Ontogeny of Complement Regulatory Proteins – Concentrations of Factor H, Factor I, C4b‐Binding Protein, Properdin and Vitronectin in Healthy Children of Different Ages and in Adults

Paula, P. Ferreira de; Barbosa, José Elpídio; Chi, P. R.; Ferriani, Virgínia Paes Leme; Latorre, Maria R. D. O.; Nudelman, Victor; Isaac, Lourdes

doi:10.1046/j.1365-3083.2003.01326.x

Cited by 65 publications

(50 citation statements)

References 32 publications

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“…It therefore is essential that an age-matched control panel be established in a reference laboratory to give interpretable results. No significant difference in CFH levels has been shown between genders (16).…”

Section: Cfh and Cfi Levelsmentioning

confidence: 83%

“…As with CFH, there are differences in CFI concentration according to age (neonate 15 to 55 g/ml; adults 39 to 100 g/ml) (16). Again, most children reach adult levels by 1 yr of age.…”

Section: Cfh and Cfi Levelsmentioning

confidence: 99%

“…Factor H serum levels, however, vary considerably, and the range changes with age (neonates 170 to 397 g/ml; adults 242 to 759 g/ml) (16). Most children reach adult levels by 1 yr of age.…”

Section: Cfh and Cfi Levelsmentioning

confidence: 99%

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Screening for Complement System Abnormalities in Patients with Atypical Hemolytic Uremic Syndrome

Kavanagh¹,

Richards²,

Frémeaux‐Bacchi³

et al. 2007

Clinical Journal of the American Society of Nephrology

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T he past decade has seen the identification of mutations in the genes for complement factor H (CFH) (1-6), membrane co-factor protein (MCP) (7-12), and factor I (CFI) (9,13-15) as predisposing factors for the development of atypical hemolytic uremic syndrome (aHUS). With this increased understanding of the genetic basis of aHUS and its implications for patient treatment, particularly transplantation, has come an increasing demand for genetic screening. A full analysis for mutations in all three of these complement proteins is expensive and time-consuming. A rational system is required to optimize the timely delivery of results and to reduce the cost of screening. We suggest some proposals that are based on our own experience with aHUS and our review of the relevant literature.The strategy that we propose ( Figure 1) involves an initial screen that is based on protein levels (either serum levels or surface expression). This offers a rapid mechanism to identify the likely gene involved. In those in whom normal levels of complement regulators are found, we propose screening genes on the basis of their order of frequency of mutation detection (CFH, approximately 30%; MCP, approximately 10%; CFI, 2 to 5%) (15). Furthermore, mutations cluster in certain exons of the genes that code for the protein (60% of CFH mutations cluster in complement control protein modules 19 and 20; 90% of MCP mutations in control protein modules 1 to 4; 60% of CFI mutations in the serine protease domain) (15). By screening these regions first, cost and detection time can be minimized. Serum MeasurementWhen possible, blood should be taken for CFH or CFI measurement before plasma infusion/exchange is commenced. If blood is taken in a convalescent period, then it should be at least 2 wk after the last infusion of plasma to ensure that the levels measured are from natively synthesized proteins.Serum C3 and C4 levels generally will form part of a basic complement screen. In almost all cases of aHUS, C4 levels are normal (9). Low C3 levels are commonly seen in patients with mutations in CFH, CFI, and MCP (9). However, this is not a sensitive screening test, and normal C3 levels do not exclude the presence of mutations in complement regulatory proteins (15). In those with mutations in CFH, approximately 50% have normal C3 levels. For CFI, this figure is 40% and for MCP approximately 70% (15). There is also a group with low C3 levels (approximately 30%) and no mutations in MCP, CFH, or CFI (9). This group likely represents a cohort with mutations in an as-yet-unidentified complement gene.

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Section: Cfh and Cfi Levelsmentioning

confidence: 83%

“…As with CFH, there are differences in CFI concentration according to age (neonate 15 to 55 g/ml; adults 39 to 100 g/ml) (16). Again, most children reach adult levels by 1 yr of age.…”

Section: Cfh and Cfi Levelsmentioning

confidence: 99%

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Screening for Complement System Abnormalities in Patients with Atypical Hemolytic Uremic Syndrome

Kavanagh¹,

Richards²,

Frémeaux‐Bacchi³

et al. 2007

Clinical Journal of the American Society of Nephrology

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“…However, it is important to point out that FH levels were in the 600-3000 μg/mL range. According to literature, while previous studies reported plasma FH concentrations ranging 265-684 μg/mL (20), recent studies using monoclonal antibodies reported mean FH concentrations of 233 μg/mL and 269 μg/mL (21). On the contrary, the FH ELISA kit used in the current study measured 400-800 μg/mL normal range according to its manual.…”

