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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.

Schmitt, Roland LU ; Ståhl, Anne-lie LU ; Olin, Anders LU ; Kristoffersson, Ann-Charlotte LU ; Rebetz, Johan LU ; Novak, Jan; Lindahl, Gunnar LU and Karpman, Diana LU (2014) In Journal of Immunology 193(1). p.317-326
Abstract
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... (More)
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. (Less)
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author
organization
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type
Contribution to journal
publication status
published
subject
in
Journal of Immunology
volume
193
issue
1
pages
317 - 326
publisher
American Association of Immunologists
external identifiers
  • pmid:24850720
  • wos:000338438900037
  • scopus:84903575263
ISSN
1550-6606
DOI
10.4049/jimmunol.1302249
language
English
LU publication?
yes
id
b48dd699-dd06-4424-8ccd-f1e2ca43fade (old id 4452799)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/24850720?dopt=Abstract
date added to LUP
2014-06-04 23:43:09
date last changed
2017-10-22 03:24:00
@article{b48dd699-dd06-4424-8ccd-f1e2ca43fade,
  abstract     = {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.},
  author       = {Schmitt, Roland and Ståhl, Anne-lie and Olin, Anders and Kristoffersson, Ann-Charlotte and Rebetz, Johan and Novak, Jan and Lindahl, Gunnar and Karpman, Diana},
  issn         = {1550-6606},
  language     = {eng},
  number       = {1},
  pages        = {317--326},
  publisher    = {American Association of Immunologists},
  series       = {Journal of Immunology},
  title        = {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.},
  url          = {http://dx.doi.org/10.4049/jimmunol.1302249},
  volume       = {193},
  year         = {2014},
}