| 11. |
- Deshmukh, Megshree, et al.
(författare)
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Gene expression of S100a8/a9 predicts Staphylococcus aureus-induced septic arthritis in mice.
- 2023
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Ingår i: Frontiers in microbiology. - 1664-302X. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Septic arthritis is the most aggressive joint disease associated with high morbidity and mortality. The interplay of the host immune system with the invading pathogens impacts the pathophysiology of septic arthritis. Early antibiotic treatment is crucial for a better prognosis to save the patients from severe bone damage and later joint dysfunction. To date, there are no specific predictive biomarkers for septic arthritis. Transcriptome sequencing analysis identified S100a8/a9 genes to be highly expressed in septic arthritis compared to non-septic arthritis at the early course of infection in an Staphylococcus aureus septic arthritis mouse model. Importantly, downregulation of S100a8/a9 mRNA expression at the early course of infection was noticed in mice infected with the S. aureus Sortase A/B mutant strain totally lacking arthritogenic capacity compared with the mice infected with parental S. aureus arthritogenic strain. The mice infected intra-articularly with the S. aureus arthritogenic strain significantly increased S100a8/a9 protein expression levels in joints over time. Intriguingly, the synthetic bacterial lipopeptide Pam2CSK4 was more potent than Pam3CSK4 in inducing S100a8/a9 release upon intra-articular injection of these lipopeptides into the mouse knee joints. Such an effect was dependent on the presence of monocytes/macrophages. In conclusion, S100a8/a9 gene expression may serve as a potential biomarker to predict septic arthritis, enabling the development of more effective treatment strategies.
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| 12. |
- Dieckmann, Regis, et al.
(författare)
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Antieosinophil Antibodies Alone or in Combination with Antineutrophil Cytoplasmic Antibodies (ANCA) Detected in Different Autoimmune Conditions
- 2023
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Ingår i: Journal of Immunology Research. - 2314-8861 .- 2314-7156. ; 2023
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Tidskriftsartikel (refereegranskat)abstract
- Circulating antieosinophil antibodies (AEOSA) have been associated with various autoimmune conditions affecting the liver, kidneys, lungs, and joints but are not part of routine clinical diagnostics. While analyzing human sera for antineutrophil cytoplasmic antibodies (ANCA) by indirect immunofluorescence (IIF) on granulocytes, 0.8% of analyzed samples were found to be reactive with eosinophils. Our aim was to determine the diagnostic relevance and antigenic specificity of AEOSA. AEOSA were seen either in combination with an myeloperoxidase (MPO)-positive p-ANCA (44%; AEOSA+/ANCA+) or on their own (56%; AEOSA+/ANCA-). AEOSA/ANCA positivity was seen in patients with thyroid disease (44%) or vasculitis (31%), while AEOSA+/ANCA- pattern was more common in patients with autoimmune disorders of the gastrointestinal tract and/or liver. Eosinophil peroxidase (EPX) was the main target recognized in 66% of the AEOSA+ sera by enzyme-linked immunosorbent assay (ELISA). Eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN) were also identified as target antigens but less frequently and only in combination with EPX. In conclusion, we confirmed that EPX is a major target of AEOSA, illustrating the high antigenic potential of EPX. Our results also demonstrate the presence of concomitant AEOSA/ANCA positivity in a defined patient group. Further research should aim to elucidate the association of AEOSA with autoimmunity.
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| 13. |
- Ekman, Diana, et al.
(författare)
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Stratified genetic analysis reveals sex differences in MPO-ANCA-associated vasculitis
- 2023
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Ingår i: Rheumatology. - : Oxford University Press. - 1462-0324 .- 1462-0332. ; 62:9, s. 3213-3218
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To identify and genetically characterize subgroups of patients with ANCA-associated vasculitides (AAV) based on sex and ANCA subtype. Methods: A previously established SNP dataset derived from DNA sequencing of 1853 genes and genotyping of 1088 Scandinavian cases with AAV and 1589 controls was stratified for sex and ANCA subtype and analysed for association with five top AAV SNPs. rs9274619, a lead variant at the HLA-DQB1/HLA-DQA2 locus previously associated with AAV positive for myeloperoxidase (MPO)-ANCA, was analysed for association with the cumulative disease involvement of ten different organ systems. Results: rs9274619 showed a significantly stronger association to MPO-ANCA-positive females than males [P = 2.0 × 10-4, OR = 2.3 (95% CI 1.5, 3.5)], whereas proteinase 3 (PR3)-ANCA-associated variants rs1042335, rs9277341 (HLA-DPB1/A1) and rs28929474 (SERPINA1) were equally associated with females and males with PR3-ANCA. In MPO-ANCA-positive cases, carriers of the rs9274619 risk allele were more prone to disease engagement of eyes [P = 0.021, OR = 11 (95% CI 2.2, 205)] but less prone to pulmonary involvement [P = 0.026, OR = 0.52 (95% CI 0.30, 0.92)]. Moreover, AAV with both MPO-ANCA and PR3-ANCA was associated with the PR3-ANCA lead SNP rs1042335 [P = 0.0015, OR = 0.091 (95% CI 0.0022, 0.55)] but not with rs9274619. Conclusions: Females and males with MPO-ANCA-positive AAV differ in genetic predisposition to disease, suggesting at least partially distinct disease mechanisms between the sexes. Double ANCA-positive AAV cases are genetically similar to PR3-ANCA-positive cases, providing clues to the clinical follow-up and treatment of these patients.
