Low anti-RhD IgG-Fc-fucosylation in pregnancy: a new variable predicting severity in haemolytic disease of the fetus and newborn.
Bottom Line: We therefore systematically analysed IgG-derived glycopeptides by mass spectrometry from 70 anti-D IgG1 antibodies purified from the plasma of alloimmunized pregnant women.This revealed a variable decrease in Fc-fucosylation in the majority of anti-D IgG1 (even down to 12%), whereas the total IgG of these patients remained highly fucosylated, like in healthy individuals (>90%).The degree of anti-D fucosylation correlated significantly with CD16 (FcγRIIIa)-mediated ADCC, in agreement with increased affinity of defucosylated IgG to human FcγRIIIa.
Affiliation: Department of Experimental Immunohaematology, Sanquin Research, Amsterdam and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.Show MeSH
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Mentions: As monocyte ADCC is used to monitor anti-D activity for diagnostic purposes, because it is more predictive for disease severity of HDFN than the antibody titre (Oepkes et al, 2001), we first investigated if glycosylation of anti-D IgG1 affected anti-D activity in this assay. A very weak, albeit significant, correlation between monocyte ADCC and the level of galactosylation was found (Fig S2). No significant correlation was found between monocyte ADCC and bisection or fucosylation. However, as IgG-Fc fucosylation only affects binding to monocyte FcγRIIIa, which is not well expressed on circulating monocytes (∼5% of cells show low expression), we also tested the functional capacity of pregnancy-induced anti-D IgG1 antibodies to mediate RBC lysis through CD16+ (FcγRIIIa) NK cell-mediated ADCC. Sufficient material from 11 samples with equal titres, and glycoprofiled in Fig4, was available to perform this assay. This set of samples did not show any significant correlation between anti-D IgG1 galactosylation or bisection and NK-cell ADCC (Fig5A, B, respectively), and also not with the monocyte ADCC (Fig S3). However, in line with the strong FcγRIIIa expression on NK cells, the degree of anti-D IgG1 fucosylation correlated significantly with NK-cell mediated ADCC, with a lower degree of anti-D Fc-fucosylation corresponding to increased NK-cell mediated ADCC (Fig5C). No correlations were found between the anti-D titre and the levels of IgG1-galactosylation, -bisection, or -fucosylation (Fig S4).
Affiliation: Department of Experimental Immunohaematology, Sanquin Research, Amsterdam and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.