| 1. |
- Andersson, Annica, 1983, et al.
(författare)
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Estrogen regulates T helper 17 phenotype and localization in experimental autoimmune arthritis
- 2015
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Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6354. ; 17:32
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The incidence and progression of many autoimmune diseases are sex-biased, which might be explained by the immunomodulating properties of endocrine hormones. Treatment with estradiol potently inhibits experimental autoimmune arthritis. Interleukin-17-producing T helper cells (Th17) are key players in several autoimmune diseases, particularly in rheumatoid arthritis. The aim of this study was to investigate the effects of estrogen on Th17 cells in experimental arthritis. Methods: Ovariectomized DBA/1 mice treated with 17 beta-estradiol (E2) or placebo were subjected to collagen-induced arthritis (CIA), and arthritis development was assessed. Th17 cells in joints and lymph nodes were studied by flow cytometry. Lymph node Th17 cells were also examined in ovariectomized estrogen receptor a-knockout mice (ERa-/-) and wild-type littermates, treated with E2 or placebo and subjected to antigen-induced arthritis. Results: E2-treated mice with established CIA showed reduced severity of arthritis and fewer Th17 cells in joints compared with controls. Interestingly, E2-treated mice displayed increased Th17 cells in lymph nodes during the early phase of the disease, dependent on ER alpha. E2 increased the expression of C-C chemokine receptor 6 (CCR6) on lymph node Th17 cells as well as the expression of the corresponding C-C chemokine ligand 20 (CCL20) within lymph nodes. Conclusions: This is the first study in which the effects of E2 on Th17 cells have been characterized in experimental autoimmune arthritis. We report that E2 treatment results in an increase of Th17 cells in lymph nodes during the early phase of arthritis development, but leads to a decrease of Th17 in joints during established arthritis. Our data suggest that this may be caused by interference with the CCR6-CCL20 pathway, which is important for Th17 cell migration. This study contributes to the understanding of the role of estrogen in the development of autoimmune arthritis and opens up new fields for research concerning the sex bias in autoimmune disease.
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| 2. |
- Andersson, Annica, 1983, et al.
(författare)
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Selective oestrogen receptor modulators lasofoxifene and bazedoxifene inhibit joint inflammation and osteoporosis in ovariectomised mice with collagen-induced arthritis.
- 2016
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Ingår i: Rheumatology (Oxford, England). - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 55:3, s. 553-563
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Tidskriftsartikel (refereegranskat)abstract
- RA predominantly affects post-menopausal women and is strongly associated with development of generalised osteoporosis. To find treatments that target both joint manifestations and osteoporosis in RA is desirable. The third generation of selective oestrogen receptor modulators (SERMs) [lasofoxifene (LAS) and bazedoxifene (BZA)] are new treatment options for post-menopausal osteoporosis. The aim of this study was to investigate the effects of LAS and BZA on arthritic disease and inflammation-associated bone loss using CIA in mice.
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| 3. |
- Andersson, Annica, 1983, et al.
(författare)
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Suppression of Experimental Arthritis and Associated Bone Loss by a Tissue-Selective Estrogen Complex.
- 2016
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Ingår i: Endocrinology. - : The Endocrine Society. - 1945-7170 .- 0013-7227. ; 157:3, s. 1013-20
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Tidskriftsartikel (refereegranskat)abstract
- In addition to the systemic inflammation present in rheumatoid arthritis (RA), decreased estradiol levels in postmenopausal RA patients further accelerate bone loss in these patients. The tissue-selective estrogen complex (TSEC), an estrogen combined with a selective estrogen receptor modulator, is a new hormone replacement therapy option. The first approved TSEC, containing conjugated estrogens and bazedoxifene (BZA), reduces menopausal symptoms and prevents osteoporosis with an improved safety profile compared with conventional hormone replacement therapy. Previous studies have shown that estrogens strongly inhibit experimental arthritis whereas BZA is mildly suppressive. In this study the antiarthritic potential of combined BZA and estradiol is explored for the first time. Female ovariectomized DBA/1 mice were subjected to collagen-induced arthritis, an experimental postmenopausal RA model, and treated with BZA, 17β-estradiol (E2), combined BZA and E2 (BZA/E2), or vehicle. BZA/E2 suppressed arthritis severity and frequency, synovitis, and joint destruction, equally efficient as E2 alone. Unwanted estrogenic proliferative effects on the endometrium were blocked by the addition of BZA, determined by collecting uterine weights. Bone mineral density was measured by peripheral quantitative computed tomography, and all treatments protected collagen-induced arthritis mice from both trabecular and cortical bone loss. Moreover, BZA/E2, but not E2 alone, inhibited preosteoclast formation and reduced serum anticollagen type II antibodies. In conclusion, a TSEC, herein combined BZA/E2, suppresses experimental arthritis and prevents associated bone loss as efficiently as E2 alone but with minimal uterine effects, highlighting the need for clinical trials that evaluate the addition of a TSEC to conventional postmenopausal RA treatment.
