The importance of IgG N-glycosylation in Health, Disease, and Neonatal hemochromatosis
Kujtim Thaçi, Robert M. Anthony
Abstract
Neonatal hemochromatosis (NH) is a unique disease with an unknown etiology, characterized by neonatal liver failure (NLF) and associated with iron deposition in the fetal liver and extrahepatic organs, except the organs in the reticuloendothelial system . The pathologic mechanism of an alloimmune attack of pathogenic maternal IgGs on the fetal liver occurs through the generation of membrane attack complex (MAC), demonstrating the interplay between maternal adaptive immunity and fetal innate immune responses . Pathogenic alloimmune IgGs can induce various inflammatory responses , ranging from hyperacute fetal liver inflammation to chronic liver injury. However, the precise mechanism by which IgG triggers distinct inflammatory responses following its binding to fetal liver antigens remains to be elucidated. Remarkably, the IgG subclass and glycosylation machinery of IgG are essential for the disparities in IgG-associated inflammatory responses. Hence, modulation of IgG glycosylation can increase or decrease IgG activity, which may severely affect human health. It is well recognized that disease-associated changes in the IgG glycome composition may function as diagnostic biomarkers or contribute to disease pathogenesis. Specific IgG glycans may elicit complex immune responses during the antenatal and postnatal periods and may facilitate future endeavors in developing novel diagnostic and therapeutic interventions for NH. Hence, analyzing glycoprofiles of class/subclass IgG in maternal and fetal blood could potentially distinguish pathogenic IgGs with pro-inflammatory properties from normal IgGs with anti-inflammatory features. These insights may unveil new strategies for developing novel diagnostic and therapeutic approaches for early detection and pre-and postnatal management of NH.