| 1. |
- Berglin, Ewa, MD, PhD, 1955-, et al.
(författare)
-
Protein profiling in individuals before onset of anca-associated vasculitis
- 2020
-
Ingår i: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 79, s. 372-372
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Etiology and pathogenesis of ANCA-associated vasculitis (AAV) is multifactorial and understanding of the processes leading from a healthy immune system to autoimmunity and on to debut of symptoms in AAV is rudimentary.Objectives:To identify inflammatory proteins related to the early processes preceding AAV development, and potential novel biomarkers, using large-scale protein analysesMethods:The Swedish National Patient Register of in-patient carevand the Swedish Cause of Death Register with discharge diagnosis from ICD-9 and-10 for AAV were co-analysed with the registers of 4 different blood biobanks to identify AAV individuals with available samples predating onset of symptom. Of the pre-AAV cases 86 (36 male, 50 female; mean age (SD); 51.9 (16.9) years) were identified with at least one plasma or serum sample (28 plasma, and 100 serum) pre-dating symptom onset (mean (SD); -4.3 (3.1) years), and 14 had 2-3 samples. Serum and plasma control samples matched for sex, age and sampling date were identified (n=198; 82 male, 116 female; mean age (SD); 51.9±15.9 years). The samples were analysed for levels of 92 proteins using proximity extension assay (OLINK inflammation panel, SciLifeLab, Uppsala, Sweden). Data were analysed using routine statistical methods, random forest and Partial Least square-discriminant analysis (PLS-DA).Results:As previously described for the assay significant difference between plasma and serum samples were observed both in pre-AAV individuals and controls. In pre-AAV plasma samples significantly increased concentrations of interleukin (IL)-2, chemokine ligand (CCL)-4, fibroblast growth factor (FGF)21, IL-4 and CCL20 were found closer to symptom onset, (<5 years) than later (> 5 years) and compared with controls. In serum tumor necrosis factor receptor superfamily member (TNFRSF)9, CXCL9, osteoprotegerin and vascular endothelial growth factor-A were significantly increased <5 years before onset vs. later (>5 years) and compared with controls. PLS-DA score scattered plot separated the pre-AAV individuals from healthy controls (R2=0.26), with significantly increased levels of CCL23, CXCL5, and matrix metalloproteinases-1 (MMP-1),transforming growth factor-ß, orosomucoid, en-rage (S100A12) and IL-7 and decreased FGF-19 level in serum. Binary logistic regression analyses comparing tertiles for these proteins confirmed significantly increased odds ratios for disease development of CCL23, CXCL5 and MMP-1. The findings were confirmed in random forest analysis where these factors were among the 20 most discriminatory factors between pre-symptomatic AAV and controls.Conclusion:In serum samples collected years before symptom onset of AAV, proteins involved in immune system activation were increased, suggesting that the inflammatory process is initiated long before clinical manifestations of the disease appear. These findings propose the elevated proteins as novel biomarkers for disease progression.References:[1]Watts et al. Ann Rheum Dis 2007;66:222-22Acknowledgments:Vasculitis Foundation, USADisclosure of Interests:Ewa Berglin: None declared, Anders Esberg: None declared, Johanna Dahlqvist: None declared, Johanna Sjöwall: None declared, Anders Lundquist: None declared, Kristina Lejon: None declared, Ingegerd Johansson: None declared, Aladdin J Mohammad Speakers bureau: lecture fees from Roche and Elli Lilly Sweden, PI (GiACTA study), Solbritt Rantapää Dahlqvist: None declared
|
|
| 2. |
- Brink, Mikael, et al.
