Response to Protocol Review Scenario: A Question of Authority

Morgan, Earl W.; Dacvpm,; Dabt,

doi:10.1038/laban1003-18b

Cited by 3 publications

(3 citation statements)

References 1 publication

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“…However, complement resembles a double-edged sword as it also contributes to the pathogenesis of ischemic injury, rheumatoid arthritis, multiple sclerosis, and many more diseases (6). It appears that the undesirable side effects of complement are mainly due to excessive activation or activation initiated by erroneous molecules.…”

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confidence: 99%

The Extracellular Matrix and Inflammation

Sjöberg

Önnerfjord

Mörgelin

et al. 2005

Journal of Biological Chemistry

156

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Components that propagate inflammation in joint disease may be derived from cartilage since the inflammation resolves after joint replacement. We found that the cartilage component fibromodulin has the ability to activate an inflammatory cascade, i.e. complement. Fibromodulin and immunoglobulins cause comparable deposition of C1q, C4b, and C3b from human serum. Using C1q and factor B-deficient sera in combination with varying contents of metal ions, we established that fibromodulin activates both the classical and the alternative pathways of complement. Further studies revealed that fibromodulin binds directly to the globular heads of C1q, leading to activation of C1. However, deposition of the membrane attack complex and C5a release were lower in the presence of fibromodulin as compared with IgG. This can be explained by the fact that fibromodulin also binds complement inhibitor factor H. Factor H and C1q bind to non-overlapping sites on fibromodulin, but none of the interactions is mediated by the negatively charged keratan sulfate substituents of fibromodulin. C1q but not factor H binds to an N-terminal fragment of fibromodulin previously implicated to be affected in cartilage stimulated with the inflammatory cytokine interleukin 1. Taken together our observations indicate fibromodulin as one factor involved in the sustained inflammation of the joint.The complement system forms the core of the innate immune system and is organized in three different routes depending on initiating agent such as antibodies (classical pathway) or certain carbohydrates (lectin pathway). The alternative pathway is started by autoactivation of unstable complement factor C3 (1) and its subsequent binding to a surface lacking complement inhibitors, mainly factor H (FH).2 FH is able to protect self-surfaces where it is localized due to its ability to bind sialic acid and heparan sulfate (2). The main event of complement activation is formation of enzymatic complexes such as C3 and C5 convertases, which leads to release of anaphylatoxins C5a and C3a (3) and deposition of C3-fragments that are recognized by phagocytes (4). The final stage is the formation of the membrane attack complex (MAC). The control of this powerful system is maintained by a number of soluble or membrane-bound inhibitory proteins. Most inhibitors such as FH act on C3 and C5 convertases either by increasing the dissociation of enzyme complexes or by promoting degradation of C3b or C4b by the serine proteinase factor I.The physiological relevance of complement is demonstrated by recurrent infections when there are deficiencies of complement components and central involvement of the system in systemic lupus erythematosus and glomerulonephritis (5). However, complement resembles a double-edged sword as it also contributes to the pathogenesis of ischemic injury, rheumatoid arthritis, multiple sclerosis, and many more diseases (6). It appears that the undesirable side effects of complement are mainly due to excessive activation or activation initiated by erroneous molecu...

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confidence: 99%

The Extracellular Matrix and Inflammation

Sjöberg

Önnerfjord

Mörgelin

et al. 2005

Journal of Biological Chemistry

156

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“…The compound XTT (internal salt of 2,3-bis(2-methoxy-4-nitro-5sulphophenyl)-2H-tetrazole-5-carboxyanilide) is the substrate in the reaction taking place under the effect of succinate dehydrogenase, as a result of which there are formed coloured water-soluble formazanes (ref. 36). The results of the test were read off from the ELISA plate reader used in the tests (wavelength λ = 450 nm, "Sigma X 425").…”

Section: Study Methodsmentioning

confidence: 99%

Polymers Used for Bone Reconstruction – Evaluation of Chosen Polymeric Materials for in Vitro Culture of Osteoblasts

Fabianowski¹,

Polak²,

Lewandowska-Szumieł³

2004

International Polymer Science and Technology

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The need to reconstruct tissues damaged as a result of trauma, congenital defects or other pathologies, or of those removed by resection of tumorous lumps, continues to be an emergent problem in surgery. Progress in the sphere of material engineering and the biological sciences has meant that more and more new compounds are put forward as materials for implants. Plastics provide an alternative to the allogenic grafts prepared in tissue banks and also to autogenic grafts, i.e. implants of the patient's own tissue taken from another site in he body. This material must be satisfactorily tolerated by the tissue of the recipient.

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“…Although both of these agents have been shown to be effective and relatively safe in models, it must be stressed that systemic inhibition of C is not without consequence. Agents that efficiently inhibit C in vivo may cause iatrogenic infections or immune complex disease, probably limiting their use to acute situations (7).…”

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confidence: 99%

Generation of a Recombinant, Membrane-targeted Form of the Complement Regulator CD59

Fraser

Harris

Williams

et al. 2003

Journal of Biological Chemistry

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Inappropriate activation of complement contributes to pathology in diverse inflammatory diseases. Soluble recombinant forms of the natural cell membrane regulators of complement are effective in animal models and some human diseases. However, their use is limited for reasons related to cost, short half lives, and propensity to cause unwanted systemic effects. Some of these limitations may be overcome by use of bacterial expression systems, specific targeting moieties, and judicious choice of regulator. Here we describe the application of these strategies to the generation of a membrane-targeted form of CD59. A recombinant soluble form of rat CD59, comprising the first 71 residues of the mature protein and missing the membrane-anchoring signal, was expressed in bacteria, purified, and refolded in a fully active form. The protein was coupled through its carboxyl terminus to a short, synthetic address tag that confers membrane binding activity. Attachment of the membrane address tag markedly increased complement-inhibitory activity assessed in vitro in hemolysis assays. Intra-articular administration of the tagged agent markedly suppressed disease in a model of rheumatoid arthritis in Lewis rats. This novel type of agent, termed sCD59-APT542, offers for the first time the prospect of efficient and specific inhibition of membrane attack complex activity in vivo.

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Response to Protocol Review Scenario: A Question of Authority

Cited by 3 publications

References 1 publication

The Extracellular Matrix and Inflammation

The Extracellular Matrix and Inflammation

Polymers Used for Bone Reconstruction – Evaluation of Chosen Polymeric Materials for in Vitro Culture of Osteoblasts

Generation of a Recombinant, Membrane-targeted Form of the Complement Regulator CD59

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