Characteristics of polymeric λ-IgA binding to leukocytes in IgA nephropathy

Abstract

IgA nephropathy (IgAN) is characterized by predominant mesangial polymeric IgA1 (pIgA1) deposits, with increased plasma IgA1 levels. Plasma IgA levels are determined by the rate of IgA production, uptake by leukocytes, and removal by hepatocytes. Fcα receptor 1 (FcαR1) is a candidate molecule for the regulation of IgA levels, but reports of its expression in leukocytes in IgAN are conflicting. Increased binding of endogenous IgA to circulating granulocytes and monocytes in IgAN was demonstrated in this study. FcαR1 expression on leukocytes was increased, independently of plasma IgA levels. FcαR1 was not saturated in leukocytes, because of internalization of IgA after uptake. Further binding of exogenous IgA isolated from individual subjects was observed with leukocytes from the same subjects. Compared with cells from control subjects, granulocytes but not monocytes from patients with IgAN exhibited a greater binding capacity for exogenous IgA, predominantly pIgA. To circumvent the possibility that endogenous IgA might alter FcαR1 expression, granulocytes or monocytes derived from the HL-60 or U937 cell lines were used to explore the nature of IgA binding. A higher affinity for pIgA was demonstrated. Inhibition studies using unlabeled IgA, other serum proteins, or a specific FcαR1-blocking antibody suggested binding mechanisms other than FcαR1 for pIgA uptake by leukocytes. This study also suggested the migration and/or sequestration of "activated" leukocytes with predominant λ-IgA in the mononuclear phagocytic system or inflammatory tissues, after the initial binding of A-pIgA. These immunologic abnormalities might contribute to the glomerulointerstitial injury in IgAN, in the presence of leukocytic infiltration.