(författare)
-
Protein Profiling in Presymptomatic Individuals Separates Myeloperoxidase-Antineutrophil Cytoplasmic Antibody and Proteinase 3-Antineutrophil Cytoplasmic Antibody Vasculitides
- 2023
-
Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 75:6, s. 996-1006
-
Tidskriftsartikel (refereegranskat)abstract
- Objective. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a chronic relapsing condition with unknown etiology. To gain insight into the molecular processes underlying the disease, we examined biomarkers in blood samples collected prior to symptom onset. Methods. The National Patient Register and Cause of Death register were searched for AAV-related International Classification of Diseases, Ninth Revision and Tenth Revision codes and linked to the registers from 5 biobanks. Eighty-five AAV patients with samples predating symptom onset of AAV were identified. For each case of AAV, 2 matched controls were included. Proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA expression levels were analyzed using enzyme-linked immunosorbent assays. Using an Olink Inflammation panel, 73 of 92 proteins were included after quality control. Data were replicated in a second cohort of 48 presymptomatic individuals and 96 controls. Results. Of the 20 proteins with the lowest P values in the original cohort, 7 were replicated in the second cohort and 5 proteins were found to be significant between the groups in a meta-analysis. Eleven different pathways were identified in network enrichment analyses and were found to be significant in both cohorts. Stratification of samples obtained <= 5 years before symptom onset showed significant levels of CCL23, vascular endothelial growth factor A, and hepatocyte growth factor, which were also increased at borderline significant levels in the replication cohort (interleukin-6 was found to be significantly increased in the replication cohort). In presymptomatic AAV patients, 6 proteins were associated with MPO-ANCA positivity, and 7 proteins were associated with PR3-ANCA positivity. Conclusion. To our knowledge, this is the first study to identify protein markers preceding symptom onset in AAV patients. These findings set the stage for further research into the underlying cellular and molecular mechanisms in the pathogenesis of AAV and the diversification of patients into PR3-ANCA+ and MPO-ANCA+ subphenotypes.
|
|
| 3. |
- Do, Lan, et al.
(författare)
-
Anti-CD74 IgA autoantibodies in radiographic axial spondyloarthritis : a longitudinal Swedish study
- 2021
-
Ingår i: Rheumatology. - : Oxford University Press. - 1462-0324 .- 1462-0332 .- 1310-0505. ; 60:9, s. 4085-4093
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Antibodies against anti-CD74 are related to axial spondyloarthritis (axSpA). The objectives were (i) to study IgA anti-CD74 in radiographic (r)-axSpA patients in the Backbone cohort and to calculate the sensitivity and specificity of anti-CD74, (ii) to study the fluctuation of IgA anti-CD74 levels in prospectively collected samples, and (iii) to explore the relation between IgA anti-CD74 and radiographic spinal changes.METHODS: IgA anti-CD74 was analysed by ELISA in 155 patients with r-axSpA and age- and sex-matched controls. BASDAI, ASDAS, BASFI and BASMI were assessed and spinal radiographs were scored for r-axSpA-related changes with mSASSS. Previously donated samples, before inclusion in the Backbone study, were identified in the Medical Biobank of Northern Sweden.RESULTS: A total of 155 patients comprising 69% men and 31% women, age [mean (s.d.)] 55.5 (11.4) years and 152 (98.1%) HLA-B27 positive, were included. The plasma level of IgA anti-CD74 was significantly higher in the patients [median (interquartile range), 12.9 (7.9-17.9) U/ml] compared with controls [10.9 (7.2-14.6) U/ml, P = 0.003]. IgA anti-CD74 was above the cut-off level of 20 U/ml in 36/155 (23.2%) patients and in 15/151 (9.9%) controls (P = 0.002). Multivariable logistic regression analyses revealed ≥1 syndesmophyte associated with IgA anti-CD74 (odds ratio 5.64; 95% CI: 1.02, 35.58; P = 0.048) adjusted for hsCRP, smoking, BMI, sex and age. No distinct pattern of IgA anti-CD74 over time was revealed.CONCLUSION: Plasma levels of IgA anti-CD74 were increased in r-axSpA and independently associated with radiographic spinal changes, which suggests that IgA anti-CD74 could play a role in the pathogenies of r-axSpA.
|
|
| 4. |
- Forsblad-D'elia, H., et al.
