| 1. |
- Grimsholm, Ola, 1979, et al.
(författare)
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Absence of surrogate light chain results in spontaneous autoreactive germinal centres expanding V(H)81X-expressing B cells
- 2015
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Random recombination of antibody heavy- and light-chain genes results in a diverse B-cell receptor (BCR) repertoire including self-reactive BCRs. However, tolerance mechanisms that prevent the development of self-reactive B cells remain incompletely understood. The absence of the surrogate light chain, which assembles with antibody heavy chain forming a pre-BCR, leads to production of antinuclear antibodies (ANAs). Here we show that the naive follicular B-cell pool is enriched for cells expressing prototypic ANA heavy chains in these mice in a non-autoimmune background with a broad antibody repertoire. This results in the spontaneous formation of T-cell-dependent germinal centres that are enriched with B cells expressing prototypic ANA heavy chains. However, peripheral tolerance appears maintained by selection thresholds on cells entering the memory B-cell and plasma cell pools, as exemplified by the exclusion of cells expressing the intrinsically self-reactive V(H)81X from both pools.
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| 2. |
- Andersson, Sofia E M, 1979, et al.
(författare)
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Activation of Fms-like tyrosine kinase 3 signaling enhances survivin expression in a mouse model of rheumatoid arthritis.
- 2012
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 7:10
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Tidskriftsartikel (refereegranskat)abstract
- Survivin is known as an inhibitor of apoptosis and a positive regulator of cell division. We have recently identified survivin as a predictor of joint destruction in patients with rheumatoid arthritis (RA). Flt3 ligand (Flt3L) is expressed in the inflamed joints and has adjuvant properties in arthritis. Studies on 90 RA patients (median age 60.5 years [range, 24-87], disease duration 10.5 years [range, 0-35]) show a strong positive association between the levels of survivin and Flt3L in blood. Here, we present experimental evidence connecting survivin and Flt3L signaling. Treatment of BALB/c mice with Flt3L led to an increase of survivin in the bone marrow and in splenic dendritic cells. Flt3L changed the profile of survivin splice variants, increasing transcription of the short survivin40 in the bone marrow. Treatment with an Flt3 inhibitor reduced total survivin expression in bone marrow and in the dendritic cell population in spleen. Inhibition of survivin transcription in mice, by shRNA lentiviral constructs, reduced the gene expression of Flt3L. We conclude that expression of survivin is a downstream event of Flt3 signaling, which serves as an essential mechanism supporting survival of leukocytes during their differentiation, and maturation of dendritic cells, in RA.
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| 3. |
- Andersson, Sofia E M, 1979, et al.
(författare)
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Collagen epitope expression on B cells is sufficient to confer tolerance to collagen-induced arthritis
- 2016
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Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: The mechanisms underlying tolerance induction and maintenance in autoimmune arthritis remain elusive. In a mouse model of rheumatoid arthritis, collagen type II (CII)-induced arthritis, we explore the contribution of B cells to antigen-specific tolerance. Methods: To generate expression of the CII-peptide specifically on B-cell major histocompatibility complex type II, lentiviral-based gene therapy including a B-cell-specific Igk promoter was used. Results: Presentation of the CII-peptide on B cells significantly reduced the frequency and severity of arthritis as well as the serum levels of CII -specific IgG antibodies. Further, both frequency and suppressive function of regulatory T cells were increased in tolerized mice. Adoptive transfer of regulatory T cells from tolerized mice to naive mice ameliorated the development of CII-induced arthritis. Conclusion: Our data suggest that endogenous presentation of the CII-peptide on B cells is one of the key contributors to arthritis tolerance induction and maintenance.
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| 4. |
- Andersson, Sofia E M, 1979, et al.
