During pregnancy, the mother faces a major immunological challenge. Most of the major plasma proteins have important immunological functions, and altered levels of these major proteins have been reported during pregnancy, potentially providing immunosuppression. A large number of the high abundance plasma proteins are post-translationally modified by N-glycans, and while it is now understood that these glycans may also affect the immunological functions, their pattern has not been studied in relation to pregnancy. Here, the N-glycosylation profile of 32 pregnant women was determined over the course of their pregnancy using a multiplexed CGE-LIF method. Moreover, for 6 women, the glycosylation profiles of the proteins IgG, IgA, and alpha1-antitrypsin were monitored. For total plasma, 16 glycan signals showed differential expression during pregnancy. In general the levels of largely sialylated bi-, tri-, and tetra-antennary glycans were increased during pregnancy, while biantennary glycans with no more than one sialic acid were decreased. Similarly altered glycosylation profiles were observed for the individual proteins IgG, with a decrease of digalactosylated biantennary glycans after delivery, and alpha1-antitrypsin, on which increased levels of triantennary glycans were observed during pregnancy. Overall, these results show altered glycosylation profiles both for total plasma glycoproteins and on individual proteins during pregnancy, which may contribute to immunosuppression and have other biological functions.
Background:Fc neonatal receptor (FcRn) is crucial for IgG half-life and transplacental transport. Different sites of IgG carry glycans which may affect binding to FcRn. While the effect of Fc-glycans has been investigated, the impact of Fab-glycosylation (~14% IgG) on IgG-FcRn interaction remains unclear. Anti-citrullinated protein antibodies (ACPA) of rheumatoid arthritis patients exhibit remarkably high Fab-glycosylation (~90%). This makes ACPA an ideal model to investigate how Fab-glycosylation influences IgG-FcRn interaction.Objectives:To investigate the potential impact of IgG Fab-glycosylation on IgG transplacental transfer and interaction with FcRn.Methods:To investigate transplacental transport of ACPA and total IgG, serum of ACPA-positive RA patients (mothers) as well as of healthy mothers and their respective newborns was analyzed. IgG Fab- and Fc-glycosylation was investigated with liquid chromatography and mass-spectrometry. Furthemore, ACPA monoclonal IgG were produced and glycoengineered to acquire several variants of the same monoclonal antibody differing only in their glycosylation profile. These glycovariants were then used to investigate the impact of Fab-glycans on the affinity of IgG for FcRn. Surface plasmon resonance (SPR) and affinity chromatography were implemented.Results:When measured in mothers’ serum and cord blood samples, Fab-glycosylation of IgG antibodies was ~20% lower in newborns compared to their mothers, which was observed for ACPA IgG, non-ACPA IgG in RA patients and total IgG of healthy controls (Figure 1). This may indicate that transplacental transfer of Fab-glycosylated antibodies is impaired. SPR results suggested that presence of Fab-glycans slightly lowered the affinity of IgG for FcRn. However, presence of Fab-glycans did not have a significant effect on the results of FcRn affinity chromatography. Together, these results suggest that Fab-glycans may impair association of IgG with FcRn, while dissociation likely stays intact.Conclusion:Our results suggest that Fab-glycans inhibit IgG-FcRn binding which negatively affects the transplacental transfer of Fab-glycosylated IgG. The impact of Fab-glycosylation on IgG half-life requires further investigation.Figure 1.Disclosure of Interests:Mikhail Volkov: None declared, Karin van Schie: None declared, Albert Bondt: None declared, Theresa Kissel: None declared, Maximilian Brinkhaus Grant/research support from: argenx, Arthur Bentlage: None declared, Carolien Koeleman: None declared, Steven de Taeye Grant/research support from: Genmab, Radboud Dolhain: None declared, Manfred Wuhrer: None declared, Rene Toes: None declared, Gestur Vidarsson: None declared, Diane van der Woude: None declared
Background:Sexual health (SH) can be impaired in men with inflammatory arthritis (IA) (1). In addition to biological factors, such as inflammation, subjective factors such as personal beliefs can also impair SH. The Q methodology combines aspects of qualitative and quantitative approaches to systematically study subjectivity, and has been applied successfully in other medical fields.Objectives:To describe the viewpoints of adult men with IA on the impact of IA on their SH using the Q methodology.Methods:Men, 18 years and older, diagnosed with RA or JIA were invited by their rheumatologist. Participants ranked 34 opinion statements about potential impacts of IA on their SH on an agreement scale. A by-person factor analysis identified common patterns in the rankings. These patterns represent the different viewpoints among the men. Data from interviews, in which the men explained their ranking, was used to further interpret the viewpoints. A Q-methodology study usually consists of 30-40 participants.Results:30 men with IA were included. Their mean age was 43.2 (range 22–77) years. The analysis revealed three viewpoints:1.“I am satisfied with my sex life”Men with viewpoint 1 experience no significant impact of IA on their SH. However, most men indicated that when their disease was active, IA had a negative impact on their SH.2.“Arthritis has a negative influence on my sex life”Men with viewpoint 2 experience a dramatic impact, due to pain, fatigue and gloom. Their relationship worsened and they feel guilty towards their partner. Discussing their problems is not difficult.3.“I am keeping up appearances”Men with viewpoint 3 experience SH impairment mainly as a result of pain. IA impairs them physically, makes them feel less of a man, less attractive and reduces their self-confidence. Due to problems with accepting their disease and communicating their problems, these men tend to hide their problems.Conclusion:We identified 3 viewpoints on the impact of IA on male SH, 2 of them revealing a negative influence that goes beyond the physical act of sex. IA can also affect relationships, self-confidence and manhood. Future research will focus on identifying men with SH problems in the clinic and the best counseling approach.References:[1]Perez-Garcia LF, Te Winkel B, Carrizales JP, Bramer W, Vorstenbosch S, van Puijenbroek E, et al. Sexual function and reproduction can be impaired in men with rheumatic diseases: A systematic review. Semin Arthritis Rheum. 2020;50(3):557-73.Disclosure of Interests:Luis Fernando Perez-Garcia Consultant of: Galapagos, Esther Röder: None declared, Hester Pastoor: None declared, Hanneke Bolt: None declared, Job van Exel: None declared, Radboud Dolhain Speakers bureau: Abbvie, UCB, Genzyme, Consultant of: Galapagos, Grant/research support from: UCB.
