Twelve IgA nephropathy (IgAN) patients and 18 controls were immunized with novel protein antigens, cholera toxin subunit B (CTB) via the nasal route and keyhole limpet hemocyanin (KLH) subcutaneously. Antibody secreting cells and antibody response in body fluids were determined by ELISPOT assay and ELISA, respectively. Analysis of variance showed, in contrast to controls (P < 0.001), no CTB-specific IgA response in the nasal washes of patients with IgAN. Significantly lower numbers of CTB-specific antibody-secreting cells in peripheral blood (P < 0.001) and CTB-specific antibodies in plasma (P < 0.005) were found in IgAN, both restricted to the IgA1 subclass. The proportions of CTB-specific IgA1-secreting cells in bone marrow aspirates correlated significantly with the corresponding ratios in plasma, with significantly lower values (P < 0.005) in IgAN as compared to controls. These results support the existence of a "mucosa-bone marrow axis" in humans, but no dysregulation of this axis was found in IgAN. The deficient mucosal IgA immune response to CTB observed in this study after primary mucosal immunization indicates that patients with IgAN have a defective immune response when challenged intranasally. These patients may depend on more frequent and/or prolonged antigen encounter at mucosal sites before efficient mucosal immunity is established. Repeated seeding of antigen-specific cells to secondary lympoid organs could result secondarily in the relative hyperresponsiveness found in IgAN upon reactivation by parenteral immunization.

SummarySecretory immunoglobulin A (SIgA), although generated at mucosal surfaces, is also found in low concentrations in the circulation. Recently, SIgA was demonstrated in mesangial deposits of patients with immunoglobulin A nephropathy (IgAN), suggesting a role in the pathogenesis. This finding is in line with the belief that high molecular weight (HMW) immunoglobulin A (IgA) is deposited in the kidney. However, there is little information on the size distribution of antigen-specific IgA in circulation upon mucosal challenge. In this study we measured antigen-specific IgA, including SIgA, in serum following challenge of IgAN patients and controls via intranasal vaccination with a neoantigen, cholera toxin subunit B (CTB). We sizefractionated serum and nasal washes to study the size distribution of total IgA, SIgA and CTB-specific IgA. Finally, we compared the size distribution of antigen-specific IgA after mucosal immunization with the distribution upon systemic immunization. A significant induction of antigen-specific SIgA was detectable in serum of both patients with IgAN and controls after mucosal immunization with CTB. Independent of the route of immunization, in both groups the antigen-specific IgA response was predominantly in the polymeric IgA fractions. This is in contrast to total IgA levels in serum that are predominantly monomeric. We conclude that mucosal challenge results in antigenspecific SIgA in the circulation, and that the antigen-specific IgA response in both IgAN patients and in controls is of predominantly HMW in nature. No differences between IgAN patients and controls were detected, suggesting that the size distribution of antigen-specific IgA in the circulation is not disturbed specifically in IgAN patients.