The pathogenic role of IgA1 O-linked glycosylation in the pathogenesis of IgA nephropathy.
Numerous abnormalities of the IgA immune system have been reported in IgAN but the most consistent finding remains aberrant IgA1 O-linked glycosylation of the IgA1 hinge region. The defect comprises reduced galactosylation of O-linked N-acetylgalactosamine residues with or without changes in the terminal sialylation of the O-linked sugars. Aberrant O-galactosylation has been found in serum IgA1, in IgA1 isolated from tonsillar lymphocytes, and in IgA1 eluted from mesangial deposits. There is evidence that changes in IgA1 O-galactosylation lead to IgA immune complex formation and mesangial IgA deposition. Mesangial cells exposed to these IgA immune complexes proliferate and adopt a pro-inflammatory phenotype; they secrete cytokines, chemokines, growth factors and extracellular matrix components promoting glomerular inflammation and glomerulosclerosis. Recent evidence suggests that the control of IgA1 O-glycosylation is linked to class switching from IgD to IgA1 synthesis and that the pattern of IgA1 O-glycosylation may be programmed at the time of initial antigen encounter. IgA1 glycosylation varies between systemic and mucosal sites and the association of aberrant IgA1 galactosylation with low affinity, polymeric IgA1 antibodies against mucosal antigens suggests undergalactosylated IgA1 may in fact be a mucosal glycoform of IgA1. Although suited to the mucosal compartment, when these IgA1 glycoforms enter the systemic circulation in appreciable quantities they deposit in the mesangium and trigger glomerular inflammation. This review will discuss the evidence for the role of IgA1 O-glycosylation in the pathogenesis of IgAN and propose an explanation for the presence of aberrantly O-glycosylated IgA1 in the circulation of patients with IgAN.
Barratt
Jonathan
J
The John Walls Renal Unit, Leicester General Hospital, and Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK. jb81@le.ac.uk
Smith
Alice C
AC
Feehally
John
J
D000595:Amino Acid Sequence; D000936:Antigen-Antibody Complex / Q000378:metabolism*; D003167:Complement Activation / Q000502:physiology; D005922:Glomerulonephritis, IGA / Q000503:physiopathology*; D006031:Glycosylation; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D050527:Mesangial Cells / Q000378:metabolism*
D000936:Antigen-Antibody Complex; D007070:Immunoglobulin A