Background:An elevated sFlt-1 indicates soluble Fms-like tyrosine kinase-1 (sFlt-1)/ placental growth factor (PlGF) ratio has recently been validated as significant predictor of preeclampsia (PE)(1). However, raised sFlt-1 levels due to inflammation are observed in patients with rheumatoid arthritis (RA)(2). The use of the sFlt-1/PlGF ratio for the prediction of PE has not been evaluated in pregnant women with diseases that are characterized by high levels of inflammation, such as RAObjectives:We investigated whether sFlt-1 and/or PlGF are altered in pregnant women with RA according to disease activity, and evaluated whether a sFlt-1/PlGF ratio of ≤38 could be used to predict the absence of PE in pregnant RA-patients.Methods:This study was embedded in a nationwide, observational, prospective cohort study on pregnant women with RA (PARA-study). sFlt-1 and PlGF levels were measured, using automated analyzer (Cobas-6000, e-module; Roche-Diagnostics), in the third trimester of pregnancy.Results:A total of 221 women, aged 21–42 years, were included. Values of sFlt-1, PlGF and sFlt-1/PlGF ratio were not significantly correlated with the DAS28-CRP (Figure 1). CRP correlated weakly with PlGF (r=-0.14, p=0.03), while no correlation was found with sFlt-1 or the sFlt-1/PlGF ratio.Preeclampsia occurred in four out of 214 women with a ratio ≤38 (2%) in contrast to three out of seven women with a ratio >38 (43%), p<0.001 (Table 1). When stratified to a sFlt-1/PlGF ratio of ≤38 only 2% of women developed preeclampsia, compared to 43% of the women with a ratio >38. The observed sensitivity and specificity for a sFlt-1/PlGF ratio cut-off of ≤38 were 42.1% and 98.1%, respectively, with a negative predictive value (NPV) of 98%. All women that developed PE, developed PE >4 weeks after collecting of blood samples in the 3rd trimester, therefore the observed NPV could be even higher.Table 1.Pregnancy Outcome according to sFlt-1/PlGF ratio with a cut-off value of 38.ParameterRatio ≤38Ratio >38P-valueN2147GA at birth, weeks39 (38 - 40)37 (36 - 40)0.05<342 (1)0(0)1.0034 - 3718 (8)2 (29)0.12Male, n (%)113 (53)5 (71)0.45Birth weight, grams3420 (2998 - 3800)2620 (2360 - 2850)<0.01Maternal OutcomeGestational Hypertension15 (7)2 (29)0.09Preeclampsia4 (2)3 (43)<0.001Time to delivery, days66 (52 - 75)52 (44 - 66)0.08Fetal OutcomeBirth weight percentile <1033 (15)5 (71)<0.01Fetal/Neonatal Death1 (1)0 (0)1.00Data are reported as median (interquartile range) or number (percentage). sFlt-1 indicates soluble Fms-like tyrosine kinase-1; PlGF, placental growth factor; GA, gestational age. Time to delivery is defined as the amount of days between blood sampling and delivery.Conclusion:Our study shows that in pregnant women with RA, the sFlt-1/PlGF ratio is not altered due to disease activity, and a cut-off of ≤38 of this ratio can be used to exclude preeclampsia.References:[1]H. Zeisler et al. Predictive Value of the sFlt-1:PlGF Ratio in Women with Suspected Preeclampsia. N Engl J Med 2016; 374: 13-22. DOI 10.1056/NEJMoa1414838.[2]S. Ballara et al. Paleolog. Raised serum vascular endothelial growth factor levels are associated with destructive change in inflammatory arthritis. Arthritis Rheum 2001; 44: 2055-2064. DOI 10.1002/1529-0131(200109)44:9<2055::AID-ART355>3.0.CO;2-2.Figure 1.Correlations between sFlt-1, PlGF and sFlt-1/PlGF ratio with DAS28-CRP and CRP. Correlation coefficients for sFlt-1 (A-B), PlGF (C-D) and sFlt-1/PlGF ratio (E-F) with DAS28-CRP and CRP.Acknowledgements:The kits for measurement of sFlt-1/PlGF ratio were a kind gift from Roche Diagnostics, Germany. We thank all participants of the PARA study. Additionally, we extend our gratitude to the laboratory workers, in particular Nadine Davelaar and Priyanka Bangoer, and research assistants for their contribution to the data collection. We thank ReumaNederland (LLP project number: LLP-26) for their financial support.Disclosure of Interests:Hieronymus TW Smeele: None declared, R.I. Neuman: None declared, A.H.J. Danser: None declared, Radboud Dolhain Speakers bureau: Yes UCB, Roche, Abbvie, Genzyme, Novartis, Consultant of: Yes, Galapagos, Grant/research support from: Yes, UCB, W. Visser: None declared
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