Kidney transplantation in patients with atypical hemolytic uremic syndrome (aHUS) carrying mutations in the soluble complement regulators factor H (CFH) or factor I (CFI) is associated with elevated ...risk of disease recurrence and almost certain graft loss. In contrast, recurrence is unusual in patients with mutations in the membrane‐associated complement regulator membrane cofactor protein (MCP) (CD46). Therefore, a panel of experts recently recommended the combined liver–kidney transplantation to minimize aHUS recurrence in patients with mutations in CFH or CFI. There was, however, very limited information regarding transplantation in patients carrying mutations in both soluble and membrane‐associated complement regulators to support a recommendation. Here, we report the case of an aHUS patient with a heterozygous mutation in both CFI and MCP who received an isolated kidney transplant expressing normal MCP levels. Critically, the patient suffered from a severe antibody‐mediated rejection that was successfully treated with plasmapheresis and IvIgG. Most important, despite the complement activation in the allograft, there was no evidence of thrombotic microangiopathy, suggesting that the normal MCP levels in the grafted kidney were sufficient to prevent the aHUS recurrence. Our results suggest that isolated kidney transplantation may be a good first option for care in aHUS patients carrying CFI/MCP combined heterozygous mutations.
Isolated kidney transplantation may be a good first option for care in cases of chronic kidney disease due to aHUS associated with CFI/MCP combined heterozygous mutations.
A subgroup of patients with the most severe form of the Hemolytic Uremic Syndrome (HUS) presents mutations in the complement regulatory protein factor H. The functional analyses of the factor H ...mutant proteins purified from some of these patients have shown a specific defect in the capacity to control complement activation on cellular surfaces. Here, we show that these factor H-related complement regulatory defects can be detected in the patients’ serum with a simple hemolytic assay. Data obtained from HUS patients and control individuals indicate that this assay is a useful tool for the molecular diagnosis of factor H-related HUS.
Hemolytic-uremic syndrome (HUS) is a microvasculature disorder leading to microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Most cases of HUS are associated with epidemics ...of diarrhea caused by verocytotoxin-producing bacteria, but atypical cases of HUS not associated with diarrhea (aHUS) also occur. Early studies describing the association of aHUS with deficiencies of factor H suggested a role for this complement regulator in aHUS. Molecular evidence of factor H involvement in aHUS was first provided by Warwicker et al., who demonstrated that aHUS segregated with the chromosome 1q region containing the factor H gene (
HF1) and who identified a mutation in
HF1 in a case of familial aHUS with normal levels of factor H. We have performed the mutational screening of the
HF1 gene in a novel series of 13 Spanish patients with aHUS who present normal complement profiles and whose plasma levels of factor H are, with one exception, within the normal range. These studies have resulted in the identification of five novel
HF1 mutations in four of the patients. Allele
HF1Δexon2, a genomic deletion of exon 2, produces a null
HF1 allele and results in plasma levels of factor H that are 50% of normal. T956M, W1183L, L1189R, and V1197A are missense mutations that alter amino acid residues in the C-terminal portion of factor H, within a region—SCR16–SCR20—that is involved in the binding to solid-phase C3b and to negatively charged cellular structures. This remarkable clustering of mutations in
HF1 suggests that a specific dysfunction in the protection of cellular surfaces by factor H is a major pathogenic condition underlying aHUS.
Summary
Several polymorphisms in the complement components factor H and CFHR1 are associated with higher risk to develop atypical Haemolytic Uraemic Syndrome (aHUS) in Caucasians. We have determined ...the prevalence of these polymorphisms in Tunisian controls by using genetic and immunological techniques. No differences in the frequency of the factor H risk alleles c.−331C>T, c.2089A>G or c.2881G>T between Tunisian and Caucasians were found. On the contrary, the analysis of CFHR1 polymorphism revealed a higher frequency of Tunisian individuals homozygous for the CFHR1*Del (deleted) allele, and of individuals presenting the CFHR1*A phenotype. These results suggest distinct contributions of factor H and CFHR1 polymorphisms to aHUS in Tunisian and Caucasian populations.
The efficiency of the complement system as an innate immune defense mechanism depends on a fine control that restricts its action to pathogens and prevents non-specific damage to host tissues. ...Genetic and functional analyses have shown that this critical control of complement activation may be impaired in atypical hemolytic uremic syndrome (aHUS) patients. Mutations in HF1, MCP or FI have been found in aHUS patients, but incomplete penetrance of the disease in individuals carrying these mutations is relatively frequent and no genetic defect has yet been found in a majority of aHUS patients. We report here the identification of a specific SNP haplotype block, spanning the MCP gene in the regulators of complement activation gene cluster, which is over-represented in aHUS patients and strongly associates with the severity of the disease. Linkage disequilibrium analyses suggest that this SNP haplotype also includes the CR1, DAF and C4BP genes. Initial studies identified two SNPs in the haplotype that influence the transcription activity of the MCP promoter in transient transfection experiments. Notably, the SNP haplotype block was found to be particularly frequent among patients who carry mutations in HF1, MCP or FI. These findings and the identification of aHUS patients carrying mutations in two complement regulatory genes provide an important insight into the etiology of aHUS. Together, they suggest that complement regulatory molecules act as a protein network and that multiple hits, involving plasma- and membrane-associated complement regulatory proteins, are necessary to impair protection to host tissues and to confer significant predisposition to aHUS.
