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.

Current perspectives on fetal and neonatal alloimmune thrombocytopenia – increasing clinical concerns and new treatment opportunities

“…Two research groups recently described decreased fucosylation of anti-HPA-1a antibodies causing FNAIT, and that fucosylation may be useful to predict disease severity 104,105…”

Multi-level glyco-engineering techniques to generate IgG with defined Fc-glycans

“…Although IgG produced in most human immune responses are highly fucosylated, we recently found that allogeneic immune responses against red blood cells and platelets can be skewed towards non-fucosylated IgG, the level of which correlates with disease outcome14152627. Similarly, immune responses with low-core fucosylation can also be found directed against HIV – particularly in elite controllers28.…”

Antigen specificity determines anti‐red blood cell IgG‐Fc alloantibody glycosylation and thereby severity of haemolytic disease of the fetus and newborn

“…We recently found that IgG1‐responses against platelet antigens and RhD on RBCs can be particularly skewed towards IgG with low core‐fucosylation (Wuhrer et al , ; Kapur et al , ; Sonneveld et al , ), a feature that has only previously been described for anti‐human immunodeficiency virus (HIV) antibodies, but never for any other immune response (Ackerman et al , ). This is reflected in total serum IgG‐Fc having ~94% fucose on the glycopeptide level (Selman et al , ; Fokkink et al , ; Vestrheim et al , ).…”