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Published ahead of print on December 1, 2004
J Am Soc Nephrol 16: 52-57, 2005
© 2005 American Society of Nephrology
doi: 10.1681/ASN.2004090778
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Fast Track

Complement Factor H Limits Immune Complex Deposition and Prevents Inflammation and Scarring in Glomeruli of Mice with Chronic Serum Sickness

Jessy J. Alexander*, Matthew C. Pickering{dagger}, Mark Haas{ddagger}, Iyabo Osawe* and Richard J. Quigg*

* Section of Nephrology, The University of Chicago, Chicago, Illinois; {dagger} Rheumatology Section, Imperial College, Hammersmith Campus, London, United Kingdom; and the {ddagger} Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland

Address correspondence to: Dr. Jessy J. Alexander, Section of Nephrology, The University of Chicago, 5841 S. Maryland Avenue, MC5100, Chicago, IL 60637, Phone: 773-702-4796; Fax: 773-702-5818; jalexand{at}medicine.bsd.uchicago.edu


   Abstract
Top
 Abstract
Introduction
 Experimental Model
 Results and Discussion
 References
 
Factor H is the major complement regulator in plasma. Abnormalities in factor H have been implicated in membranoproliferative glomerulonephritis in both humans and experimental animals. It has been shown that factor H on rodent platelets functions analogously to human erythrocyte complement receptor 1 in its role to traffic immune complexes to the mononuclear phagocyte system. C57BL/6 factor H-deficient mice (Cfh–/–) and wild-type (wt) controls were immunized daily for 5 wk with heterologous apoferritin to study the chronic serum sickness GN model. Immunizations were started in 6- to 8-wk-old mice, which was before the development of spontaneous membranoproliferative glomerulonephritis in some Cfh–/– animals. Glomerular deposition of IgG immune complexes in glomeruli was qualitatively and quantitatively increased in Cfh–/– mice compared with wt mice. Consistent with the increase in glomerular immune complexes and possibly because of alternative pathway complement activation, Cfh–/– mice had increased glomerular C3 deposition. Wt mice developed no glomerular pathology. In contrast, Cfh–/– mice developed diffuse proliferative GN with focal crescents and glomerulosclerosis. In addition, there was significantly increased expression of collagen IV, fibronectin, and laminin mRNA in Cfh–/– glomeruli. These data show a role for platelet-associated factor H to process immune complexes and limit their accumulation in glomeruli. Once deposited in glomeruli, excessive complement activation can lead to glomerular inflammation and the rapid development of a scarring phenotype.


   Introduction
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 Abstract
 Introduction
Experimental Model
 Results and Discussion
 References
 
Activation of the complement cascade leads to the production of a number of proteins that contribute to inflammation. This system is beneficial when contributing to host defense, but can be detrimental if activated on self tissue. To prevent this, a number of naturally occurring complement regulatory proteins are present to restrict complement activation throughout the cascades of the three pathways. The regulators of complement activation family comprise a collection of plasma- and cell-associated proteins that limit activation of C3 and C5 (1–3). Each family member has between 4 and 44 tandemly arranged amino acid complement control protein modules (4,5). An important member of this family is factor H, which was originally isolated in 1965 as {beta}1H globulin by Nilsson and Müller-Eberhard (6), and 10 yr later its function was determined by both the Ruddy and Fearon laboratories (7,8). By virtue of its affinity for C3b, factor H inhibits the formation and accelerates the decay of alternative pathway C3 convertases and serves as a cofactor for the factor I-mediated cleavage and inactivation of C3b (9).

It is not surprising, given that factor H is a major fluid phase complement regulator, that abnormalities in this protein are associated with several renal diseases. The most consistent associations are with membranoproliferative glomerulonephritis (MPGN) and hemolytic uremic syndrome. Humans with dysfunctional factor H molecules (10–12) and animals with factor H deficiencies (13,14) develop renal disease with features of MPGN. These associations of abnormal factor H molecules with glomerular disease support the commonly held belief that activation of the complement cascade contributes to immunologically mediated glomerular diseases (15,16). Additional circumstantial evidence for this is the presence of complement activation products in glomeruli and in urine (17–19). The use of animal models has strengthened the case for a role of complement activation in many glomerular diseases.