Factor H is an essential regulatory protein that plays a critical role in the homeostasis of the complement system in plasma and in the protection of bystander host cells and tissues from damage by ...complement activation. Genetic and structural data generated during recent years have been instrumental to delineate the functional domains responsible for these regulatory activities in factor H, which is helping to understand the molecular basis underlying the different pathologies associated to factor H. This review summarises our current knowledge of the role of factor H in health and disease.
It is well known that meteorology plays an important role in the diurnal evolution of pollutants, especially those variables related to atmospheric dispersion. Most studies typically relate the ...concentration of some pollutants with wind speed from conventional anemometers; however, the use of turbulence variables is less common, in part because the needed instruments are not so typical in standard air-quality stations. In this work, we compare the wind-NO2 relationship with the turbulence-NO2 one using observational data from two field campaigns developed in Madrid (winter and summer). The turbulence data comes from two sonic anemometers deployed at different locations: one close to the street and the other at the top of a nearby tall building. The results indicate that the turbulent variables correlate better with the pollutant concentration than the wind speed when using data from the street sonic, while the contrary is found when using the terrace sonic. These data are also used to perform a fine-scale analysis of the turbulent diffusion-NO2 behaviour during a very-stable period in winter, when the turbulence typically shows a decrease in the evening transition, causing the highestNO2 concentrations. Conversely, under these conditions, the formation of thermally-driven winds is also favoured later in the night, which favours the pollutant dispersion and cleaning of the air. The important role of these dynamical processes on the NO2 evolution highlights the importance of the correct understanding of small-scale atmospheric processes to understand their relationship with the concentration of pollutants.
•Turbulence measurements relate better to NO2 concentration than wind speed.•Sonic anemometers located at the street level provide adequate estimations of diffusion.•The highest NO2 concentrations are found during the evening transition of stable days.•Thermally-driven flows formed in the nighttime of stable days clean the air effectively.•The NO2 concentration is highly affected by transient dynamical phenomena.
The complement system is a crucial component of innate immunity against microbial infection. It contains several plasma and membrane-associated proteins that are organized in two activation pathway: ...the classical/lectin pathway and the alternative pathway. Upon activation by molecules on the surface of microorganisms, both pathways result in the formation and deposition of a proteolytic fragment called C3b on the activator surface. C3b deposition leads to complement-mediated lysis or to phagocytosis by polymorphonuclear cells and macrophages (Law and Reid 1995; Liszewski et al. 1996). In human plasma, regulation of complement activation is provided by C4b-binding protein (C4BP) and factor H, two members of a family of complement receptors and plasma protein (RCA family) that collectively regulate complement and share a structural organization based on repetitive units of 60 amino acids denominated SCRs (Law and Reid 1995; Pardo-Manuel et al. 1990; Reid and Day 1989; Reid et al. 1986). Factor H binds to C3b, accelerates the decay of the alternative pathway C3 convertase (C3bBb), and functions as a cofactor in the factor I-mediated proteolytic inactivation of C3b (Pangburn et al. 1977; Whaley and Thompson 1978). Recently, a role for factor H in adhesion to human neutrophils (Di Scipio et al. 1988), and as a ligand of lipo-oligosaccharides present at the surface of some pathogens has been described.
A key step in the elimination of invading pathogens from the body is the covalent binding of complement proteins C3b and C4b to their surface. However, many pathogens have evolved mechanisms to avoid ...the complement system of the host. Understanding how these mechanisms work may lead to more efficacious forms of therapy. Here we provide an insight into the molecular basis of how Streptococcus pyogenes binds human plasma C4b-binding protein (hC4BP), a complement regulatory molecule that may decrease C3b and C4b deposition on the streptococcal surface. We show that streptococcal surface molecules bind to a site on hC4BP that is indistinguishable from the C4b binding site. This site involves multiple binding surfaces that span short consensus repeats 1 to 3 of the alpha-chain of hC4BP. We propose that hC4BP is bound to the bacterial surface because the streptococcal surface molecules involved in the interaction mimic human C4b epitopes.
Genetic studies have demonstrated the involvement of the complement regulator factor H in nondiarrheal, nonverocytotoxin (i.e., atypical) cases of hemolytic uremic syndrome. Different factor H ...mutations have been identified in 10%–30% of patients with atypical hemolytic uremic syndrome (aHUS), and most of these mutations alter single amino acids in the C-terminal region of factor H. Although these mutations are considered to be responsible for the disease, the precise role that factor H plays in the pathogenesis of aHUS is unknown. We report here the structural and functional characterization of three different factor H proteins purified from the plasma of patients with aHUS who carry the factor H mutations W1183L, V1197A, or R1210C. Structural anomalies in factor H were found only in R1210C carriers; these individuals show, in their plasma, a characteristic high-molecular-weight factor H protein that results from the covalent interaction between factor H and human serum albumin. Most important, all three aHUS-associated factor H proteins have a normal cofactor activity in the proteolysis of fluid-phase C3b by factor I but show very low binding to surface-bound C3b. This functional impairment was also demonstrated in recombinant mutant factor H proteins expressed in COS7 cells. These data support the hypothesis that patients with aHUS carry a specific dysfunction in the protection of cellular surfaces from complement activation, offering new possibilities to improve diagnosis and develop appropriate therapies.
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