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| 14. |
- Erlandsson, Malin, 1972, et al.
(författare)
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Clinical Significance of Diabetes-Mellitus-Associated Antibodies in Rheumatoid Arthritis
- 2022
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 11:22
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Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid arthritis (RA) is a canonical autoimmune disease that shares numerous risk factors with diabetes mellitus (DM). The production of autoantibodies is a characteristic feature in both diseases. To determine the frequency and specificity of DM-related antibodies (DMab) in RA patients and to study whether DMab associates with new DM cases in RA patients, we measured DMab defined as IgG against glutamic acid decarboxylase (GADA), tyrosine phosphatase (IA2-ab), and zinc transporter (ZnT8-ab) in a cohort of 290 RA patients (215 women and 75 men, median disease duration 11 years). Of those, 21 had a DM diagnosis at baseline. The development of new DM cases and mortality were traced in a 10-year prospective follow-up. Predictive analyses for DM and mortality were carried out by the Mantel-Cox regression. We found that 27 of the patients (9.3%) had DMab, equally often men and women. The presence of DMab was more frequent in patients with DM (p = 0.027. OR 4.01, 95%CI [1.20; 11.97]), suggesting their specificity for the disease. Men had more prevalent incidental DM at the baseline (12% vs. 5%, p = 0.030) and among the new DM cases (p = 0.012. HR 6.08, 95%CI [1.57; 25]). New DM developed equally frequently in DMab-positive and DMab-negative patients. DM, but not DMab, significantly increased the estimated mortality rate in RA patients (p = 0.021, OR 4.38 [1.2; 13.52]). Taken together, we conclude that DMab are associated with DM in RA patients, but they are not solely enough to predict disease development or mortality in those patients.
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| 15. |
- Erlandsson, Malin, 1972, et al.
(författare)
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IGF1R signalling is a guardian of self-tolerance restricting autoantibody production.
- 2022
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Ingår i: Frontiers in immunology. - : Frontiers Media SA. - 1664-3224. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Insulin-like growth factor 1 receptor (IGF1R) acts at the crossroad between immunity and cancer, being an attractive therapeutic target in these areas. IGF1R is broadly expressed by antigen-presenting cells (APC). Using mice immunised with the methylated albumin from bovine serum (BSA-immunised mice) and human CD14+ APCs, we investigated the role that IGF1R plays during adaptive immune responses.The mBSA-immunised mice were treated with synthetic inhibitor NT157 or short hairpin RNA to inhibit IGF1R signalling, and spleens were analysed by immunohistology and flow cytometry. The levels of autoantibody and cytokine production were measured by microarray or conventional ELISA. The transcriptional profile of CD14+ cells from blood of 55 patients with rheumatoid arthritis (RA) was analysed with RNA-sequencing.Inhibition of IGF1R resulted in perifollicular infiltration of functionally compromised S256-phosphorylated FoxO1+ APCs, and an increased frequency of IgM+CD21+ B cells, which enlarged the marginal zone (MZ). Enlargement of MHCII+CD11b+ APCs ensured favourable conditions for their communication with IgM+ B cells in the MZ. The reduced expression of ICOSL and CXCR5 by APCs after IGF1R inhibition led to impaired T cell control, which resulted in autoreactivity of extra-follicular B cells and autoantibody production. In the clinical setting, the low expression of IGF1R on CD14+ APCs was associated with an involuted FOXO pathway, non-inflammatory cell metabolism and a high IL10 production characteristic for tolerogenic macrophages. Furthermore, autoantibody positivity was associated with low IGF1R signalling in CD14+ APCs.In experimental model and in patient material, this study demonstrates that IGF1R plays an important role in preventing autoimmunity. The study raises awareness of that immune tolerance may be broken during therapeutic IGF1R targeting.