Serum sickness and the resultant GN have been studied in different animal species, using a variety of immunization protocols. Daily immunization with heterologous apoferritin leads to crescentic GN in susceptible strains of mice (20), which can progress to glomerulosclerosis (21). A dependence on the presence of C5 was shown by Falk and Jennete in this model, implicating C5a and/or C5b-9 (22). Because the 129 and C57BL/6 strains used for gene targeting are relatively resistant to this model (see (23) and below), a modification was adopted by Welch et al. in which lipopolysaccharide was administered with apoferritin (24). In this model of progressive glomerular and tubular inflammation, signaling of the anaphylatoxin C5a through its receptor on inflammatory cells and potentially on renal tubular epithelium (25) led to tubulointerstitial disease but did not affect glomerular disease (26).

In vitro studies have clearly shown that complement is required for solubilization of large antigen–antibody immune complexes, presumably by disrupting lattice formation when C3 and C4 bind covalently to constituents of the complex (27). Complement also plays an important role in the in vivo trafficking of immune complexes. In humans, immune complexes bearing C4b and C3b bind to complement receptor 1 (CR1), which transports them to the cells of the mononuclear phagocyte system in the liver and spleen (28). In mice and other subprimate species, the functional homologue of erythrocyte CR1, which we have identified as factor H (29), is present on platelets and not erythrocytes (30,31). In addition to affecting the fate of systemic immune complexes, activation of C3 clearly can facilitate the processing of immune complexes directly in glomeruli (32).


   Experimental Model
Top
 Abstract
 Introduction
 Experimental Model
Results and Discussion
 References
 
For these studies, C57BL/6 factor H-deficient (Cfh–/–) mice generated and generously provided by Dr. Marina Botto (Hammersmith Hospital, London, UK) were used (14). These mice have been backcrossed >10 generations onto the C57BL/6 strain, including in our lab. As such, normal C57BL/6 mice (Jackson Laboratories, Bar Harbor, ME) were used as wild-type (wt) strain controls in these studies. Immune complex GN was induced by immunizing 6- to 8-wk-old male Cfh–/– (n = 10) or wt (n = 6) mice for 5 wk with a daily intraperitoneal dose of 4 mg horse spleen apoferritin (Sigma Chemical Co., St. Louis, MO), as we and others have described (20,22,23). Control Cfh–/– (n = 5) and wt (n = 3) mice were treated identically, except they received the saline diluent alone. Although Cfh–/– mice on mixed 129 and C57BL/6 background are known to develop MPGN later in life (14), our studying Cfh–/– on a pure C57BL/6 background at an early age made it unlikely that spontaneous GN would occur, which was confirmed in these studies. There was no spontaneous mortality in the control groups, while four of 10 Cfh–/– mice and one of six wt mice actively immunized with apoferritin died over the 5-wk study period. Although these results suggested that factor H could limit spontaneous mortality in this model (21), these differences were not statistically different. A total of 19 mice remained at the end of 5 wk, of which 11 were Cfh–/– mice and eight were wt mice. These animals were sacrificed and a comprehensive assessment of disease phenotype was performed, as we have described previously in this model (23) and in lupus mice (33,34).


   Results and Discussion
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 Abstract
 Introduction
 Experimental Model
 Results and Discussion
References
 
As expected, there were no anti-apoferritin antibodies in all groups at baseline and after 5 wk of saline administration. With apoferritin immunization, all mice mounted a humoral immune response. After 5 wk, Cfh–/– mice had greater quantities of free anti-apoferritin IgG antibodies compared with wt animals (0.38 ± 0.03 and 0.25 ± 0.02 U/ml in Cfh–/– and wt mice, respectively; P = 0.018 by t test). Antibodies complexed in plasma immune complexes were also measured by virtue of their ability to bind solid-phase C1q (34). In contrast to free anti-apoferritin antibodies, Cfh–/– mice had no change in circulating immune complexes compared with baseline, and these were significantly less than that present in wt mice (0.26 ± 0.03 and 0.68 ± 0.11 U/ml in apoferritin-immunized Cfh–/– and wt mice, respectively; P = 0.024 by t test). These data illustrate the complexities of the complement system in the humoral immune response (35) and immune complex processing (27,28,34). Taken together, it appears that both groups of animals produced anti-apoferritin IgG antibodies, but it was only in the presence of functional factor H that immune complexes were generated and retained in plasma.

We were then interested in whether factor H affected glomerular localization of IgG-containing immune complexes in this experimental serum sickness model. There was minimal IgG in the glomeruli of Cfh–/– animals immunized with saline for 5 wk (Figure 1A), which was no different than wt animals (not shown). In glomeruli of wt mice immunized for 5 wk with apoferritin, there was a significant quantity of IgG in mesangia along with extension to peripheral capillary loops (Figure 1B). In Cfh–/– mice with serum sickness, there was a qualitative (Figure 1C) and quantitative difference (as scored in Figure 1D), in that factor H-deficient animals had more intense mesangial staining as well as greater involvement in peripheral capillary loops.



