Seminar: Gestur Vidarsson, theme Cancer development and immunce defence

Immune modulation through glycan-coding of IgG

Date:
7 March 2016 11:00 hrs. - 12:00 hrs.
Location:
Figdor Lecture Theatre, 8th floor RIMLS Building, Geert Grooteplein 26-28, route 289
Title:
Immune modulation through glycan-coding of IgG
Speaker(s):

Gestur Vidarsson, Sanquin, Amsterdam

Host(s):

Annemiek van Spriel, Dept. of Tumor Immunology, RIMLS

07-03-2016 11:00:0007-03-2016 12:00:00Europe/AmsterdamImmune modulation through glycan-coding of IgG Figdor Lecture Theatre, 8th floor RIMLS Building, Geert Grooteplein 26-28, route 289Rimlsrimls@radboudumc.nl

Remarks / more information:

undefinedIgG responses against platelets or red blood cells in pregnancy can lead to Fetal or neonatal alloimmune thrombocytopenia (FNAIT) or hemolytic disease of the newborn (HDN), and are both potentially life-threatening diseases. Similar responses can be observed after incompatible transfusions. Antibody titer does not give reliable correlation with severity, making screening for pregnancies at risk impractical. We have recently found IgG Fc-glycosylation in responses towards platelet and red blood cell antigens to be skewed towards a unique type of N-linked IgG Fc-glycan profile with decreased fucosylation, increased galactosylation and sialylation. The lowered core-fucosylation increases the affinity of the pathogenic antibodies to FcγRIIIa and FcγRIIIb, and hence target destruction. Here we analyzed human platelet antigen (HPA)-1a specific IgG1 with mass spectrometry in large series of FNAIT cases (n=166) including longitudinal samples. Besides a significant decrease in Fc-fucosylation after the first pregnancy, Fc-glycosylation levels remained stable during and after pregnancy and in subsequent pregnancies. Anti-HPA-1a -fucosylation combined with galactosylation and antibody level correlated with bleeding severity, making these parameters a feasible marker in screening for severe cases of FNAIT. A model based on clinical severity, IgG levels, and glycan features, will be presented predicting who are most at risk. In addition, through unique glycan engineering of IgG we probed the affinity-changes to all IgG-Fc receptors associated with 14 natural glycan changes.  This biochemical approach corroborates the findings found in the most severe FNAIT patients and identifies a unique glycan combination to be detrimental for enhanced effector functions.

Key Publications:



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