IGA INDUCED ACTIVATION OF HUMAN MESANGIAL CELLS - INDEPENDENT OF FC-ALPHA-R1 (CD-89)

Background. IgA nephropathy (IgAN) is characterized by deposition of p olymers of IgA(1) in the mesangium, accumulation of mesangial matrix a nd mesangial cell proliferation. Activation of the mesangial cell by I gA, via an IgA receptor, may be an initiating event in the pathology o f IgAN. Methods. We examined the ability of radiolabeled, normal serum IgA(1) to bind human mesangial cells (HMC). Activation of HMC by mono meric (mIgA(1))and heat aggregated IgA(1) (AIgA(1)) was compared by No rthern analysis of c-jun expression. The expression of Fc alpha R1 (CD 89) mRNA on our cultured mesangial cells was also assessed by Northern analysis, reverse transcription-polymerase chain reaction (RT-PCR) an d flow cytometry. Results. I-125-mIgA(1) and I-125-AIgA(1) bound to HM C in a dose-dependent, saturable manner with similar affinities. There were 1.2 x 10(6) binding sites per cell, with an affinity constant of 2.3 x 10(6) M-1. AIgA(1) induced c-jun expression in a time and dose- dependent manner (2.4-fold above baseline after 60 min exposure to AIg A(1) 200 mu g/ml) while mIgA(1) had no effect on c-jun expression. No message for CD 89 was detectable in quiescent or AIgA(1) stimulated HM C by Northern analysis or RT-PCR using several primer sequences based on the sequence of U937 Fc alpha R cDNA. Flow cytometry on the mesangi al cells, using My 43, a monoclonal antibody to Fc alpha R1 confirmed that CD 89 was not present on the cell. Conclusion. These results demo nstrate that HMC bind mIgA(1) and AIgA(1) with similar affinity. Howev er, activation of HMC requires an aggregated form of IgA(1). These pro cesses are independent of Fc alpha R1, suggesting the presence of a ne w IgA receptor on mesangial cells.