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IgM exacerbates glomerular disease progression in complement-induced glomerulopathy.

Panzer SE, Laskowski J, Renner B, Kulik L, Ljubanovic D, Huber KM, Zhong W, Pickering MC, Holers VM, Thurman JM - Kidney Int. (2015)

Bottom Line: However, recent studies found that IgM specifically binds damaged glomeruli.Immunofluorescence microscopy demonstrated mesangial and capillary loop deposition of IgM, whereas ultrastructural analysis found IgM deposition on endothelial cells and subendothelial areas.A monoclonal natural IgM-recognizing phospholipids also bound to glomeruli in vivo and induced albuminuria.

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology, Department of Medicine, University of Wisconsin Madison, Madison, Wisconsin, USA.

ABSTRACT
Although glomerular immunoglobulin M (IgM) deposition occurs in a variety of glomerular diseases, the mechanism of deposition and its clinical significance remain controversial. Some have theorized IgM becomes passively trapped in areas of glomerulosclerosis. However, recent studies found that IgM specifically binds damaged glomeruli. Therefore, we tested whether natural IgM binds to neo-epitopes exposed after insults to the glomerulus and exacerbates disease in mice deficient in the complement regulatory protein factor H; a model of non-sclerotic and nonimmune-complex glomerular disease. Immunofluorescence microscopy demonstrated mesangial and capillary loop deposition of IgM, whereas ultrastructural analysis found IgM deposition on endothelial cells and subendothelial areas. Factor H-deficient mice lacking B cells were protected from renal damage, as evidenced by milder histologic lesions on light and electron microscopy. IgM, but not IgG, from wild-type mice bound to cultured murine mesangial cells. Furthermore, injection of purified IgM into mice lacking B cells bound within the glomeruli and induced proteinuria. A monoclonal natural IgM-recognizing phospholipids also bound to glomeruli in vivo and induced albuminuria. Thus, our results indicate specific IgM antibodies bind to glomerular epitopes and that IgM contributes to the progression of glomerular damage in this mouse model of non-sclerotic glomerular disease.

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Factor H deficient animals lacking B cells demonstrate milder pathologic lesions than factor H deficient animals by electron microscopy(a) Electron microscopy of kidney sections from 9 month-old fH−/− mice demonstrate numerous sub-endothelial and intramembranous deposits (arrowheads), mesangial interposition (arrow), areas of glomerular basement membrane duplications forming double contours (double-headed arrows), and increased cellularity (asterisk shows location of monocytes and/or endothelial cells). (b) These pathologic lesions were less prominent in 9 month-old fH−/−/μMT mice. There are relatively small sub-endothelial deposits (arrowheads), otherwise the glomerulus has normal ultra-structure. Original magnification × 3000. Bar = 2 μm.
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Figure 10: Factor H deficient animals lacking B cells demonstrate milder pathologic lesions than factor H deficient animals by electron microscopy(a) Electron microscopy of kidney sections from 9 month-old fH−/− mice demonstrate numerous sub-endothelial and intramembranous deposits (arrowheads), mesangial interposition (arrow), areas of glomerular basement membrane duplications forming double contours (double-headed arrows), and increased cellularity (asterisk shows location of monocytes and/or endothelial cells). (b) These pathologic lesions were less prominent in 9 month-old fH−/−/μMT mice. There are relatively small sub-endothelial deposits (arrowheads), otherwise the glomerulus has normal ultra-structure. Original magnification × 3000. Bar = 2 μm.

Mentions: At 9 months, fH−/−/μMT double knockout mice demonstrated reduced ultra-structural pathology by electron microscopy compared to the fH−/− mice. The fH−/− mice demonstrated numerous sub-endothelial and intramembranous electron-dense deposits (Figure 10a, areas of electron dense deposits marked with arrowheads), lesions of basement membrane duplications (identified by double-headed arrows), and mesangial interposition (marked with arrow), and hypercellularity (asterisk marks monocytes and/or endothelial cells). In contrast, kidney sections from fH−/−/μMT mice had relatively small sub-endothelial deposits (Figure 10b, deposits marked by arrowheads), otherwise the glomeruli had normal appearance by electron microscopy. Kidney sections from wild-type animals demonstrated normal glomerular ultra-structure.


