Nephritic factors predispose to chronic glomerulonephritis. (1995 Jan)
nephritic factors predispose to chronic glomerulonephritis . chronic glomerulonephritis has been reported in three rare conditions in which factor H of the complement system does not function normally . factor H is essential for the inactivation of the C3b dependent convertase , C3b , Bb , which is constantly being formed in vivo . With factor H dysfunction , this convertase accumulates and produces hypocomplementemia . twenty two individuals have been reported with the three forms of H dysfunction , and 12 have displayed evidence of chronic glomerulonephritis . In addition , matings of certain yorkshire pigs result in offspring that are homozygous deficient in factor H and have a high incidence of a severe hypocomplementemic glomerulonephritis closely resembling membranoproliferative glomerulonephritis type II . The hypothesis proposed is that the nephritis that develops with these forms of H dysfunction is in some way the result of circulating convertase . The corollary is that nephritic factors , also producing H dysfunction and higher than normal circulating levels of the C3b dependent convertase , are responsible for the glomerulonephritides with which they are associated , mainly membranoproliferative glomerulonephritis types II and III . nephritic factors are autoantibodies that bind to the C3b dependent convertase and render it resistant to dissociation by factor H . although nephritic factors are currently considered epiphenomena , their role in the pathogenesis of membranoproliferative glomerulonephritis should be reconsidered based on the evidence that circulating convertase is nephritogenic .

Rat glomerular epithelial cells produce and bear factor H on their surface that is up regulated under complement attack. (2003 Aug)
Rat glomerular epithelial cells produce and bear factor H on their surface that is up regulated under complement attack . background : factor H is a potent complement inhibitory molecule that is primarily produced by the liver and appears in plasma as a soluble protein . Yet there is evidence that other cells , including those in the kidney , can produce factor H , and that it can be cell associated as well as present as a plasma protein . Here we studied factor H in rat glomerular epithelial cells ( GEC ) . methods : A polyclonal antibody to factor H was used to identify factor H protein . A polymerase chain reaction ( PCR ) based strategy was utilized to clone the full length cDNA of GEC factor H . The relative quantity of factor H mRNA was measured by quantitative reverse transcription ( RT ) PCR in cultured GEC exposed to complement activation and in the passive heymann nephritis ( PHN ) model of membranous nephropathy . results : By immunofluorescence microscopy , factor H protein was present on the plasma membranes of cultured GEC . based upon western blot studies , this appeared to be the full length 150 kD factor H protein . factor H cDNA cloned from GEC was identical to the newly deposited sequence for rat liver factor H cDNA . In cultured GEC in which complement was activated , factor H mRNA increased over time . similarly , in the PHN …

Erythrocyte complement receptor type 1 in patients with systemic lupus erythematosus. (1989 Dec)
erythrocyte complement receptor type 1 in patients with systemic lupus erythematosus . erythrocyte complement receptor type 1 ( CR1 ) was measured in 71 patients with systemic lupus erythematosus ( SLE ) and 43 healthy controls . The level of erythrocyte CR1 in patients with SLE was significantly lower than that of controls and correlated with the disease activity of SLE . The more active the disease , the greater the decrease in erythrocyte CR1 . The level of erythrocyte CR1 was inversely correlated with the level of circulating immune complexes ( CIC ) and was positively correlated with C3 , CH50 , factor B , and factor H . We also found lupus nephritis more frequently in patients with decreased erythrocyte CR1 than in those with normal levels of erythrocyte CR1 . Our results suggest that the deficiency of erythrocyte CR1 in patients with SLE is acquired and may serve as a variable of clinical disease activity and may play a role in the pathogenesis of SLE .