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| 16. |
- Erlandsson, Malin, 1972, et al.
(författare)
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Low serum IGF1 is associated with hypertension and predicts early cardiovascular events in women with rheumatoid arthritis
- 2019
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Ingår i: BMC Med. - : Springer Science and Business Media LLC. - 1741-7015. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesSince low insulin-like growth factor (IGF) 1 is often linked to inflammation, we analyze whether serum levels of IGF1 are associated with cardiovascular disease (CVD) in rheumatoid arthritis (RA) in a longitudinal observational study.MethodsA CVD risk was estimated (eCVR) in 184 female RA patients (mean age 52years) and in 132 female patients after ischemic stroke (mean age 56years) with no rheumatic disease, using the Framingham algorithm. The median level of IGF1 divided the cohorts in IGF1(high) and IGF1(low) groups. A 5-year prospective follow-up for new CVD events was completed in all RA patients. The Mantel-Cox analysis and event-free survival curves were prepared. Unsupervised clustering of proteins within the IGF1 signaling pathway was employed to identify their association with eCVR.ResultsLow IGF1 resulted in a higher eCVR in RA patients (7.2% and 3.3%, p=0.0063) and in stroke (9.3% and 7.1%, p=0.033). RA had higher rate for new CVD events at prospective follow-up (OR 4.96, p=0.028). Hypertension was the major risk factor associated with low IGF1 in RA and stroke. In hypertension, IGF1 was no longer responsible for intracellular activation and lost its correlation to IRS1/2 adaptor proteins. The clustering analysis confirmed that combination of low IGF1 and IRS1/2 with high IL6, insulin, and glucose predisposed to high eCVR and emphasized the functional role of serum IGF1.ConclusionsLow serum IGF1 precedes and predicts development of early CVD events in female RA patients. Hypertension and aberrant IGF1 receptor signaling are highlighted as the important contributors to IGF1-related CVD events.
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| 17. |
- Erlandsson, Malin, 1972, et al.
(författare)
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Survivin improves the early recognition of rheumatoid arthritis among patients with arthralgia : A population-based study within two university cities of Sweden
- 2018
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Ingår i: Seminars in Arthritis & Rheumatism. - : Saunders Elsevier. - 0049-0172 .- 1532-866X. ; 47:6, s. 778-785
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Forskningsöversikt (refereegranskat)abstract
- Objectives: The aim of this study was to validate the use of survivin for preclinical recognition of rheumatoid arthritis (RA) among patients with unexplained arthralgia.Methods: Serum levels of survivin and the arthritis-specific autoantibodies RF and ACPA were measured in total of 5046 patients with musculoskeletal complains during 12 consecutive months in Gothenburg and in Umea. Among them, 303 arthralgia patients were identified and prospectively followed.Results: After 48 months, 12.2% of the arthralgia patients developed RA. Most of RA cases had high serum survivin, which increased the relative risk for RA (RR = 5.90,p = 3 x 10(-7)). Combination of survivin with autoantibodies was present in only 4.6% of the arthralgia patients and increased further the risk of RA and shortened time to RA development. Presence of any single autoantibody in the survivin-negative patients was associated with a minor risk for RA and had RA-free survival similar to the reference group.Conclusion: This study shows that measurement of survivin in serum improves estimation of RA risk and prospectively predicts RA development in patients with arthralgia. Survivin may indicate a phase preceding autoantibody production.
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| 18. |
- Erlandsson, Malin, 1972, et al.
(författare)
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Survivin Measurement improves Clinical Prediction of Transition From Arthralgia to RA - Biomarkers to Improve Clinical Sensitivity of Transition From Arthralgia to RA
- 2018
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Ingår i: Frontiers in Medicine. - : Frontiers Media SA. - 2296-858X. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Background: Arthralgia often predates development of rheumatoid arthritis (RA). A set of joint symptoms commonly found in patients during their transition from arthralgia to RA, has been recently proposed. Aim: To combine clinical and serological markers and to improve recognition of imminent rheumatoid arthritis (RA) among patients with arthralgia. Methods: The total of 1,743 first-visit patients attending the rheumatology ward in Gothenburg for joint symptoms were identified during 12 consecutive months. Among those, 63 patients were classified as RA, 73 had undifferentiated arthritis and 180 had unexplained arthralgia. New RA cases, which prospectively developed during 48 months, comprised the preclinical (pre) RA group. The joint symptoms of the first-visit were analyzed aiming to distinguish patients with arthralgia and arthritis, and patients with pre-RA, who later developed the disease. The receiver operating characteristics curves were constructed. In the model, symptoms with the odds ratio >2.0 between the arthralgia and pre-RA were combined with information about RA-specific antibodies, C-reactive protein (CRP), and survivin in serum. Results: The proposed set of clinical symptoms distinguished the arthralgia patients from RA and pre-RA. Presence of survivin in serum showed strong association with clinical joint symptoms in arthralgia. A combination of symptoms in several small joint areas, increasing number of joints with symptoms, and patient's experience of swelling in small hand joints at the first visit identified pre-RA cases with 93% specificity. Grouping those symptoms with information about survivin, RA-specific antibodies, and CRP (or gender) in the final algorithm achieved 91% specificity and 55.2% of positive prediction for transition from arthralgia to RA. Conclusion: Clinical and serological parameters in combination aid recognition of imminent RA among arthralgia patients with appropriate sensitivity.
