Multifactorial aspects of antibody-mediated blood cell destruction

The research described in this thesis focuses on diseases of antibody-mediated blood cell destruction via FcγRs on phagocytes, in particular regarding platelets in fetal or neonatal alloimmune thrombocytopenia (FNAIT) and red blood cells (RBC) in hemolytic disease of the fetus and newborn (HDFN). Diagnostically, for HDFN laboratory tests are in place in order to predict risk for severe fetal RBC destruction and thereby initiate appropriate treatments. This test is sensitive, but has relatively low specificity. For FNAIT, no diagnostic laboratory test is currently available to predict severe fetal platelet destruction. For FNAIT it has been suggested that the decrease in platelet numbers is determined by the antibody titer, but this correlation does not appear to be that strict. This indicates that other factors, besides antibody-titer are involved and as such C-reactive protein (CRP) and anti-platelet IgG-fucosylation are identified. CRP, which bound to platelets after platelet-oxidation, enhanced antibody-mediated platelet destruction both in vitro and in vivo and was found to be elevated in immune thrombocytopenic patients. CRP levels dropped after IVIg-treatment, accompanied by normalization of platelet counts and decreased clinical bleeding severity. A low Fc-fucosylation was observed for anti- platelet antibodies in FNAIT (and not for total IgG), which resulted in increased binding affinity to FcγRIIIa/b, increased platelet phagocytosis, correlated with neonatal platelet counts and also correlated with an adverse clinical scenario. The clinical data need to be validated in larger patient cohorts, but monitoring of Fc-fucosylation levels in FNAIT has promising diagnostic potential. A lowered Fc-fucosylation was also found for anti-RBC (anti-D) antibodies in pregnancy, which correlated with increased hemolysis in a small pilot-study, however more research is needed. The low anti-D Fc-fucose also occurred in male hyperimmunized anti-D donors (although to a lesser extent than pregnant women), indicating that the regulation of a lowered fucosylation is not strictly dependent upon a pregnancy setting. The implications of antibody-fucosylation in anti-D immunoprophylaxis, derived from hyperimmunized donors, are also discussed.