Rheumatoid Arthritis: Magnusson M

Bokarewa M, Tarkowski A, Magnusson M. · Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Göteborg University, S-41346 Göteborg, Sweden. · Scand J Immunol. · Pubmed #17635796 No free full text.

Abstract: Rheumatoid arthritis (RA) is an inflammatory joint disease leading to cartilage and bone destruction. Insufficient apoptosis in the inflamed RA synovium along with accumulation of highly differentiated B- and T-lymphocytes as well as invasive growth of macrophages and fibroblasts is among the major mechanisms supporting joint destruction. We have recently shown that circulating survivin, an apoptosis inhibitor tightly bound to tumorigenesis, is an independent predictor of development and progression of joint destruction in RA. In this review we discuss the possible connectivity between viral infection, leading to interferon (IFN)-alpha production, survivin expression, and subsequent joint inflammation. The role of IFN-alpha and the involvement of IFN transcription factors and phosphoinositide-3-kinase signalling as essential modulators of arthritogenic process are discussed in the context of survivin.

Bokarewa M, Tarkowski A, Lind M, Dahlberg L, Magnusson M. · Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Göteborg, Sweden. · Eur J Immunol. · Pubmed #18991285 No free full text.

Abstract: Viruses may be part of the pathogenesis of rheumatoid arthritis (RA). Double stranded RNA (dsRNA) is a prototypic viral conformation of nucleic acid that is highly arthritogenic in mice. Therefore, we developed an ELISA to detect dsRNA in sera and synovial fluids (SF) in RA patients and in osteoarthritic controls. The developed ELISA recognizes picogram levels of viral or synthetic dsRNA but shows no reactivity against DNA, synthetic ssRNA, or total RNA prepared from mammalian cells. Before analysis by ELISA, each sample was subjected to RNA precipitation. The RA patients had significantly higher levels of dsRNA than the osteoarthritis patients in SF and in sera. In 7 of 17 RA patients, EBV was present in SF and in all but one of these this was accompanied by the presence of dsRNA. No parvovirus, cytomegalovirus, or polyomavirus was detected. The anti-viral cytokine IFN-alpha was detected in SF in 10 of 21 RA patients, but in none of the osteoarthritis patients. Notably, RA patients with erosive disease course had significantly higher levels of dsRNA in SF than non-erosive patients, but no correlation between dsRNA levels and the presence of RF or levels of C-reactive protein, IL-6, or IFN-alpha was observed.

Dehlin M, Bokarewa M, Rottapel R, Foster SJ, Magnusson M, Dahlberg LE, Tarkowski A. · Department of Rheumatology and Inflammation Research, Göteborg University, Göteborg, Sweden. · PLoS One. · Pubmed #18982072 links to  free full text

Abstract: BACKGROUND: One of the hallmarks of rheumatoid arthritis (RA) is hyperplasia and inflammation of the synovial tissue being characterized by in situ occurrence of highly differentiated leukocytes. Fms-like tyrosine kinase 3 (Flt3) has a crucial role in hematopoiesis, regulation of cell proliferation, differentiation and apoptosis. Typically, Flt3 is expressed on early myeloid and lymphoid progenitors and is activated by its soluble ligand (Flt3-L). The highly differentiated cellular pattern in the synovium of the RA patients made us hypothesize that Flt3-L, with its ability to induce proliferation and differentiation, could be of importance in induction and/or progression of arthritis. METHODOLOGY/PRINCIPAL FINDINGS: To investigate occurrence of Flt3-L in RA we have measured its levels in matched serum and synovial fluid samples from 130 patients and 107 controls. To analyse the pro-inflammatory role of Flt3-L, we continuously overexpressed this protein locally in healthy mouse joints using homologous B-cell line transfected with Flt3-L gene. Additionally, recombinant Flt3-L was instillated intra-articularly in combination with peptidoglycans, a Toll Like Receptor 2-ligand with stong arthritogenic properties. Our results show significantly higher levels of Flt3-L in the synovial fluid as compared to serum levels in RA subjects (p = 0.0001). In addition, RA synovial fluid levels of Flt-3-L were significantly higher than these obtained from synovial fluids originating from non-inflammatory joint diseases (p = 0.022). Intra-articular administration of B-cell line transfected with Flt3-L gene resulted in highly erosive arthritis while inoculation of the same B-cell line without hyperexpression of Flt3-L did not induce erosivity and only in a minority of cases caused synovial proliferation! Flt3-ligand potentiated peptidoglycan induced arthritis as compared to mice injected with peptidoglycan alone (p<0.05). CONCLUSIONS/SIGNIFICANCE: Our findings indicate that Flt3-L is strongly expressed at the site of inflammation in human RA. It exerts both pro-inflammatory and tissue destructive properties once in the joint cavity. Owing to these properties, treatment attempts to neutralize this molecule should be considered in RA.

Mera S, Magnusson M, Tarkowski A, Bokarewa M. · Department of Rheumatology and Inflammation Research, Guldhedsgatan 10, S-413 46 Göteborg, Sweden. · J Leukoc Biol. · Pubmed #17938276 links to  free full text

Abstract: Rheumatoid arthritis (RA) is an autoimmune disease with joints as a principal target of inflammation. We have shown recently that the extracellular expression of the antiapoptotic protein survivin is associated with a destructive course of RA. Here, we address the potential impact of extracellular survivin on peripheral blood leukocytes (PBL). The binding of survivin to the surface of human PBL as well as the expression of adhesion molecules were assessed by FACS. The expression of adhesion molecules on leukocytes as a function of circulating survivin was analyzed in blood of 24 patients with RA and compared with eight healthy individuals. We show that extracellular survivin expresses immunomodulatory properties. It binds to the surface of the majority of granulocytes and a significant part of lymphocytes and monocytes inducing the activation of alpha-chains of beta-integrins and their ligand ICAM-1. Survivin-induced expression of alpha-chains of beta 2-integrins is regulated by p38 MAPK and PI-3K but not by the NF-kappaB signaling pathway. Clinical relevance of our findings is supported by the in vivo association of high circulating survivin levels with an increased expression of CD11c on monocytes and granulocytes in RA patients. The results of our study demonstrate that extracellular survivin affects the phenotype of leukocytes having a possible impact on homing of inflammatory cells during arthritis.