IgA nephropathy: "State of the art": a report from the 15th International Symposium on IgA Nephropathy celebrating the 50th anniversary of its first description.

On September 27-29, 2018, the International Symposium on IgA Nephropathy, organized by the International IgA Nephropathy Network, was held in Buenos Aires, Argentina, celebrating the 50th anniversary of the first description of IgA nephropathy by Berger and Hinglais in 1968. The meeting was attended by over 200 scientists and clinicians from 26 different countries across the globe. We report some key insights drawn from the meeting-including the molecular pathogenesis, genetics, pathology, and therapeutics of IgA nephropathy.

From Schönlein-Henoch purpura to IgA-vasculitis: pathogenetic aspects of the disease.

Investigation's history and nomenclature's evolution of the IgA-vasculitis are presented in the article. Pathogenesis of the renal and skin damages is discussed in details, particularly abnormalities of the IgA-immunity and systemic endotoxemia. Relevant world's literature is cited.

IgA nephropathy enigma.

IgA nephropathy (IgAN) is the leading cause of primary glomerulonephritis in the world. The disease is characterized by the presence of IgA-containing immune complexes in the circulation and in mesangial deposits with ensuing glomerular injury. Although in humans there are two IgA subclasses, only IgA1 molecules are involved. The exclusivity of participation of IgA1 in IgAN prompted extensive structural and immunological studies of the unique hinge region (HR) of IgA1, which is absent in otherwise highly homologous IgA2. HR of IgA1 with altered O-glycans serves as an antigen recognized by autoantibodies specific for aberrant HR glycans leading to the generation of nephritogenic immune complexes. However, there are several unresolved questions concerning the phylogenetic origin of human IgA1 HR, the structural basis of its antigenicity, the origin of antibodies specific for HR with altered glycan moieties, the regulatory defects in IgA1 glycosylation pathways, and the potential approaches applicable to the disease-specific interventions in the formation of nephritogenic immune complexes. This review focuses on the gaps in our knowledge of molecular and cellular events that are involved in the immunopathogenesis of IgAN.

Immunoglobulin A Glycosylation and Its Role in Disease.

Human IgA is comprised of two subclasses, IgA1 and IgA2. Monomeric IgA (mIgA), polymeric IgA (pIgA), and secretory IgA (SIgA) are the main molecular forms of IgA. The production of IgA rivals all other immunoglobulin isotypes. The large quantities of IgA reflect the fundamental roles it plays in immune defense, protecting vulnerable mucosal surfaces against invading pathogens. SIgA dominates mucosal surfaces, whereas IgA in circulation is predominately monomeric. All forms of IgA are glycosylated, and the glycans significantly influence its various roles, including antigen binding and the antibody effector functions, mediated by the Fab and Fc portions, respectively. In contrast to its protective role, the aberrant glycosylation of IgA1 has been implicated in the pathogenesis of autoimmune diseases, such as IgA nephropathy (IgAN) and IgA vasculitis with nephritis (IgAVN). Furthermore, detailed characterization of IgA glycosylation, including its diverse range of heterogeneity, is of emerging interest. We provide an overview of the glycosylation observed for each subclass and molecular form of IgA as well as the range of heterogeneity for each site of glycosylation. In many ways, the role of IgA glycosylation is in its early stages of being elucidated. This chapter provides an overview of the current knowledge and research directions.

Role of IgA receptors in the pathogenesis of IgA nephropathy.

Immunoglobulin A nephropathy (IgAN) or Berger's disease is the most common form of primary glomerulonephritis in the world and one of the first causes of end-stage renal failure. IgAN is characterized by the accumulation of immune complexes containing polymeric IgA1 in mesangial areas. The pathogenesis of this disease involves the deposition of polymeric and hypogalactosylated IgA1 (Gd-IgA1) in the mesangium. Quantitative and structural changes of Gd-IgA1 play a key role in the development of the disease due to functional abnormalities of two IgA receptors: the FcαRI (CD89) expressed by blood myeloid cells and the transferrin receptor (CD71) on mesangial cells. Abnormal Gd-IgA1 induces release of soluble CD89, which participates in the formation of circulating IgA1 complexes. These complexes are trapped by CD71 that is overexpressed on mesangial cells in IgAN patients together with the crosslinking enzyme transglutaminase 2 allowing pathogenic IgA complex formation in situ and mesangial cell activation. A humanized mouse model expressing IgA1 and CD89 develops IgAN in a similar manner as patients. In this model, a food antigen, the gliadin, was shown to be crucial for circulating IgA1 complex formation and deposition, which could be prevented by a gluten-free diet. Identification of these new partners opens new therapeutic prospects for IgAN treatment.