Functional consequences of the binding of gliadin to cultured rat mesangial cells: bridging immunoglobulin A to cells and modulation of eicosanoid synthesis and altered cytokine production.

Oral immunization with gliadin (GLI) can induce immunoglobulin A mesangial deposits (IgA nephropathy [IgAN]) in mice. A role for GLI in human IgAN has been inferred from an association with celiac disease, increased serum anti-GLI IgA in patients with IgAN, and benefit from a gluten-free diet observed in some IgAN patients. These effects might be due to the antigenic or lectinic properties of GLI. The aim of our study was to investigate whether GLI binding to glycosylated residues (ie, lectinic activity) favors binding of GLI to cultured rat mesangial cells, bridging IgA macromolecules. We also sought to determine whether GLI binding alters mesangial cell function. Gliadin binds to rat mesangial cells in the third and fourth passages, as determined by immunofluorescence. Gliadin binding is inhibited by co-incubation with 1 mol/L N-acetyl-D-glucosamine and 1 mol/L alpha-D-mannose, sugars competitive for this lectinic bond. Quantification by biotinylated GLI revealed a significant dose-dependent binding of GLI (P < 0.001) inhibited by N-acetyl-D-glucosamine (P < 0.05). Some saccharolytic enzymes, like invertase, modify the cell surface to decrease GLI binding (P < 0.02). In addition, GLI promoted the binding of purified mouse polymeric IgA to mesangial cells. The binding of GLI to mesangial cells modulates arachidonic acid metabolism by cultured mesangial cells, significantly inhibiting prostaglandin E2 production (P < 0.02), increasing synthesis of thromboxane B2 (P < 0.01) and tumor necrosis factor (P < 0.001), but not interleukin-1 beta. These responses were abrogated by co-incubation with N-acetyl-D-glucosamine and/or pretreatment with invertase. Non-immune binding of an environmental alimentary lectin, GLI, to mesangial cells in culture might favor the binding of IgA and IgAIC to mesangial cells, enhancing both IgA mesangial trapping and in situ IgA deposit formation. This could occur via GLI-specific antibodies or by virtue of the binding of nonspecific IgA on a lectinic basis, or both. Moreover, related changes in eicosanoid synthesis might stimulate mesangial cell growth and mesangial matrix production, together with mesangial cell contraction, contributing to the pathogenesis of IgAN.