The combined role of galactose-deficient IgA1 and streptococcal IgA-binding M Protein in inducing IL-6 and C3 secretion from human mesangial cells: implications for IgA nephropathy.
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.
Department of Pediatrics, Clinical Sciences Lund, Lund University, 22185 Lund, Sweden;
Roland
R
Schmitt
Department of Pediatrics, Clinical Sciences Lund, Lund University, 22185 Lund, Sweden;
Anne-Lie
AL
Ståhl
Department of Infection Medicine, Clinical Sciences Lund, Lund University, 22185 Lund, Sweden;
Anders I
AI
Olin
Department of Pediatrics, Clinical Sciences Lund, Lund University, 22185 Lund, Sweden;
Ann-Charlotte
AC
Kristoffersson
Department of Pediatrics, Clinical Sciences Lund, Lund University, 22185 Lund, Sweden;
Johan
J
Rebetz
Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294; and.
Jan
J
Novak
Division of Medical Microbiology, Department of Laboratory Medicine, Lund University, 22362 Lund, Sweden.
Gunnar
G
Lindahl
Department of Pediatrics, Clinical Sciences Lund, Lund University, 22185 Lund, Sweden; Diana.Karpman@med.lu.se.
Diana
D
Karpman
D000293:Adolescent; D000942:Antigens, Bacterial / Q000276:immunology*; D001425:Bacterial Outer Membrane Proteins / Q000276:immunology*; D002352:Carrier Proteins / Q000276:immunology*; D003176:Complement C3 / Q000276:immunology*; D005260:Female; D005922:Glomerulonephritis, IGA / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007070:Immunoglobulin A / Q000276:immunology*; D015850:Interleukin-6 / Q000276:immunology*; D008297:Male; D050527:Mesangial Cells / Q000276:immunology* / Q000473:pathology; D008875:Middle Aged; D013291:Streptococcus / Q000276:immunology*
D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; D003176:Complement C3; C508600:IL6 protein, human; D007070:Immunoglobulin A; D015850:Interleukin-6; C014689:streptococcal M protein