Increased binding of polymeric lambda-IgA to cultured human mesangial cells in IgA nephropathy

IgA nephropathy (IgAN) is characterized by raised plasma lambda-IgA(1) and mesangial polymeric lambda-IgA(1) deposits. It remains uncertain whether the predominant glomerular lambda-IgA(1) deposits represent a selective uptake of polymeric IgA or a non-specific uptake due to elevated circulating lambda-IgA(1) levels in response to an unidentified antigen. In this study, we explored whether there is an increased binding of monomeric IgA(1) (mIgA(1)) or polymeric IgA(1) (pIgA(1)) from patients with IgAN to cultured human mesangial cells (HMC). Total IgA(1) in plasma from patients or healthy controls was isolated by jacalin-agarose column as jacalin-bound proteins (JBP). Monomeric IgA(1) and pIgA(1) were distinctly separated by FPLC. HMC were incubated with IgA preparations and IgA bound to HMC was determined by flow cytometry analysis using standard curves constructed by known concentrations of kappa-IgA(1) or lambda-IgA(1). In order to avoid any increased binding of IgA to HMC due to elevated kappa- or lambda-IgA concentrations in JBP samples from patients, JBP samples from patients or controls were appropriately diluted to achieve comparable levels of total IgA(1). No differences in the total mIgA(1) or pIgA(1) concentration, percentage of mIgA(1) or pIgA(1), or the kappa/lambda ratio of mIgA(1) or pIgA(1) were found between adjusted JBP samples from patients or healthy controls. We found a sharp rise in percentage of pIgA(1) among IgA(1) bound to HMC (70%), despite the fact that only 3% of the IgA(1) in the adjusted JBP samples were polymeric, suggesting that pIgA(1) had a higher affinity to HMC than mIgA(1). Furthermore, the kappa/lambda ratios of pIgA(1) bound to HMC were significantly lower than the kappa/lambda ratios of pIgA(1) in adjusted JBP only with IgAN patients but not healthy controls (P = 0.0026). Our data suggest a preferential mesangial binding of polymeric lambda-IgA(1) from patients with IgAN. These polymeric lambda-IgA immune complexes are likely to be ''pathogenic'' and are important in the pathogenesis of IgAN.