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PubMed1998

M protein of the group A Streptococcus binds to the seventh short consensus repeat of human complement factor H.

Streptococcus pyogenes evades complement by binding the complement-regulatory protein factor H (fH) via the central conserved C-repeat region of M protein. However, the corresponding binding region within fH has not previously been precisely localized. fH is composed of 20 conserved modules called short consensus repeats (SCRs), each of which contains approximately 60 amino acids. A series of fH truncated and deletion mutants were prepared, and their interaction with M6 protein was examined. The M protein binding site was initially localized to SCRs 6 to 15 as demonstrated by ligand dot blotting, chemical cross-linking, and enzyme-linked immunosorbent assay. SCR 7 was then shown to contain the M protein binding site, as a construct consisting of the first seven SCRs bound M protein but a construct containing the first six SCRs did not bind. In addition, deletion of SCR 7 from full-length fH abolished binding to M protein. SCR 7 is known to contain a heparin binding domain, and binding of fH to M6 protein was almost totally inhibited in the presence of 400 U of heparin per ml. These results localize the M6 protein binding site of fH to SCR 7 and indicate that it is in close proximity to the heparin binding site.

Animals↗
PubMed1987

Human complement factor H: expression of an additional truncated gene product of 43 kDa in human liver.

The human complement factor H is an important factor in the control of the alternative pathway and also induces the stimulation of B cells and macrophages in vitro. Using a human factor H cDNA clone as probe, two factor H-specific transcripts of 4.4 and 1.8 kb were detected in four human livers. Both mRNAs were found independently of the expression of an acute phase marker SAA, in these livers, indicating that their presence is not linked to an acute phase state. The shorter transcript was cloned in two cDNA plasmids H-19 and H-20, lacking only seven amino acids of the N-terminus of the mature factor H protein. The deduced protein sequence showed that this protein is identical to the N-terminal portion of the large classical factor H of 150 kDa mol. mass. Parallel to the finding that the N-terminal sequence of factor H is expressed by two distinct mRNA species, evidence is presented that the C-terminal sequence is also contained on two different transcripts, the common 4.4-kb mRNA and an additional 1.0-kb mRNA. A novel, short form of human complement factor H of 43 kDa was detected in human sera which represents the translation product of the 1.8-kb factor H-specific mRNA detected in human liver. Five distinct epitopes detected with 6 monoclonal antibodies are present on both the 150-kDa factor H protein and the truncated 43-kDa molecule. We conclude that additional H-specific mRNAs are found in human liver and that at least one of them is translated yielding a truncated form of factor H.

Amino Acid Sequence↗
PubMed1986

Partial characterization of human complement factor H by protein and cDNA sequencing: homology with other complement and non-complement proteins.

Factor H, a control protein of the human complement system, is closely related in functional activity to two other complement control proteins, C4b-binding protein (C4bp) and complement receptor type 1 (CR1). C4bp is known to have an unusual primary structure consisting of eight homologous units each about 60 amino acids long. Such units also occur in the N-terminal regions of the complement proteins C2 and factor B, and in the non-complement serum glycoprotein beta 2I. Amino acid sequencing, and sequencing of a factor H cDNA clone, show that factor H also contains internal repeating units, and is homologous to the proteins listed above.

Amino Acid Sequence↗
PubMed1991

Human complement factor H: two factor H proteins are derived from alternatively spliced transcripts.

The human complement factor H is an important component in the control of the alternative pathway of complement activation. We have previously shown that a least three factor H homologous mRNA species of 4.3 kb, 1.8 kb and 1.4 kb in length are constitutively expressed in human liver. In addition, several factor H-related proteins have been detected in human sera using antibodies directed against the classical human factor H glycoprotein of 150 kDa. The structure of the additional polypeptides has not been shown so far. Circumstantial evidence suggests that the 1.8-kb mRNA might encode the 43-kDa factor H-like polypeptide. Here we report the isolation, characterization and eukaryotic expression of the first full-length cDNA representing the major 4.3-kb mRNA and the 1.8-kb mRNA of human factor H. We show that the 4.3-kb transcript encodes the 150-kDa-factor H glycoprotein and the 1.8-kb mRNA the 43-kDa factor H polypeptide. The identity of the two cDNA in a region of 1400 nucleotides suggests that the two factor H-related transcripts are derived from one gene by a process of alternative splicing.

