Skewing towards Decreased Fc-Fucosylation of Platelet-Alloantibodies in Pregnancy

Abstract 3331

IgG-antibody responses during pregnancy against human platelet antigens (HPA) of the fetus can result in fetal or neonatal alloimmune thrombocytopenia (FNAIT) with various clinical scenarios, as patients can be asymptomatic, suffer from petechiae, major organ bleedings, or even intracranial hemorrhages. Various biological activities of IgG including antibody-dependent cellular cytotoxicity (ADCC) can be modulated by the structural features of the N-glycans in the Fc-part. The extent of sialylation, galactosylation, and fucosylation have been described to affect the binding of IgG to Fc-receptors (FcγR). Fucosylation is particularly important, as a lack of IgG-Fc-fucose has >50 times greater affinity and associated activity through FcγRIIIa, as compared to fucosylated IgG, which normally comprises >90% of normal serum IgG. By extensive analysis of the Fc-glycosylation using mass spectrometry, we found slightly increased levels of galactosylation (p<0.0001) but markedly decreased levels of core-fucosylation (p<0.0001) of the pathogenic IgG (anti-HPA1a) formed in FNAIT compared to the total IgG1 in the same patients. This unique response led us to question whether lack of fucose was specific for antibodies formed against platelets or due to the immune response during pregnancy. Analyses of anti-HLA antibodies formed after platelet transfusion (refractory thrombocytopenia) unveiled a similar increase in anti-platelet IgG galactosylation (p: 0.0002) as seen in FNAIT, but without any change in IgG fucosylation. Also when analyzing autoantibodies to platelet-glycoprotein IIb/IIIa in auto-immune thrombocytopenia (ITP), we could not detect any changes in IgG-glycosylation including fucosylation. We therefore conclude that the atypical fucosylation seen in the FNAIT-anti-platelet response is related to the immune milieu defined by pregnancy. This infuences IgG effector functions, including ADCC activity and may have a profound effect on disease severity and prognosis of alloimmune-mediated reactions against fetal cells and tissues.