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  		Figure 1. Factor H limits the accumulation of IgG-containing immune complexes in glomeruli of mice with chronic serum sickness. Shown is representative immunofluorescence staining for IgG in (A) control C57BL/6 factor H-deficient mice (Cfh–/–) mice given saline for 5 wk, and (B) wild-type (wt) or (C) Cfh–/– mice immunized for 5 wk with apoferritin. Staining intensity scores compiled from all mice are also shown (D). *P < 0.002 versus all other groups by ANOVA followed by Fisher’s pairwise comparisons. Original magnifications, 200x.

 
The reasons behind the increased quantities of IgG in glomeruli of Cfh–/– mice are undoubtedly complex, as factor H has a number of potentially relevant functions. Factor H on mouse platelets appears to serve the function of the related CR1 protein on human erythrocytes (29); both have affinity for classical pathway-generated C3b on immune complexes (28,29). Once bound to platelet factor H (or erythrocyte CR1), transfer of immune complexes to the mononuclear phagocyte system is facilitated by factor H (or CR1) serving as cofactor for the factor I-mediated cleavage of C3b to iC3b, which binds to CR3 on phagocytes (28,36). In human glomeruli, CR1 on podocytes also serves an immune adherence function (37,38). As with the circulating immune adherence receptor, it is conceivable that the function of CR1 in human podocytes is served by factor H in rodents (39), which could include immune complex processing within glomeruli. One other consideration is that due to unrestricted complement activation, Cfh–/– mice have acquired deficiency of C3 (14), which can profoundly affect immune complex processing (23,40). However, in our past studies applying this same serum sickness model in C3-deficient mice, IgG deposition in glomeruli was considerably less in C3-deficient mice compared with wt controls (23), making this mechanism less likely. Whatever the mechanism(s), factor H deficiency is associated with defective immune complex processing, leading to a significant increase in immune complex retention in glomeruli.

In control wt mice given saline for 5 wk, there was no glomerular IgG or C3 (not shown), while in wt mice immunized with apoferritin, staining for C3 was of similar distribution and intensity (Figure 2B and scored in Figure 2D) as that for IgG (Figure 1B), suggesting that glomerular IgG-containing immune complexes activated the complement locally. In contrast, although glomeruli of control Cfh–/– mice contained negligible quantities of IgG, there was significant glomerular C3 (Figure 2A). Even as these mice age and spontaneously develop MPGN, C3 and C9 are present in subendothelial deposits while IgG is only present in mesangia (14). Thus, control Cfh–/– mice appear to have unrestricted alternative pathway complement activation in glomeruli rather than immune complex–directed classical pathway activation. In Cfh–/– mice immunized with apoferritin, there was marked complement activation above this baseline (Figure 2C). As with wt mice, IgG and C3 were present together in Cfh–/– mice (in this case throughout the glomerular capillary), supporting the idea that immune complexes were responsible for this increased complement activation. C3 activation by IgG-bearing immune complexes should occur through the classical pathway, which is not appreciably affected by factor H (but rather by C4-binding protein). However, there is growing evidence that such classical pathway activation can contribute to activation of the alternative pathway (41). Thus, it appears that in Cfh–/– mice with serum sickness, impaired systemic and local immune complex processing leads to a significant increase in glomerular IgG-containing complexes, which are capable of activating the classical complement pathway and contributing to unrestricted alternative pathway activation.



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  		Figure 2. Functional factor H limits complement activation in glomeruli of normal mice and in those with chronic serum sickness. Shown is representative immunofluorescence staining for C3 in (A) control Cfh–/– mice given saline for 5 wk, and (B) wt or (C) Cfh–/– mice immunized for 5 wk with apoferritin. Staining intensity scores compiled from all mice are also shown (D). *P < 0.006 versus all other groups by ANOVA followed by Fisher’s pairwise comparisons (i.e. each group was different from another). Original magnification, 200x.