Amino Acid Sequence↗
PubMed1992

Limited tryptic cleavage of complement factor H abrogates recognition of sialic acid-containing surfaces by the alternative pathway of complement.

The potency of complement factor H (H) in accelerating the decay of the alternative pathway C3 convertase, C3b,Bb (decay-accelerating activity), was used as a measure of the affinity of native versus trypsin-treated H for the complement protein C3b bound to surfaces. When about 99% of H was cleaved at the primary tryptic cleavage site 34 kDa from the N-terminus, its decay-accelerating activity on C3b,Bb on sheep erythrocytes fell about 60-fold, whereas the trypsin-treated H was only 3-4 times less potent than native H in dissociating C3b,Bb on Sepharose 4B. The residual decay-accelerating activity, remaining after the primary cleavage, was not affected by secondary cleavage at a site 120 kDa from the N-terminus, as shown with H preparations cleaved to different degrees. Because cell surface sialic acid is known to be responsible for the high affinity of H for C3b bound on sheep erythrocytes, the results strongly suggest that the integrity of the primary tryptic cleavage site of H is essential for the recognition of sialic acid-containing surfaces by the C3b-H complex.

Animals↗
PubMed2003

Association between complement factor H and proteoglycans in early human coronary atherosclerotic lesions: implications for local regulation of complement activation.

OBJECTIVE: Complement activation has been suggested to play a role in atherogenesis. To study the regulation of complement activation in human coronary atherosclerotic lesions, we examined the spatial relationships between the major complement inhibitor, factor H, and the complement activation products C3d and C5b-9. METHODS AND RESULTS: In early lesions (American Heart Association types II and III), factor H was immunohistochemically found in the superficial proteoglycan-rich layer in association with numerous macrophages and C3d, whereas C5b-9 was found deeper in the intima, where factor H was virtually absent. In vitro experiments involving surface plasmon resonance and affinity chromatography analyses demonstrated that isolated human arterial proteoglycans bind factor H, and functional complement assays showed that glycosaminoglycans inhibit the complement activation induced by modified low density lipoprotein or by a foreign surface. CONCLUSIONS: The present observations raise the possibility that proteoglycans, because of their ability to bind the major complement inhibitor factor H, may inhibit complement activation in the superficial layer of the arterial intima. In contrast, deeper in the intima, where factor H and proteoglycans are absent, complement may be activated and proceed to C5b-9. Thus, the superficial and the deep layers of the human coronary artery appear to differ in their ability to regulate complement activation.

Adult↗
PubMed1996

Efficient destruction of human immunodeficiency virus in human serum by inhibiting the protective action of complement factor H and decay accelerating factor (DAF, CD55).

Activation of the human complement system leads to complement deposition on human immunodeficiency virus (HIV) and HIV-infected cells without causing efficient complement-mediated lysis. Even in the presence of HIV-specific antibodies, only a few particles are destroyed, demonstrating that HIV is intrinsically resistant to human complement. Here we report that, in addition to decay accelerating factor (DAF) being partially responsible, human complement factor H (CFH), a humoral negative regulator of complement activation, is most critical for this resistance. In the presence of HIV-specific antibodies, sera devoid of CFH (total genetic deficiency or normal human serum depleted of CFH by affinity chromatography) lysed free virus and HIV-infected but not uninfected cells. In the presence of CFH, lysis of HIV was only obtained when binding of CFH to gp41 was inhibited by a monoclonal antibody against a main CFH-binding site in gp41. Since CFH is an abundant protein in serum, and high local concentration of CFH can be obtained at the surface of HIV as the result of specific interactions of CFH with the HIV envelope, it is proposed that the resistance of HIV and HIV-infected cells against complement-mediated lysis in vivo is dependent on DAF and CFH and can be overcome by suppressing this protection. Neutralization of HIV may be achieved by antibodies against DAF and, more importantly, antibodies against CFH-binding sites on HIV envelope proteins.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Complement factor H mutation in familial thrombotic thrombocytopenic purpura with ADAMTS13 deficiency and renal involvement.