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| 4. |
- Bergquist, Maria, et al.
(författare)
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Expression of the glucocorticoid receptor is decreased in experimental Staphylococcus aureus sepsis
- 2013
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Ingår i: Journal of Infection. - : Elsevier BV. - 0163-4453 .- 1532-2742. ; 67:6, s. 574-583
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Glucocorticoid treatment in septic shock remains controversial after recent trials. We hypothesized that failure to respond to steroid therapy may be caused by decreased expression and/or function of glucocorticoid receptors (GR) and studied this in a mouse model of Staphylococcus aureus sepsis. The impact of timing of dexamethasone treatment was also investigated. Methods: Male C57BL/6J mice were intravenously inoculated with S. aureus and GR expression and binding ability in blood, spleen and lymph nodes were analysed by means of flow cytometry. GR translocation was analysed using Image Stream. Septic mice were administered dexamethasone at 22, 26, 48, 72 and 96 h after inoculation and body weight, as a sign of dehydration, was observed. Results: GR expression was decreased in septic animals, but not the ligand binding capacity. GR translocation was decreased in septic mice compared to control animals. Early dexamethasone treatment (22 and 26 h) improved clinical outcome as studied by weight gain compared to when treatment was started at later time points (48, 72 and 96 h). Conclusion: Our data provide evidence that GR expression is progressively decreased in experimental sepsis and that dexamethasone has a decreased ability to translocate into the cell nucleus. This may explain why steroid treatment is only beneficial when administered early in sepsis and septic shock.
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| 5. |
- Bergquist, Maria, et al.
(författare)
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Glucocorticoid receptor function is decreased in neutrophils during endotoxic shock
- 2014
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Ingår i: Journal of Infection. - : Elsevier BV. - 0163-4453 .- 1532-2742. ; 69:2, s. 113-122
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: It remains unclear whether glucocorticoid treatment can improve the outcome of sepsis. The aim of the present study was to investigate if glucocorticoid receptor (GR) expression and function is impaired in lipopolysaccharide (LPS) induced shock, and whether the time point for start of glucocorticoid treatment affects the outcome.METHODS: Male C57BL/6J mice were administered LPS i.p. and GR expression and binding ability in blood and spleen leukocytes were analysed by flow cytometry. GR translocation was analysed using Image Stream technique. The effect of dexamethasone treatment started 2 h before or 2, 12 or 36 h after LPS administration on survival was studied.RESULTS: Despite increased GR expression in neutrophils after LPS administration, the GR binding capacity was reduced. In addition, GR translocation was decreased in neutrophils and T lymphocytes from endotoxic mice at 12 h compared to control animals. Dexamethasone treatment improved survival only when started early (2 h) after LPS administration.CONCLUSION: The decreased glucocorticoid responsiveness displayed by neutrophils, in combination with their increased numbers, may explain why survival is increased only when dexamethasone treatment is given early during LPS induced shock.
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| 6. |
- Bernardi, Angelina I, et al.
(författare)
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Effects of lasofoxifene and bazedoxifene on B cell development and function.
