Down-regulation of Fcα receptors on blood cells of IgA nephropathy patients: Evidence for a negative regulatory role of serum IgA

Down-regulation of Fcα receptors on blood cells of IgA nephropathy patients: Evidence for a negative regulatory role of serum IgA. IgA nephropathy (IgAN) is associated with increased serum IgA1 and IgA1-immune complexes (IC). As Fcα receptors (FcαR) are candidate molecules to regulate IgA levels, increased receptor occupation by IgA1 prompted us to study the expression of FcαR on blood cells of IgAN patients. Surface and cytoplasmic FcαR expression were markedly decreased on monocytes, despite normal levels of transcripts. FcαR expression on patients’ neutrophils was slightly decreased, exclusively at the cell surface. However, when autologous plasma was removed from the cells FcαR was up-regulated. This observation led us to search for circulating regulatory factors. In vitro experiments revealed that FcαR was down-regulated on normal monocytes following long-term culture with control or patient purified serum IgA at high concentrations (5 mg/ml). Moreover, polymeric myeloma IgA1 induced stronger down-regulation than monomeric IgA1. These results point to a negative regulatory role of serum IgA on surface FcαR expression. This is also supported by a negative correlation between levels of FcαR on blood cells and serum IgA. On the other hand, endogenous IgA bound to IgAN cells was significantly higher than IgA bound to control cells pre-incubated with patients’ plasma, suggesting abnormalities in the receptor-ligand interaction. Patient FcαR had a higher Mr (60 to 85 kDa) than those of controls (55 to 75 kDa) and a decreased binding to a sialic acid-specific lectin on blots, indicating post-translational modifications with impaired sialylation of surface FcαR molecules that might be involved in enhanced IgA binding. Continuous FcαR occupation by IgA, associated with receptor down-regulation, might contribute to the enhancement of circulating IgA1 and IgA1-IC by impairing their binding and degradation. Finally, increased receptor occupation by IgA on monocytes was linked to mesangial proliferation and glomerular sclerosis, suggesting a role for IgA-bound cells in the pathogenesis of mesangial damage.