Combined homozygous factor H and heterozygous C2 deficiency in an italian family. (1988 Jun)
combined homozygous factor H and heterozygous C2 deficiency in an italian family . three of four children in a family have homozygous ( less than 1 of normal ) deficiency of factor H of the complement system and both parents , who are first cousins , are heterozygous for the same defect . The father and two of the H deficient siblings also have a partial C2 deficiency . One of the children with combined deficiencies is affected by systemic lupus erythematosus with nephritis . No increased susceptibility to infections has been observed in the family . H deficiency is inherited in an autosomal codominant manner and is independently transmitted from C2 deficiency and HLA haplotypes . In the homozygous state it is associated with very low serum concentrations of B and C3 , barely demonstrable as activated molecules . C5 is greatly reduced ( less than 5 ) . Also , properdin and C6 9 are decreased . The findings in this family demonstrate that the occurrence of systemic lupus erythematosus in one of the children affected by a combined deficiency of factor H and C2 raises the question whether this pathology is related to the complete factor H or to the heterozygous C2 deficiency . complete H deficiency is not necessarily accompanied by overt illness .

Urinary complement factor H in renal disease. (2002 Oct)
urinary complement factor H in renal disease . background : complement factor H ( hCFH ) plays a key inhibitory role in the control of the alternative complement pathway . We examined whether urinary hCFH ( U hCFH ) levels is useful as an indirect indicator of renal damage . methods : urine samples were obtained from 104 patients with renal disease . urine was collected with 10 mM EDTA and U hCFH levels were measured using the BTA TRAK assay Kit . results : In the 62 patients with nephritis , the levels of U hCFH were elevated ( range 15 52 , 198 U / ml ) over the normal range ( 0 14 U / ml ) . U hCFH levels of patients with chronic renal failure , lupus nephritis , membranoproliferative glomerulonephritis , focal glomerulosclerosis were higher than that of IgA nephropathy patients ( p 0 . 05 ) . In the patients with minimal change disease , showed high levels of U hCFH during the nephrotic syndrome . U hCFH was correlated significantly with urinary protein and urinary N acetyl beta D glucosaminidase . conclusions : We demonstrated that U hCFH was detected in the urine of nephritis patients .

Complement and glomerulonephritis : new insights. (2005 Apr)
complement and glomerulonephritis : new insights . purpose OF review : The last few years have seen a huge increase in our understanding of the role of the complement system and its regulation in glomerular disease . Our aim is to summarize the most important advances in this field . recent findings : The role of complement in systemic lupus erythematosus continues to be elucidated . classical pathway components protect from the development of autoimmunity , at least in part , through their role in the clearance of apoptotic cells . In contrast , the alternative pathway plays a direct role in exacerbating glomerular injury . Anti C1q antibodies are related to activity in lupus nephritis and recent studies have shown that they are directly pathogenic in animal models . proteinuria , whatever the cause , may lead to tubulointerstitial injury and complement activation adds to this process . In particular , deposition of terminal components of complement in the tubular lumen contributes to interstitial myofibroblast activation . there is increasing evidence for the role of complement regulatory proteins in glomerular injury . In particular , abnormalities of factor H or of CD46 may predispose to atypical haemolytic uraemic syndrome . The control proteins also protect against injury in immune complex glomerulonephritis . summary : advances in our understanding of the role of complement in glomerular injury point to the likely therapeutic benefits of targeting the complement system . Many new drugs are becoming available . careful dissection of the …

Modulation of renal disease in MRL / lpr mice genetically deficient in the alternative complement pathway factor B. (2000 Feb)
modulation of renal disease in MRL / lpr mice genetically deficient in the alternative complement pathway factor B . In systemic lupus erythematosus , the renal deposition of complement containing immune complexes initiates an inflammatory cascade resulting in glomerulonephritis . activation of the classical complement pathway with deposition of C3 is pathogenic in lupus nephritis . although the alternative complement pathway is activated in lupus nephritis , its role in disease pathogenesis is unknown . To determine the role of the alternative pathway in lupus nephritis , complement factor B deficient mice were backcrossed to MRL / lpr mice . MRL / lpr mice develop a spontaneous lupus like disease characterized by immune complex glomerulonephritis . We derived complement factor B wild type ( B / ) , homozygous knockout ( B / ) , and heterozygous ( B / ) MRL / lpr mice . compared with B / or B / mice , MRL / lpr B / mice developed significantly less proteinuria , less glomerular IgG deposition , and decreased renal scores as well as lower IgG3 cryoglobulin production and vasculitis . serum C3 levels were normal in the B / mice compared with significantly decreased levels in the other two groups . these results suggest that : 1 ) factor B plays an important role in the pathogenesis of glomerulonephritis and vasculitis in MRL / lpr mice ; and 2 ) activation of the alternative pathway , either by the amplification loop or by IgA immune …

Prevention of C5 activation ameliorates spontaneous and experimental glomerulonephritis in factor H deficient mice. (2006 Jun)
prevention of C5 activation ameliorates spontaneous and experimental glomerulonephritis in factor H deficient mice . 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 .