(författare)
-
DECREASED LEVELS OF T FOLLICULAR HELPER (CD4+CXCR5+) CELLS AND CD27+CD38+ AND CD27+CD38- B CELLS IN ANKYLOSING SPONDYLITIS PATIENTS CORRELATE WITH MARKER OF INFLAMMATION
- 2021
-
Ingår i: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 80:Suppl 1, s. 13-14
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The role of different lymphocyte subsets in ankylosing spondylitis (AS) is still to be elucidated. It has previously been reported contradictory data concerning the levels of T Follicular Helper (TFH) cells and differentiated B cells in peripheral blood of AS patients. In addition, the connection to disease related parameters is still to be fully revealed.Objectives:The purpose of this study was to investigate the level of CD4+TFH cells and CD27+CD38+/CD38- B cells in patients with AS from northern Sweden and to compare the levels with age and sex-matched controls. We also studied associations between these cell subsets and disease related factors.Methods:Peripheral blood mononuclear cells (PBMSc) from a cohort of 50 patients with AS from Region Västerbotten (mean age 52±9.1 years, 33 (66 %) men, 50 (100 %) HLAB27 positive) and 50 pair wise matched blood donor controls (mean age 54±8.8 years, 33 (66 %) men) were stained with a combination of antibodies allowing for the detection of CD27, CD38, CD19, CD3, CD4 and CXCR5 markers and analyzed by flow cytometry. In addition, the patient with AS were examined with spinal x-ray for radiographic alterations assessed with mSASSS. CRP and ESR were measured and physical function and disease activity were registered with BASMI and BASFI respectively ASDAS-CRP and BASDAI.Results:When comparing AS patients and controls pair wise, we observed on average a 50% reduction of TFH (CD3+CD4+CXCR5+) cells among CD45+ lymphocytes in PBMCs from patients (p=0,000008). Furthermore, a 20-30% reduction among memory/plasma cells (CD19+CD27+CD38+ and CD19+CD27+CD38-) among CD45+ lymphocytes in PBMCs from patients (p=0,002 and p=0,007 respectively). For female patients a correlation between TFH and ESR (Rs=-0,551 p=0,022) was observed. Moreover, negative correlations between the two B cell subsets (CD19+CD27+CD38+ and CD19+CD27+CD38-) and ESR were observed for female patients (Rs =–0,476 p=0,053 and Rs =–0,522 p=0,032 respectively).Conclusion:TFH cells was reduced in AS patients and this reduction correlated with a reduction in differentiated (CD27+CD38+ and CD27+CD38-) B cells. In addition, the inflammation marker ESR was negatively correlated with TFH as well as with the differentiated B cell subsets in female patients. Our observations indicates a role of the humoral immune response in AS.Disclosure of Interests:None declared
|
|
| 5. |
- Hellman, Urban, et al.
(författare)
-
Immunological biomarkers in patients with radiographic axial spondyloarthritis, an exploratory longitudinal Swedish study.
- 2024
-
Ingår i: Modern rheumatology. - 1439-7609.
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives There is a need for more specific biomarkers to diagnose and predict disease course in patients with axial spondyloarthritis (axSpA). This study aimed to study immunological plasma biomarkers, at different time-points in radiographic (r)-axSpA patients overall and stratified by sex and compare these biomarker pattern in r-axSpA patients concerning disease phenotypes and disease activity. Methods Plasma samples were analysed from r-axSpA patients at and prior (Pre-Backbone) inclusion in the Backbone study. Interferon gamma, interleukin-10, -17A, -17F, -22, -23, -6, MCP-1, TNF-α, VEGF-A, MIF, IgA anti-CD74, zonulin, ESR, hsCRP, white blood cell count, and blood lipids were measured. Results Biomarker pattern discriminated significantly between r-axSpA patients in Backbone and Pre-Backbone compared with controls. When stratifying by sex, it was possible to discriminate between male and female r-axSpA patients in Backbone vs controls and between male r-axSpA patients in pre-Backbone and controls. In Backbone, markers with high discriminative capacity were MIF, IgA anti-CD74, and MCP-1. In Pre-Backbone, IL-6, TNF-α, MIF, triglycerides, cholesterol, IL-10, and zonulin displayed high discriminative capacity. Conclusion Based on their temporal pattern and mutual relationship, we suggest studying MIF, IgA anti-CD74, and MCP-1 in depth, at more time points, to further elucidate disease-driving mechanisms in this complex disease.
|
|
| 6. |
- Law, Lucy, et al.
