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The C5a receptor has a key role in immune complex glomerulonephritis in complement factor H-deficient mice.

Alexander JJ, Chaves L, Chang A, Quigg RJ - Kidney Int. (2012)

Bottom Line: Chronic serum sickness leads to the formation of glomerular immune complexes; however, C57BL/6 mice do not develop glomerulonephritis unless complement factor H (CFH) is absent from the plasma.Here we studied the role for C5a receptor (R) in this setting.There was no interstitial inflammation by histologic criteria or flow cytometry for F4/80+ Ly6C(hi)CCR2(hi) inflammatory macrophages.

View Article: PubMed Central - PubMed

Affiliation: Section of Nephrology, Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA. jalexand@medicine.bsd.uchicago.edu

ABSTRACT
Chronic serum sickness leads to the formation of glomerular immune complexes; however, C57BL/6 mice do not develop glomerulonephritis unless complement factor H (CFH) is absent from the plasma. Here we studied the role for C5a receptor (R) in this setting. The exaggerated humoral immune response in CFH(-/-) mice was normalized in CFH(-/-)C5aR(-/-) double knockout mice, highlighting the C5aR dependence. The CFH knockout mice developed proliferative glomerulonephritis with endocapillary F4/80+ macrophage infiltration, a process reduced in the double knockout mice. There was no interstitial inflammation by histologic criteria or flow cytometry for F4/80+ Ly6C(hi)CCR2(hi) inflammatory macrophages. There were, however, more interstitial CD3+ CD4+ T lymphocytes in CFH knockout mice with chronic serum sickness, while double knockout mice had greater than 5-fold more Ly6C(lo)CCR2(lo) anti-inflammatory macrophages compared to the CFH knockout mice. Mice lacking C5aR were significantly protected from functional renal disease as assessed by blood urea nitrogen levels. Thus, IgG- and iC3b-containing immune complexes are not inflammatory in C57BL/6 mice. Yet when these mice lack CFH, sufficient C3b persists in glomeruli to generate C5a and activate C5aR.

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Representative immunofluorescence staining for C3 (green) and immunoglobulin G (IgG, red) in glomeruli of CFH−/− and CFH−/−C5aR−/− mice with chronic serum sickness. (a) Linear glomerular capillary wall C3 staining typical for unmanipulated CFH−/− mice was present in both groups. Mesangial IgG was present in both groups, but in greater relative amounts and with more extension to the peripheral capillary wall in CFH−/− mice compared with CFH−/−C5aR−/− mice. (b) Individual staining for C3 and IgG are shown, along with the merged image. The arrows depict regions with colocalized C3 and IgG. CFH, complement factor H.
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fig4: Representative immunofluorescence staining for C3 (green) and immunoglobulin G (IgG, red) in glomeruli of CFH−/− and CFH−/−C5aR−/− mice with chronic serum sickness. (a) Linear glomerular capillary wall C3 staining typical for unmanipulated CFH−/− mice was present in both groups. Mesangial IgG was present in both groups, but in greater relative amounts and with more extension to the peripheral capillary wall in CFH−/− mice compared with CFH−/−C5aR−/− mice. (b) Individual staining for C3 and IgG are shown, along with the merged image. The arrows depict regions with colocalized C3 and IgG. CFH, complement factor H.

Mentions: Glomeruli of CFH−/− mice with CSS had immunoglobulin G (IgG) within mesangial regions with some extension to peripheral capillary walls, which was significantly reduced in CFH−/−C5aR−/− mice with CSS (stained red in Figure 4); respective median staining scores were 3.0 (2.0–3.0) and 2.0 (1.5–2.5; P<0.015). As anticipated, glomeruli from CFH−/− mice had linear glomerular capillary wall staining for C3 (stained green in Figure 4). As we have seen in prior studies,14, 26, 27 the baseline bright C3 staining was reduced in areas of IgG staining (Figure 4b, white arrows). Besides immunofluorescence microscopy, our past studies have shown that glomerular capillary wall complement regulation is insufficient when plasma CFH is absent; this allows ongoing C3 activation by immune complexes.26


The C5a receptor has a key role in immune complex glomerulonephritis in complement factor H-deficient mice.

