Aberrant IgG galactosylation precedes disease onset, correlates with disease activity, and is prevalent in autoantibodies in rheumatoid arthritis.
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.
Ercan
Altan
A
Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Cui
Jing
J
Chatterton
Dereck E W
DE
Deane
Kevin D
KD
Hazen
Melissa M
MM
Brintnell
William
W
O'Donnell
Colin I
CI
Derber
Lezlie A
LA
Weinblatt
Michael E
ME
Shadick
Nancy A
NA
Bell
David A
DA
Cairns
Ewa
E
Solomon
Daniel H
DH
Holers
V Michael
VM
Rudd
Pauline M
PM
Lee
David M
DM
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
D001323:Autoantibodies; D007074:Immunoglobulin G; D011134:Polysaccharides; D002097:C-Reactive Protein