(författare)
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Moderate- to high intensity aerobic and resistance exercise reduces peripheral blood regulatory cell populations in older adults with rheumatoid arthritis
- 2020
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Ingår i: Immunity & Ageing. - : Springer Science and Business Media LLC. - 1742-4933. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- Objective Exercise can improve immune health and is beneficial for physical function in patients with rheumatoid arthritis (RA), but the immunological mechanisms are largely unknown. We evaluated the effect of moderate- to high intensity exercise with person-centred guidance on cells of the immune system, with focus on regulatory cell populations, in older adults with RA. Methods Older adults (>= 65 years) with RA were randomized to either 20-weeks of moderate - to high intensity aerobic and resistance exercise (n = 24) or to an active control group performing home-based exercise of light intensity (n = 25). Aerobic capacity, muscle strength, DAS28 and CRP were evaluated. Blood samples were collected at baseline and after 20 weeks. The frequency of immune cells defined as adaptive regulatory populations, CD4 + Foxp3 + CD25 + CD127- T regulatory cells (Tregs) and CD19 + CD24hiCD38hi B regulatory cells (Bregs) as well as HLA-DR-/lowCD33 + CD11b + myeloid derived suppressor cells (MDSCs), were assessed using flow cytometry. Results After 20 weeks of moderate- to high intensity exercise, aerobic capacity and muscle strength were significantly improved but there were no significant changes in Disease Activity Score 28 (DAS28) or CRP. The frequency of Tregs and Bregs decreased significantly in the intervention group, but not in the active control group. The exercise intervention had no effect on MDSCs. The reduction in regulatory T cells in the intervention group was most pronounced in the female patients. Conclusion Moderate- to high intensity exercise in older adults with RA led to a decreased proportion of Tregs and Bregs, but that was not associated with increased disease activity or increased inflammation.
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| 5. |
- Baran, M, et al.
(författare)
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SURVIVIN IS AN ESSENTIAL MEDIATOR OF ARTHRITIS INTERACTING WITH UROKINASE SIGNALLING.
- 2009
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Ingår i: Journal of cellular and molecular medicine. - : Wiley. - 1582-4934 .- 1582-1838. ; 13:9B, s. 3797-3808
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT Proto-oncogene survivin has recently been identified as a prognostic marker distinguishing patients with destructive rheumatoid arthritis (RA). In the present material of 132 RA patients and 82 controls the levels of survivin correlated to urokinase (uPA) (r=0.46), a plasminogen activator over expressed in inflamed joints and known to exhibit potent arthritogenic properties. Here we evaluate the functional relationship between these proteins using primary synovial fibroblasts and leukocytes of RA patients, human monocytic (THP-1) and fibroblast (MRC-5) cell lines. Using inhibitors of intracellular signalling we show that uPA and survivin share common transduction pathways being in synovial fibroblasts dependent on the activity of tyrosine kinases, PI3-kinase and MEK. Moreover, uPA production is significantly reduced in fibroblasts if survivin synthesis has been silenced by siRNA. Importantly, silencing of survivin in fibroblasts prevented their invasive growth in knee joints of SCID mice. Interaction of uPA with receptor up regulates survivin expression in leukocytes. In turn, survivin is required for the upregulation of uPA receptor on cell surface. These findings indicate that survivin is an essential mediator of arthritogenic properties of uPA regulating its synthesis in synovial fibroblasts and uPAR expression in leukocytes. Close correlation between survivin and uPA levels in patients with RA supports the importance of this connection for the pathogenesis of arthritis.
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| 6. |
- Erlandsson, Malin, 1972, et al.
(författare)
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Expression of metastasin S100A4 is essential for bone resorption and regulates osteoclast function.
- 2013
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Ingår i: Biochimica et biophysica acta. - : Elsevier BV. - 0006-3002. ; 1833:12, s. 2653-2663
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Tidskriftsartikel (refereegranskat)abstract
- S100A4 is a Ca-binding protein that regulates cell growth, survival, and motility. The abundant expression of S100A4 in rheumatiod arthritis contributes to the invasive growth of joint tissue and to bone damage. In the present study, we analysed the role of S100A4 in bone homeostasis.
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| 7. |
- Khan, Omar M., 1980, et al.
(författare)
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Geranylgeranyltransferase type I (GGTase-I) deficiency hyperactivates macrophages and induces erosive arthritis in mice.
