uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Structural Basis of Cross-Reactivity of Anti-Citrullinated Protein Antibodies
Karolinska Inst, Stockholm, Sweden.
Karolinska Inst, Stockholm, Sweden.
Karolinska Inst, Stockholm, Sweden;Southern Med Univ, Guangzhou, Guangdong, Peoples R China.
Karolinska Inst, Stockholm, Sweden.
Show others and affiliations
2019 (English)In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 71, no 2, p. 210-221Article in journal (Refereed) Published
Abstract [en]

Objective: Anti-citrullinated protein antibodies (ACPAs) develop many years before the clinical onset of rheumatoid arthritis (RA). This study was undertaken to address the molecular basis of the specificity and cross-reactivity of ACPAs from patients with RA.

Methods: Antibodies isolated from RA patients were expressed as monoclonal chimeric antibodies with mouse Fc. These antibodies were characterized for glycosylation using mass spectrometry, and their cross-reactivity was assessed using Biacore and Luminex immunoassays. The crystal structures of the antigen-binding fragment (Fab) of the monoclonal ACPA E4 in complex with 3 different citrullinated peptides were determined using x-ray crystallography. The prevalence of autoantibodies reactive against 3 of the citrullinated peptides that also interacted with E4 was investigated by Luminex immunoassay in 2 Swedish cohorts of RA patients.

Results: Analysis of the crystal structures of a monoclonal ACPA from human RA serum in complex with citrullinated peptides revealed key residues of several complementarity-determining regions that recognized the citrulline as well as the neighboring peptide backbone, but with limited contact with the side chains of the peptides. The same citrullinated peptides were recognized by high titers of serum autoantibodies in 2 large cohorts of RA patients.

Conclusion: These data show, for the first time, how ACPAs derived from human RA serum recognize citrulline. The specific citrulline recognition and backbone-mediated interactions provide a structural explanation for the promiscuous recognition of citrullinated peptides by RA-specific ACPAs.

Place, publisher, year, edition, pages
WILEY , 2019. Vol. 71, no 2, p. 210-221
National Category
Rheumatology and Autoimmunity
Identifiers
URN: urn:nbn:se:uu:diva-377677DOI: 10.1002/art.40698ISI: 000457458100005PubMedID: 30152126OAI: oai:DiVA.org:uu-377677DiVA, id: diva2:1291694
Funder
Swedish Foundation for Strategic Research Knut and Alice Wallenberg FoundationSwedish Research CouncilEU, FP7, Seventh Framework Programme, 283570Available from: 2019-02-26 Created: 2019-02-26 Last updated: 2019-02-26Bibliographically approved

Open Access in DiVA

No full text in DiVA

Other links

Publisher's full textPubMed

Authority records BETA

Dobritzsch, Doreen

Search in DiVA

By author/editor
Nilsson, PeterSkogh, ThomasKastbom, AlfDobritzsch, Doreen
By organisation
Biochemistry
In the same journal
Arthritis & Rheumatology
Rheumatology and Autoimmunity

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 55 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf