Deficient IgA1 immune response to nasal cholera toxin subunit B in primary IgA nephropathy

Abstract

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.

Differential Glycosylation of Polymeric and Monomeric IgA

“…There is accumulating evidence that the pathogenesis of IgAN is related to aberrant production of IgA. In this respect, in vivo studies indicated that patients with IgAN have a disturbed mucosal immune response, which was restricted to production of antibodies of the IgA1 subclass (49). Our observation that SIgA is increased in the pIgA fraction of patients with IgAN further supports a role for abnormal mucosal immunity.…”

O-Glycosylation of Serum IgA1 Antibodies against Mucosal and Systemic Antigens in IgA Nephropathy

“…This excess of serum IgA1 antibodies to mucosally encountered antigens in IgAN is intriguing, because the IgA production at mucosal sites (28) and the mucosal response to mucosal antigen exposure (27) are reduced in these patients. Overall, there is a clear disturbance of mucosal antigen handling in IgAN, resulting in inappropriately high and persistent circulating levels of polymeric IgA1 against mucosal antigens, which also carries an O-glycosylation pattern that is more suited to antibodies that are destined for mucosal secretion.…”

Pathogenetic Aspects of IgA Nephropathy

“…This connection between the mucosal immune system and the bone marrow is known as the mucosa-marrow axis, which, an addition to T-cells, may also include antigen-presenting cells [5, 6]. It has been shown that activation of the mucosal immune system can result in an increased production of polymeric IgA1 in the bone marrow [7]. As to IgAN, there is also evidence for the existence of the mucosa-marrow axis.…”