Thrombotic thrombocytopenic purpura is a rare disorder of small vessels that is associated with deficiency of the von Willebrand factor-cleaving protease ADAMTS13, which favors platelet adhesion and aggregation in the microcirculation. The disease manifests mainly with central nervous system symptoms, but cases of renal insufficiency have been reported. Presented are findings of the genetic basis of phenotype heterogeneity in thrombotic thrombocytopenic purpura in two sisters within one family. The patients had ADAMTS13 deficiency as a result of two heterozygous mutations (causing V88M and G1239V changes). In addition, a heterozygous mutation (causing an S890I change) in factor H of complement was found in the patient who developed chronic renal failure but not in her sister, who presented with exclusive neurologic symptoms.

ADAM Proteins↗
PubMed2005

A case of atypical hemolytic uremic syndrome with a transient decrease in complement factor H.

We report a case of sporadic atypical hemolytic uremic syndrome (HUS) with a transient decrease in complement factor H. Referred for hemolysis and azotemia without diarrhea prodrome, this 31-month-old boy showed a decreased complement 3 (C3) and complement factor H (FH) level. However, the factor H gene (HF1) mutation was missing. After the hemolysis was controlled with plasma infusion, the C3 and FH levels recovered. The patient's renal function fully recovered and remained normal, and there was no recurrence of the HUS.

Child, Preschool↗
PubMed1989

Serological survey of complement factor H in common laboratory and wild mice: a new third allotype.

Antigenic specificities of complement factor H from mice were studied serologically. In addition to previously reported allotypes, referred to as H.1 and H.2, a new allotype of complement factor H, H.3, was identified in the BFM/2Ms strain derived from European wild mice. Using three different alloantisera raised against the various mouse factor H allotype, a serological survey of the common laboratory strains and wild-derived strains of Mus musculus and its relatives, Mus spretus, Mus spretoides, and Mus spicilegus was carried out. All of the common laboratory strains examined in this survey had the H.1 allotype except for STR/N which had H.2. The geographical distributions of factor H allotypes in M. musculus were specific to the subspecies. Mice derived from Mus musculus domesticus and Mus musculus castaneus had the H.1 allotype. Mice derived from M. m. musculus, Mus musculus bactrianus, and Mus musculus molossinus had the H.2 allotype. Only BFM/2Ms and BFM/1Mpl strains derived from M. m. domesticus had the novel H.3 allotype. Sera of mice from strains derived from M. spretoides and M. spicilegus cross-reacted with H.2-specific antiserum, and those from M. spretus cross-reacted with H.3-specific antiserum.

Alleles↗
PubMed1987

Sequence analysis of a cDNA clone encoding the C-terminal end of human complement factor H.

Peptide sequencing of the complement system regulatory protein, factor H, permitted the synthesis of a mixed sequence oligonucleotide probe. Human liver cDNA libraries were screened and factor H-specific clones selected. No full-length clone was obtained, but the largest available clone, R2a, was found to encode the C-terminal 657 amino acids of factor H. The derived amino acid sequence consists of 10 contiguous internally homologous segments, each about 60 amino acids long. Sequences homologous to these are found in several other complement and non-complement proteins. Such sequences are likely to represent a particular type of tertiary structure subunit.

Amino Acid Sequence↗
PubMed2006

The simple design of complement factor H: Looks can be deceiving.

The complement system is a powerful component of innate immunity which recognizes and facilitates the elimination of pathogens and unwanted host material. Since complement can also lead to host tissue injury and inflammation, strict regulation of its activation is important. One of the key regulators is complement factor H (CFH), a protein with an ever-expanding list of relevant functions. Inherited mutations in CFH can account for membranoproliferative glomerulonephritis (MPGN) type II, atypical hemolytic uremic syndrome, and age-related macular degeneration. The former can be associated with excessive systemic complement activation from dysfunctional CFH, while the latter two are associated with mutations affecting the ability of CFH to bind to anionic surfaces such as on endothelial cells and glomerular and retinal capillary walls. Mice with targeted deletion of CFH can spontaneously develop MPGN and have increased susceptibility to models of GN. In the rodent, CFH on platelets functions as the immune adherence receptor, analogous to CR1 on primate erythrocytes. In mice, platelets lacking CFH are unable to effectively clear immune complexes which results in their accumulation in glomeruli. The same switch also appears to be true in the rodent podocyte where CFH is present in place of CR1 in human podocytes. Thus, CFH has a variety of functions which can affect the diverse roles the complement system plays in health and disease.

