| 1. |
- Andersson, Karin, 1972, et al.
(author)
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Pathogenic Transdifferentiation of Th17 Cells Contribute to Perpetuation of Rheumatoid Arthritis during Anti-TNF Treatment.
- 2015
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In: Molecular medicine (Cambridge, Mass.). - : Springer Science and Business Media LLC. - 1528-3658 .- 1076-1551. ; 21, s. 536-43
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Journal article (peer-reviewed)abstract
- T-helper cells producing interleukin (IL)-17A and IL-17F cytokines (Th17 cells) are considered the source of autoimmunity in rheumatoid arthritis (RA). In this study, we characterized specific pathogenic features of Th17 cells in RA. By using nano-string technology, we analyzed transcription of 419 genes in the peripheral blood CCR6(+)CXCR3(-) CD4(+) cells of 14 RA patients and 6 healthy controls and identified 109 genes discriminating Th17 cells of RA patients from the controls. Th17 cells of RA patients had an aggressive pathogenic profile and in addition to signature cytokines IL-17, IL-23 and IL-21, and transcriptional regulators RAR-related orphan receptor gamma of T cells (RORγt) and Janus kinase 2 (JAK2), they produced high levels of IL-23R, C-C chemokine ligand type 20 (CCL20), granulocyte-monocyte colony-stimulating factor (GM-CSF ) and transcription factor Tbet required for synovial homing. We showed that Th17 cells are enriched with Helios-producing Foxp3- and IL2RA-deficient cells, indicating altered regulatory profile. The follicular T-helper (Tfh) cells presented a functional profile of adaptor molecules, transcriptional regulator Bcl-6 and B-cell activating cytokines IL-21, IL-31 and leukemia inhibitory factor (LIF ). We observed that anti-tumor necrosis factor (TNF) treatment had a limited effect on the transcription signature of Th17 cells. Patients in remission retained the machinery of receptors (IL-23R and IL-1R1), proinflammatory cytokines (IL-17F, IL-23, IL-21 and TNF ) and adaptor molecules (C-X-C chemokine receptor 5 [CXCR5] and cytotoxic T-lymphocyte-associated protein 4 [CTLA-4]), essential for efficient transdifferentiation and accumulation of Th17 cells. This study convincingly shows that the peripheral blood CCR6(+)CXCR3(-) CD4(+) cells of RA patients harbor pathogenic subsets of Th17 and Tfh cells, which may transdifferentiate from Tregs and contribute to perpetuation of the disease.
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| 2. |
- Andersson, Karin, 1972, et al.
(author)
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Survivin controls biogenesis of microRNA in smokers: A link to pathogenesis of rheumatoid arthritis.
- 2017
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In: Biochimica et biophysica acta. - : Elsevier BV. - 0006-3002. ; 1863:3, s. 663-673
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Journal article (peer-reviewed)abstract
- MicroRNAs (miRs) represent a part of epigenetic control of autoimmunity gaining increasing attention in rheumatoid arthritis (RA). Since cigarette smoking plays important role in RA pathogenesis and reprograms transcriptional profile of miRNAs, we ask if the onco-protein survivin, a novel biomarker of RA, may provide a link between smoking and miRNA. Studying survivin expression in leukocytes of 144 female RA patients we observed that smoking patients had higher survivin transcription and a remarkable spreading of survivin isoforms. This was associated with restricted pattern and low production of miRs. Additionally, miRNA processing enzymes Dicer and DGRC8 were decreased in the patients with survivin isoform spreading. The direct contribution of survivin in miRs biogenesis was confirmed by a massive increase of miRs production following inhibition of survivin in leukocyte cultures. Dicer is shown to mediate these effects of survivin. Chromatin immunoprecipitation analysis demonstrated binding of survivin to the Dicer promoter region. Dicer expression increased 5-folds following survivin inhibition. Taken together, this study presents experimental evidence of a novel cellular function of survivin, control of miRs biogenesis. Up-regulation of survivin in smokers suggests its role as effector of the adverse epigenetic control in RA.
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| 3. |
- Bokarewa, Maria, 1963, et al.
