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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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Relationship between measured variables in CFH−/− (•) and CFH−/−C5aR−/− mice (○) after 5 weeks of chronic serum sickness. (a) Semiquantitative scores for glomerular immunoglobulin G (IgG; y-axis) were plotted against anti-apoferritin IgG levels (x-axis). The box enclosed by dashed lines separates the two groups completely. Measured blood urea nitrogen (BUN) concentrations (y-axes) were plotted against anti-apoferritin IgG levels (b) and semiquantitative glomerulonephritis scores (c, x-axes). The dashed lines are best-fit regression lines for data from both groups. CFH, complement factor H.
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fig5: Relationship between measured variables in CFH−/− (•) and CFH−/−C5aR−/− mice (○) after 5 weeks of chronic serum sickness. (a) Semiquantitative scores for glomerular immunoglobulin G (IgG; y-axis) were plotted against anti-apoferritin IgG levels (x-axis). The box enclosed by dashed lines separates the two groups completely. Measured blood urea nitrogen (BUN) concentrations (y-axes) were plotted against anti-apoferritin IgG levels (b) and semiquantitative glomerulonephritis scores (c, x-axes). The dashed lines are best-fit regression lines for data from both groups. CFH, complement factor H.

Mentions: Measured anti-apoferritin IgG, glomerular IgG deposits, GN scores, and BUN values were all decreased in CSS in CFH−/−C5aR−/− mice relative to CFH−/− mice. We were interested to determine whether these variables were related; in particular, whether the observed effects of C5aR deficiency on renal disease could be attributed to reduction of anti-apoferritin IgG to wild-type levels. Glomerular IgG deposition positively correlated with serum anti-apoferritin IgG (r=0.46, P=0.013), with the two experimental groups being completely distinct in this analysis (as shown by the box in Figure 5a). Neither serum anti-apoferritin nor glomerular IgG had any relation to GN scores (r=0.27–0.37). BUN levels positively correlated with both anti-apoferritin IgG values (Figure 5b; r=0.65, P<0.001) and the extent of GN (Figure 5c; r=0.48, P=0.010). Each had an independent contribution to BUN levels, as shown by the equation [BUN]=−6.2 + 17.3 anti-apoferritin/2 + 6.5 GN (r=0.72, P<0.001); even though anti-apoferritin was weighted in half (to be comparable to GN scores), it remained the principal determinant of BUN. Thus, C5aR-dependent excessive production of anti-apoferritin IgG antibodies in CFH−/− mice tracks strongly with several end-organ disease features.


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)

Relationship between measured variables in CFH−/− (•) and CFH−/−C5aR−/− mice (○) after 5 weeks of chronic serum sickness. (a) Semiquantitative scores for glomerular immunoglobulin G (IgG; y-axis) were plotted against anti-apoferritin IgG levels (x-axis). The box enclosed by dashed lines separates the two groups completely. Measured blood urea nitrogen (BUN) concentrations (y-axes) were plotted against anti-apoferritin IgG levels (b) and semiquantitative glomerulonephritis scores (c, x-axes). The dashed lines are best-fit regression lines for data from both groups. CFH, complement factor H.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig5: Relationship between measured variables in CFH−/− (•) and CFH−/−C5aR−/− mice (○) after 5 weeks of chronic serum sickness. (a) Semiquantitative scores for glomerular immunoglobulin G (IgG; y-axis) were plotted against anti-apoferritin IgG levels (x-axis). The box enclosed by dashed lines separates the two groups completely. Measured blood urea nitrogen (BUN) concentrations (y-axes) were plotted against anti-apoferritin IgG levels (b) and semiquantitative glomerulonephritis scores (c, x-axes). The dashed lines are best-fit regression lines for data from both groups. CFH, complement factor H.
Mentions: Measured anti-apoferritin IgG, glomerular IgG deposits, GN scores, and BUN values were all decreased in CSS in CFH−/−C5aR−/− mice relative to CFH−/− mice. We were interested to determine whether these variables were related; in particular, whether the observed effects of C5aR deficiency on renal disease could be attributed to reduction of anti-apoferritin IgG to wild-type levels. Glomerular IgG deposition positively correlated with serum anti-apoferritin IgG (r=0.46, P=0.013), with the two experimental groups being completely distinct in this analysis (as shown by the box in Figure 5a). Neither serum anti-apoferritin nor glomerular IgG had any relation to GN scores (r=0.27–0.37). BUN levels positively correlated with both anti-apoferritin IgG values (Figure 5b; r=0.65, P<0.001) and the extent of GN (Figure 5c; r=0.48, P=0.010). Each had an independent contribution to BUN levels, as shown by the equation [BUN]=−6.2 + 17.3 anti-apoferritin/2 + 6.5 GN (r=0.72, P<0.001); even though anti-apoferritin was weighted in half (to be comparable to GN scores), it remained the principal determinant of BUN. Thus, C5aR-dependent excessive production of anti-apoferritin IgG antibodies in CFH−/− mice tracks strongly with several end-organ disease features.

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