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

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−/− 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-dependent GN in FH−/− mice with CSS. CSS was induced in FH−/− mice by daily immunization with apoferritin, or saline alone as control. Groups of animals also received C5aRant and/or CPinh after 2 and 3 weeks, respectively. (A) Individual values of semiquantitative GN scores from all mice studied. 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. (B–E) Representative PAS staining of glomeruli from mice from the different groups. Original magnifications, ×400.
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fig2: C5a-dependent GN in FH−/− mice with CSS. CSS was induced in FH−/− mice by daily immunization with apoferritin, or saline alone as control. Groups of animals also received C5aRant and/or CPinh after 2 and 3 weeks, respectively. (A) Individual values of semiquantitative GN scores from all mice studied. 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. (B–E) Representative PAS staining of glomeruli from mice from the different groups. Original magnifications, ×400.

Mentions: Histopathological features of ICGN were evaluated at the end of the 5-week experimental protocol (Figure 2). As in past studies18,21 a minority (4 of 13) of control FH−/− mice (i.e., without CSS) had some glomerular inflammation with GN scores between 0.5 and 1.5 (Figure 2A and B). All FH−/− mice with CSS developed GN with 13 of 17 mice having scores of 1.5 or 2.0 (Figure 2A). The primary histopathological feature was of diffuse hypercellularity of the glomerular tufts (Figure 2C). There was no evidence for thrombotic microangiopathy. As with BUN measurements, mice that received C5aR1ant for the final 3 weeks had significantly less GN (Figure 2D). Here, CPinh worsened GN (Figure 2E), including in those mice also receiving C5aR1ant. That the extent of GN was related to renal functional impairment is supported by the significant correlation between the two (BUN = 25.3 + (6.0 × GN); r = 0.63, P < 0.001). Thus, endocapillary diffuse proliferative GN occurring in this model relies upon C5aR1 signaling. These data illustrate that physiological complement regulation by FH and CP lessen the amount of C5a available to bind its receptor in states of IC deposition in glomeruli.


Abrogation of immune complex glomerulonephritis by native carboxypeptidase and pharmacological antagonism of the C5a receptor
C5a-dependent GN in FH−/− mice with CSS. CSS was induced in FH−/− mice by daily immunization with apoferritin, or saline alone as control. Groups of animals also received C5aRant and/or CPinh after 2 and 3 weeks, respectively. (A) Individual values of semiquantitative GN scores from all mice studied. 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. (B–E) Representative PAS staining of glomeruli from mice from the different groups. Original magnifications, ×400.
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Related In: Results  -  Collection

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fig2: C5a-dependent GN in FH−/− mice with CSS. CSS was induced in FH−/− mice by daily immunization with apoferritin, or saline alone as control. Groups of animals also received C5aRant and/or CPinh after 2 and 3 weeks, respectively. (A) Individual values of semiquantitative GN scores from all mice studied. 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. (B–E) Representative PAS staining of glomeruli from mice from the different groups. Original magnifications, ×400.
Mentions: Histopathological features of ICGN were evaluated at the end of the 5-week experimental protocol (Figure 2). As in past studies18,21 a minority (4 of 13) of control FH−/− mice (i.e., without CSS) had some glomerular inflammation with GN scores between 0.5 and 1.5 (Figure 2A and B). All FH−/− mice with CSS developed GN with 13 of 17 mice having scores of 1.5 or 2.0 (Figure 2A). The primary histopathological feature was of diffuse hypercellularity of the glomerular tufts (Figure 2C). There was no evidence for thrombotic microangiopathy. As with BUN measurements, mice that received C5aR1ant for the final 3 weeks had significantly less GN (Figure 2D). Here, CPinh worsened GN (Figure 2E), including in those mice also receiving C5aR1ant. That the extent of GN was related to renal functional impairment is supported by the significant correlation between the two (BUN = 25.3 + (6.0 × GN); r = 0.63, P < 0.001). Thus, endocapillary diffuse proliferative GN occurring in this model relies upon C5aR1 signaling. These data illustrate that physiological complement regulation by FH and CP lessen the amount of C5a available to bind its receptor in states of IC deposition in glomeruli.

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.