(author)
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Balance between survivin, a key member of the apoptosis inhibitor family, and its specific antibodies determines erosivity in rheumatoid arthritis
- 2005
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In: Arthritis Res Ther. - 1478-6362. ; 7:2
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Journal article (peer-reviewed)abstract
- Rheumatoid arthritis (RA) is a highly heterogeneous disease with respect to its joint destructivity. The reasons underlying this heterogeneity are unknown. Deficient apoptosis in rheumatoid synovial tissue has been recently demonstrated. We have therefore decided to study the synovial expression of survivin, a key member of the apoptosis inhibitor family. The levels of survivin and antibodies against survivin were assessed by an ELISA in matched blood and synovial fluid samples collected from 131 RA patients. Results were related to joint erosivity at the time of sampling. Monocytes were transfected with survivin anti-sense oligonucleotides and were assessed for their ability to produce inflammatory cytokines. Survivin levels were significantly higher in patients with destructive disease as compared with in RA patients displaying a non-erosive disease. High survivin levels were an independent prognostic parameter for erosive RA. In contrast, high levels of antibodies against survivin were found in patients with non-erosive RA, and were negatively related to erosivity. Survivin levels in RA patients were influenced by treatment, being significantly lower among patients treated with disease-modifying anti-rheumatic drugs. Specific suppression of survivin mRNA resulted in downregulation of IL-6 production. We conclude that survivin determines the erosive course of RA, whereas survivin antibodies lead to a less aggressive course of the disease. These findings together with decreased survivin levels upon disease-modifying anti-rheumatic drug treatment, and the downregulation of inflammatory response using survivin anti-sense oligonucleotides, suggest that extracellular survivin expression mediates the erosive course of joint disease whereas autoimmune responses to the same molecule, manifested as survivin targeting antibodies, mediate protection.
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| 4. |
- Erlandsson, Malin, 1972, et al.
(author)
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IGF-1R signalling contributes to IL-6 production and T cell dependent inflammation in rheumatoid arthritis.
- 2017
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In: Biochimica et Biophysica Acta - Molecular basis of disease. - : Elsevier BV. - 0005-2728 .- 0925-4439. ; 1863:9, s. 2158-2170
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Journal article (peer-reviewed)abstract
- Signalling through insulin-like growth factor 1 receptor (IGF-1R) is essential for cell survival, but may turn pathogenic in uncontrolled tissue growth in tumours. In rheumatoid arthritis (RA), the IGF-1R signalling is activated and supports expansion of the inflamed synovia.In the present study, we assess if disruption of IGF-1R signalling resolves arthritis.Clinical associations of IGF-1R expression in leukocytes of the peripheral blood were studied in 84 RA patients. Consequences of the IGF-1R signalling inhibition for arthritis were studied in mBSA immunised Balb/c mice treated with NT157 compound promoting degradation of insulin receptor substrates.In RA patients, high expression of IGF-1R in leukocytes was associated with systemic inflammation as verified by higher expression of NF-kB, serum levels of IL6 and erythrocyte sedimentation rate, and higher pain perception. Additionally, phosphorylated IGF-1R and STAT3 enriched T cells infiltrate in RA synovia. Treatment with NT157 inhibited the phosphorylation of IGF-1R and STAT3 in synovia, and alleviated arthritis and joint damage in mice. It also reduced expression of IGF-1R and despaired ERK and Akt signalling in spleen T cells. This limited IL-6 production, changed RoRgt/FoxP3 balance and IL17 levels.IGF-1R signalling contributes to T cell dependent inflammation in arthritis. Inhibition of IGF-1R on the level of insulin receptor substrates alleviates arthritis by restricting IL6-dependent formation of Th17 cells and may open for new treatment strategies in RA.
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| 5. |
- Erlandsson, Malin, 1972, et al.
(author)
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Smoking Functions as a Negative Regulator of IGF1 and Impairs Adipokine Network in Patients with Rheumatoid Arthritis.
- 2016
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In: Mediators of inflammation. - : Hindawi Limited. - 1466-1861 .- 0962-9351. ; 2016
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Journal article (peer-reviewed)abstract
- Objectives. Smoking is pathogenic for rheumatoid arthritis (RA) being tightly connected to the genetic and serological risk factors for this disease. This study aims to understand connections between cigarette smoking and serum levels of IGF1 and adipokines in RA. Methods. Serum levels of IGF1 and adipokines leptin, adiponectin, resistin, and visfatin were measured in two independent cohorts of RA patients from Gothenburg (n = 350) and Leiden (n = 193). An association of these parameters with smoking was tested in a direct comparison and proved by bivariate correlation analysis. The obtained associations were further tested in multivariate regression models where the confounders (age, gender, disease duration, and BMI) were controlled. Results. The smokers had significantly lower serum levels of IGF1, adiponectin, and leptin compared to never smokers. In regression analysis, smoking and low leptin, but not adiponectin, were associated and predicted low IGF1. Additionally, high disease activity and high BMI increased the probability of low leptin. Conclusions. The study indicates cigarette smoking as an important cause of a relative IGF1 and leptin deficiency in RA patients. This novel association between smoking and hypoleptinemia may be of importance for long-term prognosis of RA and for prediction of comorbidities.
