IgA nephropathy: a novel pathway in immunopathogenesis dependent on the timing of Epstein-Barr virus infection

IgA nephropathy (IgAN) is an autoimmune disease in which polymeric IgA1, with joining (J) chain and altered glycosylation of the hinge region (HR), acts as an autoantigen recognized by naturally occurring IgG antibodies, resulting in generation of nephritogenic immune complexes (IC) that deposit in the kidney mesangium. By these criteria, IgA in IC and mesangial deposits displays properties identical to those of IgA produced by plasma cells infected by Epstein-Barr virus (EBV). Although ~95% of adults worldwide are EBV infected, there are important differences in the timing of infection in countries and areas with marked dissimilarities in socio-economic conditions. Epidemiological data convincingly documented that early EBV infection in children who live in developing countries, or in economically disadvantaged areas, display a significantly reduced frequency of IgAN compared to individuals from economically developed countries in which IgAN has been recognized as the leading cause of glomerulonephritis. Because physiological maturation of the IgA system is normally delayed until adolescence, in young children EBV infects B cells of Ig isotypes other than IgA, as these are relatively sparse. This early infection induces EBV-specific immune responses that prevent later infection of IgA-producing cells at older ages when these cells are more plentiful.