Animals↗
PubMed2006

Individuals homozygous for the age-related macular degeneration risk-conferring variant of complement factor H have elevated levels of CRP in the choroid.

Polymorphisms in the complement factor H gene (CFH) are associated with a significantly increased risk for, or protection against, the development of age-related macular degeneration (AMD). The most documented risk-conferring single-nucleotide polymorphism results in a tyrosine-to-histidine substitution at position 402 (Y402H) of the CFH protein. In this work, we examined the ocular distributions and relative abundance of CFH, several CFH-binding proteins, and abundant serum proteins in the retinal pigmented epithelium (RPE), Bruch's membrane, and choroid (RPE-choroid) in CFH homozygotes possessing either the "at-risk" 402HH or "normal" 402YY variants. Although CFH immunoreactivity is high in the choroid and in drusen, no differences in CFH-labeling patterns between genotypes are apparent. In contrast, at-risk individuals have significantly higher levels of the CFH-binding protein, C-reactive protein (CRP), in the choroidal stroma. Immunoblots confirm that at-risk individuals have approximately 2.5-fold higher levels of CRP in the RPE-choroid; no significant differences in the levels of CFH or other serum proteins are detected. Similarly, we find no differences in CFH transcription levels in the RPE-choroid nor evidence for local ocular CRP transcription. Increased levels of CRP in the choroid may reflect a state of chronic inflammation that is a by-product of attenuated CFH complement-inhibitory activity in those who possess the CFH at-risk allele. Because the CRP-binding site in CFH lies within the domain containing the Y402H polymorphism, it is also possible that the AMD risk-conferring allele alters the binding properties of CFH, thereby leading to choroidal CRP deposition, contributing to AMD pathogenesis.

Age Distribution↗
PubMed2004

Expression of complement factor H by lung cancer cells: effects on the activation of the alternative pathway of complement.

The complement system is important in immunosurveillance against tumors. However, malignant cells are usually resistant to complement-mediated lysis. In this study, we examine the expression of factor H, an inhibitor of complement activation, and factor H-like protein 1 (FHL-1), its alternatively spliced form, in lung cancer. We also evaluate the potential effect of factor H/FHL-1 in the protection of lung cancer cells against the activation of the complement cascade. By Northern blot analysis we demonstrate a high expression of factor H and FHL-1 in most non-small cell lung cancer cell lines, although neuroendocrine pulmonary tumors (small cell lung carcinoma and carcinoid cell lines) had undetectable levels. Western blot analysis of conditioned medium showed the active secretion of factor H and FHL-1 by cells that were positive by Northern blot. Expression of factor H/FHL-1 mRNA was also shown in a series of non-small cell lung cancer biopsies by in situ hybridization. Interestingly, many cultured lung cancer cells were able to bind fluorescence-labeled factor H to their surfaces. Deposition of C3 fragments from normal human serum on H1264, a lung adenocarcinoma cell line, was more efficient when factor H/FHL-1 activity was blocked by specific antibodies. Blocking factor H/FHL-1 activity also enhanced the release of anaphylatoxin C5a and moderately increased the susceptibility of these cells to complement-mediated cytotoxicity. In summary, we demonstrate the expression of factor H and FHL-1 by some lung cancer cells and analyze the contribution of these proteins to the protection against complement activation.

Blood Proteins↗
PubMed1997

Identification of human complement factor H as a chemotactic protein for monocytes.

We used chromatographic separation to purify to homogeneity a monomeric monocyte chemotactic protein of 150 kDa contained in mesothelioma pleural effusions. It was identified by N-terminal amino acid sequencing and immunoblotting as complement factor H, an inhibitor of the alternative complement pathway. Specific antibodies against factor H inhibited the monocyte chemotactic activity of the purified protein, which was most active at 10 nM. Factor H is a restrictive factor of alternative complement pathway activation. The new chemotactic function assigned to factor H in recruiting monocytes to the mesothelioma site might contribute to malignant cell phagocytosis via the iC3b/complement receptor type 3 pathway. These functions link the humoral and cellular immune systems.

Amino Acid Sequence↗
PubMed2006

Complement factor H: spatial and temporal expression and localization in the eye.

