Patterns of Complement Activation in Idiopathic Membranoproliferative Glomerulonephritis, Types I, II, and III

Varade, William S.; Forristal, Judith; West, Clark D.

doi:10.1016/s0272-6386(12)81018-3

Cited by 55 publications

(35 citation statements)

References 26 publications

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“…Type II MPGN usually is associated with a reduction in C3 only, with involvement of terminal components in type III disease. Evidence of either classical activation or terminal component depression is seen in type I MPGN [3]. …”

Section: Evidence Of Complement Activation In Glomerulonephritismentioning

confidence: 99%

The Complement System in Renal Diseases

Welch¹

2001

Nephron

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The complement system has long been recognized as having a role in immune glomerular disease. This review provides an update on this association, some strategies for the clinical testing of complement in disease, and a brief commentary on current research directions. Evidence of complement activation in glomerulonephritis comes from characteristic patterns of a decrease in the serum concentrations of specific components, some of which are virtually diagnostic of certain nephritides. These patterns are often accompanied by the presence of complement components in the glomeruli and the detection of complement breakdown products in the circulation. In certain diseases, circulating complement-activating substances can be detected. Although there are over 20 complement proteins, clinical analysis is most often directed at C3 and C4, with occasional measurement of B and C5. Recently, a variety of mechanisms for complement-induced injury has been recognized. These mechanisms go far beyond simple passive lysis of erythrocytes, the earliest functional effect of complement studied. The role of such mechanisms in renal disease is just beginning to be studied. Local synthesis of complement components in the kidney may play a role both in host defense and in the promotion of interstitial inflammation and scarring. Such mechanisms will likely be defined more precisely with the availability of animals with specific complement deficiencies. Ultimately, an understanding of the role of complement in renal disease may permit specific targeted inhibition of one or more complement functions as a form of therapy.

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Section: Evidence Of Complement Activation In Glomerulonephritismentioning

confidence: 99%

The Complement System in Renal Diseases

Welch¹

2001

Nephron

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“…Since the original characterizations of the pathologic features defining MPGN II were reported, numerous studies have linked the development of MPGN to abnormalities in the alternative pathway of the complement system [4]. Evidence supporting a primary role for alternative pathway dysregulation includes the near universal finding of persistently low serum C3 with normal C4 levels; the identification in many patients of a circulating autoantibody (nephritic factor) which stabilizes the alternative pathway C3 convertase, and the development of MPGN II in individuals deficient in the alternative pathway regulatory protein factor H (FH) [3,5,6,7]. Despite these advances, the pathogenic mechanisms that link alternative pathway activation to the development of the pathologic lesions of MPGN II remain elusive.…”

Section: Introductionmentioning

confidence: 99%

Proteomic Profiling of Urinary Protein Excretion in the Factor H-Deficient Mouse

Braun

et al. 2006

Am J Nephrol

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Background: Since the 1970s a variety of experimental techniques have been employed in an attempt to identify urinary biomarkers of renal injury. While these approaches have met with some success, modern proteomic tools now permit broad based high-throughput analysis of the urinary proteome. Methods: Using the ICAT isotopic labeling based LC/MS/MS approach, comparative urinary protein profiling was performed in a murine model of membranoproliferative glomerulonephritis. Paired samples were analyzed mice with a targeted deletion of the complement regulatory protein factor H (FH^–/–) and control mice. Results: 25 distinct urinary proteins were identified of which 7 were differentially expressed in the FH^–/– mice. Two proteins were markedly altered in the urine of FH^–/– mice compared to controls: uromodulin (5.5-fold lower) and the MHC class II molecule H2^e (8.6-fold higher). Differential expression was confirmed by Western blot and RT-PCR. Immunofluorescent staining demonstrated a marked increased expression of H2^e and a reduction of uromodulin expression in the tubular epithelium of FH^–/– mice. Conclusions: These findings provide insight into early complement-dependent alterations in tubular protein expression which may play critical roles in the development of tubulointerstitial disease, and provide experimental support for the use of urinary proteomic profiling in murine models of renal injury.

