approximately 1:1 in Asia.16 The nephrotic syndrome is uncommon at presentation, except in patients with the pathological features of minimal-change disease on kidney biopsy. Patho genesis IgA nephropathy appears to be a systemic disease in which the kidneys are damaged as innocent bystanders, because IgA nephropathy frequently recurs after transplantation. Conversely, IgA glomerular deposits in a kidney from a donor with subclinical IgA nephropathy were reported to clear within weeks after engraftment in a patient with a different kidney disease.17 Data from clinical and basic research have led to a multihit hypothesis about the pathogenesis of IgA nephropathy (Fig. S2 in the Supplementary Appendix).18 Of primary importance is the glycosylation pattern of IgA1. In IgA nephropathy, an increased fraction of circulatory IgA1 has a galactose deficiency in some carbohydrate side chains (O-glycans) that are attached to the hingeregion segment of the heavy chain (Fig. 2).9 The O-glycosylated sites are not randomly distributed.19,20 This pattern of glycosylation mostly affects polymeric IgA1 produced in mucosal tissues, but galactose-deficient polymeric IgA1 is a minor molecular form in the circulation.21 Synthesis of poorly galactosylated IgA1 apparently results from an imbalance in the activities of the relevant enzymes in IgA1-secreting cells in patients with IgA nephropathy.18 Homing of these cells between the mucosal and systemic compartments may be altered, allowing the mucosal cells to reach systemic sites and secrete poorly galactosylated, mucosal-type IgA1 into the circulation.21,22 Synthesis by IgA1-secreting cells of galactose-deficient IgA1 directed against mucosal pathogens23 may be influenced by the innate immune system through toll-like receptors.24 Although microbial or foodderived antigens are occasionally deposited in the mesangium, there is no evidence that these environmental antigens are directly involved in the pathogenesis of IgA nephropathy. As a consequence of the galactose deficiency, N-acetylgalactosamine in truncated IgA1 hingeregion glycans is exposed. Recognition of this IgA1 hinge-region neoepitope by naturally occurring IgG or IgA1 antibodies leads to the formation of immune complexes in the circulation or perhaps in situ after glomerular deposition of galactose-deficient IgA1. On the basis of autoantibody binding to autoantigen, IgA nephropathy is an autoimmune disease.25 Virtually all circulating galactose-deficient IgA1 is found within immune complexes bound to a glycan-specific antibody that probably blocks access to the asialoglycoprotein receptor on hepatocytes. This galactose-deficient IgA1 thereby eludes the normal IgA1 catabolic pathway in the liver to reach the glomerular capillary network with large fenestrae overlying the mesangium. Some complexes have IgA1 as the exclusive isotype of antiglycan antibodies,20 perhaps explaining why IgA can be the sole immunoglobulin in the mesangium.3 Glycan-specific IgG antibodies have an unusual structural feature that increases their affinity for binding to galactose-deficient IgA1 O-glycans.25 The third amino acid in the complementarity-determining region 3 of its VH (variable region of the heavy chain) antigen–binding portion is frequently serine rather than alanine. This alteration arises from a somatic mutation during an active immune response. The origin of anti-glycan antibodies is not fully defined. Some viruses and bacteria express N-acetylgalactosamine on their cell surfaces; an infection with such microbes may facilitate synthesis of anti-glycan antibodies that cross-react with galactose-deficient IgA1. The formation of immune complexes is critical for the nephritogenicity of galactose-deficient IgA1. The addition of uncomplexed galactosedeficient IgA1 to the culture medium for human mesangial cells does not stimulate them to proliferate or become metabolically active.20 In contrast, galactose-deficient IgA1–containing immune complexes isolated from the blood of patients with IgA nephropathy induce such activity. The biologic properties of IgA1-containing immune complexes may be modulated by various components, such medical progress n engl j med 368;25 nejm.org june 20, 2013 2405 COLOR FIGURE AUTHOR PLEASE NOTE: Figure has been redrawn and type has been reset Please check carefully Draft 5 06/04/12 2 SBL Author Wyatt Fig # Title ME DE Artist Issue date Figure 2. Structure of Human IgA1. IgA exists in several forms in the circulation: monomers, dimers, trimers, larger polymers, and secretory IgA. The IgA1 dimer depicted in Panel A is composed of two monomers linked by a joining chain. Each heavy chain has two N-linked (attached to a nitrogen molecule) glycan (carbohydrate) side chains and a hinge region between the first and second constant-region domains (Cα1 and Cα2, respectively). This hinge region is longer in IgA1 than in IgA2, and the longer IgA1 segment is rich in proline, threonine, and serine amino acid residues. Within the IgA1 hinge region, three to six glycans are attached to an oxygen molecule of a serine or threonine residue (O-linked). The dimer depicted has five O-linked glycans at each of the four hinge regions. The numbered amino acids indicate the six most common sites of attachment of O-glycans. The composition and number of the O-glycans differ