PURPOSE: Complement factor H (CFH) is a component of the mammalian complement system, which regulates the alternative pathway of complement activation and protects the host cell from inappropriate complement activation. CFH is a key regulator of innate immunity, and CFH deficiency leads to membranoproliferative glomerulonephritis type II. A variation in human CFH, Y402H, has been shown to be associated with an increased risk for age-related macular degeneration. The authors describe studies on the spatial and temporal expression of the CFH gene and localization of this protein in ocular tissues to gain insight into its role in the eye. METHODS: CFH expression in human and mouse tissues was studied by quantitative RT-PCR and Western blot analysis, and localization of CFH was studied by immunohistochemical analysis followed by fluorescence microscopy. RESULTS: In human and mouse, CFH expression was found to be similar to the highest level of expression in the liver. In ocular tissue, CFH was detected in the distalmost optic nerve (3 mm) cut from the scleral surface of the eyeball, sclera, RPE-choroid, retina, lens, and ciliary body. In mouse, Cfh expression was observed from early embryonic stages, and in the eye its expression increased with age. CONCLUSIONS: A significant level of CFH expression is maintained in different ocular tissues during development and aging. Sustained high levels of CFH expression in eye tissues suggest that this protein may play a role in protecting these tissues from indiscriminate complement activation and inflammatory insult.

Aged↗
PubMed2006

Determination of complement factor H functional polymorphisms (V62I, Y402H, and E936D) using sequence-specific primer PCR and restriction fragment length polymorphisms.

BACKGROUND: Complement factor H (CFH; HF) is an essential regulatory protein that plays a critical role in the homeostasis of the complement system in plasma. Several polymorphisms and mutations in the complement factor H gene (CFH; HF1) have been identified. These have revealed interesting associations with hemolytic-uremic syndrome and age-related macular degeneration. METHODS AND RESULTS: The aim of this study was to develop a rapid and reliable assay for determining genotypic variants of the CFH gene. Sequence-specific primer PCR and restriction fragment length polymorphism techniques were chosen for the analysis of CFH polymorphisms. The assays detected the following published single nucleotide polymorphisms of CFH in our Caucasian population (n = 271): rs800292, 257G-->A (V62I); rs1061170, 1277T-->C (Y402H); and rs1065489, 2881G-->T (E936D). The allele frequencies (257G = 0.850, 1277T = 0.574, and 2881G = 0.839) that we obtained from a healthy Hungarian population were consistent with previously published results. CONCLUSION: These analytical methods are simple, reliable, and rapid to perform, and are amenable to automation. Therefore, they could facilitate large-scale genotypic analyses of the CFH gene in various diseases, such as hemolytic-uremic syndrome, age-related macular degeneration, and cardiovascular diseases.

Adult↗
PubMed2007

Population-based study of early age-related macular degeneration: role of the complement factor H Y402H polymorphism in bilateral but not unilateral disease.

OBJECTIVE: Recently, a strong association has been observed for the complement factor H (CFH) Tyr402His polymorphism with early and advanced age-related macular degeneration (AMD) in independent non-Hispanic White, clinic-based, case-control studies. These studies suggest the CFH His402 allele is a major risk allele in early and advanced AMD, explaining 43% to 70% of all AMD in older adults. We utilized a population-based case-control study design of early AMD among Latinos/Hispanics to evaluate the CFH Tyr402His polymorphism for an association with early AMD phenotypes. DESIGN: Retrospective population-based case-control study. PARTICIPANTS: This study cohort consists of 285 early AMD cases and 570 controls matched on age, birthplace, and smoking status. METHODS: Genotype determination was performed by allele-specific digestion of polymerase chain reaction products. MAIN OUTCOME MEASURES: Complement factor H Tyr402His polymorphism. RESULTS: We observed no overall statistically significant association with early AMD among Latinos. However, a subset of early AMD cases that have bilateral, not unilateral, intermediate-to-large soft macular drusen were 1.7 times more likely to carry either the homozygous or heterozygous His402 genotype. CONCLUSIONS: Our data suggest that the CFH Tyr402His is not a major risk factor for overall early AMD in this Latino population, but may play a role in susceptibility to phenotypes of early AMD likely to progress to late AMD.

Alleles↗