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“…Intramembranous glomerular basement membrane (GBM) deposits together with C3 (10), C5 (11), and C9 (12) staining along the GBM in the absence of Ig characterize type II MPGN (13). Patients typically have low C3 levels while C5 levels remain normal (14). MPGN type II is frequently associated with the presence of C3 nephritic factor (C3NeF), an autoantibody that stabilizes the alternative pathway C3 convertase, preventing its inactivation by factor H and resulting in excessive C3 activation (15).…”

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confidence: 99%

Prevention of C5 activation ameliorates spontaneous and experimental glomerulonephritis in factor H-deficient mice

Pickering¹,

Warren²,

Rose³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

147

119

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Membranoproliferative glomerulonephritis (MPGN) type II (dense deposit disease) is an inflammatory renal disease characterized by electron-dense deposits and complement C3 on the glomerular basement membrane. There is no effective therapy. We investigated the role of C5 activation in a model of MPGN that develops spontaneously in complement factor H-deficient mice (Cfh ؊/؊ ). At 12 months there was a significant reduction in mortality, glomerular cellularity, neutrophil numbers, and serum creatinine levels in Cfh ؊/؊ mice deficient in C5. Excessive glomerular neutrophil numbers, frequently seen in patients with MPGN during disease flares, were also observed in Cfh ؊/؊ mice after the administration of an antiglomerular basement membrane antibody. This exaggerated injurious phenotype was absent in Cfh ؊/؊ mice deficient in C5 but not in Cfh ؊/؊ mice deficient in C6, indicating a key role for C5 activation in the induction of renal lesions. Importantly, the renal injury was completely reversed in Cfh ؊/؊ mice pretreated with an anti-murine C5 antibody. These results demonstrate an important role for C5 in both spontaneous MPGN and experimentally induced nephritis in factor H-deficient mice and provide preliminary evidence that C5 inhibition therapy might be useful in human MPGN type II.complement ͉ inflammation T he complement system is a key component of innate immunity contributing to host defenses against invading pathogens through multiple mechanisms, which include opsonization, cell lysis, and inflammatory cell recruitment, an action principally mediated through the anaphylatoxin C5a. Complement activation is regulated by a complex group of membrane-bound and fluid-phase proteins (1). Factor H is an abundant serum complement regulatory protein that inhibits the alternative pathway of complement activation. It achieves this through several mechanisms, which include inhibition of the alternative pathway C3 convertase enzyme complex (C3bBb) and acting as a cofactor for the factor I-mediated proteolytic degradation of activated C3 (termed C3b) (2, 3). Its critical importance as a regulator of C3 activation in vivo is illustrated by the complement profile reported in factor H-deficient individuals, where alternative pathway activation proceeds unhindered, resulting in markedly reduced C3 levels (4).Factor H deficiency in humans (5, 6), pigs (7), and mice (8) is associated with membranoproliferative glomerulonephritis (MPGN) type II (dense deposit disease). MPGN is characterized by glomerular capillary wall thickening with increased mesangial matrix and mesangial cells (9). Intramembranous glomerular basement membrane (GBM) deposits together with C3 (10), C5 (11), and C9 (12) staining along the GBM in the absence of Ig characterize type II MPGN (13). Patients typically have low C3 levels while C5 levels remain normal (14). MPGN type II is frequently associated with the presence of C3 nephritic factor (C3NeF), an autoantibody that stabilizes the alternative pathway C3 convertase, preventing its inactivation by factor...

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Patterns of Complement Activation in Idiopathic Membranoproliferative Glomerulonephritis, Types I, II, and III

Cited by 55 publications

References 26 publications

The Complement System in Renal Diseases

The Complement System in Renal Diseases

Proteomic Profiling of Urinary Protein Excretion in the Factor H-Deficient Mouse

Prevention of C5 activation ameliorates spontaneous and experimental glomerulonephritis in factor H-deficient mice

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