Soluble complement receptor 1 (sCR1) protects against experimental autoimmune myasthenia gravis

Piddlesden, Sara J.; Jiang, Shisong; Levin, Jeffrey S.; Vincent, Angela; Morgan, B. Paul

doi:10.1016/s0165-5728(96)00144-0

Cited by 105 publications

(80 citation statements)

References 20 publications

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“…Much data exist implicating complement as a major effector in neuromuscular junction damage in MG. [1][2][3][4][5][6][7][8][9][10][11][12][14][15][16] Knockout experiments have shown that complement regulators such as DAF, at least in the EAMG model, influences the severity of damage by complement-fixing antibodies at the muscle endplate. 2,15,16 Although basal complement regulatory protein (CRP) mRNA transcripts were lower in mouse EOMs compared with their diaphragm muscles, the induction of EAMG resulted in a further reduction of EOM CRP expression and particularly of DAF.…”

Section: Discussionmentioning

confidence: 99%

“…1,3,5 Animal models became resistant to the induction of EAMG when circulating complement was either depleted by cobra venom toxin or functionally inhibited by the administration of a monoclonal C5 antibody or soluble C1 receptor. [6][7][8] Rodent models either deficient in C4, critical for the generation of C3 convertase, or C6, an important constituent of the membrane attack complex, were more resistant to EAMG induction 9,10 and showed less endplate damage than control animals. 9 Complement-mediated damage at the muscle endplate has been shown to result in the loss of AChRs, alter the architecture of endplate folds and likely reduce Na þ channel density in these folds, all of which affects neuromuscular transmission.…”

Section: Introductionmentioning

confidence: 99%

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A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis

et al. 2009

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Complement activation in myasthenia gravis (MG) may damage muscle endplate and complement regulatory proteins such as decay-accelerating factor (DAF) or CD55 may be protective. We hypothesize that the increased prevalence of severe extraocular muscle (EOM) dysfunction among African MG subjects reported earlier may result from altered DAF expression. To test this hypothesis, we screened the DAF gene sequences relevant to the classical complement pathway and found an association between myasthenics with EOM paresis and the DAF regulatory region c.-198C4G SNP (odds ratio ¼ 8.6; P ¼ 0.0003). This single nucleotide polymorphism (SNP) results in a twofold activation of a DAF 5 0 -flanking region luciferase reporter transfected into three different cell lines. Direct matching of the surrounding SNP sequence within the DAF regulatory region with the known transcription factor-binding sites suggests a loss of an Sp1-binding site. This was supported by the observation that the c.-198C4G SNP did not show the normal lipopolysaccharide-induced DAF transcriptional upregulation in lymphoblasts from four patients. Our findings suggest that at critical periods during autoimmune MG, this SNP may result in inadequate DAF upregulation with consequent complement-mediated EOM damage. Susceptible individuals may benefit from anti-complement therapy in addition to immunosuppression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis

et al. 2009

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“…Animal models, which induce EAMG either by administration of AChR antibodies or immunization with purified AChR, support the hypothesis: complement drives pathology in mouse and rat EAMG [49,50]; agents that block, inhibit or deplete complement protect animals from EAMG [51][52][53]; mice with a genetic deficit in complement components are resistant or less susceptible to EAMG [54]; inability to activate complement is associated with many immunological factors (e.g., in IL-12-deficient mice) [55], antibody, C3, C9 and MAC are uniformly found at the junctions of EAMG animals; and mice deficient in cell surface regulators of complement are particularly susceptible to EAMG induced by administration of AChR antibodies [50,56,57]. The following sections discuss the function of individual complement components as they relate primarily to EAMG pathogenesis.…”

Section: Complement Components and Their Roles In Mg And Eamgmentioning

confidence: 99%

“…sCR1 has also been found to reduce weight loss and weakness in passively induced EAMG [52] through its action of binding C4b and C3b and accelerating the decay of C3 and C5 convertases.…”

Section: C1mentioning

confidence: 99%

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Effect of complement and its regulation on myasthenia gravis pathogenesis

Kusner¹,

Kaminski²,

Šoltýs³

2008

Expert Review of Clinical Immunology

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Myasthenia gravis (MG) is primarily caused by antibodies directed towards the skeletal muscle acetylcholine receptor, leading to muscle weakness. Although these antibodies may induce compromise of neuromuscular transmission by blocking acetylcholine receptor function or antigenic modulation, the predominant mechanism of injury to the neuromuscular junction is complement-mediated lysis of the postsynaptic membrane. The vast majority of data to support the role of complement derives from experimentally acquired MG (EAMG). In this article, we review studies that demonstrate the central role of complement in EAMG and MG pathogenesis along with the emerging role of complement in T-and B-cell function, as well as the potential for complement inhibitor-based therapy to treat human MG.

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Soluble complement receptor 1 (CD35) delivered by retrovirally infected syngeneic cells or by naked DNA injection prevents the progression of collagen-induced arthritis

Dreja¹,

Annenkov

Chernajovsky

2000

Arthritis & Rheumatism

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Objective. The complement system is important in the development of autoimmune inflammation, including rheumatoid arthritis (RA) and collagen-induced arthritis (CIA). Complement receptor 1 (CR1) is involved in regulation of complement activity. Studies on models of autoimmunity have demonstrated that soluble CR1 (sCR1) is a potent therapeutic agent. The present study was thus undertaken to investigate the feasibility of antiinflammatory gene therapy to prevent CIA by delivery of genes encoding truncated sCR1 (tsCR1) and dimeric tsCR1-Ig.Methods. Syngeneic fibroblasts or arthritogenic splenocytes, engineered to express tsCR1 using retrovirus-mediated gene transfer, were injected into DBA/1 recipients that had been immunized with bovine type II collagen (CII). In separate experiments, naked DNA containing tsCR1 and tsCR1-Ig genes was injected intramuscularly into the immunized animals. The clinical development of arthritis was monitored, anti-CII levels measured, and antigenic T cell response studied. Affinity-purified tsCR1-Ig was assayed for its inhibitory effect on the alternative complement pathway in mouse serum.Results. Treatment of CII-immunized mice with the tsCR1-expressing cells inhibited development of CIA, reduced anti-CII antibody levels, and inhibited T cell response to CII in vitro. Intramuscular injections of DNA encoding the CR1 genes prevented the progression of disease. Furthermore, compared with full-length sCR1, purified tsCR1-Ig was more active in inhibiting the murine alternative complement pathway.Conclusion. Our findings demonstrated that tsCR1 and tsCR1-Ig, when delivered via gene therapy, had a beneficial effect on autoimmune inflammation. These results indicate that targeting the complement system in RA patients may be of clinical importance.

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Soluble complement receptor 1 (sCR1) protects against experimental autoimmune myasthenia gravis

Cited by 105 publications

References 20 publications

A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis

A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis

Effect of complement and its regulation on myasthenia gravis pathogenesis

Soluble complement receptor 1 (CD35) delivered by retrovirally infected syngeneic cells or by naked DNA injection prevents the progression of collagen-induced arthritis

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