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

Abstract

IntroductionImprovement of rheumatoid arthritis (RA) during pregnancy has been causatively associated with increased galactosylation of immunoglobulin G (IgG) N-glycans. Since previous studies were small, did not include the postpartum flare and did not study sialylation, these issues were addressed in the present study.MethodsSerum from 148 RA cases and 32 healthy controls was collected at several time points before, during and after pregnancy. Improvement during pregnancy and postpartum flare were determined according to the European League Against Rheumatism (EULAR) response criteria. Galactosylation and sialylation of Immunoglobulin G (IgG) and the presence of bisecting N-acetylglucosamine (GlcNAc) were analyzed by matrix-assisted laser desorption/ionization - time of flight - mass spectrometry (MALDI-TOF-MS).ResultsIgG1 and IgG2 galactosylation of the cases and controls increased during pregnancy with a maximum in the third trimester. Galactosylation decreased directly postpartum. IgG galactosylation of controls was at a higher level than cases (P < 0.001 at all time points) and a similar pattern was observed for sialylation. Moreover, there was a good association between galactosylation and sialylation. The increase in galactosylation was significantly more pronounced for cases with improvement than cases without improvement during pregnancy. The reverse was true for deteriorators and non-deteriorators postpartum. The presence of bisecting GlcNAc was not significantly influenced by pregnancy or postpartum for cases and controls.ConclusionsThis large cohort study demonstrates the association of changes in galactosylation with both pregnancy-induced improvement and postpartum flare in RA-patients, suggesting a role for changes in glycosylation in the pregnancy-induced improvement of RA.

Controlled tetra-Fc sialylation of IVIg results in a drug candidate with consistent enhanced anti-inflammatory activity

“…Additional studies have shown that this translates particularly to the pathogenic antibodies in inflamed joints of arthritis patients (17). It has also been shown that IgG sialylation increases during pregnancy and that this increase may be associated with the remission of rheumatoid arthritis during pregnancy (18,19). In addition, pathogenic proteinase 3 autoantibodies are less sialylated in patients with active Wegener's vasculitis (granulomatosis with polyangiitis) (20).…”

Diversification of IgG effector functions

“…Indeed, recent analyses of the Fc glycan composition revealed distinct fluctuations at the levels of specific glycoforms upon vaccination, during pregnancy, in chronic inflammatory and neoplastic diseases, in response to systemic metabolic changes and during infection (34,(60)(61)(62)(63)(64)(65). Examples include inflammatory diseases, such as rheumatoid arthritis and Wegener's granulomatosis, which are characterized by reduced galactosylation and sialylation, as well as infectious diseases, such as Dengue infection, in which increased levels of afucosylated glycoforms are associated with clinical disease severity and thrombocytopenia (60,61,(63)(64)(65).…”

Production of Highly Sialylated Monoclonal Antibodies

“…reported that the increased levels of IgG1 galactosylation and sialylation during pregnancy may be responsible for the improved condition of RA-affected pregnant women [22].…”