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| 6. |
- Gravina, Giacomo, et al.
(author)
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Survivin in autoimmune diseases.
- 2017
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In: Autoimmunity reviews. - : Elsevier BV. - 1873-0183 .- 1568-9972. ; 16:8, s. 845-855
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Research review (peer-reviewed)abstract
- Survivin is a protein functionally important for cell division, apoptosis, and possibly, for micro-RNA biogenesis. It is an established marker of malignant cell transformation. In non-malignant conditions, the unique properties of survivin make it indispensable for homeostasis of the immune system. Indeed, it is required for the innate and adaptive immune responses, controlling differentiation and maintenance of CD4(+) and CD8(+) memory T-cells, and in B cell maturation. Recently, survivin has emerged as an important player in the pathogenesis of autoimmune diseases. Under the conditions of unreserved inflammation, survivin enhances antigen presentation, maintains persistence of autoreactive cells, and supports production of autoantibodies. In this context, survivin takes its place as a diagnostic and prognostic marker in rheumatoid arthritis, psoriasis, systemic sclerosis and pulmonary arterial hypertension, neuropathology and multiple sclerosis, inflammatory bowel diseases and oral lichen planus. In this review, we summarise the knowledge about non-malignant properties of survivin and focus on its engagement in cellular and molecular pathology of autoimmune diseases. The review highlights utility of survivin measures for clinical applications. It provides rational for the survivin inhibiting strategies and presents results of recent reports on survivin inhibition in modern therapies of cancers and autoimmune diseases.
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| 7. |
- Jonsson, Ing-Marie, 1949, et al.
(author)
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Ethanol prevents development of destructive arthritis
- 2007
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In: Proc Natl Acad Sci U S A. - Washington, DC : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 104:1, s. 258-63
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Journal article (peer-reviewed)abstract
- Environmental factors are thought to play a major role in the development of rheumatoid arthritis. Because the use of ethanol is widespread, we assessed the role of ethanol intake on the propensity to develop chronic arthritis. Collagen type II-immunized mice were given water or water containing 10% (vol/vol) ethanol or its metabolite acetaldehyde. Their development of arthritis was assessed, as well as the impact of ethanol on leukocyte migration and activation of intracellular transcription factors. Mice exposed daily to this dose of ethanol did not display any liver toxicity, and the development of erosive arthritis was almost totally abrogated. In contrast, the antibody-mediated effector phase of collagen-induced arthritis was not influenced by ethanol exposure. Also, the major ethanol metabolite, acetaldehyde, prevented the development of arthritis. This antiinflammatory and antidestructive property of ethanol was mediated by (i) down-regulation of leukocyte migration and (ii) up-regulation of testosterone secretion, with the latter leading to decreased NF-kappaB activation. We conclude that low but persistent ethanol consumption delays the onset and halts the progression of collagen-induced arthritis by interaction with innate immune responsiveness.
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| 8. |
- Malmhäll-Bah, Eric, et al.
(author)
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Metabolic signature and proteasome activity controls synovial migration of CDC42hiCD14+ cells in rheumatoid arthritis.
- 2023
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In: Frontiers in immunology. - 1664-3224. ; 14
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Journal article (peer-reviewed)abstract
- Activation of Rho-GTPases in macrophages causes inflammation and severe arthritis in mice. In this study, we explore if Rho-GTPases define the joint destination of pathogenic leukocytes, the mechanism by which they perpetuate rheumatoid arthritis (RA), and how JAK inhibition mitigates these effects.CD14+ cells of 136 RA patients were characterized by RNA sequencing and cytokine measurement to identify biological processes and transcriptional regulators specific for CDC42 hiCD14+ cells, which were summarized in a metabolic signature (MetSig). The effect of hypoxia and IFN-γ signaling on the metabolic signature of CD14+ cells was assessed experimentally. To investigate its connection with joint inflammation, the signature was translated into the single-cell characteristics of CDC42 hi synovial tissue macrophages. The sensitivity of MetSig to the RA disease activity and the treatment effect were assessed experimentally and clinically.CDC42 hiCD14+ cells carried MetSig of genes functional in the oxidative phosphorylation and proteasome-dependent cell remodeling, which correlated with the cytokine-rich migratory phenotype and antigen-presenting capacity of these cells. Integration of CDC42 hiCD14+ and synovial macrophages marked with MetSig revealed the important role of the interferon-rich environment and immunoproteasome expression in the homeostasis of these pathogenic macrophages. The CDC42 hiCD14+ cells were targeted by JAK inhibitors and responded with the downregulation of immunoproteasome and MHC-II molecules, which disintegrated the immunological synapse, reduced cytokine production, and alleviated arthritis.This study shows that the CDC42-related MetSig identifies the antigen-presenting CD14+ cells that migrate to joints to coordinate autoimmunity. The accumulation of CDC42 hiCD14+ cells discloses patients perceptive to the JAKi treatment.
