Structural features of IgA molecules which contribute to IgA nephropathy

IgA nephropathy (IgAN) is characterised by the mesangial deposition of poly meric IgAl (pIgAl). pIgAl production is reduced in the mucosal immune syste m in IgAN and increased in the marrow; this switch may be secondary to a de fect in gamma delta T cell control of IgA production. However this does not explain the mechanism by which pIgAl deposits in the mesangium. There is n o direct evidence that classical immune complex deposition occurs in IgAN a nd alternative mechanisms resulting from physicochemical abnormalities of t he IgAl molecule, particular altered glycosylation, have been proposed. IgA l has a distinctive hinge region which is a site for O-glycosylation, There is reduced terminal galactose on the hinge region O-glycans of circulating IgAl in IgAN, perhaps due to a defect in B cell beta 1,3 galactosyltransfe rase. A concomitant O-glycan defect in mesangial IgAl has not yet been prov en. Altered hinge O-glycosylation may have substantial impact on the quater nary structure of the IgAl molecule influencing its capacity to interact wi th matrix proteins, IgA receptors on mesangial cells and leucocytes, and co mplement; it may therefore play a key role in the pathogenesis of mesangial deposition of IgAl and subsequent glomerular injury in IgAN.