Serum Protein N-Glycosylation Changes with Rheumatoid Arthritis Disease Activity during and after Pregnancy

Abstract

Symptoms of rheumatoid arthritis (RA) improve during pregnancy, a phenomenon that was found to be associated with N-glycosylation changes of immunoglobulin G. Recent advances in high-throughput glycosylation analysis allow the assessment of the N-glycome of human sera as well. The aim of this study was to identify new protein N-glycosylation properties that associate with changes in RA disease activity during and after pregnancy. A longitudinal cohort of serum samples was collected during 285 pregnancies (32 control individuals and 253 RA patients). Per individual one sample was collected before conception, three during pregnancy, and three after delivery. Released serum protein N-glycans were measured by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) after employing chemical modification of the sialic acids to allow discrimination of sialic acid linkage isomers. Serum protein N-glycosylation showed strongly modified during pregnancy, with similar changes visible in control individuals and RA pregnancies. Namely, a decrease in bisection and an increase in galactosylation in diantennary glycans were found, as well as an increase in tri- and tetraantennary species and α2,3-linked sialylation thereof. The change in RA disease activity [DAS28(3)-CRP] proved negatively associated with the galactosylation of diantennary N-glycans, and positively with the sialylation of triantennary fucosylated species (A3FGS). While the protein source of the novel finding A3FGS is thus far unknown, its further study may improve our understanding of the etiology of RA disease severity.

Plasma N-Glycan Signatures Are Associated With Features of Inflammatory Bowel Diseases

“…A3FGL decreased after surgery in UC patients only, which is in line with our meta-analysis finding of a lower A3FGL in HCs and indicates improvement in UC patients after surgical intervention. In a study of the serum glycome in rheumatoid arthritis, this trait did not differ between HCs and patients, 49 which might point at a possible diseasespecificity of A3FGL in IBD. The lack of significance in postoperative glycan changes in CD despite a higher sample size (n ¼ 19 in CD vs n ¼ 9 in UC) could be related to the fact that relapses occur more frequently in CD, whereas in UC surgery is able to cure the disease.…”

“…Similar N-glycome associations with disease and disease activity were found in a longitudinal study on rheumatoid arthritis, in which the serum N-glycome was measured with the same method as used here. 49 This was linked to an increase in the levels of acute phase proteins containing large, highly sialylated glycans, such as a1-acid glycoprotein and a1-antitrypsin. 50,51 Plasma glycoproteins can contain SAs in 2 major linkage variants, that is, linked in the a2,3or a2,6-position to an antenna galactose.…”

Plasma protein N-glycan signatures of type 2 diabetes

“…Also, in an independent large cohort of mostly healthy individuals, the A2FSB trait showed a positive trend (p = 0.017) with increasing glucose-to-insulin ratio [15], indicative of a higher insulin sensitivity and supporting our finding in diabetes. Interestingly, A2FSB showed a positive association with rheumatoid arthritis, which is characterized by chronic inflammation [53]. In IgG, bisection enhances antibody-dependent cytotoxicity [50].…”

Dissecting Total Plasma and Protein-Specific Glycosylation Profiles in Congenital Disorders of Glycosylation

“…The three major classes of human N -glycans are schematically presented ( A ) and the major structural features of complex-type N -glycans are introduced ( B ). Adaptation from [ 19 ].…”