DOWN-REGULATION OF FC-ALPHA 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 IgA 1-immune complexes (IC). As Fc alpha receptors (Fc alpha R) are candid ate molecules to regulate IgA levels, increased receptor occupation by IgA1 prompted us to study the expression of Fc alpha R on blood cells of IgAN patients. Surface and cytoplasmic Fc alpha R expression were markedly decreased on monocytes, despite normal levels of transcripts. Fc alpha R expression on patients' neutrophils was slightly decreased , exclusively at the cell surface. However, when autologous plasma was removed from the cells Fc alpha R was up-regulated. This observation led us to search for circulating regulatory factors. In vitro experime nts revealed that Fc alpha R was down-regulated on normal monocytes fo llowing long-term culture with control or patient purified serum IgA a t high concentrations (5 mg/ml). Moreover, polymeric myeloma IgA1 indu ced stronger down-regulation than monomeric IgA1. These results point to a negative regulatory role of serum IgA on surface Fc alpha R expre ssion. This is also supported by a negative correlation between levels of Fc alpha R on blood cells and serum IgA. On the other hand, endoge nous IgA bound to IgAN cells was significantly higher than IgA bound t o control cells pre-incubated with patients' plasma, suggesting abnorm alities in the receptor-ligand interaction. Patient Fc alpha R had a h igher Mr (60 to 85 kDa) than those of controls (55 to 75 kDa) and a de creased binding to a sialic acid-specific lectin on bl(,ts, indicating post-translational modifications with impaired sialylation of surface Fc alpha R molecules that might be involved in enhanced IgA binding. Continuous Fc alpha R occupation by IgA, associated with receptor down -regulation, might contribute to the enhancement of circulating IgA1 a nd IgA1-IC by impairing their binding and degradation. Finally, increa sed receptor occupation by IgA on monocytes was linked to mesangial pr oliferation and glomerular sclerosis, suggesting a role for IgA-bound cells in the pathogenesis of mesangial damage.