant association was found among the patients who were non-adherent or randomized to no-CPAP. The participants carrying the TNF-α A allele were less responsive to CPAP treatment regarding the decline in circulating TNF-α despite CPAP adherence (standardized β-coefficient −0.212, (95% CI −5.66; −1.01); p = 0.005). Conclusions: Our results suggest that TNF-α (-308G/A) gene polymorphism is associated with changes in circulating TNF-α levels in response to CPAP treatment in adults with CAD and OSA.
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| 2. |
- Klingberg, Eva, et al.
(författare)
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A longitudinal study of fecal calprotectin and the development of inflammatory bowel disease in ankylosing spondylitis
- 2017
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Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 19
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patients with ankylosing spondylitis (AS) are at increased risk of developing inflammatory bowel disease (IBD). We aimed to determine the variation in fecal calprotectin in AS over 5 years in relation to disease activity and medication and also to study the incidence of and predictors for development of IBD. Methods: Fecal calprotectin was assessed at baseline (n = 204) and at 5-year follow-up (n = 164). The patients answered questionnaires and underwent clinical evaluations. At baseline and at 5-year follow-up, ileocolonoscopy was performed in patients with fecal calprotectin = 500 mg/kg and = 200 mg/kg, respectively. The medical records were checked for diagnoses of IBD during the follow-up period. Results: Fecal calprotectin > 50 mg/kg was found in two-thirds of the patients at both study visits. In 80% of the patients, fecal calprotectin changed by < 200 mg/kg between the two measuring points. Baseline fecal calprotectin was positively correlated with Ankylosing Spondylitis Disease Activity Score based on C-reactive protein, Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, C-reactive protein, erythrocyte sedimentation rate, and fecal calprotectin at 5-year follow-up. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with higher fecal calprotectin, and 3-week cessation of NSAIDs resulted in a drop of a median 116 mg/kg in fecal calprotectin. The use of tumor necrosis factor (TNF) blockers was associated with lower fecal calprotectin at both visits, but the users of TNF receptor fusion proteins had significantly higher fecal calprotectin than users of anti-TNF antibodies at 5-year follow-up. The 5-year incidence of Crohn's disease (CD) was 1.5% and was predicted by high fecal calprotectin. Conclusions: Fecal calprotectin was elevated in a majority of the patients and was associated with disease activity and medication at both visits. CD developed in 1.5% of the patients with AS, and a high fecal calprotectin was the main predictor thereof. The results support a link between inflammation in the gut and the musculoskeletal system in AS. We propose that fecal calprotectin may be a potential biomarker to identify patients with AS at risk of developing IBD
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| 3. |
- Friman, Vanda, 1952, et al.
(författare)
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Defective peripheral B cell selection in common variable immune deficiency patients with autoimmune manifestations
- 2023
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Ingår i: Cell Reports. - : Elsevier. - 2211-1247. ; 42:5
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Tidskriftsartikel (refereegranskat)abstract
- Common variable immune deficiency (CVID) is a heterogeneous disorder characterized by recurrent infections, low levels of serum immunoglobulins, and impaired vaccine responses. Autoimmune manifestations are common, but B cell central and peripheral selection mechanisms in CVID are incompletely understood. Here, we find that receptor editing, a measure of central tolerance, is increased in transitional B cells from CVID patients and that these cells have a higher immunoglobulin κ:λ ratio in CVID patients with autoimmune manifestations than in those with infection only. Contrariwise, the selection pressure in the germinal center on CD27bright memory B cells is decreased in CVID patients with autoimmune manifestations. Finally, functionally, T cell-dependent activation showed that naive B cells in CVID patients are badly equipped for activation and induction of mismatch repair genes. We conclude that central tolerance is functional whereas peripheral selection is defective in CVID patients with autoimmune manifestations, which could underpin the development of autoimmunity.
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| 4. |
- Jensen, Poul Erik H., et al.
(författare)
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Detection and kinetics of persistent neutralizing anti-interferon-beta antibodies in patients with multiple sclerosis : Results from the ABIRISK prospective cohort study
- 2019
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Ingår i: Journal of Neuroimmunology. - : Elsevier. - 0165-5728 .- 1872-8421. ; 326, s. 19-27
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Tidskriftsartikel (refereegranskat)abstract
- Two validated assays, a bridging ELISA and a luciferase-based bioassay, were compared for detection of anti-drug antibodies (ADA) against interferon-beta (IFN-β) in patients with multiple sclerosis. Serum samples were tested from patients enrolled in a prospective study of 18 months. In contrast to the ELISA, when IFN-β-specific rabbit polyclonal and human monoclonal antibodies were tested, the bioassay was the more sensitive to detect IFN-β ADA in patients' sera. For clinical samples, selection of method of ELISA should be evaluated prior to the use of a multi-tiered approach. A titer threshold value is reported that may be used as a predictor for persistently positive neutralizing ADA.
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| 5. |
- McGrath, Sarah, 1993, et al.