Section: Plasma Fh Levelsmentioning

confidence: 99%

The possible role of factor H in complement activation-related pseudoallergy (CARPA): a failed attempt to correlate blood levels of FH with liposome-induced hypersensitivity reactions in patients with autoimmune disease

Fülöp

Józsi

Metselaar

et al. 2015

European Journal of Nanomedicine

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Abstract:Factor H (FH) is a natural inhibitor of the alternative pathway (AP) of complement (C) activation, an abundant protein in blood whose reduced level has been associated with proneness for increased C activation. There are also 5 FH-related proteins (FHR), which have different impacts on C function. After brief outlines of the C system and its activation via the AP, this review focuses on FH and FHR, collecting data from the literature that suggest that reduced levels or function of FH is associated with C activation-related hypersensitivity reactions (HSRs), called C activation related pseudoallergy (CARPA). Based on such observations we initiated the measurement of FH in the blood of patients with inflammatory bowel disease (IBD) and rheumatoid arthritis (RA), and examined the correlation between FH levels and HSRs following i.v. administration of PEGylated liposomal prednisolone phosphate (PLPP). ELISA assay of FH was conducted on plasma samples before treatment, immediately after treatment and at follow-up visits up to 7 weeks, and an attempt was made to correlate the FH levels obtained with the presence or absence of HSR that occurred in five of twenty patients. However, the initial data presented here on three reactive and three non-reactive patients showed FH levels > 600 μg/mL, while the normal range of FH is 2-300 μg/mL. This unexpected outcome of the test led us to realize that the ELISA we used was based on antibodies raised against the short consensus repeats (SCR) in FH, which are also present in FHR. Thus the kit cannot distinguish these proteins and we most likely measured the combined levels of FH and FHR. These initial data highlighted an unforeseen technical problem in assessing FH function when using a FH ELISA that cross reacts with FHR, information that helps in further studies exploring the role of FH in CARPA.

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“…3 It is encoded by the CFH gene on chromosome 1q32. The locus contains 23 exons, CFH is encoded by exons 1-9 and 11-23 while the alternative splice variant factor H-like protein 1 (FHL-1) is encoded by exon 1-10.…”

mentioning

confidence: 99%

Complement factor H deficiency and endocapillary glomerulonephritis due to paternal isodisomy and a novel factor H mutation

et al. 2011

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Complement factor H (CFH) is a regulator of the alternative complement activation pathway. Mutations in the CFH gene are associated with atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis type II and C3 glomerulonephritis. Here, we report a 6-month-old CFH-deficient child presenting with endocapillary glomerulonephritis rather than membranoproliferative glomerulonephritis (MPGN) or C3 glomerulonephritis. Sequence analyses showed homozygosity for a novel CFH missense mutation (Pro139Ser) associated with severely decreased CFH plasma concentration (o6%) but normal mRNA splicing and expression. The father was heterozygous carrier of the mutation, but the mother was a non-carrier. Thus, a large deletion in the maternal CFH locus or uniparental isodisomy was suspected. Polymorphic markers across chromosome 1 showed homozygosity for the paternal allele in all markers and a lack of the maternal allele in six informative markers. This combined with a comparative genomic hybridization assay demonstrated paternal isodisomy. Uniparental isodisomy increases the risk of homozygous variations in other genes on the affected chromosome. Therefore, we analyzed other susceptibility genes on chromosome 1 and found no sequence variation in membrane cofactor protein, but homozygosity for the common deletion of CFH-related proteins 1 and 3, which may contribute to the early onset of disease.

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Ontogeny of Complement Regulatory Proteins – Concentrations of Factor H, Factor I, C4b‐Binding Protein, Properdin and Vitronectin in Healthy Children of Different Ages and in Adults

Cited by 65 publications

References 32 publications

Screening for Complement System Abnormalities in Patients with Atypical Hemolytic Uremic Syndrome

Screening for Complement System Abnormalities in Patients with Atypical Hemolytic Uremic Syndrome

The possible role of factor H in complement activation-related pseudoallergy (CARPA): a failed attempt to correlate blood levels of FH with liposome-induced hypersensitivity reactions in patients with autoimmune disease

Complement factor H deficiency and endocapillary glomerulonephritis due to paternal isodisomy and a novel factor H mutation

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