IgM exacerbates glomerular disease progression in complement-induced glomerulopathy.

Panzer SE, Laskowski J, Renner B, Kulik L, Ljubanovic D, Huber KM, Zhong W, Pickering MC, Holers VM, Thurman JM - Kidney Int. (2015)

Factor H deficient animals lacking B cells demonstrate milder pathologic lesions than factor H deficient animals by electron microscopy(a) Electron microscopy of kidney sections from 9 month-old fH−/− mice demonstrate numerous sub-endothelial and intramembranous deposits (arrowheads), mesangial interposition (arrow), areas of glomerular basement membrane duplications forming double contours (double-headed arrows), and increased cellularity (asterisk shows location of monocytes and/or endothelial cells). (b) These pathologic lesions were less prominent in 9 month-old fH−/−/μMT mice. There are relatively small sub-endothelial deposits (arrowheads), otherwise the glomerulus has normal ultra-structure. Original magnification × 3000. Bar = 2 μm.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4556608&req=5

Figure 10: Factor H deficient animals lacking B cells demonstrate milder pathologic lesions than factor H deficient animals by electron microscopy(a) Electron microscopy of kidney sections from 9 month-old fH−/− mice demonstrate numerous sub-endothelial and intramembranous deposits (arrowheads), mesangial interposition (arrow), areas of glomerular basement membrane duplications forming double contours (double-headed arrows), and increased cellularity (asterisk shows location of monocytes and/or endothelial cells). (b) These pathologic lesions were less prominent in 9 month-old fH−/−/μMT mice. There are relatively small sub-endothelial deposits (arrowheads), otherwise the glomerulus has normal ultra-structure. Original magnification × 3000. Bar = 2 μm.
Mentions: At 9 months, fH−/−/μMT double knockout mice demonstrated reduced ultra-structural pathology by electron microscopy compared to the fH−/− mice. The fH−/− mice demonstrated numerous sub-endothelial and intramembranous electron-dense deposits (Figure 10a, areas of electron dense deposits marked with arrowheads), lesions of basement membrane duplications (identified by double-headed arrows), and mesangial interposition (marked with arrow), and hypercellularity (asterisk marks monocytes and/or endothelial cells). In contrast, kidney sections from fH−/−/μMT mice had relatively small sub-endothelial deposits (Figure 10b, deposits marked by arrowheads), otherwise the glomeruli had normal appearance by electron microscopy. Kidney sections from wild-type animals demonstrated normal glomerular ultra-structure.

Bottom Line: However, recent studies found that IgM specifically binds damaged glomeruli.Immunofluorescence microscopy demonstrated mesangial and capillary loop deposition of IgM, whereas ultrastructural analysis found IgM deposition on endothelial cells and subendothelial areas.A monoclonal natural IgM-recognizing phospholipids also bound to glomeruli in vivo and induced albuminuria.

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology, Department of Medicine, University of Wisconsin Madison, Madison, Wisconsin, USA.

ABSTRACT
Although glomerular immunoglobulin M (IgM) deposition occurs in a variety of glomerular diseases, the mechanism of deposition and its clinical significance remain controversial. Some have theorized IgM becomes passively trapped in areas of glomerulosclerosis. However, recent studies found that IgM specifically binds damaged glomeruli. Therefore, we tested whether natural IgM binds to neo-epitopes exposed after insults to the glomerulus and exacerbates disease in mice deficient in the complement regulatory protein factor H; a model of non-sclerotic and nonimmune-complex glomerular disease. Immunofluorescence microscopy demonstrated mesangial and capillary loop deposition of IgM, whereas ultrastructural analysis found IgM deposition on endothelial cells and subendothelial areas. Factor H-deficient mice lacking B cells were protected from renal damage, as evidenced by milder histologic lesions on light and electron microscopy. IgM, but not IgG, from wild-type mice bound to cultured murine mesangial cells. Furthermore, injection of purified IgM into mice lacking B cells bound within the glomeruli and induced proteinuria. A monoclonal natural IgM-recognizing phospholipids also bound to glomeruli in vivo and induced albuminuria. Thus, our results indicate specific IgM antibodies bind to glomerular epitopes and that IgM contributes to the progression of glomerular damage in this mouse model of non-sclerotic glomerular disease.

Show MeSH
Related in: MedlinePlus