Effects of complement factor D deficiency on the renal disease of MRL / lpr mice. (2003 Dec)
effects of complement factor D deficiency on the renal disease of MRL / lpr mice . background : The alternative complement pathway ( AP ) is activated in individuals with lupus nephritis and in murine models of systemic lupus erythematosus , including MRL / lpr mice . A previous study from our laboratory evaluated the development of renal disease in MRL / lpr mice genetically deficient in factor B ( Bf / ) , a protein necessary for AP activation . MRL / lpr Bf / mice developed less renal disease and had improved survival ; however , these mice were also a different major histocompatibility complex ( MHC ) haplotype ( H 2b ) than their wild type littermates ( H 2k ) due to the gene for Bf being located in the MHC gene complex . We undertook the current study to determine if the decreased renal disease in MRL / lpr Bf / mice was due to the lack of AP activation or the H 2b haplotype by studying the effects of factor D ( Df ) deficiency , a critical protein for AP activation , on disease development in MRL / lpr mice . methods : Df deficient mice were backcrossed with MRL / lpr mice for four to nine generations . MRL / lpr H 2k Df / , Df / , and Df / littermates were evaluated for disease development . Lack of AP activation in MRL / lpr Df / mice was determined …

Serum immunoglobulins in heymann s experimental nephritis modulate binding of properdin and factor H to sulpho glycosphingolipids ii3so3 ( ) … (1995 Feb)
serum immunoglobulins in heymann s experimental nephritis modulate binding of properdin and factor H to sulpho glycosphingolipids ii3so3 ( ) gg3cer and iii3so3 ( ) , ii3so3 ( ) gg3cer . The nephropathic effects of heymann s experimental nephrites involve autoallergic serum antibodies directed against rat kidney membrane constituents . In assessing the action of glycolipids as possible autoallergens in these conditions , it was found that heterologous and autologous heymann s nephritis sera antibodies recognize that rat kidney sulphatides , ii3so3 ( ) gg3cer ( stri1 ) , and iii3so3 ( ) , ii3so3 ( ) gg3cer ( stri2 ) . Two antibody populations in heymann s sera , each reacting with only one of the two sulphatides , could be observed . It was further shown that human factor H and properdin , pivotal regulators of the alternative pathway of complement activation , both bound to stri2 in vitro . This binding of factor H and properdin was differentially affected by affinity purified anti stri2 antibodies of heymann s nephritis sera . whereas the interaction between factor H and stri2 was inhibited by the antibody , that of properdin was enhanced .

Hypocomplementemic glomerulonephritis in an infant and mother. (1988 Apr)
hypocomplementemic glomerulonephritis in an infant and mother . evidence for an abnormal form of C3 . A mother developed hematuria during the fourth month of pregnancy , and her nursing infant son from this otherwise uncomplicated pregnancy developed hematuria at 3 . 5 months of age . Both had a mild glomerulonephritis characterized by mesangial prominence , focal thickening and mottling of the glomerular basement membrane and electron dense deposits , predominantly in the intramembranous and subendothelial positions . immunofluorescence studies revealed striking accumulations of C3 and other complement components associated with alternative complement pathway activation within glomeruli , and the presence of small or equivocal amounts of immunoglobulin . C1q , C4 and factor B were not detectable . The glomerular lesion was accompanied by hypocomplementemia . Sera of both mother and infant displayed half normal levels of C3 and factor B , increased levels of C4 , and normal levels of 12 other complement proteins . High normal or slight elevation in nephritic factor like activity was observed in serial serum samples . studies suggested that this mother and son represent the second kindred having an abnormal form of C3 which produces an alternative complement pathway C3 convertase , C3b , Bb , resistant to control by factor H . No additional affected family members were identified . The course of the nephritis over 7 years without drug therapy has been mild with resolving hematuria and no abnormal proteinuria or decrease in creatinine clearance .