Alexander JJ, Chaves L, Chang A, Quigg RJ - Kidney Int. (2012)

Representative immunofluorescence staining for C3 (green) and immunoglobulin G (IgG, red) in glomeruli of CFH−/− and CFH−/−C5aR−/− mice with chronic serum sickness. (a) Linear glomerular capillary wall C3 staining typical for unmanipulated CFH−/− mice was present in both groups. Mesangial IgG was present in both groups, but in greater relative amounts and with more extension to the peripheral capillary wall in CFH−/− mice compared with CFH−/−C5aR−/− mice. (b) Individual staining for C3 and IgG are shown, along with the merged image. The arrows depict regions with colocalized C3 and IgG. CFH, complement factor H.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3472160&req=5

fig4: Representative immunofluorescence staining for C3 (green) and immunoglobulin G (IgG, red) in glomeruli of CFH−/− and CFH−/−C5aR−/− mice with chronic serum sickness. (a) Linear glomerular capillary wall C3 staining typical for unmanipulated CFH−/− mice was present in both groups. Mesangial IgG was present in both groups, but in greater relative amounts and with more extension to the peripheral capillary wall in CFH−/− mice compared with CFH−/−C5aR−/− mice. (b) Individual staining for C3 and IgG are shown, along with the merged image. The arrows depict regions with colocalized C3 and IgG. CFH, complement factor H.
Mentions: Glomeruli of CFH−/− mice with CSS had immunoglobulin G (IgG) within mesangial regions with some extension to peripheral capillary walls, which was significantly reduced in CFH−/−C5aR−/− mice with CSS (stained red in Figure 4); respective median staining scores were 3.0 (2.0–3.0) and 2.0 (1.5–2.5; P<0.015). As anticipated, glomeruli from CFH−/− mice had linear glomerular capillary wall staining for C3 (stained green in Figure 4). As we have seen in prior studies,14, 26, 27 the baseline bright C3 staining was reduced in areas of IgG staining (Figure 4b, white arrows). Besides immunofluorescence microscopy, our past studies have shown that glomerular capillary wall complement regulation is insufficient when plasma CFH is absent; this allows ongoing C3 activation by immune complexes.26

Bottom Line: Chronic serum sickness leads to the formation of glomerular immune complexes; however, C57BL/6 mice do not develop glomerulonephritis unless complement factor H (CFH) is absent from the plasma.Here we studied the role for C5a receptor (R) in this setting.There was no interstitial inflammation by histologic criteria or flow cytometry for F4/80+ Ly6C(hi)CCR2(hi) inflammatory macrophages.

View Article: PubMed Central - PubMed

Affiliation: Section of Nephrology, Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA. jalexand@medicine.bsd.uchicago.edu

ABSTRACT
Chronic serum sickness leads to the formation of glomerular immune complexes; however, C57BL/6 mice do not develop glomerulonephritis unless complement factor H (CFH) is absent from the plasma. Here we studied the role for C5a receptor (R) in this setting. The exaggerated humoral immune response in CFH(-/-) mice was normalized in CFH(-/-)C5aR(-/-) double knockout mice, highlighting the C5aR dependence. The CFH knockout mice developed proliferative glomerulonephritis with endocapillary F4/80+ macrophage infiltration, a process reduced in the double knockout mice. There was no interstitial inflammation by histologic criteria or flow cytometry for F4/80+ Ly6C(hi)CCR2(hi) inflammatory macrophages. There were, however, more interstitial CD3+ CD4+ T lymphocytes in CFH knockout mice with chronic serum sickness, while double knockout mice had greater than 5-fold more Ly6C(lo)CCR2(lo) anti-inflammatory macrophages compared to the CFH knockout mice. Mice lacking C5aR were significantly protected from functional renal disease as assessed by blood urea nitrogen levels. Thus, IgG- and iC3b-containing immune complexes are not inflammatory in C57BL/6 mice. Yet when these mice lack CFH, sufficient C3b persists in glomeruli to generate C5a and activate C5aR.

Show MeSH
Related in: MedlinePlus