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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 mice demonstrate progressive IgM deposition within the glomerulus over timeGlomerular IgM and C3 deposition were assessed by immunofluorescence microscopy of kidney sections from fH−/− mice. (a and b) IgM is seen in the mesangium of young mice (3 months old). IgM deposition expands into capillary loops in older mice (9 months old). (c and d) Glomerular deposition of C3 appears in glomerular capillary loops at both ages. (e and f) Dual staining with IgM and C3 demonstrate distinct locations of IgM and C3 in fH−/− mice at 3 months of age and diffuse deposition of IgM at 9 months of age. Representative glomeruli from mice in each group are shown. Original magnification × 200. Bar = 100 μm.
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Figure 1: Factor H deficient mice demonstrate progressive IgM deposition within the glomerulus over timeGlomerular IgM and C3 deposition were assessed by immunofluorescence microscopy of kidney sections from fH−/− mice. (a and b) IgM is seen in the mesangium of young mice (3 months old). IgM deposition expands into capillary loops in older mice (9 months old). (c and d) Glomerular deposition of C3 appears in glomerular capillary loops at both ages. (e and f) Dual staining with IgM and C3 demonstrate distinct locations of IgM and C3 in fH−/− mice at 3 months of age and diffuse deposition of IgM at 9 months of age. Representative glomeruli from mice in each group are shown. Original magnification × 200. Bar = 100 μm.

Mentions: Kidney sections from fH−/− mice at three, six, and nine months of age were assessed for glomerular deposition of IgM by immunofluorescence. Glomeruli of fH−/− mice demonstrated consistent IgM deposition occurring in a progressive fashion as the mice aged (representative glomeruli are shown in Figure 1a and b). Further localization of the IgM deposits demonstrated a change over time in mice with fH−/− mediated glomerulonephritis. In the fH−/− strain the areas of glomerular IgM deposition appear mesangial in distribution at three months of age (Figure 1a). At this time point the IgM deposits are distinct from glomerular C3 (Figure 1e). However, as the mice age and as disease worsens IgM deposition expands from the mesangium into glomerular capillary loops (Figure 1b and f). In contrast to IgM, glomerular IgG deposition in the fH−/− strain was negative. Figure 2e shows a representative tissue section from a nine month-old fH−/− mouse demonstrating negative staining by immunofluorescence for IgG. Wild-type mice developed minimal IgM deposition over time. Assessment of fH−/−/μMT kidney sections confirmed there was no glomerular IgM present in this strain.


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 mice demonstrate progressive IgM deposition within the glomerulus over timeGlomerular IgM and C3 deposition were assessed by immunofluorescence microscopy of kidney sections from fH−/− mice. (a and b) IgM is seen in the mesangium of young mice (3 months old). IgM deposition expands into capillary loops in older mice (9 months old). (c and d) Glomerular deposition of C3 appears in glomerular capillary loops at both ages. (e and f) Dual staining with IgM and C3 demonstrate distinct locations of IgM and C3 in fH−/− mice at 3 months of age and diffuse deposition of IgM at 9 months of age. Representative glomeruli from mice in each group are shown. Original magnification × 200. Bar = 100 μm.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4556608&req=5

Figure 1: Factor H deficient mice demonstrate progressive IgM deposition within the glomerulus over timeGlomerular IgM and C3 deposition were assessed by immunofluorescence microscopy of kidney sections from fH−/− mice. (a and b) IgM is seen in the mesangium of young mice (3 months old). IgM deposition expands into capillary loops in older mice (9 months old). (c and d) Glomerular deposition of C3 appears in glomerular capillary loops at both ages. (e and f) Dual staining with IgM and C3 demonstrate distinct locations of IgM and C3 in fH−/− mice at 3 months of age and diffuse deposition of IgM at 9 months of age. Representative glomeruli from mice in each group are shown. Original magnification × 200. Bar = 100 μm.
Mentions: Kidney sections from fH−/− mice at three, six, and nine months of age were assessed for glomerular deposition of IgM by immunofluorescence. Glomeruli of fH−/− mice demonstrated consistent IgM deposition occurring in a progressive fashion as the mice aged (representative glomeruli are shown in Figure 1a and b). Further localization of the IgM deposits demonstrated a change over time in mice with fH−/− mediated glomerulonephritis. In the fH−/− strain the areas of glomerular IgM deposition appear mesangial in distribution at three months of age (Figure 1a). At this time point the IgM deposits are distinct from glomerular C3 (Figure 1e). However, as the mice age and as disease worsens IgM deposition expands from the mesangium into glomerular capillary loops (Figure 1b and f). In contrast to IgM, glomerular IgG deposition in the fH−/− strain was negative. Figure 2e shows a representative tissue section from a nine month-old fH−/− mouse demonstrating negative staining by immunofluorescence for IgG. Wild-type mice developed minimal IgM deposition over time. Assessment of fH−/−/μMT kidney sections confirmed there was no glomerular IgM present in this strain.

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