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Citrullination of C...
Citrullination of C1-inhibitor as a mechanism of impaired complement regulation in rheumatoid arthritis
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- Martin, Myriam (författare)
- Lund University,Lunds universitet,Proteinkemi, Malmö,Forskargrupper vid Lunds universitet,Protein Chemistry, Malmö,Lund University Research Groups,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Nilsson, Sara C. (författare)
- Lund University,Lunds universitet,Proteinkemi, Malmö,Forskargrupper vid Lunds universitet,Protein Chemistry, Malmö,Lund University Research Groups
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- Eikrem, David (författare)
- Uppsala University,Uppsala universitet,Institutionen för immunologi, genetik och patologi
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- Fromell, Karin (författare)
- Uppsala University,Uppsala universitet,Institutionen för immunologi, genetik och patologi
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- Scavenius, Carsten (författare)
- Aarhus Univ, Dept Mol Biol & Genet, Aarhus, Denmark,Aarhus University
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- Vogt, Leonie M. M. (författare)
- Lund University, Sweden
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- Bielecka, Ewa (författare)
- Jagiellonian Univ, Malopolska Ctr Biotechnol, Krakow, Poland,Jagiellonian University
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- Potempa, Jan (författare)
- Jagiellonian Univ, Fac Biochem Biophys & Biotechnol, Dept Microbiol, Krakow, Poland.;Univ Louisville, Sch Dent, Dept Oral Immunol & Infect Dis, Louisville, KY USA,University of Louisville Health Sciences Center,Jagiellonian University
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- Enghild, Jan J. J. (författare)
- Aarhus Univ, Dept Mol Biol & Genet, Aarhus, Denmark,Aarhus University
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- Nilsson, Bo (författare)
- Uppsala University,Uppsala universitet,Institutionen för immunologi, genetik och patologi
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- Nilsson Ekdahl, Kristina (författare)
- Linnaeus University,Linnéuniversitetet,Institutionen för kemi och biomedicin (KOB),Uppsala University, Sweden,Linnaeus Ctr Biomat Chem, BMC,Uppsala Univ, Dept Immunol Genet & Pathol, Rudbeck Lab, Uppsala, Sweden.;Linnaeus Univ, Sch Nat Sci, Kalmar, Sweden.
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- Kapetanovic, Meliha C. (författare)
- Lund University,Lunds universitet,Lund Arthritis Research Group (LARG),Forskargrupper vid Lunds universitet,Lund University Research Groups,Skåne University Hospital
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- Blom, Anna M. M. (författare)
- Lund University, Sweden
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(creator_code:org_t)
- Frontiers Media S.A. 2023
- 2023
- Engelska.
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Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 14
- Relaterad länk:
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https://doi.org/10.3...
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https://urn.kb.se/re...
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https://doi.org/10.3...
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https://urn.kb.se/re...
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https://lup.lub.lu.s...
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Abstract
Ämnesord
Stäng
- BackgroundDysregulated complement activation, increased protein citrullination, and production of autoantibodies against citrullinated proteins are hallmarks of rheumatoid arthritis (RA). Citrullination is induced by immune cell-derived peptidyl-Arg deiminases (PADs), which are overactivated in the inflamed synovium. We characterized the effect of PAD2- and PAD4-induced citrullination on the ability of the plasma-derived serpin C1-inhibitor (C1-INH) to inhibit complement and contact system activation. MethodsCitrullination of the C1-INH was confirmed by ELISA and Western blotting using a biotinylated phenylglyoxal probe. C1-INH-mediated inhibition of complement activation was analyzed by C1-esterase activity assay. Downstream inhibition of complement was studied by C4b deposition on heat-aggregated IgGs by ELISA, using pooled normal human serum as a complement source. Inhibition of the contact system was investigated by chromogenic activity assays for factor XIIa, plasma kallikrein, and factor XIa. In addition, autoantibody reactivity to native and citrullinated C1-INH was measured by ELISA in 101 RA patient samples. ResultsC1-INH was efficiently citrullinated by PAD2 and PAD4. Citrullinated C1-INH was not able to bind the serine protease C1s and inhibit its activity. Citrullination of the C1-INH abrogated its ability to dissociate the C1-complex and thus inhibit complement activation. Consequently, citrullinated C1-INH had a decreased capacity to inhibit C4b deposition via the classical and lectin pathways. The inhibitory effect of C1-INH on the contact system components factor XIIa, plasma kallikrein, and factor XIa was also strongly reduced by citrullination. In RA patient samples, autoantibody binding to PAD2- and PAD4-citrullinated C1-INH was detected. Significantly more binding was observed in anti-citrullinated protein antibody (ACPA)-positive than in ACPA-negative samples. ConclusionCitrullination of the C1-INH by recombinant human PAD2 and PAD4 enzymes impaired its ability to inhibit the complement and contact systems in vitro. Citrullination seems to render C1-INH more immunogenic, and citrullinated C1-INH might thus be an additional target of the autoantibody response observed in RA patients.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Reumatologi och inflammation (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Rheumatology and Autoimmunity (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Immunology in the medical area (hsv//eng)
Nyckelord
- citrullination
- C1-inhibitor
- complement system
- PAD
- rheumatoid arthritis
- synovial fluid
- ACPA
- Immunologi
- Immunology
- ACPA
- C1-inhibitor
- citrullination
- complement system
- PAD
- rheumatoid arthritis
- synovial fluid
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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- Av författaren/redakt...
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Martin, Myriam
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Nilsson, Sara C.
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Eikrem, David
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Fromell, Karin
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Scavenius, Carst ...
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Vogt, Leonie M. ...
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visa fler...
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Bielecka, Ewa
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Potempa, Jan
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Enghild, Jan J. ...
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Nilsson, Bo
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Nilsson Ekdahl, ...
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Kapetanovic, Mel ...
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Blom, Anna M. M.
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