 
In spite of significant immune complex deposition and complement activation, wt mice immunized with apoferritin had no histologic evidence for glomerular disease (Figure 3A). Thus, C57BL/6 mice are relatively resistant to the development of GN in the setting of chronic serum sickness (23,24). Control Cfh–/– mice receiving saline for 5 wk similarly had mild to no evident glomerular pathology (Figure 3B illustrates mesangial prominence, the most severe abnormality in this group), which is consistent with the late development of MPGN in unmanipulated Cfh–/– mice (14). In contrast, all six Cfh–/– mice immunized with apoferritin developed significant GN, characterized by diffuse hypercellularity of the glomerular tufts with focal crescents (Figure 3C, arrow), in addition to the presence of focal and segmental glomerular sclerosis/hyalinosis (Figure 3D). All of these histopathological features were significantly different than in the other groups (Figures 3, E through G). Consistent with the development of glomerular sclerosis in apoferritin-immunized Cfh–/– mice, there was an increase in mRNA for collagen IV, fibronectin, and laminin compared with the other groups as measured by quantitiative RT-PCR (Table 1).



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  		Figure 3. Factor H prevents the development of glomerular pathology in chronic serum sickness. (A) Wt mice immunized with apoferritin for 5 wk had normal glomerular and tubulointerstitial histology. (B) Control Cfh–/– mice administered saline for 5 wk had either normal glomeruli or mild mesangial changes. In contrast, Cfh–/– mice immunized for 5 wk with apoferritin developed GN, characterized by diffuse hypercellularity and focal crescent formation (C, arrow) as well as focal and segmental hyalinosis/sclerosis (D, glomerulus at right). Scoring for the extent of glomerulonephritis (E), percent involvement of glomeruli with crescents (F), and sclerosis/hyalinosis (G) in all mice is also shown. *P < 0.001 and **P < 0.0025 versus all other groups by ANOVA followed by Fisher’s pairwise comparisons. Original magnification, 200x (A), 400x (B through D).

 

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  		Table 1. Expression of mRNA for matrix components in renal cortices of mice immunized with apoferritin or salinea

 
Urinary albumin excretion in apoferritin-immunized wt mice was elevated compared with that of control animals, while blood urea nitrogen levels were normal (Table 2). These data are consistent with our past findings in this model (23). In spite of the marked difference in renal pathologic findings in apoferritin-immunized wt and Cfh–/– mice, there was no difference in albuminuria between the two groups. Hence, there is not a direct relationship between the presence of glomerular immune complexes, C3 deposition or glomerular sclerosis/hyalinosis, and impaired glomerular permselectivity in this model. Although blood urea nitrogen levels were elevated in apoferritin-immunized Cfh–/– mice, because of the variability of these values in this group of animals (range, 28 to 126 mg/dl), they were not statistically different from the other groups. Given the renal pathologic findings of significant GN and glomerular sclerosis/hyalinosis (≥4.3% glomerular involvement) in all six Cfh–/– mice surviving the full 5 wk of apoferritin immunization, it does seem likely that if the study were extended each of these animals would have developed renal insufficiency. It is also conceivable that the four apoferritin-immunized Cfh–/– mice that died before the study conclusion did so as a result of renal failure, and hence were informatively censored from these analyses (42).


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  		Table 2. Renal functional data in mice immunized with apoferritin or salinea

 
These results show an important role for factor H to limit glomerular deposition of immune complexes. The two leading explanations for this are that platelet-associated factor H processes immune complexes in the circulation and that factor H inhibits systemic alternative pathway activation, preventing consumption of functional complement proteins. Other possibilities include local factor H effects in glomeruli and prevention of complement activation directly on immune complexes. Once deposited in glomeruli, immune complexes activate complement through the classical pathway; in the absence of factor H, this can initiate alternative pathway activation. The presence of IgG and complement activation products in glomeruli are proinflammatory, both by their actions on Fc{gamma} and complement receptors on inflammatory and resident glomerular cells, as well as via the direct effects of complement activation products, such as C5b-9 (15,16,43,44). Although the C57BL/6 strain is resistant to chronic serum sickness, the superimposed presence of factor H deficiency in this strain leads to an increase in glomerular immune complex and complement deposition. These overcome an inherent resistance that can have a genetic basis (20) and result in acute and chronic inflammatory changes in glomeruli.


   Acknowledgments
 
This work was supported by National Institutes of Health grant R01DK41873 and by a grant to J.J.A. from Kidneeds. We thank Dr. Marina Botto (Hammersmith Hospital, London, UK) for providing us with the factor H-deficient mouse strain and Dr. Yasushi Nakagawa (University of Chicago) for clinical measurements.


   References
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 Abstract
 Introduction
 Experimental Model
 Results and Discussion
 References
 

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Received for publication September 18, 2004. Accepted for publication October 24, 2004.




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