(författare)
-
Increased carotid intima-media thickness in patients with radiographic axial spondyloarthritis compared to controls and associations with markers of inflammation
- 2024
-
Ingår i: CLINICAL RHEUMATOLOGY. - : Springer Nature. - 0770-3198 .- 1434-9949.
-
Tidskriftsartikel (refereegranskat)abstract
- Objective There is an increased risk for cardiovascular disease (CVD) in patients with radiographic axial spondyloarthritis (r-axSpA). In this cross-sectional study, we aimed to, overall and stratified by sex, (i) compare ultrasound derived carotid intima media thickness (cIMT), between patients and controls, and (ii) investigate associations between cIMT, clinical disease activity and inflammation-related laboratory markers in patients with r-axSpA. Method In total, 155 patients diagnosed with r-axSpA using the modified New York criteria and 400 controls were included. Bilateral carotid ultrasound, laboratory testing, and questionaries were acquired. Disease-specific assessments were carried out for patients. Linear regression analysis was used to assess associations. Results Linear regression analyses showed that patients with r-axSpA had increased mean cIMT compared to controls (mean +/- SD, 0.8 +/- 0.1 mm vs 0.7 +/- 0.1 mm, respectively, unstandardized beta (95% CI) -0.076 (-0.10, -0.052), P < 0.001) adjusted for smoking status and age. Linear regression analyses for patients with r-axSpA showed that only males presented significant associations between cIMT and inflammation-related laboratory markers, white blood cell (WBC) count (mean +/- SD, 6.8 +/- 1.6 10(9)/L) and monocytes (0.6 +/- 0.2 10(9)/L); WBC count (unstandardized beta (95% CI) 0.019 (0.0065, 0.031), P = 0.003, R-2 = 0.57) and monocytes (0.13 (0.0047, 0.26), P = 0.041, R-2 = 0.55), adjusted for age, smoking status, body mass index, hypertension, dyslipidemia, diabetes mellitus, ASDAS-CRP, and treatment with DMARDs and glucocorticoids. No significant association was found between cIMT and clinical disease activity assessed by ASDAS-CRP. Conclusion Patients with r-axSpA had significantly increased cIMT compared to controls. In male patients, higher WBC and monocyte count were associated with an increase in cIMT suggesting the role of inflammation in the development of atherosclerosis.
|
|
| 7. |
- Lejon, Kristina, 1967-, et al.
(författare)
-
Decreased levels of T follicular helper (CD4+CXCR5+) cells and CD27+CD38+and CD27+CD38-B cells in ankylosing spondylitis patients correlate with markers of inflammation
- 2023
-
Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 97:1
-
Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to study CD4+CXCR5+ T follicular helper (TFH) cells, CD27+CD38+ plasmablasts and CD27+CD38- memory B cells, as well as disease-related factors in patients with ankylosing spondylitis (AS) from northern Sweden. Peripheral blood mononuclear cells (PBMC) from 50 patients with AS (mean age 52 +/- 9 years, 66% men, 100% HLA-B27 positive) and 50 pairwise matched blood donor controls (mean age 54 +/- 9 years, 66% men) were stained with antibodies for CD27, CD38, CD19, CD3, CD4 and CXCR5 markers and analysed by flow cytometry. Patients with AS were examined with spinal x-ray for radiographic alterations (mSASSS), and plasma levels of C-reactive protein, erythrocyte sedimentation rate, as well as selected proinflammatory and regulatory cytokines were determined. Physical mobility, function and disease activity were registered by BASMI, BASFI and ASDAS-CRP, BASDAI, respectively. Comparing AS patients and controls pairwise, we observed a 56% reduction of TFH cells in PBMCs from AS patients (P = .000008). Furthermore, a 20%-30% reduction in plasmablasts and B memory cells (P <= .002 and P <= .007, respectively) was observed. In female patients, negative correlations between ESR and TFH, plasmablasts and B memory cells were observed; Rs = -0.551, P <= .02; Rs = -0.476, P <= .05 and Rs = -0.522, P <= .03, respectively. In addition, positive correlations between the regulatory cytokine IL-10 and the proportion of B cells, IL-22, and the proportion of plasmablasts as well as a negative correlation between levels of the proinflammatory cytokine IL-6 and TFH were detected. Our observations indicate a role of an aberrant humoral immune response related to inflammation in AS.
