IgA nephropathy enigma

Abstract

IgA nephropathy (IgAN) is the leading cause of primary glomerulonephritis in the world. The disease is characterized by the presence of 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.

Secondary IgA nephropathy

“…57 In primary IgAN, the tissue origin of galactose-deficient IgA1 (Gd-IgA1) is still debated, but evidence indicates its mucosal origin: (i) Gd-IgA1 in mesangial deposits is polymeric, typical of IgA1 produced in mucosal tissues; (ii) macroscopic hematuria frequently manifests during an active respiratory tract and gastrointestinal tract infection; and (iii) polymeric IgA1 produced at mucosal sites has a higher capacity for binding to a lectin specific for N-acetylgalactosamine (the terminal sugar in galactose-deficient glycans of Gd-IgA1) than does serum IgA1 in healthy individuals. 58,59 In contrast, other studies support the concept that polymeric IgA1 is produced in the bone marrow in patients with IgAN. 58 Thus, it has been postulated that patients with IgAN have IgA1-producing cells with altered homing receptors when migrating from an inductive site to an effector site in gut mucosa and therefore mistakenly "home" to the bone marrow.…”

“…58,59 In contrast, other studies support the concept that polymeric IgA1 is produced in the bone marrow in patients with IgAN. 58 Thus, it has been postulated that patients with IgAN have IgA1-producing cells with altered homing receptors when migrating from an inductive site to an effector site in gut mucosa and therefore mistakenly "home" to the bone marrow. 5 TCD mechanisms involve 2 pathways: (i) CD40L on activated effector T cells and its interaction with CD40 on B cells; and (ii) involvement of cytokines, transforming growth factor, and interleukins.…”

Long-Term Risk of Comorbidity after IgA Vasculitis in Childhood: A Population-Based Cohort Study

“…A significant number of IgAV patients require ongoing symptomatic and/or immune modulating treatment and disease relapses have been described in up to 30% of patients [14,15]. Earlier work has shown that the typical abnormalities in IgA glycosylation in IgAV may have a hereditary base [16] leading to possibly continued production of abnormally glycosylated IgA1 and increased risk for conditions associated with abnormal IgA levels and/or function [17][18][19][20]. The two pathways combined constitute risk factors for subsequent development of comorbidity in IgAV patients.…”

Immunoproteasome in IgA Nephropathy: State-of-Art and Future Perspectives

“…Aberrantly glycosylated IgA1 might be recognized as an autoantigen, and thus the immune response against it may lead to the production of anti-IgA1-antibodies. However, of interest, more recent studies suggest that some pathogens such as Epstein-Barr virus and Streptococcus bacteria possess GalNAc-containing structures on their surfaces, which might subsequently cross-react with glycans on IgA1 resulting in the formation of pathological immune complexes 29 - 31 . This 'molecular mimicry' might explain the association of macroscopic hematuria with upper respiratory tract infections 23 .…”