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- Chalise, Jaya Prakash, et al.
(författare)
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IDO1 and TGF- 1 β mediate protective effects of IFN-α in antigen-induced arthritis
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Interferon-α (IFN-α) prevents antigen-induced arthritis (AIA) in mice by an unknown mechanism. Indoleamine 2, 3 dioxygenase 1 (IDO1) is an immunoregulator via enzymatic as well as signalling activity, which can be activated by TGF-β and further mediated via non canonical NF-κB signalling. We here investigated whether IDO1 and TGF-β are involved in IFN-α protective effects in AIA. Arthritis was induced in wt, Ido1-/- or Ifnar-/- mice, treated or not with IFN-α or kynurenine, the main IDO1 product, and antibodies neutralizing TGF-β or 1-methyltryptophan (1-MT), an inhibitor of IDO1 catalytic activity. IDO1 expression and enzymatic activity were determined by RT-PCR and HPLC, respectively. Proliferation was measured by 3H-Thymidine incorporation. Non-canonical NF-κB signalling was evaluated by ELISA and Western blot in plasmacytoid DCs (pDCs) from treated mice. Protective effects of IFN-α in AIA were associated with increased IDO1 expression and kynurenine production in spleen cells, particularly at the time of mBSA sensitization. Lack of IDO1 ablated IFN-α protection and kynurenine prevented AIA in an IFNAR-independent manner. The IDO1 catalytic activity was crucial for IFN-α effects at the sensitization but not effector phase of AIA. The disease effector phase in mice treated with IFN-α was instead characterized by sustained IDO1 and TGF-β expression and activation of the noncanonical NF-κB pathway in pDCs. IFN-α protective effects in AIA involves IDO1 enzymatic and signalling activity in the disease sensitization and effector phase, respectively. Kynurenine, the main IDO1 metabolite, can be used as an alternative treatment to IFN-α in protecting mice from AIA.
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| 2. |
- Chalise, Jaya Prakash, et al.
(författare)
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Regulatory T cells manifest IFN-α mediated protection during antigen induced arthritis
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- IntroductionType I interferon induces tolerance against arthritogenic antigen and protects against antigen induced arthritis (AIA). Regulatory T cells (Treg cells) resolve aberrant immune reaction, maintain self-tolerance and prevent the development of autoimmune diseases. We here investigated the impact of Interferon alpha (IFN-α) on Treg cells development and function during antigen induced arthritis.MethodsFor AIA, mice were immunized with methylated bovine serum albumin (mBSA) at day 1 and 7 in presence or absence of IFN-α. At day 21, arthritis was induced by intra-articular injection of mBSA and arthritis was evaluated at day 28. At various days of AIA, CD4, CD25, Foxp3 and CTLA-4 expression was quantified by FACS in blood cells, splenocytes, lymph nodes cells and in ex vivo re-stimulated leucocytes (pooled splenocytes and lymph nodes cells) isolated at same days. To investigate the importance of Treg cells in IFN-α protection in AIA, Foxp3DTReGFP+mice were used, where Treg cells can be depleted transiently by administration of diptherin toxin. CFSE based suppression assay was used to assess the suppression by Treg cells isolated day 4, 10, 20 of AIA against proliferation of mBSA or anti-CD3 stimulated responder T cells (Tresp cells) isolated at same days. For adoptive transfer experiments, 250,000 Treg cells from IFN-α treated or untreated mice day 20 of AIA were intravenously injected to recipient pre-immunized mice without IFN-α treatment during the induction of arthritis. The importance of IFN-α signalling on T cells for the IFN-α protection was evaluated by using CD4-Cre+/- IFNAR flox/flox mice.ResultsProtective effects of IFN-α in AIA were associated with significant TGF-β dependent increase in Foxp3+ T cells in blood at day 4 and minor increase of Foxp3+T cells in spleen and lymph node cells. However IFN-α signalling in T cells is not required for IFN-α-protection. Upon ex vivo re-stimulation in presence of IFN-α with mBSA but not anti-CD3, the Treg cells numbers were increased in leucocytes isolated from day 4 and day 10 of AIA. Transient depletion of Treg cells during induction of arthritis (day 21) abolished IFN-α-protection however the protection was not affected when Treg cells are depleted during immunization phase (day 1 and day 7). Against mBSA-stimulated proliferation of Tresp cells, suppression by Treg cells isolated from day 10 and day 20 from IFN-α treated mice are significantly higher than Treg cells from untreated mice. Treg cells isolated from IFN-α or untreated mice at day 20 of AIA when transferred to pre-immunized untreated mice prevent the development of arthritis.ConclusionTreg cells are critically associated with IFN-α protective effects in AIA. IFN-α enhances TGF-β dependent early development of Treg cells and later IFN-α enhances their suppressive capacity against T cells proliferation in antigen specific manner during AIA.
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| 5. |
- Gustafsson, Mika, 1977-, et al.