- 2011
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Ingår i: The Journal of clinical investigation. - 1558-8238. ; 121:2, s. 628-39
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Tidskriftsartikel (refereegranskat)abstract
- RHO family proteins are important for the function of inflammatory cells. They are modified with a 20-carbon geranylgeranyl lipid in a process catalyzed by protein geranylgeranyltransferase type I (GGTase-I). Geranylgeranylation is viewed as essential for the membrane targeting and activity of RHO proteins. Consequently, inhibiting GGTase-I to interfere with RHO protein activity has been proposed as a strategy to treat inflammatory disorders. However, here we show that mice lacking GGTase-I in macrophages develop severe joint inflammation resembling erosive rheumatoid arthritis. The disease was initiated by the GGTase-I-deficient macrophages and was transplantable and reversible in bone marrow transplantation experiments. The cells accumulated high levels of active GTP-bound RAC1, CDC42, and RHOA, and RAC1 remained associated with the plasma membrane. Moreover, GGTase-I deficiency activated p38 and NF-κB and increased the production of proinflammatory cytokines. The results challenge the view that geranylgeranylation is essential for the activity and localization of RHO family proteins and suggest that reduced geranylgeranylation in macrophages can initiate erosive arthritis.
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| 8. |
- Svensson, Mattias, 1982, et al.
(författare)
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Fms-like tyrosine kinase 3 ligand controls formation of regulatory T cells in autoimmune arthritis.
- 2013
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Fms-like tyrosine kinase 3 ligand (Flt3L) is known as the primary differentiation and survival factor for dendritic cells (DCs). Furthermore, Flt3L is involved in the homeostatic feedback loop between DCs and regulatory T cell (Treg). We have previously shown that Flt3L accumulates in the synovial fluid in rheumatoid arthritis (RA) and that local exposure to Flt3L aggravates arthritis in mice, suggesting a possible involvement in RA pathogenesis. In the present study we investigated the role of Flt3L on DC populations, Tregs as well as inflammatory responses in experimental antigen-induced arthritis. Arthritis was induced in mBSA-immunized mice by local knee injection of mBSA and Flt3L was provided by daily intraperitoneal injections. Flow cytometry analysis of spleen and lymph nodes revealed an increased formation of DCs and subsequently Tregs in mice treated with Flt3L. Flt3L-treatment was also associated with a reduced production of mBSA specific antibodies and reduced levels of the pro-inflammatory cytokines IL-6 and TNF-α. Morphological evaluation of mBSA injected joints revealed reduced joint destruction in Flt3L treated mice. The role of DCs in mBSA arthritis was further challenged in an adoptive transfer experiment. Transfer of DCs in combination with T-cells from mBSA immunized mice, predisposed naïve recipients for arthritis and production of mBSA specific antibodies. We provide experimental evidence that Flt3L has potent immunoregulatory properties. Flt3L facilitates formation of Treg cells and by this mechanism reduces severity of antigen-induced arthritis in mice. We suggest that high systemic levels of Flt3L have potential to modulate autoreactivity and autoimmunity.
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| 9. |
- Bergquist, Maria, et al.
(författare)
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Increased RANKL/OPG ratio and sclerostin in patients with septic shock
- 2017
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Ingår i: Clinical Microbiology and Infectious Diseases. - 2398-8096. ; 2:1, s. 1-3
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Tidskriftsartikel (refereegranskat)abstract
- We report an increased RANKL/OPG ratio and increased sclerostin levels in patients with septic shock one day after admission compared to healthy subjects,indicating an increased risk for bone loss in survivors of septic shock. No increase in RANKL/OPG ratio was observed in patients treated with hydrocortisone during septic shock.
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| 10. |
- Boström, Elisabeth Almer, 1983, et al.
(författare)
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Resistin and insulin/insulin-like growth factor signaling in rheumatoid arthritis.
- 2011
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Ingår i: Arthritis and rheumatism. - : Wiley. - 1529-0131 .- 0004-3591. ; 63:10, s. 2894-904
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Tidskriftsartikel (refereegranskat)abstract
- Human resistin has proinflammatory properties that activate NF-κB-dependent pathways, whereas its murine counterpart is associated with insulin resistance. The aim of this study was to examine potential cross-talk between resistin and insulin/insulin-like growth factor (IGF) signaling in rheumatoid arthritis (RA).
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