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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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C5aR-dependent impairment of renal function in CFH−/− mice with CSS. Blood urea nitrogen (BUN) levels were measured after 5 weeks of active immunization of CFH−/− and CFH−/−C5aR−/− mice with apoferritin or saline as controls. Data from each group were normally distributed. Shown are individual values from all mice studied, with the mean value in each group as a horizontal line. Groups were significantly different by analysis of variance (P<0.001). *P<0.001 vs. CFH−/−C5aR−/− plus apoferritin. CFH, complement factor H; CSS, chronic serum sickness.
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fig1: C5aR-dependent impairment of renal function in CFH−/− mice with CSS. Blood urea nitrogen (BUN) levels were measured after 5 weeks of active immunization of CFH−/− and CFH−/−C5aR−/− mice with apoferritin or saline as controls. Data from each group were normally distributed. Shown are individual values from all mice studied, with the mean value in each group as a horizontal line. Groups were significantly different by analysis of variance (P<0.001). *P<0.001 vs. CFH−/−C5aR−/− plus apoferritin. CFH, complement factor H; CSS, chronic serum sickness.

Mentions: Here we used the CSS model induced with heterologous (apo)ferritin as originally described by Stilmant et al.19 and modified by Iskandar et al.20, 21 C57BL/6 CFH−/− and CFH−/−C5aR−/− mice (n=14 each) were actively immunized with daily intraperitoneal horse spleen apoferritin. As controls, CFH−/− (n=4) and CFH−/−C5aR−/− (n=8) mice were treated identically, except that apoferritin was omitted from the injections. As shown in Figure 1, control CFH−/− mice had normal renal function at the end of the 5-week experimental protocol as assessed by blood urea nitrogen (BUN) levels. In contrast, CFH−/− mice with CSS had impaired renal function (BUN=51.4±12.4 mg/dl), which was prevented in CFH−/−C5aR−/− mice (BUN=34.0±8.9 mg/dl; P<0.001 vs. CFH−/− mice). Thus, functional renal insufficiency in the CSS model requires both the absence of CFH and the presence of C5aR.


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)

C5aR-dependent impairment of renal function in CFH−/− mice with CSS. Blood urea nitrogen (BUN) levels were measured after 5 weeks of active immunization of CFH−/− and CFH−/−C5aR−/− mice with apoferritin or saline as controls. Data from each group were normally distributed. Shown are individual values from all mice studied, with the mean value in each group as a horizontal line. Groups were significantly different by analysis of variance (P<0.001). *P<0.001 vs. CFH−/−C5aR−/− plus apoferritin. CFH, complement factor H; CSS, chronic serum sickness.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: C5aR-dependent impairment of renal function in CFH−/− mice with CSS. Blood urea nitrogen (BUN) levels were measured after 5 weeks of active immunization of CFH−/− and CFH−/−C5aR−/− mice with apoferritin or saline as controls. Data from each group were normally distributed. Shown are individual values from all mice studied, with the mean value in each group as a horizontal line. Groups were significantly different by analysis of variance (P<0.001). *P<0.001 vs. CFH−/−C5aR−/− plus apoferritin. CFH, complement factor H; CSS, chronic serum sickness.
Mentions: Here we used the CSS model induced with heterologous (apo)ferritin as originally described by Stilmant et al.19 and modified by Iskandar et al.20, 21 C57BL/6 CFH−/− and CFH−/−C5aR−/− mice (n=14 each) were actively immunized with daily intraperitoneal horse spleen apoferritin. As controls, CFH−/− (n=4) and CFH−/−C5aR−/− (n=8) mice were treated identically, except that apoferritin was omitted from the injections. As shown in Figure 1, control CFH−/− mice had normal renal function at the end of the 5-week experimental protocol as assessed by blood urea nitrogen (BUN) levels. In contrast, CFH−/− mice with CSS had impaired renal function (BUN=51.4±12.4 mg/dl), which was prevented in CFH−/−C5aR−/− mice (BUN=34.0±8.9 mg/dl; P<0.001 vs. CFH−/− mice). Thus, functional renal insufficiency in the CSS model requires both the absence of CFH and the presence of C5aR.

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