Patterns of N-Glycosylation of IgG Fc Regions: Role in Regulation of Immune Responses against Leishmania infantum and Application in New Therapeutical Strategies for Kala Azar

Abstract

Visceral leishmaniasis (VL) may be fatal if not treated and, although hypergammaglobulinemia is a hallmark of VL, the actual contribution of antibodies in progression of disease remains unknown. Effector and regulatory functions of antibodies rely on their interactions with type I and II Fc receptors and these interactions are tuned by the patterns of antibody Fc N-glycosylation. We recently showed that, in comparison to healthy individuals, the overall IgG Fc N-glycan profiles are profoundly altered in VLpatients and, together with serum regulators of immune responses (cytokines and C reactiveprotein), we demonstrated the ability of IgG Fc glyco features to predict disease severity in VL patients. Importantly, we showed that Fc N-glycosylation profiles change after treatment of VL. We will begin to uncover the potential role of IgG Fc glyco features in the pathogenesis of VL and the mechanisms that participate in those alterations with the following studies: (i) we will evaluate global gene expression profiles of B cells isolated from patients stratified into categories of disease severity, and associate them with titers and profiles of Fc N-glycosylationof IgG specific for leishmania antigens~ (ii) based on the knowledge acquired in aim (i), we will test the viability and efficacy of strategies of therapy in an experimental hamster model of progressive VL. We will evaluate the effectsof treatment of hamsters chronically infected with L. infantum with intravenous immunoglobulin preparations (IVIG) enriched with sialic acid, and in vivo enzymatic deglycosylation of IgG Fc. Thus, we expect to obtain insights into the mechanisms by which IgG Fc glycofeatures influence progression and severity of VL and to innovate the treatment of the disease. (AU)