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-dependent manner, with a similar M(r) as observed for ALC patient Fc alpha R (60 to 90 kDa). Fc alpha R endocytosis was induced by anti-Fc alpha R 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 receptors detected on the cell surface even after 90 min at 37 degrees C. Similarly, delayed Fc alpha R endocytosis was observed on IFN-gamma-treated U937 cells as compared with PMA-activated cells. Defective internalization of surface-bound IgA with reflux of IgA to cell surface was also observed on ALC monocytes, but not on normal cells preincubated with patients' plasma, ruling out direct effects of IgA. The inverse correlation between monocyte Fc alpha R levels and serum IgA levels associated with defective endocytosis suggest that altered Fc alpha R expression might contribute to receptor saturation and generation of increased plasma levels of IgA and IgA-immune complexes in ALC patients.
Silvain
C
C
Institut National de la Santé et de la Recherche Médicale, Unité 25, Hôpital Necker, Paris, France.
Patry
C
C
Launay
P
P
Lehuen
A
A
Monteiro
R C
RC
D000911:Antibodies, Monoclonal / Q000276:immunology; D004705:Endocytosis; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007070:Immunoglobulin A / Q000378:metabolism*; D007153:Immunologic Deficiency Syndromes / Q000209:etiology*; D007371:Interferon-gamma / Q000502:physiology*; D008104:Liver Cirrhosis, Alcoholic / Q000150:complications / Q000276:immunology*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000473:pathology; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism; D011961:Receptors, Fc / Q000235:genetics / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000911:Antibodies, Monoclonal; C045281:IgA receptor; D007070:Immunoglobulin A; D011961:Receptors, Fc; D007371:Interferon-gamma; D013755:Tetradecanoylphorbol Acetate