Factor I Autoantibodies in Patients with Atypical Hemolytic Uremic Syndrome: Disease-Associated or an Epiphenomenon?

Institutes of Cellular and Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, United Kingdom.
Clinical Journal of the American Society of Nephrology (Impact Factor: 4.61). 03/2012; 7(3):417-26. DOI: 10.2215/CJN.05750611
Source: PubMed


Atypical hemolytic uremic syndrome is a disease associated with mutations in the genes encoding the complement regulators factors H and I. In addition, factor H autoantibodies have been reported in ∼10% of patients with atypical hemolytic uremic syndrome. This study searched for the presence of factor I autoantibodies in atypical hemolytic uremic syndrome.
This study screened 175 atypical hemolytic uremic syndrome patients for factor I autoantibodies using ELISA with confirmatory Western blotting. Functional studies using purified immunoglobulin from one patient were subsequently undertaken.
Factor I autoantibodies were detected in three patients. In one patient with a high titer of autoantibody, the titer was tracked over time and was found to have no association with disease activity. This study found evidence of an immune complex of antibody and factor I in this patient, but purified IgG, isolated from current serum samples, had only a minor effect on fluid phase and cell surface complement regulation. Genetic analysis of the three patients with factor I autoantibodies revealed that they had two copies of the genes encoding factor H-related proteins 1 and 3 and therefore, did not have a deletion commonly associated with factor H autoantibodies in atypical hemolytic uremic syndrome. Two patients, however, had functionally significant mutations in complement factor H.
These findings reinforce the concept of multiple concurrent risk factors being associated with atypical hemolytic uremic syndrome but question whether autoantibodies per se predispose to atypical hemolytic uremic syndrome.

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Available from: Pietro Roversi, Oct 06, 2015
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    • "Screening for mutations in AP proteins or anti-FH autoantibodies has become a common practice in aHUS diagnosis. This screening will eventually include autoantibodies recognising other proteins since anti-FB and anti-FI autoantibodies have also been reported (Strobel et al., 2010; Kavanagh et al., 2012) A recent guideline suggests determining protein levels including anti-FH antibodies and performing genetic screening (Roumenina et al., 2011); however, FH measurement varies depending on the method used and can be disturbed in some pathogenic conditions. Our initial observation that FH levels using anti-FH monoclonal antibody A229 (Quidel, CA, USA) were nearly undetectable in a patient with high levels of anti-FH antibodies; this induced us to test FH levels with another antibody, OX24, recognising a different epitope obtaining different results. "
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    ABSTRACT: Complement factor H (FH) serum levels can be affected by the presence of immune complexes of FH with autoantibodies like in autoimmune forms of atypical haemolytic uraemic syndrome (aHUS) or with C3b in homozygous factor I (FI) deficiency. These complexes reduce the amount of free functional circulating FH. In this study we aimed to determine whether FH levels measurement is disturbed in some pathological conditions and to establish a method for quantifying free and total FH in serum. For that purpose, FH levels were measured in serum samples from aHUS patients having anti-FH autoantibodies or mutations in FH gene, in patients with homozygous FI deficiency, and in healthy controls. Two anti-FH monoclonal antibodies, OX24 and A229, recognizing different functional regions in FH, were used as capture antibodies in an ELISA assay. In the control group and in the group of patients with FH mutations, the FH levels obtained with the two monoclonal antibodies were similar. In patients with anti-FH autoantibodies or with homozygous FI deficiency, however, FH levels measured with both antibodies were significantly different. As these patients had complexes of FH with autoantibodies or C3b, we interpreted that OX24 was detecting total FH and A229 was recognising free FH. Therefore, quantification of FH in plasma using these two monoclonal antibodies provides not only total FH level but also gives an estimation of how much FH circulates free and is thus available to properly control complement activation.
    Molecular Immunology 12/2013; 58(2):194-200. DOI:10.1016/j.molimm.2013.11.021 · 2.97 Impact Factor
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    • "This phenomenon may be explained by the high proportion of patients with CFI mutations having an additional mutation in another complement-related gene associated with a more severe phenotype [51]. Recently, factor I autoantibodies have been identified in three patients with aHUS, although their role in disease is uncertain [52]. A single patient is reported with aHUS and a familial mutation in the CLU gene on chromosome 8p21 encoding clusterin [53]. "
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    ABSTRACT: Thrombotic microangiopathy (TMA) is a pathological process involving thrombocytopenia, microangiopathic haemolytic anaemia and microvascular occlusion. TMA is common to haemolytic uraemic syndrome (HUS) associated with shiga toxin or invasive pneumococcal infection, atypical HUS (aHUS), thrombotic thrombocytopenic purpura (TTP) and other disorders including malignant hypertension. HUS complicating infection with shiga toxin-producing Escherichia coli (STEC) is a significant cause of acute renal failure in children worldwide, occurring sporadically or in epidemics. Studies in aHUS have revealed genetic and acquired factors leading to dysregulation of the alternative complement pathway. TTP has been linked to reduced activity of the ADAMTS13 cleaving protease (typically with an autoantibody to ADAMTS13) with consequent disruption of von Willebrand factor multimer processing. However, the convergence of pathogenic pathways and clinical overlap create diagnostic uncertainty, especially at initial presentation. Furthermore, recent developments are challenging established management protocols. This review addresses the current understanding of molecular mechanisms underlying TMA, relating these to clinical presentation with an emphasis on renal manifestations. A diagnostic and therapeutic approach is presented, based on international guidelines, disease registries and published trials. Early treatment remains largely empirical, consisting of plasma replacement/exchange with the exception of childhood STEC-HUS or pneumococcal sepsis. Emerging therapies such as the complement C5 inhibitor eculizumab for aHUS and rituximab for TTP are discussed, as is renal transplantation for those patients who become dialysis-dependent as a result of aHUS.
    Nephrology Dialysis Transplantation 07/2012; 27(7):2673-85. DOI:10.1093/ndt/gfs279 · 3.58 Impact Factor
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    • "Moreover, functional studies have revealed that autoantibodies provoke the same dysfunction in CFH as mutations in its C-terminal domain, and there seems to be a direct correlation between the extent of CFH dysfunction and the amount of CFH-autoantibody complexes [34]. Recently, anti-CFI autoantibodies have been described in aHUS, but their relationship with the development of the disease remains uncertain [35]. We have not tested the presence of anti-CFI antibodies in these 5 families, although this possibility could be explored in cases in which CFI deficiency is suspected. "
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    ABSTRACT: Complement Factor I (CFI) is a serine protease with an important role in complement alternative pathway regulation. Complete factor I deficiency is strongly associated with severe infections. Approximately 30 families with this deficiency have been described worldwide. We have studied five new Spanish families suffering from CFI deficiency. From 19 screened people, 7 homozygous, 10 heterozygous and 2 healthy subjects were identified. Clinical, biochemical and genetic descriptions are included. Molecular studies demonstrated 4 novel mutations in the screened individuals; amongst them, we describe here the first great gene deletion reported in the CFI locus, which includes full exon 2 and part of the large intron 1. CFI deficiency is possibly an underestimated defect and the eventual existence of this deficiency should be tested in those patients exhibiting low C3 and recurrent bacterial infections. We propose a simple diagnostic flowchart to help clinicians in the identification and correct diagnosis of such patients.
    Orphanet Journal of Rare Diseases 06/2012; 7(1):42. DOI:10.1186/1750-1172-7-42 · 3.36 Impact Factor
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