IgA nephropathy (IgAN) is characterized by mesangial IgA deposition, and up-regulation of the IgA system is frequently described. This study investigated in vitro immunoglobulin isotype production by peripheral blood mononuclear cells from patients with IgAN and controls, without mitogenic stimulation and under the influence of cell cycle inhibitors and cyclosporin A (CyA). In controls, only IgM production was suppressed by cell cycle inhibitors, and no isotype was affected by CyA. This suppressible IgM production may represent antigen-independent 'natural antibody'. In IgAN, IgM, IgA and IgG were all suppressed by cell cycle inhibitors, and CyA suppressed IgA production. This state of altered immune activation in IgAN demonstrates T-cell-independent IgA production, suggesting that it is IgA 'natural antibody'. In conclusion, we suggest that mesangial IgA deposition may not be antigen dependent but due to some non-immune characteristic of the IgA molecule.