Limits...
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.

Show MeSH

Related in: MedlinePlus

Chronic serum sickness (CSS) leads to C5aR-dependent glomerulonephritis (GN) with macrophage infiltration in CFH−/− mice. Histopathological features of disease were determined after 5 weeks of active immunization of CFH−/− and CFH−/−C5aR−/− mice with apoferritin or saline as controls. (a) Semiquantitative GN scores from each mouse were compiled. Shown are individual values from all mice studied. Groups were significantly different by Kruskal–Wallis testing (P<0.001). *P=0.024 vs. CFH−/−C5aR−/− plus apoferritin. Representative periodic acid–Schiff staining (b) and immunofluorescence staining for F4/80+ cells (c) is shown for CFH−/− and CFH−/−C5aR−/− mice with CSS. Original magnification, × 400.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3472160&req=5

fig2: Chronic serum sickness (CSS) leads to C5aR-dependent glomerulonephritis (GN) with macrophage infiltration in CFH−/− mice. Histopathological features of disease were determined after 5 weeks of active immunization of CFH−/− and CFH−/−C5aR−/− mice with apoferritin or saline as controls. (a) Semiquantitative GN scores from each mouse were compiled. Shown are individual values from all mice studied. Groups were significantly different by Kruskal–Wallis testing (P<0.001). *P=0.024 vs. CFH−/−C5aR−/− plus apoferritin. Representative periodic acid–Schiff staining (b) and immunofluorescence staining for F4/80+ cells (c) is shown for CFH−/− and CFH−/−C5aR−/− mice with CSS. Original magnification, × 400.

Mentions: Histopathological features of GN were evaluated at the end of the 5-week experimental protocol. As in past studies,11, 14 some control CFH−/− mice had GN scores of 0.5–1.0, as was also true of control CFH−/−C5aR−/− mice (Figure 2a). CFH−/− mice with CSS developed GN, which was significantly reduced in CFH−/−C5aR−/− mice (Figure 2a and b; P=0.024). The primary histopathological feature was diffuse hypercellularity of the glomerular tufts (Figure 2b). The cellular composition of the observed GN was due, at least in part, to F4/80+ monocytic cells (Figure 2c). Thus, endocapillary diffuse proliferative GN in CSS appears to require absent complement regulation from CFH allowing signals through 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)

Chronic serum sickness (CSS) leads to C5aR-dependent glomerulonephritis (GN) with macrophage infiltration in CFH−/− mice. Histopathological features of disease were determined after 5 weeks of active immunization of CFH−/− and CFH−/−C5aR−/− mice with apoferritin or saline as controls. (a) Semiquantitative GN scores from each mouse were compiled. Shown are individual values from all mice studied. Groups were significantly different by Kruskal–Wallis testing (P<0.001). *P=0.024 vs. CFH−/−C5aR−/− plus apoferritin. Representative periodic acid–Schiff staining (b) and immunofluorescence staining for F4/80+ cells (c) is shown for CFH−/− and CFH−/−C5aR−/− mice with CSS. Original magnification, × 400.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig2: Chronic serum sickness (CSS) leads to C5aR-dependent glomerulonephritis (GN) with macrophage infiltration in CFH−/− mice. Histopathological features of disease were determined after 5 weeks of active immunization of CFH−/− and CFH−/−C5aR−/− mice with apoferritin or saline as controls. (a) Semiquantitative GN scores from each mouse were compiled. Shown are individual values from all mice studied. Groups were significantly different by Kruskal–Wallis testing (P<0.001). *P=0.024 vs. CFH−/−C5aR−/− plus apoferritin. Representative periodic acid–Schiff staining (b) and immunofluorescence staining for F4/80+ cells (c) is shown for CFH−/− and CFH−/−C5aR−/− mice with CSS. Original magnification, × 400.
Mentions: Histopathological features of GN were evaluated at the end of the 5-week experimental protocol. As in past studies,11, 14 some control CFH−/− mice had GN scores of 0.5–1.0, as was also true of control CFH−/−C5aR−/− mice (Figure 2a). CFH−/− mice with CSS developed GN, which was significantly reduced in CFH−/−C5aR−/− mice (Figure 2a and b; P=0.024). The primary histopathological feature was diffuse hypercellularity of the glomerular tufts (Figure 2b). The cellular composition of the observed GN was due, at least in part, to F4/80+ monocytic cells (Figure 2c). Thus, endocapillary diffuse proliferative GN in CSS appears to require absent complement regulation from CFH allowing signals through 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