IgA nephropathy (IgAN) is characterized by mesangial cell proliferation and extracellular matrix expansion associated with immune deposits consisting of
galactose-deficient polymeric
IgA1 and C3. We have previously shown that
IgA-binding regions of streptococcal M
proteins colocalize with
IgA in mesangial immune deposits in patients with IgAN. In the present study, the
IgA-binding M4
protein from group A Streptococcus was found to bind to
galactose-deficient polymeric
IgA1 with higher affinity than to other forms of
IgA1, as shown by surface plasmon resonance and solid-phase immunoassay. The M4
protein was demonstrated to bind to mesangial cells not via the
IgA-binding region but rather via the C-terminal region, as demonstrated by flow cytometry.
IgA1 enhanced binding of M4 to mesangial cells, but not vice versa. Costimulation of human mesangial cells with M4 and
galactose-deficient polymeric
IgA1 resulted in a significant increase in
IL-6 secretion compared with each stimulant alone.
Galactose-deficient polymeric
IgA1 alone, but not M4, induced C3 secretion from the cells, and costimulation enhanced this effect. Additionally, costimulation enhanced mesangial cell proliferation compared with each stimulant alone. These results indicate that
IgA-binding M4
protein binds preferentially to
galactose-deficient polymeric
IgA1 and that these
proteins together induce excessive proinflammatory responses and proliferation of human mesangial cells. Thus, tissue deposition of streptococcal
IgA-binding M
proteins may contribute to the pathogenesis of IgAN.