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Carbamylation of immunoglobulin abrogates activation of the classical complement pathway

In English

Författare

  • Catalin Koro
  • Ewa Bielecka
  • Anders Dahl-Knudsen
  • Jan J. Enghild
  • Carsten Scavenius
  • Johan G. Brun
  • Veronika Binder
  • Annelie Hellvard
  • Brith Bergum
  • Roland Jonsson
  • Jan Potempa
  • Anna Blom
  • Piotr Mydel
Visa allt

Summary, in English

Post-translational modifications of proteins significantly affect their structure and function. The carbamylation of positively charged lysine residues to form neutral homoitrulline occurs primarily under inflammatory conditions through myeloperoxidase-dependent cyanate (CNO-) formation. We analyzed the pattern of human IgG(1) carbamylation under inflammatory conditions and the effects that this modification has on the ability of antibodies to trigger complement activation via the classical pathway. We found that the lysine residues of IgG(1) are rapidly modified after brief exposure to CNO-. Interestingly, modifications were not random, but instead limited to only few lysines within the hinge area and the N-terminal fragment of the CH2 domain. A complement activation assay combined with mass spectrometry analysis revealed a highly significant inverse correlation between carbamylation of several key lysine residues within the hinge region and N-terminus of the CH2 domain and the proper binding of C1q to human IgG(1) followed by subsequent complement activation. This severely hindered complement-dependent cytotoxicity of therapeutic IgG(1). The reaction can apparently occur in vivo, as we found carbamylated antibodies in synovial fluid from rheumatoid arthritis patients. Taken together, our data suggest that carbamylation has a profound impact on the complement-activating ability of IgG(1) and reveals a pivotal role for previously uncharacterized lysine residues in this process.

Publiceringsår

2014

Språk

Engelska

Sidor

3403-3412

Publikation/Tidskrift/Serie

European Journal of Immunology

Volym

44

Issue

11

Dokumenttyp

Artikel i tidskrift

Förlag

John Wiley & Sons Inc.

Ämne

  • Immunology in the medical area

Nyckelord

  • Carbamylation
  • IgG(1)
  • Complement
  • Inflammation
  • Rheumatoid arthritis

Status

Published

Forskningsgrupp

  • Protein Chemistry, Malmö

ISBN/ISSN/Övrigt

  • ISSN: 1521-4141