- 2014
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Ingår i: Immunity, inflammation and disease. - : Wiley. - 2050-4527. ; 2:4, s. 214-25
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Tidskriftsartikel (refereegranskat)abstract
- The third generation selective estrogen receptor modulators lasofoxifene (las) and bazedoxifene (bza) are indicated for treatment of postmenopausal osteoporosis. 17β-Estradiol (E2) and the second generation SERM raloxifene (ral) have major effects on the immune system, particularly on B cells. Treatment with E2 or ral inhibits B lymphopoiesis and treatment with E2, but not ral, stimulates antibody production. The effects of las and bza on the immune system have not been studied. Therefore, the aim of this study was to investigate their role in B cell development, maturation, and function. C57BL/6 mice were sham-operated or ovariectomized (ovx) and treated with vehicle, E2, ral, las, or bza. All substances increased total bone mineral density in ovx mice, as measured by peripheral quantitative computed tomography. In uterus, bza alone lacked agonistic effect in ovx mice and even acted as an antagonist in sham mice. As expected, E2 decreased B cell numbers at all developmental stages from pre-BI cells (in bone marrow) to transitional 1 (T1) B cells (in spleen) and increased marginal zone (MZ) B cells as determined by flow cytometry. However, treatment with las or bza only decreased the last stages of bone marrow B cell development and splenic T1 B cells, but had no effect MZ B cells. E2 increased antibody-producing cells quantified by ELISPOT, but las or bza did not. In conclusion, las and bza differ from E2 by retaining normal number of cells at most B cell stages during B lymphopoiesis and maturation and by not increasing antibody-producing cells.
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| 7. |
- Chandy, Annie George, 1969, et al.
(författare)
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Therapeutic dendritic cell vaccination with Ag coupled to cholera toxin in combination with intratumoural CpG injection leads to complete tumour eradication in mice bearing HPV 16 expressing tumours.
- 2007
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Ingår i: Vaccine. - : Elsevier BV. - 0264-410X. ; 25:32, s. 6037-46
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Tidskriftsartikel (refereegranskat)abstract
- We have evaluated whether cholera toxin (CT) can enhance the efficiency of therapeutic dendritic cell (DC) vaccination in mice bearing a human papilloma virus (HPV) 16 antigen (Ag) expressing tumour. Mice were therefore injected with the TC-1 cancer cell line expressing E6 and E7, which are the major oncogenic proteins produced in HPV-induced cervical cancer, and they were then vaccinated with Ag pulsed DCs. While vaccination with E7 pulsed DCs had no impact on tumour growth, DCs pulsed with CT conjugated E7 (CT-E7) significantly reduced tumour size. However, this treatment was only able to eradicate the tumour in 11% of the affected animals. For complete tumour eradication, combinational therapy with CT-E7 pulsed DCs and local treatment of the tumour with CpG oligodeoxynucleotides (CpG) was required. Combinational therapy was associated with increased expression of MHC I and MHC II and increased levels of chemokine production in the tumour. These results suggest that combined treatment with CT-Ag pulsed DCs and local CpG administration offers an efficient strategy to eradicate an already existing HPV-E7 expressing tumour in mice.
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| 8. |
- Deminger, Anna, 1973, et al.
(författare)
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Elevated serum level of hepatocyte growth factor predicts development of new syndesmophytes in men with ankylosing spondylitis
- 2021
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Ingår i: Rheumatology (Oxford, England). - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 60:4, s. 1804-1813
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To study baseline serum hepatocyte growth factor (s-HGF) as a predictor of spinal radiographic progression overall and by sex and to analyse factors correlated to changes in s-HGF in patients with AS. METHODS: At baseline and the 5-year follow-up, s-HGF was analysed with ELISA. Spinal radiographs were graded according to modified Stoke Ankylosing Spondylitis Spinal Score. Radiographic progression was defined as ≥2 modified Stoke Ankylosing Spondylitis Spinal Score units/5 years or development of ≥1 syndesmophyte. Logistic regression analyses were used. RESULTS: Of 204 baseline participants, 163 (80%) completed all examinations at the 5-year follow-up (54% men). Baseline s-HGF was significantly higher in men who developed ≥1 syndesmophyte compared with non-progressors, median (interquartile range) baseline s-HGF 1551 (1449-1898) vs 1436 (1200-1569) pg/ml, P = 0.003. The calculated optimal cut-off point for baseline s-HGF ≥1520 pg/ml showed a sensitivity of 70%, a specificity of 69% and univariate odds radio (95% CI) of 5.25 (1.69, 14.10) as predictor of development of ≥1 new syndesmophyte in men. Baseline s-HGF ≥1520 pg/ml remained significantly associated with development of ≥1 new syndesmophyte in men in an analysis adjusted for the baseline variables age, smoking, presence of syndesmophytes and CRP, odds radio 3.97 (1.36, 11.60). In women, no association with HGF and radiographic progression was found. Changes in s-HGF were positively correlated with changes in ESR and CRP. CONCLUSION: In this prospective cohort study elevated s-HGF was shown to be associated with development of new syndesmophytes in men with AS.
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| 9. |
- Deminger, Anna, et al.
(författare)
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Hepatocyte growth factor is a predictor of development of new syndesmophytes in men with ankylosing spondylitis. A five year prospective study
- 2019
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 78, s. 1240-1240
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Patients with ankylosing spondylitis (AS) have an increased risk of spinal new bone formation characterized by the development of syndesmophytes. Knowledge of predictors for development of syndesmophytes is limited. Hepatocyte growth factor (HGF) has regulatory effects on a variety of cells in many different organs. HGF signaling can affect both osteoclast and osteoblast lineages and has been shown to promote osteogenesis. Cross-sectional association between increased HGF and increased modified Stoke Ankylosing Spine Score (mSASSS) has previously been shown [1], whereas knowledge of HGF as a predictor for new bone formation is lacking.Objectives: To study serum HGF as a predictor for development of new syndesmophytes in patients with AS followed for five years.Methods: Serum levels of HGF was analyzed using ELISA in patients with AS (modified NY-criteria) and in healthy controls (HC) at baseline. Spinal lateral radiographs were obtained at baseline and at the 5-year follow-up and assessed for development of new syndesmophytes using mSASSS. Univariate and multivariable logistic regression analyses were used to assess predictors for development of ≥ 1 new syndesmophyte.Results: Serum HGF and radiographs at baseline and follow-up were available for 163 patients, 88 men and 75 women, baseline mean age 50±12 years. AS patients had higher serum HGF than HC (n=80), p=0.050. In the AS group, 36 patients (22%) developed ≥ 1 syndesmophyte, 27 men and 9 women. In the total AS group, neither did baseline serum HGF differ between those who developed ≥ 1 new syndesmophyte and those who did not progress, nor did it predict development of ≥ 1 new syndesmophyte in the univariate analysis, p=0.25. Interestingly, men who developed ≥1 new syndesmophyte had higher serum HGF than the non-progressors (1706±454 vs 1420±338 pg/mL, p=0.001) and increased serum HGF at baseline predicted development of ≥ 1 syndesmophyte (OR per 1 SD HGF 2.39, 95% CI 1.31 to 4.36) in the univariate analysis. Serum HGF did not predict new syndesmophytes in women, p=0.13. Multivariable analysis for men including age, smoking, baseline syndesmophyte and serum HGF showed high HGF (OR per 1SD 1.90, 95% CI 1.01 to 3.59) and ≥1 baseline syndesmophyte (OR 3.48, 95% CI 1.09 to 11.07) to independently predict development of ≥ 1 new syndesmophyte. If baseline CRP was included in the multivariable model, serum HGF and baseline syndesmophytes remained the significant predictors.Conclusion: High baseline serum HGF was shown to independently predict the development of at least one new syndesmophyte over five years in men with AS.
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| 10. |
- Grahnemo, Louise, et al.
(författare)
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Trabecular bone loss in collagen antibody-induced arthritis
- 2015
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Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6354. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Postmenopausal women with rheumatoid arthritis (RA) have increased risk of developing osteoporosis due to chronic inflammation and estrogen deprivation. Collagen antibody-induced arthritis (CAIA), an experimental polyarthritis model representing the effector phase of arthritis, is mainly mediated by the innate immune system. Compared to the widely used collagen-induced arthritis model, CAIA is conveniently short and can be used in C57BL/6 mice, enabling studies with knock-out mice. However, the impact on bone of the CAIA model in C57BL/6 mice has not previously been studied. Therefore, the aim of this study was to determine if CAIA can be used to study postmenopausal arthritis-induced osteoporosis. Methods: CAIA was induced by administration of collagen-type II antibodies and lipopolysaccharide to ovariectomized female C57BL/6J mice. Control mice received lipopolysaccharide, but no antibodies. Nine days later, femurs were collected for high-resolution micro-CT and histomorphometry. Serum was used to assess cartilage breakdown and levels of complement. Frequencies of immune cell subsets from bone marrow and lymph nodes were analyzed by flow cytometery. Results: Trabecular bone mass was decreased and associated with increased number of osteoclasts per bone surface in the CAIA model. Also, the frequency of interleukin-17(+) cells in lymph nodes was increased in CAIA. Conclusion: The present study show that CAIA, a short reproducible arthritis model that is compatible with C57BL/6 mice, is associated with increased number of osteoclasts and trabecular bone loss.
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