A Role for Complement in Antibody-Mediated Inflammation: C5-Deficient DBA/1 Mice Are Resistant to Collagen-Induced Arthritis

Wang, Yi; Kristan, Jane; Hao, Liming; Lenkoski, Catherine S.; Shen, Yamin; Matis, Louis A.

doi:10.4049/jimmunol.164.8.4340

Cited by 177 publications

(54 citation statements)

References 52 publications

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“…Likewise, studies have also shown that perpetuation of inflammation coincides with increased levels of the anaphylatoxin C5a in the synovial fluid of RA patients [9]. Further studies in mice identifying C5 as a candidate gene and showing that C5 deficiency results in lower incidence and less-severe disease course support the role of this gene in inflammation [7,11]. It is therefore likely that although the primary function of the complement system is to protect the host from microorganisms, a deregulated activity of its central component, C5, can play a substantial role in inflammatory diseases as well.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, in several experimental animal models for RA, innate immune responses mediated by a diversity of players have been implicated in arthritis. In this respect, a prominent role for the complement system has been identified as mice deficient in complement factors are resistant to arthritis, and as it has been shown that targeting complement component 5 (C5) by antibodies prevents the onset of arthritis and reduces the clinical severity in mouse models for arthritis [7,8]. Likewise, the observation that high levels of C5a , a potent chemoattractant, are found in synovial fluid of RA patients combined with the fact that C5a receptor -deficient mice are also resistant to arthritis induction, indicate a central role for these mediators in arthritis [9,10].…”

Section: Introductionmentioning

confidence: 99%

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A Candidate Gene Approach Identifies the TRAF1/C5 Region as a Risk Factor for Rheumatoid Arthritis

et al. 2007

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BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disorder affecting ∼1% of the population. The disease results from the interplay between an individual's genetic background and unknown environmental triggers. Although human leukocyte antigens (HLAs) account for ∼30% of the heritable risk, the identities of non-HLA genes explaining the remainder of the genetic component are largely unknown. Based on functional data in mice, we hypothesized that the immune-related genes complement component 5 (C5) and/or TNF receptor-associated factor 1 (TRAF1), located on Chromosome 9q33–34, would represent relevant candidate genes for RA. We therefore aimed to investigate whether this locus would play a role in RA.Methods and FindingsWe performed a multitiered case-control study using 40 single-nucleotide polymorphisms (SNPs) from the TRAF1 and C5 (TRAF1/C5) region in a set of 290 RA patients and 254 unaffected participants (controls) of Dutch origin. Stepwise replication of significant SNPs was performed in three independent sample sets from the Netherlands (n cases/controls = 454/270), Sweden (n cases/controls = 1,500/1,000) and US (n cases/controls = 475/475). We observed a significant association (p < 0.05) of SNPs located in a haplotype block that encompasses a 65 kb region including the 3′ end of C5 as well as TRAF1. A sliding window analysis revealed an association peak at an intergenic region located ∼10 kb from both C5 and TRAF1. This peak, defined by SNP14/rs10818488, was confirmed in a total of 2,719 RA patients and 1,999 controls (odds ratiocommon = 1.28, 95% confidence interval 1.17–1.39, p combined = 1.40 × 10−8) with a population-attributable risk of 6.1%. The A (minor susceptibility) allele of this SNP also significantly correlates with increased disease progression as determined by radiographic damage over time in RA patients (p = 0.008).ConclusionsUsing a candidate-gene approach we have identified a novel genetic risk factor for RA. Our findings indicate that a polymorphism in the TRAF1/C5 region increases the susceptibility to and severity of RA, possibly by influencing the structure, function, and/or expression levels of TRAF1 and/or C5.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Candidate Gene Approach Identifies the TRAF1/C5 Region as a Risk Factor for Rheumatoid Arthritis

et al. 2007

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“…Autoantibodies prevalent in RA might play an important role in the disease development and most widely used animal models are dependent on antibody-mediated pathologies [14]–[17]. Antibodies in the form of immune complexes might play a central role in triggering inflammatory pathways in the joint [18], especially C5a binding to these immune complexes can attract granulocytes to the articular cartilage that can release inflammatory mediators (proteases, cytokines, chemokines, and reactive oxygen and nitrogen radicals) perpetuating inflammation and autoimmunity. In the present study, breaking tolerance towards C5a by vaccination to induce polyclonal anti-C5a response, C5a/C5b neutralizing capacity of the induced antibodies and their effect on arthritis development in various mouse models were assessed.…”

Section: Introductionmentioning

confidence: 99%

A Recombinant Vaccine Effectively Induces C5a-Specific Neutralizing Antibodies and Prevents Arthritis

Nandakumar

Jansson²,

Xu³

et al. 2010

PLoS ONE

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ObjectivesTo develop and validate a recombinant vaccine to attenuate inflammation in arthritis by sustained neutralization of the anaphylatoxin C5a.MethodsWe constructed and expressed fusion protein of C5a and maltose binding protein. Efficacy of specific C5a neutralization was tested using the fusion protein as vaccine in three different arthritis mouse models: collagen induced arthritis (CIA), chronic relapsing CIA and collagen antibody induced arthritis (CAIA). Levels of anti-C5a antibodies and anti-collagen type II were measured by ELISA. C5a neutralization assay was done using a rat basophilic leukemia cell-line transfected with the human C5aR. Complement activity was determined using a hemolytic assay and joint morphology was assessed by histology.ResultsVaccination of mice with MBP-C5a led to significant reduction of arthritis incidence and severity but not anti-collagen antibody synthesis. Histology of the MBP-C5a and control (MBP or PBS) vaccinated mice paws confirmed the vaccination effect. Sera from the vaccinated mice developed C5a-specific neutralizing antibodies, however C5 activation and formation of the membrane attack complex by C5b were not significantly altered.ConclusionsExploitation of host immune response to generate sustained C5a neutralizing antibodies without significantly compromising C5/C5b activity is a useful strategy for developing an effective vaccine for antibody mediated and C5a dependent inflammatory diseases. Further developing of such a therapeutic vaccine would be more optimal and cost effective to attenuate inflammation without affecting host immunity.

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“…For example, complement activation is associated with the chronic inflammation in rheumatoid arthritis and osteoarthritis (33). Recent studies in mice deficient in various complement factors have shown that both the classical and alternative pathways are important in the development of collageninduced arthritis (34,35). It has been proposed that inhibition of C5a generation may be a successful therapeutic approach for treatment of rheumatoid arthritis (36).…”

Section: Discussionmentioning

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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A Role for Complement in Antibody-Mediated Inflammation: C5-Deficient DBA/1 Mice Are Resistant to Collagen-Induced Arthritis

Cited by 177 publications

References 52 publications

A Candidate Gene Approach Identifies the TRAF1/C5 Region as a Risk Factor for Rheumatoid Arthritis

A Candidate Gene Approach Identifies the TRAF1/C5 Region as a Risk Factor for Rheumatoid Arthritis

A Recombinant Vaccine Effectively Induces C5a-Specific Neutralizing Antibodies and Prevents Arthritis

The Extracellular Matrix and Inflammation

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