The role of complement in immunological demyelination of the mammalian spinal cord

Dyer, Jason K.; Bourque, Jason; Steeves, John D.

doi:10.1038/sj.sc.3101737

Cited by 14 publications

(10 citation statements)

References 51 publications

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“…32 Deficiency in serum C3 and C4, but not C5, C6, or factor B was protective against demylineation, suggesting a role for the classic pathway of complement activation and no role for the MAC (C4 is a classic pathway protein, factor B is an alternative pathway protein, and C6 is a terminal pathway protein involved in MAC formation 32 ). In the context of relating our findings to human therapy, there are three human membrane inhibitors of complement activation that function at the C3 level; decay accelerating factor, membrane cofactor protein, and CR1.…”

Section: Discussionmentioning

confidence: 99%

Complement Plays an Important Role in Spinal Cord Injury and Represents a Therapeutic Target for Improving Recovery following Trauma

Qiao

Atkinson

Song

et al. 2006

The American Journal of Pathology

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Initiation of an inflammatory cascade following traumatic spinal cord injury (SCI) is thought to cause secondary injury and to adversely impact functional recovery, although the mechanisms involved are not well defined. We report on the dynamics of complement activation and deposition in the mouse spinal cord following traumatic injury, the role of complement in the development of SCI, and the characterization of a novel targeted complement inhibitor. Following traumatic injury, mice deficient in C3 had a significantly improved locomotor score when compared with wild-type controls, and analysis of their spinal cords revealed significantly more tissue sparing, with significantly less necrosis, demyelination, and neutrophil infiltration. Wild-type mice were also treated with CR2-Crry, a novel inhibitor of complement activation that targets to sites of C3 deposition. A single intravenous injection of CR2-Crry 1 hour after traumatic injury improved functional outcome and pathology to an extent similar to that seen in C3-deficient animals. CR2-Crry specifically targeted to the injured spinal cord in a distribution pattern corresponding to that seen for deposited C3. As immunosuppression is undesirable in patients following SCI, targeted CR2-Crry may provide appropriate bioavailability to treat SCI at a dose that does not significantly affect systemic levels of serum complement activity.

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Section: Discussionmentioning

confidence: 99%

Complement Plays an Important Role in Spinal Cord Injury and Represents a Therapeutic Target for Improving Recovery following Trauma

Qiao

Atkinson

Song

et al. 2006

The American Journal of Pathology

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“…Along with myelin degeneration, demyelinating lesions are also characterized by astrocytosis and microgliosis [26,27]. Regarding this issue and knowing that S100B is mainly secreted by astrocytes and is involved in the activation of both astrocytes and microglia, we decided to evaluate the degree of reactive gliosis in the course of the demyelinating insult with LPC ( Figs.…”

Section: Abrogation Of S100b Decreases Astroglial Reactivity Induced mentioning

confidence: 99%

S100B as a Potential Biomarker and Therapeutic Target in Multiple Sclerosis

et al. 2015

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Multiple sclerosis (MS) pathology is characterized by neuroinflammation and demyelination. Recently, the inflammatory molecule S100B was identified in cerebrospinal fluid (CSF) and serum of MS patients. Although seen as an astrogliosis marker, lower/physiological levels of S100B are involved in oligodendrocyte differentiation/maturation. Nevertheless, increased S100B levels released upon injury may induce glial reactivity and oligodendrocyte demise, exacerbating tissue damage during an MS episode or delaying the following remyelination. Here, we aimed to unravel the functional role of S100B in the pathogenesis of MS. Elevated S100B levels were detected in the CSF of relapsing-remitting MS patients at diagnosis. Active demyelinating MS lesions showed increased expression of S100B and its receptor, the receptor for advanced glycation end products (RAGE), in the lesion area, while chronic active lesions displayed increased S100B in demyelinated areas with lower expression of RAGE in the rim. Interestingly, reactive astrocytes were identified as the predominant cellular source of S100B, whereas RAGE was expressed by activated microglia/macrophages. Using an ex vivo demyelinating model, cerebral organotypic slice cultures treated with lysophosphatidylcholine (LPC), we observed a marked elevation of S100B upon demyelination, which co-localized mostly with astrocytes. Inhibition of S100B action using a directed antibody reduced LPC-induced demyelination, prevented astrocyte reactivity and abrogated the expression of inflammatory and inflammasome-related molecules. Overall, high S100B expression in MS patient samples suggests its usefulness as a diagnostic biomarker for MS, while the beneficial outcome of its inhibition in our demyelinating model indicates S100B as an emerging therapeutic target in MS.

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“…Cleavage of C3, and its resultant activation, leads to the release of the cleavage product C3a and the deposition of C3b on the bacterial surface, the latter of which gives rise to subsequent amplification of the complement cascade (17). To verify the involvement of complement in MAb 5C7.31-mediated R. conorii killing, we examined deposition of C3 components on the bacterial surface.…”

Section: Fig 1 Epitope Mapping Of R Conorii Rompb By Western Blottmentioning

confidence: 99%

Molecular Basis of Immunity to Rickettsial Infection Conferred through Outer Membrane Protein B

et al. 2011

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Pathogenic rickettsiae are the causative agents of Rocky Mountain spotted fever, typhus, and other human diseases with high mortality and an important impact on society. Although survivors of rickettsial infections are considered immune to disease, the molecular basis of this immunity or the identification of protective antigens that enable vaccine development was hitherto not known. By exploring the molecular pathogenesis of Rickettsia conorii, the agent of Mediterranean spotted fever, we report here that the autotransporter protein, rickettsial outer membrane protein B (rOmpB), constitutes a protective antigen for this group of pathogens. A recombinant, purified rOmpB passenger domain fragment comprised of amino acids 36 to 1334 is sufficient to elicit humoral immune responses that protect animals against lethal disease. Protective immunity requires folded antigen and production of antibodies that recognize conformational epitopes on the rickettsial surface. Monoclonal antibodies (MAbs) 5C7.27 and 5C7.31, which specifically recognize a conformation present in the folded, intact rOmpB passenger domain, are sufficient to confer immunity in vivo. Analyses in vitro indicate this protection involves a mechanism of complement-mediated killing in mammalian blood, a means of rickettsial clearance that has not been previously described. Considering the evolutionary conservation of rOmpB and its crucial contribution to bacterial invasion of host cells, we propose that rOmpB antibody-mediated killing confers immunity to rickettsial infection.

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The role of complement in immunological demyelination of the mammalian spinal cord

Cited by 14 publications

References 51 publications

Complement Plays an Important Role in Spinal Cord Injury and Represents a Therapeutic Target for Improving Recovery following Trauma

Complement Plays an Important Role in Spinal Cord Injury and Represents a Therapeutic Target for Improving Recovery following Trauma

S100B as a Potential Biomarker and Therapeutic Target in Multiple Sclerosis

Molecular Basis of Immunity to Rickettsial Infection Conferred through Outer Membrane Protein B

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