title: Glycosylation pattern of anti-platelet IgG is stable during pregnancy and predicts clinical outcome in alloimmune thrombocytopenia.
abstract: Fetal or neonatal alloimmune thrombocytopenia (FNAIT) is a potentially life-threatening disease where fetal platelets are destroyed by maternal anti-platelet IgG alloantibodies. The clinical outcome varies from asymptomatic, to petechiae or intracranial haemorrhage, but no marker has shown reliable correlation with severity, making screening for FNAIT impractical and highly inefficient. We recently found IgG Fc-glycosylation towards platelet and red blood cell antigens to be skewed towards decreased fucosylation, increased galactosylation and sialylation. The lowered core-fucosylation increases the affinity of the pathogenic antibodies to FcγRIIIa and FcγRIIIb, and hence platelet destruction. Here we analysed the N-linked glycans of human platelet antigen (HPA)-1a specific IgG1 with mass spectrometry in large series of FNAIT cases (n = 166) including longitudinal samples (n = 26). Besides a significant decrease in Fc-fucosylation after the first pregnancy (P = 0·0124), Fc-glycosylation levels remained stable during and after pregnancy and in subsequent pregnancies. Multiple logistic regression analysis identified anti-HPA-1a -fucosylation (P = 0·006) combined with galactosylation (P = 0·021) and antibody level (P = 0·038) correlated with bleeding severity, making these parameters a feasible marker in screening for severe cases of FNAIT.
authors.affiliation: Department of Experimental Immunohaematology, Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Myrthe E
authors.initials: ME
authors.lastname: Sonneveld
authors.affiliation: Finnish Red Cross Blood Service, Helsinki, Finland.
authors.forename: Suvi
authors.initials: S
authors.lastname: Natunen
authors.affiliation: Finnish Red Cross Blood Service, Helsinki, Finland.
authors.forename: Susanna
authors.initials: S
authors.lastname: Sainio
authors.affiliation: Centre for Proteomics and Metabolomics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Carolien A M
authors.initials: CA
authors.lastname: Koeleman
authors.affiliation: Centre for Proteomics and Metabolomics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Holst
authors.affiliation: Department of Experimental Immunohaematology, Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Gillian
authors.initials: G
authors.lastname: Dekkers
authors.affiliation: Department of Experimental Immunohaematology, Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Joke
authors.initials: J
authors.lastname: Koelewijn
authors.affiliation: Finnish Red Cross Blood Service, Helsinki, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Partanen
authors.affiliation: Department of Experimental Immunohaematology, Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: C Ellen
authors.initials: CE
authors.lastname: van der Schoot
authors.affiliation: Centre for Proteomics and Metabolomics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Manfred
authors.initials: M
authors.lastname: Wuhrer
authors.affiliation: Department of Experimental Immunohaematology, Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Gestur
authors.initials: G
authors.lastname: Vidarsson
mesh_terms: D000888:Antibodies, Anti-Idiotypic / Q000737:chemistry; D016824:Antigens, Human Platelet / Q000276:immunology; D001792:Blood Platelets / Q000276:immunology*; D005260:Female; D005643:Fucose / Q000737:chemistry; D005690:Galactose / Q000737:chemistry; D006031:Glycosylation; D006470:Hemorrhage / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000032:analysis*; D039661:Integrin beta3; D007518:Isoantibodies / Q000097:blood / Q000737:chemistry*; D013058:Mass Spectrometry; D019158:N-Acetylneuraminic Acid / Q000737:chemistry; D011237:Predictive Value of Tests; D011247:Pregnancy; D012720:Severity of Illness Index; D054098:Thrombocytopenia, Neonatal Alloimmune / Q000276:immunology*; D006023:Glycoproteins
chemical_list: D000888:Antibodies, Anti-Idiotypic; D016824:Antigens, Human Platelet; D005643:Fucose; D005690:Galactose; D007074:Immunoglobulin G; D039661:Integrin beta3; D007518:Isoantibodies; D019158:N-Acetylneuraminic Acid; C061248:ITGB3 protein, human; C048844:anti-IgG; C046179:glycosylated IgG; D006023:Glycoproteins
keywords: Fc-fucosylation; Fc-glycosylation; Fetal or neonatal alloimmune thrombocytopenia; alloantibodies; immunology