ALTERED EXPRESSION OF MONOCYTE IGA FC-RECEPTORS IS ASSOCIATED WITH DEFECTIVE ENDOCYTOSIS IN PATIENTS WITH ALCOHOLIC CIRRHOSIS - POTENTIAL ROLE FOR IFN-GAMMA

Expression, saturation, and endocytosis of IgA Fc receptors (Fc alpha R) were analyzed in blood phagocytic cells of patients with alcoholic liver cirrhosis (ALC). Surface Fc alpha R expression was decreased in monocytes but not in neutrophils, as evaluated by IgA binding and anti -Fc alpha R mAb. The Fc alpha R of ALC patients were saturated by IgA1 and IgA2. ALC Fc alpha R had a higher M(r) (60 to 90 kDa) than those of controls (55 to 75 kDa) with a similar 32-kDa protein core after N- glycanase treatment, suggesting the expression of Fc alpha R molecules with altered carbohydrate moieties. Treatment of U937 cells with IFN- gamma induced a decrease of surface Fc alpha R expression in a dose-de pendent manner, with a similar M(r) as observed for ALC patient Fc alp ha R (60 to 90 kDa). Fc alpha R endocytosis was induced by anti-Fc alp ha R mAb or IgA. Neutrophils internalized Fc alpha R molecules faster than did monocytes. Endocytosed Fc alpha R co-localized with cathepsin D, suggesting an endolysosomal compartment pathway. In ALC monocytes, Fc alpha R endocytosis was defective, with nearly 50 to 60% of recept ors detected on the cell surface even after 90 min at 37 degrees C. Si milarly, delayed Fc alpha R endocytosis was observed on IFN-gamma-trea ted U937 cells as compared with PMA-activated cells. Defective interna lization of surface-bound IgA with reflux of IgA to cell surface was a lso observed on ALC monocytes, but not on normal cells preincubated Wi th patients' plasma, ruling out direct effects of IgA. The inverse cor relation between monocyte Fc alpha R levels and serum IgA levels assoc iated with defective endocytosis suggest that altered Fc alpha R expre ssion might contribute to receptor saturation and generation oi increa sed plasma levels of IgA and IgA-immune complexes in ALC patients.