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| 19. |
- Fei, Ying, et al.
(författare)
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The combination of a tumor necrosis factor inhibitor and antibiotic alleviates staphylococcal arthritis and sepsis in mice.
- 2011
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Ingår i: The Journal of infectious diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 204:3, s. 348-57
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Tidskriftsartikel (refereegranskat)abstract
- (See the editorial commentary by Chow, on pages 332-4) Background.Despite advances in medical practices, in recent decades permanent reductions in joint function have not been achieved, and the high mortality rate of patients with staphylococcal septic arthritis has not substantially improved. Methods.We evaluated the effects of a combined tumor necrosis factor (TNF) inhibitor and antibiotic therapy on the course of Staphylococcus aureus arthritis and sepsis in mice. Results.Treatment with the combination of a TNF inhibitor and an antibiotic resulted in a quicker relief of clinical arthritis in mice with septic arthritis, compared with an antibiotic monotherapy. Both histopathologically verified synovitis and the extent of joint destruction were reduced by this combined treatment. Importantly, anti-TNF treatment significantly improved the survival rate of mice with S. aureus sepsis and staphylococcal enterotoxin shock syndrome; this effect might be the result of a partial restoration of the hemostatic balance between coagulation and fibrinolysis. Finally, we demonstrated that anti-TNF treatment downregulates high-mobility group protein B1 in staphylococcal enterotoxin shock syndrome. Conclusions.Thus, simultaneous systemic TNF inhibition and antibiotic therapy has beneficial effects on the outcome of S. aureus arthritis and sepsis in a mouse model, suggesting that the combination of a TNF inhibitor and antibiotics represents a novel therapeutic strategy for the treatment of staphylococcal infections.
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| 20. |
- Forsblad d'Elia, Helena, 1961, et al.
(författare)
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Resistin in serum is associated with higher levels of IL-1Ra in post-menopausal women with rheumatoid arthritis.
- 2008
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Ingår i: Rheumatology (Oxford, England). - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 47:7, s. 1082-7
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The aim of this study was to investigate associations between serum levels of resistin, an adipokine and markers of inflammation, bone metabolism, plasma lipids and kidney function in post-menopausal RA patients and to evaluate if HRT during 2 yrs affected resistin levels. METHODS: Eighty-eight women were randomly allocated to receive HRT, vitamin D(3) and calcium or vitamin D(3) and calcium alone. Serum levels of resistin, IL-1beta, IL-1 receptor antagonist (IL-1Ra), IL-6, IL-6 soluble receptor, TNF-alpha were measured by ELISA, markers of bone metabolism, carboxyterminal cross-linked telopeptide of type I collagen (ICTP) and carboxyterminal propeptide of type I procollagen by RIA, ESR, CRP, Hb, creatinine and lipids by standard laboratory techniques, BMD and total lean mass (TLM) by DXA and joint destruction by Larsen score. Resistin was also measured in 42 healthy control women. RESULTS: There was no difference in resistin concentration between patients and healthy controls. Resistin was significantly correlated with IL-1Ra, CRP, TNF-alpha, ICTP, glucocorticosteroids and Larsen score and inversely with BMD, hip and with TLM. In multiple regression analysis, IL-1Ra, TLM and use of corticosteroids remained determinants of resistin. Patients treated with HRT displayed significant increase in resistin compared with controls in the first but not the second year. CONCLUSIONS: Resistin was associated with increased inflammation, particularly by the acute-phase reactant IL-1Ra antagonizing IL-1beta, joint destruction, glucocorticosteroids and with reduced BMD and TLM. These findings suggest resistin being a significant mediator in the inflammatory process in RA. Further studies examining the mechanisms behind the relation between resistin and IL-1Ra are encouraged. HRT does not seem to have important long-term effect on resistin.
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