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Abrogation of immune complex glomerulonephritis by native carboxypeptidase and pharmacological antagonism of the C5a receptor

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ABSTRACT

Activation of complement generates C5a which leads to signaling through C5aR1. This is tightly controlled, including by the plasma proteins factor H (FH) and carboxypeptidase N. Here we studied a chronic serum sickness (CSS) model of glomerulonephritis (GN) in which there is an active humoral immune response, formation of glomerular immune complexes (ICs), and resulting glomerular inflammation. The antibody response, glomerular IC deposition, the degree of GN, and consequent renal functional insufficiency in CSS were all worse in FH−/− mice compared to wild-type FH+/+ animals. This was ameliorated in the former by giving a C5aR1 antagonist for the final 3 weeks of the 5-week protocol. In contrast, blocking CP-mediated inactivation of C5a increased these disease measures. Thus, complement regulation by both plasma FH and CP to limit the quantity of active C5a is important in conditions where the humoral immune response is directed to a continuously present foreign antigen. Signaling through C5aR1 enhances the humoral immune response as well as the inflammatory response to ICs that have formed in glomeruli. Both effects are relevant even after disease has begun. Thus, pharmacological targeting of C5a in IC-mediated GN has potential clinical relevance.

No MeSH data available.


C5a facilitates the humoral immune response in CSS. CSS was induced in wild-type (FH+/+) mice or FH−/− mice by daily immunization with apoferritin. Groups of animals also received C5aRant or CPinh after 2 and 3 weeks, respectively. Shown are individual serum anti-apoferritin IgG values from all mice studied after 5 weeks. Data from each group were not normally distributed. The horizontal lines are the median values in each group. The boxes enclose Q1–Q3 intervals. Groups were significantly different by Kruskall–Wallis testing (P < 0.001), with between-group comparisons shown in the Figure. *P < 0.01 versus other three groups.
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fig4: C5a facilitates the humoral immune response in CSS. CSS was induced in wild-type (FH+/+) mice or FH−/− mice by daily immunization with apoferritin. Groups of animals also received C5aRant or CPinh after 2 and 3 weeks, respectively. Shown are individual serum anti-apoferritin IgG values from all mice studied after 5 weeks. Data from each group were not normally distributed. The horizontal lines are the median values in each group. The boxes enclose Q1–Q3 intervals. Groups were significantly different by Kruskall–Wallis testing (P < 0.001), with between-group comparisons shown in the Figure. *P < 0.01 versus other three groups.

Mentions: 18</citref>, FH−/− mice with CSS had higher sera titers of anti-apoferritin IgG than wild-type FH+/+ mice (Figure 4). Interestingly, inhibition of C5aR1 from 3–5 weeks of immunization led to reduction of anti-apoferritin IgG to levels comparable to wild-type mice. Moreover, inhibition of CP led to a significant increase in anti-apoferritin IgG (Figure 4). Thus, production of anti-apoferritin IgG in C57BL/6 mice appears to be fueled by C5a-C5aR1 in FH−/− mice even after the immune response has begun, which can be further increased by inhibiting CP-mediated inactivation of C5a.


Abrogation of immune complex glomerulonephritis by native carboxypeptidase and pharmacological antagonism of the C5a receptor
C5a facilitates the humoral immune response in CSS. CSS was induced in wild-type (FH+/+) mice or FH−/− mice by daily immunization with apoferritin. Groups of animals also received C5aRant or CPinh after 2 and 3 weeks, respectively. Shown are individual serum anti-apoferritin IgG values from all mice studied after 5 weeks. Data from each group were not normally distributed. The horizontal lines are the median values in each group. The boxes enclose Q1–Q3 intervals. Groups were significantly different by Kruskall–Wallis testing (P < 0.001), with between-group comparisons shown in the Figure. *P < 0.01 versus other three groups.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC5037280&req=5

fig4: C5a facilitates the humoral immune response in CSS. CSS was induced in wild-type (FH+/+) mice or FH−/− mice by daily immunization with apoferritin. Groups of animals also received C5aRant or CPinh after 2 and 3 weeks, respectively. Shown are individual serum anti-apoferritin IgG values from all mice studied after 5 weeks. Data from each group were not normally distributed. The horizontal lines are the median values in each group. The boxes enclose Q1–Q3 intervals. Groups were significantly different by Kruskall–Wallis testing (P < 0.001), with between-group comparisons shown in the Figure. *P < 0.01 versus other three groups.
Mentions: 18</citref>, FH−/− mice with CSS had higher sera titers of anti-apoferritin IgG than wild-type FH+/+ mice (Figure 4). Interestingly, inhibition of C5aR1 from 3–5 weeks of immunization led to reduction of anti-apoferritin IgG to levels comparable to wild-type mice. Moreover, inhibition of CP led to a significant increase in anti-apoferritin IgG (Figure 4). Thus, production of anti-apoferritin IgG in C57BL/6 mice appears to be fueled by C5a-C5aR1 in FH−/− mice even after the immune response has begun, which can be further increased by inhibiting CP-mediated inactivation of C5a.

View Article: PubMed Central - PubMed

ABSTRACT

Activation of complement generates C5a which leads to signaling through C5aR1. This is tightly controlled, including by the plasma proteins factor H (FH) and carboxypeptidase N. Here we studied a chronic serum sickness (CSS) model of glomerulonephritis (GN) in which there is an active humoral immune response, formation of glomerular immune complexes (ICs), and resulting glomerular inflammation. The antibody response, glomerular IC deposition, the degree of GN, and consequent renal functional insufficiency in CSS were all worse in FH&minus;/&minus; mice compared to wild-type FH+/+ animals. This was ameliorated in the former by giving a C5aR1 antagonist for the final 3 weeks of the 5-week protocol. In contrast, blocking CP-mediated inactivation of C5a increased these disease measures. Thus, complement regulation by both plasma FH and CP to limit the quantity of active C5a is important in conditions where the humoral immune response is directed to a continuously present foreign antigen. Signaling through C5aR1 enhances the humoral immune response as well as the inflammatory response to ICs that have formed in glomeruli. Both effects are relevant even after disease has begun. Thus, pharmacological targeting of C5a in IC-mediated GN has potential clinical relevance.

No MeSH data available.