Anti-Citrullinated Protein Antibody Specific Fc Glycosylation Patterns in Arthralgia Patients

Hans Ulrich Scherer¹, Yoann Rombouts², Ewoud Ewing³, Lotte van de Stadt⁴, Maurice H.J. Selman⁵, André M. Deelder³, Tom W.J. Huizinga², Manfred Wuhrer⁵, Dirkjan van Schaardenburg⁶ and René E.M. Toes², ¹Rheumatology, Leiden University Medical Centre, Leiden, Netherlands, ²Rheumatology, Leiden University Medical Center, Leiden, Netherlands, ³Biomolecular Mass Spectrometry Unit, Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands, ⁴Jan van Breemen Research Institute | Reade, Amsterdam, Netherlands, ⁵Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, Netherlands, ⁶Rheumatology, Jan van Breemen Research Institute | Reade, Amsterdam, Netherlands

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: anti-citrullinated protein/peptide antibodies (ACPA), glycoproteins and rheumatoid arthritis, pathogenesis

Session Information

Title: Rheumamtoid Arthritis - Human Etiology and Pathogenesis

Session Type: Abstract Submissions (ACR)

Background/Purpose:

Anti-citrullinated protein antibodies (ACPA) exhibit a specific, pro-inflammatory Fc glycosylation profile characterized by a low content of galactose and sialic acid residues. The absence of these residues from the Fc-linked core glycan could influence the biological activity of ACPA in rheumatoid arthritis. As ACPA can be detected in sera several years before disease development, we hypothesized that a change in ACPA Fc-glycosylation might precede the onset of arthritis.

Methods:

Serum samples (n=300) of patients with ACPA positive arthralgia (n=184) were obtained at various time points. ACPA were isolated by affinity purification using cyclic citrullinated peptides as antigen. Isolated ACPA and total serum IgG molecules were subjected to trypsin digest, and glycan profiles of IgG1 Fc glycopeptides were analyzed by mass spectrometry. 96 patients in this cohort developed arthritis after an average duration of arthralgia of 14.7 months. At the time of the onset of arthritis, patients were defined as having rheumatoid arthritis (RA, n=51) based on the 1987 ACR criteria for RA, or undifferentiated arthritis (UA, n=45).

Results:

No difference was found between ACPA-specific and total serum IgG1 Fc glycosylation patterns at the time of the patients’ first presentation with arthralgia (baseline). At diagnosis of arthritis, RA patients, but not patients with undifferentiated arthritis, exhibited increased hypogalactosylation of the ACPA Fc fragment compared to healthy donors. Although a similar degree of Fc hypogalactosylation was found for total IgG in RA patients, hypogalactosylation of the ACPA Fc-tail occurred at 6 months before diagnosis, and was significantly more pronounced at 3 months before diagnosis than that of total IgG. No significant changes were noted for sialylation or fucosylation of the Fc tail.

Conclusion:

ACPA acquire specific Fc-glycosylation patterns prior to disease onset, with a change towards hypogalactosylation occurring around 6 months before RA development. Of interest, ACPA hypogalactosylation was more pronounced than that of total IgG, indicating specific changes in the ACPA immune response several months before disease onset.

Disclosure:

H. U. Scherer,
None;

Y. Rombouts,
None;

E. Ewing,
None;

L. van de Stadt,
None;

M. H. J. Selman,

Hoffmann-La Roche, Inc.,

A. M. Deelder,
None;

T. W. J. Huizinga,
None;

M. Wuhrer,
None;

D. van Schaardenburg,
None;

R. E. M. Toes,
None.

« Back to 2012 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/anti-citrullinated-protein-antibody-specific-fc-glycosylation-patterns-in-arthralgia-patients/