Characteristics of polymeric lambda-IgA binding to leukocytes in IgA nephropathy.
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. Fc(alpha) receptor 1 (Fc(alpha)R1) 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. Fc(alpha)R1 expression on leukocytes was increased, independently of plasma IgA levels. Fc(alpha)R1 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 Fc(alpha)R1 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 Fc(alpha)R1-blocking antibody suggested binding mechanisms other than Fc(alpha)R1 for pIgA uptake by leukocytes. This study also suggested the migration and/or sequestration of "activated" leukocytes with predominant lambda-IgA in the mononuclear phagocytic system or inflammatory tissues, after the initial binding of lambda-pIgA. These immunologic abnormalities might contribute to the glomerulointerstitial injury in IgAN, in the presence of leukocytic infiltration.
Lai
Kar Neng
KN
Division of Nephrology, Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong. knlai@hkucc.hku.hk
Chan
Loretta Y Y
LY
Tang
Sydney C W
SC
Tsang
Anita W L
AW
Guo
Hong
H
Tse
Kai Chung
KC
Yip
Terrance
T
Leung
Joseph C K
JC
D000328:Adult; D005260:Female; D005922:Glomerulonephritis, IGA / Q000276:immunology*; D018922:HL-60 Cells; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood* / Q000276:immunology / Q000494:pharmacology; D007147:Immunoglobulin Light Chains / Q000276:immunology / Q000378:metabolism; D007142:Immunoglobulin gamma-Chains / Q000276:immunology / Q000378:metabolism; D007145:Immunoglobulin kappa-Chains / Q000276:immunology / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011485:Protein Binding / Q000276:immunology; D011961:Receptors, Fc / Q000378:metabolism; D020298:U937 Cells
C045281:IgA receptor; D007070:Immunoglobulin A; D007147:Immunoglobulin Light Chains; D007142:Immunoglobulin gamma-Chains; D007145:Immunoglobulin kappa-Chains; D011961:Receptors, Fc; C034639:polymeric IgA