Glomerulonephritis in a patient with complement factor I deficiency. (1999 Jun)
glomerulonephritis in a patient with complement factor I deficiency . complement factor I deficiency is known to be associated with recurrent pyogenic infections . The patient described here had recurrent attacks of otitis , sinusitis , and bronchopneumonia since childhood . At the age of 24 years , he had an acute episode of systemic vasculitis with purpura , but no nephritis . A factor I deficiency was diagnosed when he was 36 years old . because of the uncontrolled activation of the alternative pathway of complement , several other components were depleted , in particular C3 , which explained the predisposition for pyogenic infections . A progressive loss of renal function accompanied by proteinuria and hematuria started after the age of 40 years . renal biopsy showed a focal segmental glomerulonephritis ( GN ) with glomerular deposits of immunoglobulins and complement C3 and C4 fragments . The glomerular podocytes showed an almost complete loss of complement receptor 1 ( CR1 ; CD35 ) . The expression of CR1 was very low on erythrocytes , as well . Thus , CR1 , the most efficient cell bound cofactor for the inactivation of C4b / C3b by factor I , appears to be consumed when factor I is missing . although this is the first report of factor I deficiency associated with GN , it is unlikely that the development of the nephritis was fortuitous because GN has been found in many other diseases characterized by uncontrolled activation of the alternative …

Activation of the lectin complement pathway in henoch schönlein purpura nephritis. (2005 Feb)
activation of the lectin complement pathway in henoch schönlein purpura nephritis . background : We previously reported the existence of complement activation through the alternative and lectin pathways in patients with immunoglobulin A ( IgA ) glomerulonephritis ( GN ) . The current study aims to elucidate the correlation between each complement pathway and clinicopathologic findings in patients with henoch schonlein purpura nephritis ( HSPN ) . methods : immunohistologic staining was performed on renal specimens obtained from 31 patients with HSPN and 20 controls as non IgA GN by using antibodies against IgG , IgA , IgA1 , IgA2 , IgM , C1q , C3c , C4 , fibrinogen , factor B , C4 binding protein ( C4 bp ) , C5b 9 , CD59 , mannose binding lectin ( MBL ) , and MBL associated serine protease 1 ( MASP 1 ) . results : No control showed deposition of any antibody . In 16 patients with mesangial IgA1 / IgA2 codeposits , mesangial deposits of C3c , C4 , factor B , C4 bp , C5b 9 , CD59 , MBL , and MASP 1 were found . In the remaining 15 patients with mesangial IgA1 deposits alone , no mesangial deposits of C4 or MBL / MASP 1 were found , and mesangial deposits of C3c , factor B , C5b 9 , and CD59 were evident in 11 patients . glomerular deposits of fibrinogen were detected in 15 of 16 patients with IgA1 / IgA2 …

Complement mediated solubilization of immune complexes. (1984 Mar)
complement mediated solubilization of immune complexes . solubilization inhibition and complement factor levels in SLE patients . thirty two of 36 serum samples from 19 SLE patients showed reduced capacity to mediate complement dependent solubilization of immune complexes ( IC ) . SLE patients with nephritis exerted the lowest complement mediated solubilization capacity ( CMSC ) whereas sera from patients with inactive disease gave the highest CMSC values , with three out of four samples within the normal reference range . thirty five of the 36 serum samples showed inhibition of CMSC in a newly developed CMSC inhibition assay . The strongest CMSC inhibition was exerted by sera from newly discovered cases of SLE who received no medical treatment and the lowest inhibition by sera from patients with inactive disease . there was a significant negative correlation between CMSC and CMSC inhibition ( r 0 . 67 , P less than 0 . 001 ) . Sera with low concentrations of C1q , C3 , factor B or high C3d levels showed markedly reduced CMSC values . pronounced CMSC inhibition was observed only in samples with normal or high factor H values . No significant correlation was found between CMSC or CMSC inhibition and circulating IC levels , but pronounced CMSC inhibition was registered only in strongly IC positive sera .