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| 9. |
- Nadali, Mitra, et al.
(author)
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High Expression of STAT3 in Subcutaneous Adipose Tissue Associates with Cardiovascular Risk in Women with Rheumatoid Arthritis.
- 2017
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In: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 18:11
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Journal article (peer-reviewed)abstract
- Despite the predominance of female patients and uncommon obesity, rheumatoid arthritis (RA) is tightly connected to increased cardiovascular morbidity. The aim of this study was to investigate transcriptional activity in the subcutaneous white adipose tissue (WAT) with respect to this disproportionate cardiovascular risk (CVR) in RA. CVR was estimated in 182 female patients, using the modified Systematic Coronary Risk Evaluation scale, and identified 93 patients with increased CVR. The overall transcriptional activity in WAT was significantly higher in patients with CVR and was presented by higher serum levels of WAT products leptin, resistin and IL-6 (all, p < 0.001). CVR was associated with high WAT-specific transcription of the signal transducer and activator of transcription 3 (STAT3) and the nuclear factor NF-kappa-B p65 subunit (RELA), and with high transcription of serine-threonine kinase B (AKT1) in leukocytes. These findings suggest Interleukin 6 (IL-6) and leptin take part in WAT-specific activation of STAT3. The binary logistic regression analysis confirmed an independent association of CVR with IL-6 in serum, and with STAT3 in WAT. The study shows an association of CVR with transcriptional activity in WAT in female RA patients. It also emphasizes the importance of STAT3 regulatory circuits for WAT-related CVR in RA.
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| 10. |
- Silfverswärd Lindblad, Sofia, 1980
(author)
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Role of environmental toxins in chronic experimental arthrithis - in search for anti-inflammatory pathways of ethanol and nicotine
- 2010
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Doctoral thesis (other academic/artistic)abstract
- Rheumatoid arthritis (RA) is a common systemic autoimmune disorder and a debilitating disease affecting 1% of the world population. The etiology of RA is an unresolved issue. Environmental factors such as alcohol intake and cigarette smoke have been described as contributing to the pathogenesis of RA. These assumptions are based on epidemiological studies, while experimental proof on this issue is limited. This thesis studies the effect of common environmental toxins on experimental arthritis induced by collagen type II (collagen-induced arthritis, CIA), an established murine model closely resembling human RA. We propose biological mechanisms behind the anti-inflammatory properties of environmental stimuli such as ethanol and nicotine, and provide new insights into the pathogenesis of RA. Paper I shows that a continuous intake of ethanol delays the onset and halts the progression of CIA in mice. This anti-arthritic effect is mediated by increased testosterone secretion leading to (i) decreased activation of transcription factor NF-κB, (ii) down-regulation of pro-inflammatory cyto- and chemokines and (iii) down-regulation of leukocyte migration into the joints. Paper II studies the effect of cigarette smoking and nicotine exposure in CIA mice. Results show that mice exposed to cigarette smoke develop a significantly milder arthritis with reduced destruction of joints. Nicotine-exposed mice show a tendency to decreased inflammation. Notably, exposure to cigarette smoke reduces antigen response and decreases the level of CII-specific antibodies. Paper III handles intervention with ethanol-sensitive glutamate receptors. CIA mice subjected to the NMDA receptor antagonist memantine show significantly decreased severity of arthritis and reduced destructive disease. We show that memantine up-regulates transcription factor Foxp3 and enhances formation of CD4+CD25+Foxp3+ regulatory T cells, which may be a potential reason for the anti-arthritic properties of the NMDA receptor blockade. In conclusion, our results provide new insights into the anti-inflammatory properties of environmental toxins such as ethanol and nicotine, as well as of blockade of the ethanol-sensitive NMDA receptor. Our findings from experimental studies need further validation in the population of RA patients.
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