Nigrovic R21: IgG glycosylation abnormalities in pediatric immunodeficiency Project Summary Recurrent infections are a common problem in pediatric practice. Some of these patients will have defined monogenic immunodeficiencies. However, more than half will have either no defined cause or will exhibit abnormalities in serum immunoglobulins that bear an inconsistent association with clinical disease, such as mild hypogammaglobulinemia, IgG subclass deficiency, or IgA deficiency. Frequently, such patients receive empiric antibiotics or occasionally IVIG, without any mechanistic understanding of why they are symptomatic while others with similar immunoglobulin profiles remain healthy. The current submission explores a novel hypothesis to account for this discrepancy. We propose that abnormalities in IgG glycosylation represent an unrecognized contributor to humoral immunodeficiency. IgG is a glycoprotein, bearing an asparagine (N)-linked biantennary glycan on each heavy chain. Unlike most glycans, these oligosaccharides are internal to the structure of the Fc region, defining its spatial conformation and thereby its interaction with Fc receptors and complement. Intriguingly, IgG Fc glycans exhibit substantial variability, and young children appear to express a higher proportion of pro-inflammatory IgG Fc glycoforms. We speculate that this skewed representation of Fc glycoforms is physiologically and pathophysiologically important. In particular, we suggest that enhanced IgG effector potency may help children to compensate for immaturity in the humoral immune repertoire. If this is the case, then altered IgG glycosylation may help to explain some of the disconnect between quantitative immunoglobulin levels and clinical immunodeficiency in children. Here we outline a collaborative effort between investigators with expertise in immunology and glycobiology to define the normal pediatric IgG glycoform repertoire and to explore the IgG glycobiology of immunodeficiency in childhood, concentrating on common humoral immunodeficiencies. Samples will be obtained from existing biorepositories of normal controls and of patients with phenotyped immunodeficiencies, as well as from an ongoing immunodeficiency registry. IgG Fc glycans will be identified using a state-of-the-art, high-resolution, semi-automated method pioneered by one of the collaborators. Binding to Fc receptors and complement will be examined and correlated with the IgG glycoform repertoire and clinical status of the subjects. Circulating lymphocytes and patient DNA will be archived for follow-up studies. Together, these investigations will define normal patterns of IgG glycosylation in children and investigate the glycoform repertoire associated with pediatric immunodeficiency. Our findings will illuminate an novel facet of childhood immunological function, with relevance that could extend to other immunological processes in children, ranging from defense against infection to antibody-mediated autoimmunity. PUBLIC HEALTH RELEVANCE: Nigrovic R21: IgG glycosylation abnormalities in pediatric immunodeficiency Project Narrative Recurrent infections are a common problem in childhood, but frequently the immune basis for these infections is not understood even after a thorough evaluation in the immunodeficiency clinic. Interestingly, children exhibit an unusual pattern of sugars (glycans) attached to their antibodies, which can affect their function. We will evaluate the novel hypothesis that changes in glycans explain why some children with normal or mildly abnormal levels of circulating antibodies nevertheless behave as though they had weakened immune defenses.