title: Low anti-RhD IgG-Fc-fucosylation in pregnancy: a new variable predicting severity in haemolytic disease of the fetus and newborn.
abstract: Haemolytic disease of the fetus and newborn (HDFN) may occur when maternal IgG antibodies against red blood cells (RBCs), often anti-RhD (anti-D) antibodies, cross the placenta and mediate the destruction of RBCs via phagocytic IgG-Fc-receptors (FcγR). Clinical severity is not strictly related to titre and is more accurately predicted by the diagnostically-applied monocyte-based antibody-dependent cellular cytotoxicity (ADCC), a sensitive test with relatively low specificity. This suggests that other factors are involved in the pathogenesis of HDFN. Binding of IgG to FcγR requires the N-linked glycan at position 297 in the IgG-Fc-region, consisting of several different glycoforms. 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. Additionally, low anti-D fucosylation correlated significantly with low fetal-neonatal haemoglobin levels, thus with increased haemolysis, suggesting IgG-fucosylation to be an important pathological feature in HDFN with diagnostic potential.
authors.affiliation: Department of Experimental Immunohaematology, Sanquin Research, Amsterdam and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Rick
authors.initials: R
authors.lastname: Kapur
authors.forename: Luciana
authors.initials: L
authors.lastname: Della Valle
authors.forename: Myrthe
authors.initials: M
authors.lastname: Sonneveld
authors.forename: Agnes
authors.initials: A
authors.lastname: Hipgrave Ederveen
authors.forename: Remco
authors.initials: R
authors.lastname: Visser
authors.forename: Peter
authors.initials: P
authors.lastname: Ligthart
authors.forename: Masja
authors.initials: M
authors.lastname: de Haas
authors.forename: Manfred
authors.initials: M
authors.lastname: Wuhrer
authors.forename: C Ellen
authors.initials: CE
authors.lastname: van der Schoot
authors.forename: Gestur
authors.initials: G
authors.lastname: Vidarsson
mesh_terms: D000888:Antibodies, Anti-Idiotypic / Q000378:metabolism*; D004899:Erythroblastosis, Fetal / Q000209:etiology* / Q000276:immunology; D005260:Female; D005643:Fucose / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D007518:Isoantibodies / Q000378:metabolism*; D013058:Mass Spectrometry; D011247:Pregnancy; D011961:Receptors, Fc / Q000276:immunology / Q000378:metabolism; D018029:Rho(D) Immune Globulin / Q000378:metabolism
chemical_list: D000888:Antibodies, Anti-Idiotypic; D007518:Isoantibodies; C061961:RHO(D) antibody; D011961:Receptors, Fc; D018029:Rho(D) Immune Globulin; C048844:anti-IgG; D005643:Fucose
keywords: IgG-fucosylation; IgG-glycosylation; anti-RhD or anti-D alloantibodies; haemolytic disease of the fetus and newborn