(författare)
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Correlation of Professional Antigen-Presenting Tbet+CD11c+ B Cells With Bone Destruction in Untreated Rheumatoid Arthritis
- 2024
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Ingår i: Arthritis & Rheumatology. - : John Wiley & Sons. - 2326-5191 .- 2326-5205. ; 76:8, s. 1263-1277
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Subsets of CD21−/low memory B cells (MBCs), including double-negative (DN, CD27−IgD−) and Tbet+CD11c+ cells, are expanded in chronic inflammatory diseases. In rheumatoid arthritis (RA), CD21−/low MBCs correlate with joint destruction. However, whether this is due to the Tbet+CD11c+ subset, its function and pathogenic contribution to RA are unknown. This study aims to investigate the association between CD21−/lowTbet+CD11c+ MBCs and joint destruction as well as other clinical parameters and to elucidate their functional properties in patients with untreated RA (uRA). Methods: Clinical observations were combined with flow cytometry (n = 36) and single-cell RNA sequencing (scRNA-seq) and V(D)J sequencing (n = 4) of peripheral blood (PB) MBCs from patients with uRA. The transcriptome of circulating Tbet+CD11c+ MBCs was compared with scRNA-seq data of synovial B cells. In vitro coculture of Tbet+CD11c+ B cells with T cells was used to assess costimulatory capacity. Results: CD21−/lowTbet+CD11c+ MBCs in PB correlated with bone destruction but no other clinical parameters analyzed. The Tbet+CD11c+ MBCs have undergone clonal expansion and express somatically mutated V genes. Gene expression analysis of these cells identified a unique signature of more than 150 up-regulated genes associated with antigen presentation functions, including B cell receptor activation and clathrin-mediated antigen internalization; regulation of actin filaments, endosomes, and lysosomes; antigen processing, loading, presentation, and costimulation; a transcriptome mirrored in their synovial tissue counterparts. In vitro, Tbet+CD11c+ B cells induced retinoic acid receptor–related orphan nuclear receptor γT expression in CD4+ T cells, thereby polarizing to Th17 cells, a T cell subset critical for osteoclastogenesis and associated with bone destruction. Conclusion: This study suggests that Tbet+CD11c+ MBCs contribute to the pathogenesis of RA by promoting bone destruction through antigen presentation, T cell activation, and Th17 polarization. (Figure presented.).
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| 6. |
- Sundell, Timothy, et al.
(författare)
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Single-cell RNA sequencing analyses : interference by the genes that encode the B-cell and T-cell receptors
- 2023
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Ingår i: Briefings in Functional Genomics & Proteomics. - : Oxford University Press. - 2041-2649 .- 2041-2657. ; 22:3, s. 263-273
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Tidskriftsartikel (refereegranskat)abstract
- B and T cells are integral parts of the immune system and are implicated in many diseases, e.g. autoimmunity. Towards understanding the biology of B and T cells and subsets thereof, their transcriptomes can be analyzed using single-cell RNA sequencing. In some studies, the V(D)J transcripts encoding the variable regions of the B- and T-cell antigen receptors have been removed before the analyses. However, a systematic analysis of the effects of including versus excluding these genes is currently lacking. We have investigated the effects of these transcripts on unsupervised clustering and down-stream analyses of single-cell RNA sequencing data from B and T cells. We found that exclusion of the B-/T-cell receptor genes prior to unsupervised clustering resulted in clusters that represented biologically meaningful subsets, such as subsets of memory B and memory T cells. Furthermore, pseudo-time and trajectory inference analyses of early B-lineage cells resulted in a developmental pathway from progenitor to immature B cells. In contrast, when the B-/T-cell receptor genes were not removed, with the PCs used for clustering consisting of up to 70% V-genes, this resulted in some clusters being defined exclusively by V-gene segments. These did not represent biologically meaningful subsets; for instance in the early B-lineage cells, these clusters contained cells representing all developmental stages. Thus, in studies of B and T cells, to derive biologically meaningful results, it is imperative to remove the gene sequences that encode B- and T-cell receptors.
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| 7. |
- Åkesson, Julia, et al.
(författare)
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Proteomics reveal biomarkers for diagnosis, disease activity and long-term disability outcomes in multiple sclerosis
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Sensitive and reliable protein biomarkers are needed to predict disease trajectory and personalize treatment strategies for multiple sclerosis (MS). Here, we use the highly sensitive proximity-extension assay combined with next-generation sequencing (Olink Explore) to quantify 1463 proteins in cerebrospinal fluid (CSF) and plasma from 143 people with early-stage MS and 43 healthy controls. With longitudinally followed discovery and replication cohorts, we identify CSF proteins that consistently predicted both short- and long-term disease progression. Lower levels of neurofilament light chain (NfL) in CSF is superior in predicting the absence of disease activity two years after sampling (replication AUC = 0.77) compared to all other tested proteins. Importantly, we also identify a combination of 11 CSF proteins (CXCL13, LTA, FCN2, ICAM3, LY9, SLAMF7, TYMP, CHI3L1, FYB1, TNFRSF1B and NfL) that predict the severity of disability worsening according to the normalized age-related MS severity score (replication AUC = 0.90). The identification of these proteins may help elucidate pathogenetic processes and might aid decisions on treatment strategies for persons with MS.
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