Aberrant IgG galactosylation precedes disease onset, correlates with disease activity, and is prevalent in autoantibodies in rheumatoid arthritis

TY - JOUR

T1 - Aberrant IgG galactosylation precedes disease onset, correlates with disease activity, and is prevalent in autoantibodies in rheumatoid arthritis

AU - Ercan, Altan

AU - Cui, Jing

AU - Chatterton, Dereck Edward Winston

AU - Deane, Kevin D.

AU - Hazen, Melissa M.

AU - Brintnell, William

AU - O´Donnell, Colin I.

AU - Derber, Lezlie A.

AU - Weinblatt, Michael E.

AU - Shadick, Nancy A.

AU - Bell, David A.

AU - Cairns, Ewa

AU - Solomon, Daniel H.

AU - Holers, V. Michael

AU - Rudd, Pauline M.

AU - Lee, David M.

PY - 2010/8

Y1 - 2010/8

N2 - 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, anticyclic 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 ρ = 0.37, P < 0.0001). This correlation was higher in women (Spearman's ρ = 0.60, P < 0.0001) than in men (Spearman's ρ = 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. Conclusion. 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 auto-antibodies.

AB - 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, anticyclic 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 ρ = 0.37, P < 0.0001). This correlation was higher in women (Spearman's ρ = 0.60, P < 0.0001) than in men (Spearman's ρ = 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. Conclusion. 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 auto-antibodies.

U2 - 10.1002/art.27533

DO - 10.1002/art.27533

M3 - Journal article

SN - 0004-3591

VL - 62

SP - 2239

EP - 2248

JO - Arthritis & Rheumatism

JF - Arthritis & Rheumatism

IS - 8

ER -