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Multicenter Study
. 2015 Nov;67(11):2978-89.
doi: 10.1002/art.39273.

Association of systemic lupus erythematosus with decreased immunosuppressive potential of the IgG glycome

Frano Vučković  1 , Jasminka Krištić  1 , Ivan Gudelj  1 , Maria Teruel  2 , Toma Keser  3 , Marija Pezer  1 , Maja Pučić-Baković  1 , Jerko Štambuk  1 , Irena Trbojević-Akmačić  1 , Clara Barrios  4 , Tamara Pavić  3 , Cristina Menni  5 , Youxin Wang  6 , Yong Zhou  7 , Liufu Cui  8 , Haicheng Song  8 , Qiang Zeng  9 , Xiuhua Guo  6 , Bernardo A Pons-Estel  10 , Paul McKeigue  11 , Alan Leslie Patrick  12 , Olga Gornik  3 , Tim D Spector  5 , Miroslav Harjaček  13 , Marta Alarcon-Riquelme  14 , Mariam Molokhia  5 , Wei Wang  15 , Gordan Lauc  16
Affiliations
Multicenter Study

Association of systemic lupus erythematosus with decreased immunosuppressive potential of the IgG glycome

Frano Vučković et al. Arthritis Rheumatol. 2015 Nov.

Abstract

Objective: Glycans attached to the Fc portion of IgG are important modulators of IgG effector functions. Interindividual differences in IgG glycome composition are large and they associate strongly with different inflammatory and autoimmune diseases. IKZF1, HLA-DQ2A/B, and BACH2 genetic loci that affect IgG glycome composition show pleiotropy with systemic lupus erythematosus (SLE), indicating a potentially causative role of aberrant IgG glycosylation in SLE. We undertook this large multicenter case-control study to determine whether SLE is associated with altered IgG glycosylation.

Methods: Using ultra-performance liquid chromatography analysis of released glycans, we analyzed the composition of the IgG glycome in 261 SLE patients and 247 matched controls of Latin American Mestizo origin (the discovery cohort) and in 2 independent replication cohorts of different ethnicity (108 SLE patients and 193 controls from Trinidad, and 106 SLE patients and 105 controls from China).

Results: Multiple statistically significant differences in IgG glycome composition were observed between patients and controls. The most significant changes included decreased galactosylation and sialylation of IgG (which regulate proinflammatory and antiinflammatory actions of IgG) as well as decreased core fucose and increased bisecting N-acetylglucosamine (which affect antibody-dependent cell-mediated cytotoxicity).

Conclusion: The IgG glycome in SLE patients is significantly altered in a way that decreases immunosuppressive action of circulating immunoglobulins. The magnitude of observed changes is associated with the intensity of the disease, indicating that aberrant IgG glycome composition or changes in IgG glycosylation may be an important molecular mechanism in SLE.

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Figures

Figure 1
Figure 1
Differences in IgG glycosylation in patients with systemic lupus erythematosus and in healthy controls in 3 different populations. The IgG glycome was analyzed using hydrophilic interaction chromatography–ultra‐performance liquid chromatography in African Caribbeans (Afr; 108 patients and 193 controls), Latin Americans of Mestizo ethnicity (Lat; 261 patients and 247 controls), and Han Chinese (Chi; 106 patients and 105 controls). Pronounced differences were observed between patients and controls in directly measured glycan structures (A) and in derived traits that measure sialylation, galactosylation, fucosylation, and bisecting N‐acetylglucosamine (GlcNAc) (B). Data are shown as box plots. Each box represents the 25th to 75th percentiles. Lines inside the boxes represent the median. Lines outside the boxes represent the 10th and 90th percentiles. Circles indicate outliers. Glycan peak 2 (GP2) = percentage of A2 glycan in total IgG glycans; GP4 = percentage of FA2 glycan in total IgG glycans; GP6 = percentage of FA2B glycan in total IgG glycans; GP9 = percentage of FA2[3]G1 glycan in total IgG glycans; GP14 = percentage of FA2G2 glycan in total IgG glycans; GP18 = percentage of FA2G2S1 glycan in total IgG glycans; S total = proportion of sialylated structures in total IgG glycans; G0n = proportion of agalactosylated structures in neutral glycans; G1n = proportion of monogalactosylated structures in neutral glycans; G2n = proportion of digalactosylated structures in neutral glycans; Fn total = proportion of fucosylated structures in neutral glycans; FBn = proportion of fucosylated (with bisecting GlcNAc) structures in total neutral IgG glycans. Color figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.com/doi/10.1002/art.39273/abstract.
Figure 2
Figure 2
Changes in glycans are associated with symptom profile of systemic lupus erythematosus (SLE) in African Caribbean and Latin American cohorts. Prior to analysis, the 2 cohorts were pooled (n = 358). Patients were divided into groups by the number of SLE complications/symptoms. For this analysis, only symptoms that showed the strongest associations with changes in glycome composition were selected (antinuclear antibody positivity, pericarditis, proteinuria, and disease duration >8 years). Glycosylation changes were more pronounced in patients with a larger number of complications/symptoms (for G0n, P = 1.28 × 10−7; for G2n, P = 1.21 × 10−8; for Fn total, P = 5.27 × 10−2; for proportion of monosialylated structures in total IgG glycans [S1 total], P = 2.14 × 10−6; for FBn, P = 1.49 × 10−6). Data are shown as box plots. Each box represents the 25th to 75th percentiles. Lines inside the boxes represent the median. Lines outside the boxes represent the 10th and 90th percentiles. Circles indicate outliers. C = control samples (see Figure 1 for other definitions). Color figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.com/doi/10.1002/art.39273/abstract.
Figure 3
Figure 3
A, Receiver operating characteristic curves illustrating the performance of a regularized logistic regression model in predicting disease status of patients with systemic lupus erythematosus (SLE) and healthy controls in the African Caribbean (left), Latin American (middle), and Han Chinese (right) cohorts. While models based only on age and sex did not show predictive power (red lines), addition of glycan traits increased predictive power of models (black lines). AUC = area under the curve. B, Principal components analysis plots showing differences in GP6, GP9, GP10, and GP14 glycans between SLE patients and healthy controls in the African Caribbean (left), Latin American (middle), and Han Chinese (right) cohorts. Comp. = component (see Figure 1 for other definitions).
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