Session Title: Rheumamtoid Arthritis - Human Etiology and Pathogenesis
Session Type: Abstract Submissions (ACR)
Rheumatoid arthritis (RA) is known to improve during pregnancy and to flare after delivery . Changes in the glycosylation of immunoglobulin G’s fragment crystallizable (IgG-Fc) have been suggested to play a role in this phenomenon . Animal studies indicate sialylation is the effector of galactosylation mediated immune suppression . In this study technical advances allowed further insight into sialylation, a previously elusive feature. We aim to find new associations between IgG-Fc N-glycosylation (galactosylation and sialylation) and the improvement of rheumatoid arthritis during pregnancy, which can give more insight into RA pathogenesis.
Sera of RA patients (n=251 pregnancies) and healthy controls (n=32), all participating in a prospective cohort study on RA and pregnancy (PARA study), were collected before conception if possible, during pregnancy, and after delivery. At all time points disease activity (DAS28-CRP(3)) was measured, and medication was recorded. Using a newly developed mass spectrometric method  the glycosylation of IgG Fc-glycopeptides was measured in a subclass specific manner.
In both patients and controls changes in glycosylation during pregnancy have been observed. In patients IgG1 galactosylation changed from 59.3±1.1 to 64.9±1.0% (mean±SEM); sialylation from 18.7±0.5 to 21.4±0.5%. Similar results were obtained for IgG2/3 and IgG4. Patient galactosylation and sialylation levels are lower compared to controls. Our data show that in patients increased galactosylation, but not sialylation, is associated with lower disease activity. Increased sialylation rates are associated with higher DAS28-CRP(3).
In contrast to animal studies, in patients increased galactosylation, and not sialylation, is associated with low disease activity. Our data suggest sialylation could partially inhibit the positive effect of galactosylation. These data do not only have implications for understanding the pathogenesis of RA, but may also shed new light on how glycosylation determines the function of IgG. This latter could have major consequences for the development of new monoclonals to treat human disease.
This research project is financed by the Dutch Arthritis Foundation.
1. de Man, Y.A., et al., Disease activity of rheumatoid arthritis during pregnancy: Results from a nationwide prospective study. Arthritis & Rheumatism, 2008. 59(9): p. 1241-1248.
2. van de Geijn, F.E., et al., Immunoglobulin G galactosylation and sialylation are associated with pregnancy-induced improvement of rheumatoid arthritis and the postpartum flare: results from a large prospective cohort study. Arthritis Res Ther, 2009. 11(6): p. R193.
3. Kaneko, Y., F. Nimmerjahn, and J.V. Ravetch, Anti-Inflammatory Activity of Immunoglobulin G Resulting from Fc Sialylation. Science, 2006. 313(5787): p. 670-673.
4. Selman, M.H.J., et al., Fc specific IgG glycosylation profiling by robust nano-reverse phase HPLC-MS using a sheath-flow ESI sprayer interface. Journal of Proteomics, 2012. 75(4): p. 1318-1329.
M. H. J. Selman,
Hoffmann-La Roche, Inc.,
A. M. Deelder,
J. M. W. Hazes,
R. J. E. M. Dolhain,
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