title: Aberrant IgG galactosylation precedes disease onset, correlates with disease activity, and is prevalent in autoantibodies in rheumatoid arthritis.
abstract: OBJECTIVE
  To examine the association between aberrant IgG galactosylation and disease parameters in rheumatoid arthritis (RA).
  
  
  METHODS
  Analysis of N-glycan in serum samples from multiple cohorts was performed. The IgG N-glycan content and the timing of N-glycan aberrancy relative to disease onset were compared in healthy subjects and in patients with RA. Correlations between aberrant galactosylation and disease activity were assessed in the RA cohorts. The impact of disease activity, sex, age, anti-cyclic citrullinated peptide (anti-CCP) antibody titer, disease duration, and C-reactive protein level on aberrant galactosylation was determined using multivariate analysis. The N-glycan content was also compared between epitope affinity-purified autoantibodies and the remaining IgG repertoire in RA patients.
  
  
  RESULTS
  Our results confirm the aberrant galactosylation of IgG in RA patients as compared with healthy controls (mean +/- SD 1.36 +/- 0.43 versus 1.01 +/- 0.23; P < 0.0001). We observed a significant correlation between levels of aberrant IgG galactosylation and disease activity (Spearman's rho = 0.37, P < 0.0001). This correlation was higher in women (Spearman's rho = 0.60, P < 0.0001) than in men (Spearman's rho = 0.16, P = 0.10). Further, aberrant IgG galactosylation substantially predated the onset of arthritis and the diagnosis of RA (3.5 years) and resided selectively in the anticitrullinated antigen fraction.
  
  
  CONCLUSIONS
  Our findings identify aberrant IgG galactosylation as a dysregulated component of the humoral immune response in RA that begins prior to disease onset, associates with disease activity in a sex-specific manner, and resides preferentially in autoantibodies.
authors.affiliation: Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Altan
authors.initials: A
authors.lastname: Ercan
authors.forename: Jing
authors.initials: J
authors.lastname: Cui
authors.forename: Dereck E W
authors.initials: DE
authors.lastname: Chatterton
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Deane
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Hazen
authors.forename: William
authors.initials: W
authors.lastname: Brintnell
authors.forename: Colin I
authors.initials: CI
authors.lastname: O'Donnell
authors.forename: Lezlie A
authors.initials: LA
authors.lastname: Derber
authors.forename: Michael E
authors.initials: ME
authors.lastname: Weinblatt
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Shadick
authors.forename: David A
authors.initials: DA
authors.lastname: Bell
authors.forename: Ewa
authors.initials: E
authors.lastname: Cairns
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Solomon
authors.forename: V Michael
authors.initials: VM
authors.lastname: Holers
authors.forename: Pauline M
authors.initials: PM
authors.lastname: Rudd
authors.forename: David M
authors.initials: DM
authors.lastname: Lee
mesh_terms: D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism*; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism*; D002097:C-Reactive Protein / Q000378:metabolism; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011134:Polysaccharides / Q000276:immunology / Q000378:metabolism*; D012720:Severity of Illness Index; D012737:Sex Factors
chemical_list: D001323:Autoantibodies; D007074:Immunoglobulin G; D011134:Polysaccharides; D002097:C-Reactive Protein