| 1. |
- Bokarewa, Maria, 1963, et al.
(författare)
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Intraarticular release and accumulation of defensins and bactericidal/permeability-increasing protein in patients with rheumatoid arthritis.
- 2003
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Ingår i: The Journal of rheumatology. - 0315-162X. ; 30:8, s. 1719-24
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Defensins and bactericidal/permeability-increasing protein (BPI) are the components of the azurophilic granules of polymorphonuclear cells (PMNC) maintaining antimicrobial protection. Both these substances have been suggested to interact with the host immune system rather than merely kill invading pathogens. We assessed concentrations of BPI and a-defensins in synovial fluid (SF) and matching blood samples of patients with rheumatoid arthritis (RA). METHODS: Matching samples of SF and blood were collected from 67 patients with RA (aged 21-73 yrs) with acute joint effusion. Blood samples from 22 healthy individuals made up a control group. Concentrations of BPI and human neutrophil peptides (HNP 1-3) were measured by ELISA. The results were related to radiological signs of destructive arthritis, duration of the disease, and laboratory markers of inflammation. RESULTS: BPI and HNP concentrations in SF were 10-60 times higher than in matching blood samples (p < 0.0001). Strong correlations between BPI and HNP concentrations were found in both blood and SF. In SF, BPI and HNP concentrations correlated to white blood cell (WBC) count (p < 0.001), and were associated with erosive joint disease (p < 0.05). In contrast, WBC count, serum C-reactive protein, or rheumatoid factor were not significantly correlated to the BPI or HNP concentrations. Serum BPI concentrations were moderately but significantly increased in RA patients compared in blood to controls (p < 0.05). CONCLUSION: BPI and HNP are accumulated in the synovial cavity of patients with RA. Significant correlation between joint erosion and local occurrence of BPI and HNP suggests participation of these molecules in regulation of the destructive course of RA.
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| 2. |
- Jin, Tao, 1973, et al.
(författare)
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Fatal outcome of bacteraemic patients caused by infection with staphylokinase-deficient Staphylococcus aureus strains.
- 2003
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Ingår i: Journal of medical microbiology. - 0022-2615. ; 52:Pt 10, s. 919-23
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Tidskriftsartikel (refereegranskat)abstract
- Staphylokinase (SAK) is a plasminogen-activator protein produced by Staphylococcus aureus. SAK production was evaluated in vitro in S. aureus isolates from the bloodstream of patients with lethal (n = 56) and non-lethal (n = 57) bacteraemia and from anterior nares of healthy subjects (n = 48). Most isolates (93/161) produced SAK, and 68 % of SAK-producing isolates expressed both surface-bound and secreted types of SAK. SAK production was significantly less common among isolates from patients with lethal bacteraemia (39 %) than isolates from patients with non-lethal bacteraemia (68 %) or nasal carriage isolates (67 %) (P < 0.01). After adjusting for infection with methicillin-resistant S. aureus and APACHE II score, patients infected with SAK-deficient isolates were 4.3 times more likely to have lethal bacteraemia than patients whose infecting isolate produced high levels of SAK (> or =5 microg ml(-1)), suggesting that in vitro SAK production was inversely associated with clinical outcome among patients with S. aureus bacteraemia. The high frequency of SAK production in nasal isolates and in cases with uncomplicated bacteraemia suggests that SAK may be one of the adaptive mechanisms of S. aureus symbiosis with the host.
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| 3. |
- Jin, Tao, 1973, et al.