|
|
| 8. |
- Lejon, Kristina, 1967-, et al.
(författare)
-
Increased Proportion of TH17, TH22 and TC17 Cells and the Correlation to IL-22 and Clinical Parameters in Patients with Ankylosing Spondylitis from Northern Sweden
- 2020
-
Ingår i: Arthritis & Rheumatology. - : John Wiley & Sons. - 2326-5191 .- 2326-5205. ; 72
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background/Purpose: Increased levels of TH17 and TH22 as well as TC17 and TC22 cells have previously been associated with ankylosing spondylitis (AS). The correlation between these inflammatory T cell subsets and clinically relevant parameters as well as cytokines has also been reported. However, the status of these inflammatory cells in a well characterized AS cohort from northern Sweden has not been studied. The purpose of this study was to confirm the increased presence of inflammatory T cell subsets in peripheral blood of patients with AS from northern Sweden in relation to age and sex-matched controls. In addition, associations of clinically relevant parameters with the level of the inflammatory T cell subset(s) and cytokines of interest were performed.Methods: Peripheral blood mononuclear cells (PBMCs) from a cohort of 50 patients with AS from Region Västerbotten (Modif NY, mean age 52±9.1 years, 33 (66 %) men, 50 (100 %) HLAB27) and 50 pair wise matched blood donor controls (mean age 54±8.8 years, 33 (66 %) men) were stained with a combination of antibodies allowing for the detection of surface expressed CD45, CD3, CD4, CD8, intracellular IL-17 and IL-22 and analyzed by flow cytometry. In addition, levels of IL-17 and IL-22 in plasma were determined by the Meso Scale Discovery platform. The patient with AS were examined with spinal x-ray for radiographic alterations assessed with mSASSS. CRP and ESR were measured and physical function and disease activity were registered with BASMI and BASFI respectively ASDAS-CRP and BASDAI.Results: Pair wise comparison of AS patients and controls showed a 1,5 to 2-fold increase of TH17, TH22 and TC22 cells among CD45+CD3+ lymphocytes in PBMCs of male patients (p=0,013, p=0,003 and p=0,024 respectively). Levels of IL-22 in plasma and proportion of TC17 correlated in male patients (Rs=0,499 p=0,003) and plasma levels of IL10 showed an inverse correlation in relation to TC17 in all patients (Rs=-0,276 p=0,05). In female AS patients there was a negative correlation between TC22 and CRP (Rs = -0,573, p=0,016). In addition, after splitting the group of female into pre- and postmenopausal correlation between TC17 and mSASSS (Rs = 0,845, p=0,034), TC22 and BASFI (Rs = 0,986, p=0,0003) (premenopausal) and TC22 and BASMI (Rs = 0,764, p=0,006) (postmenopausal) was observed.Conclusion: We confirm an increased proportion of TH17, TH22 and TC17 cells in blood in AS male patients from northern Sweden. In addition, positive correlation of the proinflammatory cytokine IL-22 and negative correlation of anti-inflammatory cytokine IL-10 in relation to TC17 corroborate the influence of these cells in the disease process. Interestingly, in female AS patients there was a correlation between clinical relevant parameters to particular inflammatory T cell subset dependent on the menopausal status, suggesting a role of female sex hormones in AS pathogenesis.
|
|
| 9. |
- Lejon, Kristina, 1967-, et al.
