Characteristic features of IgA nephropathy (IgAN) include IgA1-containing immune complexes (IC) in the circulation, urine, and renal mesangium. IC contain IgA1 deficient in hinge region-associated galactose (Gal) and antibodies specific for antigenic determinants present on the hinge region. The biological effects of IC are primarily related to their molecular size and composition: when added to a culture of human mesangial cells, large IC exhibit a proliferative effect while small complexes are inhibitory. These activities have been observed using IC obtained from sera of IgAN patients or generated in vitro. Specifically, various preparations of human IgA1 with modified glycan moieties formed IC in vitro when incubated with sera from IgAN patients or healthy individuals, cord blood serum, or tissue culture supernatants of EBV-immortalized peripheral blood B cells secreting IgG. Interestingly, IgG antibodies specific for the IgA1 Gal-deficient hinge region are commonly found in sera of hominoid as well as non-hominoid primates and many other vertebrate species, and suggest the evolutionary uniqueness of the human IgA1 hinge region. Because of the molecular defect in IgA1 glycosylation and its subsequent recognition by naturally-occurring antibodies, experimental approaches that diminish or prevent formation of large immunostimulatory IC should be further explored.