(författare)
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Data for: Proteomics reveal biomarkers for diagnosis, disease activity and long-term disability outcomes in multiple sclerosis
- 2023
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Annan publikationabstract
- Protein levels were measured in cerebrospinal fluid samples (CSF; n = 186) and plasma samples (n = 165) from persons with multiple sclerosis and healthy controls. CSF samples and plasma samples were taken from 92 persons with CIS or RRMS at Linköping University Hospital, Sweden and 51 persons with CIS or RRMS at the Karolinska University Hospital, Sweden. Everyone fulfilled the revised McDonald criteria from 2010 and 2017 for CIS or Multiple sclerosis (MS). Age-matched healthy controls (HC) were recruited from healthy blood donors (23 at the Linköping University hospital and 20 at the Karolinska University Hospital). The concentration of 1463 proteins were measured using the Olink Explore platform which uses Proximity Extension Assay (PEA) technology. The proteins were preselected from four Olink panels: Explore 384 Cardiometabolic, Explore 384 Inflammation, Explore 384 Neurology, and Explore 384 Oncology. The protein concentrations are given as Olink’s relative protein quantification unit on log2 scale: Normalized Protein Expression (NPX). The NPX values were intensity normalized by Olink.
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| 6. |
- Robinson, Yohan, 1977-, et al.
(författare)
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Biological disease-modifying anti-rheumatic treatment delayed spinal fractures related to ankylosing spondylitis : National multi-registry cohort study from the Swedish Patient Registry and the Swedish Prescribed Drugs Registry
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- ObjectiveAnkylosing spondylitis (AS) is associated with increased spinal fracture risk due to loss of elasticity in spinal motion segments. With the introduction of biological disease modifying anti-rheumatic drugs (bDMARD) treatment for AS patients the individual course of the disease has been decelerated. This study aims to clarify whether the improved medical therapy reduced the spinal fracture incidence.MethodsIncluded were all patients with the diagnosis of AS 1987 to 2014 from the Swedish Patient Registry. From the Swedish Prescribed Drug Registry the Anatomical Therapeutic Chemical codes for bDMARD, non-steroidal anti-inflammatory drugs (NSAID), methotrexate (MTX) and sulfasalazine were extracted and numbers of prescriptions and years of treatment counted since 2005.Results 12297 patients with ankylosing spondylitis were included between 1987 and 2014 (age 67±19, 67% male). Of these 291 had spinal fractures between 2011 and 2014. The number of prescriptions of bDMARD increased during the last decade, but not of MTX, sulfasalazine and NSAID. 64% of all AS patients used NSAID, 13% used bDMARD, 13% used MTX, and 10% used sulfasalazine. A multivariate analysis of patients with spinal fractures 2011-2014 found bDMARD delaying spinal fracture debut by 1.24 years per year of bDMARD treatment (p=0.028). The use of bDMARD had no significant effect on spinal fracture risk (OR=0.93, 95%-C.I.=0.85-1.01, p=0.09).ConclusionThis study failed to demonstrate a beneficial effect on spinal fracture risk for AS patients treated with bDMARD during the last decade. Still bDMARD treatment delayed spinal fracture occurrence, which is promising with regard to results from future studies.Trial registrationClinicalTrials.gov, Identifier NCT02840695.
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- Andersson, Åsa, et al.
(författare)
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Effects on serum protein levels from one bout of high intensity interval training in individuals with axial spondyloarthritis and controls
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: Axial spondyloarthritis (axSpA) is a chronic inflammatory disease primarily affecting the axial skeleton causing pain, inflammation, and stiffness. Individuals with axSpA are at greater risk of developing cardiovascular disease, which can be counteracted by physical activity. High-intensity interval training (HIIT) has been shown to improve cardiovascular health, but the effect on disease activity and the level of inflammation in axSpA has been less studied. With the aim of investigating how levels of inflammatory cytokines, myokines, and protein markers for bone metabolism are acutely affected by one bout of HIIT, we studied serum from individuals with axSpA and healthy controls (HC). Methods: Ten participants with axSpA and 11 age- and sex-matched HC performed a single HIIT bout on a cycle ergometer: 4x4 minutes intervals with three minutes active rest in between. Blood samples were taken before and one hour after the HIIT bout. Serum proteins (IL-6, IL-17, IL-18, TNFa, CXCL-10, VEGF-A, BDNF, DKK-1, osteoprotegerin, osteocalcin, osteopontin, BMP-7, CRP) were analyzed with a Luminex system or ELISA. Descriptive data are presented as mean with standard deviation. A two-way ANOVA was used for comparisons. Results: A main effect from baseline to one hour post HIIT showed that both groups had a significant increase in serum levels (pg/ml) of IL-6: axSpA 2.2 (3.0) to 3.2 (1.8) and HC 0.4 (0.4) to 1.9 (2.0), p=0.03. VEGF-A (pg/ml) was significantly lower in the axSpA group: 159 (138) vs. HC 326 (184), p=0.03, but was not affected by the HIIT bout. BMP-7 (ng/ml) increased in both groups after the HIIT: axSpA 61.6 (13.1) to 75.2 (20.0) and HC 64.6 (20.8 to 75.0 (17.8), p<0.001. For the other proteins analyzed, there were no significant differences in serum concentrations between individuals with axSpA and HC, or within the two groups before and after one bout of HIIT. Conclusions: One acute bout of HIIT significantly increases the serum concentrations of IL-6 and BMP-7 after 1 hour in both individuals with axSpA and HC.
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