(författare)
-
Increased proportions of inflammatory T cells and their correlations with cytokines and clinical parameters in patients with ankylosing spondylitis from northern Sweden
- 2022
-
Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 96:3
-
Tidskriftsartikel (refereegranskat)abstract
- Ankylosing spondylitis (AS) is an autoimmune disease affecting parts of the skeletal structure in particular. Previously increased levels of the inflammatory cell types Th17, Th22, Tc17 and Tc22 cells have been shown to be associated with AS. Here, we analysed the levels of inflammatory T cell subsets, related cytokines and clinical characteristics of AS patients vs controls from northern Sweden. Peripheral blood mononuclear cells (PBMCs) obtained from 50 AS patients and 50 matched controls were short term stimulated with PMA/Ionomycin, stained and analysed by flow cytometry. Plasma levels of Interleukin (IL)-17, IL-22, IL-10 as well as clinically relevant markers were determined. Compared to male controls, male AS patients showed 1.5- to 2-fold increases of Th17 (P = .013), Th22 (P = .003) and Tc22 (P = .024) among CD45(+)CD3(+) lymphocytes. Plasma IL-22 levels correlated with the Tc17 proportion in male patients (R-s = 0.499, P = .003) and plasma IL-10 levels were inversely correlated with Tc17 among all patients (R-s = -0.276, P = .05). Male patients with syndesmophytes showed significantly higher Th17 proportions (P = .038). In female AS patients, Tc22 was negatively correlated with C-reactive protein (high sensitivity) (hsCRP) (R-s = -0.573, P = .016). We confirmed increased proportions of inflammatory T cells and correlations with relevant cytokines from male AS patients. The correlation between Th17 and syndesmophytes supports a role of Th17 in the pathogenic process.
|
|
| 10. |
- Renman, Emma, 1996-, et al.
(författare)
-
Dysregulated microRNA expression in rheumatoid arthritis families-a comparison between rheumatoid arthritis patients, their first-degree relatives, and healthy controls
- 2021
-
Ingår i: Clinical Rheumatology. - : Springer. - 0770-3198 .- 1434-9949. ; 40:6, s. 2387-2394
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Recent studies have demonstrated an altered expression of certain microRNAs in patients with rheumatoid arthritis (RA) as well as their first-degree relatives (FDRs) compared to healthy controls (HCs), suggesting a role of microRNA in the progression of the disease. To corroborate this, a set of well-characterized RA families originating from northern Sweden were analyzed for differential expression of a selected set of microRNAs.METHOD: MicroRNA was isolated from frozen peripheral blood cells obtained from 21 different families and included 26 RA patients, 22 FDRs, and 21 HCs. Expression of the selected microRNAs miR-22-3p, miR-26b-5p, miR-34a-3p, miR-103a-3p, miR-142-3p, miR-146a-5p, miR-155, miR-346, and miR-451a was determined by a two-step quantitative real-time polymerase chain reaction (qRT-PCR). Statistical analysis including clinical variables was applied.RESULTS: Out of the nine selected microRNAs that previously have been linked to RA, we confirmed four after adjusting for age and gender, i.e., miR-22-3p (p = 0.020), miR-26b-5p (p = 0.018), miR-142-3p (p = 0.005), and miR-155 (p = 0.033). Moreover, a significant trend with an intermediate microRNA expression in FDR was observed for the same four microRNAs. In addition, analysis of the effect of corticosteroid use showed modulation of miR-103a-3p expression.CONCLUSIONS: We confirm that microRNAs seem to be involved in the development of RA, and that the expression pattern in FDR is partly overlapping with RA patients. The contribution of single microRNAs in relation to the complex network including all microRNAs and other molecules is still to be revealed. Key Points • Expression levels of miR-22-3p, miR-26b-5p, miR-142-3p, and miR-155 were significantly altered in RA patients compared to those in controls. • In first-degree relatives, a significant trend with an intermediate microRNA expression in FDR was observed for the same four microRNAs.
|
|