(författare)
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Staphylococcus aureus resists human defensins by production of staphylokinase, a novel bacterial evasion mechanism
- 2004
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Ingår i: J Immunol. - 0022-1767. ; 172:2, s. 1169-76
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Tidskriftsartikel (refereegranskat)abstract
- Alpha-defensins are peptides secreted by polymorphonuclear cells and provide antimicrobial protection mediated by disruption of the integrity of bacterial cell walls. Staphylokinase is an exoprotein produced by Staphylococcus aureus, which activates host plasminogen. In this study, we analyzed the impact of interaction between alpha-defensins and staphylokinase on staphylococcal growth. We observed that staphylokinase induced extracellular release of alpha-defensins from polymorphonuclear cells. Moreover, a direct binding between alpha-defensins and staphylokinase was shown to result in a complex formation. The biological consequence of this interaction was an almost complete inhibition of the bactericidal effect of alpha-defensins. Notably, staphylokinase with blocked plasminogen binding site still retained its ability to neutralize the bactericidal effect of alpha-defensins. In contrast, a single mutation of a staphylokinase molecule at position 74, substituting lysine for alanine, resulted in a 50% reduction of its alpha-defensin-neutralizing properties. The bactericidal properties of alpha-defensins were tested in 19 S. aureus strains in vitro and in a murine model of S. aureus arthritis. Staphylococcal strains producing staphylokinase were protected against the bactericidal effect of alpha-defensins. When staphylokinase was added to staphylokinase-negative S. aureus cultures, it almost totally abrogated the effect of alpha-defensins. Finally, human neutrophil peptide 2 injected intra-articularly along with bacteria alleviated joint destruction. In this study, we report a new property of staphylokinase, its ability to induce secretion of defensins, to complex bind them and to neutralize their bactericidal effect. Staphylokinase production may therefore be responsible in vivo for defensin resistance during S. aureus infections.
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| 4. |
- Jin, Tao, 1973, et al.
(författare)
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Urokinase, a constitutive component of the inflamed synovial fluid, induces arthritis.
- 2003
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Ingår i: Arthritis research & therapy. - 1478-6362. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- Urokinase plasminogen activator (uPA) is an important regulator of fibrinolysis in synovial fluid. An increase of uPA activity and expression of its receptor have been reported in joints of patients with rheumatoid arthritis (RA). The aim of the present study was to assess the arthritogenic capacity of uPA and the mechanisms by which this effect is mediated. uPA was injected into the knee joints of healthy mice, and morphological signs of arthritis were assessed 4 days after the injection. The prerequisite of different leukocyte populations for the development of uPA-triggered arthritis was assessed by selective cell depletion. The inflammatory capacity of uPA was assessed in vitro. Finally, levels of uPA were measured in 67 paired blood and synovial fluid samples from RA patients. The synovial fluid from RA patients displayed higher levels of uPA compared with blood samples. Morphological signs of arthritis were found in 72% of uPA-injected joints compared with in only 18% of joints injected with PBS (P < 0.05). Synovitis was characterised by infiltration of CD4-Mac-1+ mononuclear cells, by the formation of pannus and by occasional cartilage destruction. The absence of monocytes and lymphocytes diminished the frequency of synovitis (P < 0.01), indicating an arthritogenic role of both these leukocyte populations. Synthetic uPA inhibitor downregulated the incidence of uPA-triggered arthritis by 50%. uPA induced arthritis, stimulating the release of proinflammatory cytokines IL-6, IL-1beta and tumour necrosis factor alpha. Accumulation of uPA locally in the joint cavity is a typical finding in erosive RA. uPA exerts potent arthritogenic properties and thus may be viewed as one of the essential mediators of joint inflammation.
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| 5. |
- Tarkowski, Andrej, 1951, et al.
(författare)
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Current status of pathogenetic mechanisms in staphylococcal arthritis.
- 2002
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Ingår i: FEMS microbiology letters. - 0378-1097. ; 217:2, s. 125-32
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Forskningsöversikt (refereegranskat)abstract
- Interactions between staphylococci and the joint tissues of the host lead typically to rapidly progressing and highly destructive processes. Staphylococci possess a vast arsenal of components and products that contribute to the pathogenesis of joint infection. Occasionally these compounds have overlapping activities and act either in concert or alone. Host responsiveness to staphylococcal infection displays an even more complex pattern. Most of the cells and molecules that participate in the innate immune system protect the host against bacteria. However, the staphylococci have developed systems that counteract endogenous protective mechanisms. Interestingly, certain cells and molecules of the acquired immune system potentiate the severity of infection by triggering exaggerated responses to the staphylococcal danger signals. This review deals with the intricate host-bacterium interactions that occur during experimental septic arthritis, and outlines potential preventive and treatment modalities.
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