Analysis of Linear Antibody Epitopes on Factor H and CFHR1 Using Sera of Patients with Autoimmune Atypical Hemolytic Uremic Syndrome

Trojnár, Eszter; Józsi, Mihály; Uray, Katalin; Csuka, Dorottya; Szilágyi, Ágnes; Milošević, Danko; Stojanović, Vesna; Spasojević, Brankica; Rusai, Krisztina; Müller, Thomas; Arbeiter, Klaus; Kelen, Kata; Szabó, Attila; Reusz, György; Hyvärinen, Satu; Jokiranta, T. Sakari; Prohászka, Zoltán

doi:10.3389/fimmu.2017.00302

Cited by 11 publications

(14 citation statements)

References 37 publications

(55 reference statements)

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“…The surface needs to allow AP activation, a function that is regulated by Factor H, Factor H-related (FHR) proteins, properdin etc. If it does not, there will be no AP activation (34). But if these molecules bind to the surface in a favorable proportion, disrupting the homeostasis between activation and regulation, AP activation may be triggered, which is the case in PNH, aHUS, AMD etc.…”

Section: Discussionmentioning

confidence: 99%

Assessment of the Role of C3(H2O) in the Alternative Pathway

Fromell¹,

Adler²,

Åman³

et al. 2020

Front. Immunol.

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In this study we investigate the hydrolysis of C3 to C3(H 2 O) and its ability to initiate activation via the alternative pathway (AP) of the complement system. The internal thioester bond within C3 is hydrolyzed by water in plasma because of its inherent lability. This results in the formation of non-proteolytically activated C3(H 2 O) which is believed have C3b-like properties and be able to form an active initial fluid phase C3 convertase together with Factor B (FB). The generation of C3(H 2 O) occurs at a low but constant rate in blood, but the formation can be greatly accelerated by the interaction with various surfaces or nucleophilic and chaotropic agents. In order to more specifically elucidate the relevance of the C3(H 2 O) for AP activation, formation was induced in solution by repeated freeze/thawing, methylamine or KCSN treatment and named C3(x) where the x can be any of the reactive nucleophilic or chaotropic agents. Isolation and characterization of C3(x) showed that it exists in several forms with varying attributes, where some have more C3b-like properties and can be cleaved by Factor I in the presence of Factor H. However, in common for all these variants is that they are less active partners in initial formation of the AP convertase compared with the corresponding activity of C3b. These observations support the idea that formation of C3(x) in the fluid phase is not a strong initiator of the AP. It is rather likely that the AP mainly acts as an amplification mechanism of complement activation that is triggered by deposition of target-bound C3b molecules generated by other means.

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Section: Discussionmentioning

confidence: 99%

Assessment of the Role of C3(H2O) in the Alternative Pathway

Fromell¹,

Adler²,

Åman³

et al. 2020

Front. Immunol.

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“…Autoimmune antibody‐mediated disease pathogenesis for some target antigens has been correlated with antibody affinity, although such associations have been variably observed . For some autoantigens and autoantibodies, the immune complexes themselves deposit in glomeruli and contribute to disease, and low‐affinity antibodies may generate persistently circulating immune complexes . This is not likely to be relevant for aHUS, as there is no evidence of immune complex deposition contributing to the disease .…”

Section: Discussionmentioning

confidence: 99%

“…Anti‐FH autoantibody levels in aHUS are negatively correlated with clinical outcome . They are primarily of the IgG3 isotype, and are thought to be mostly directed at the C‐terminal cell‐surface anchorage‐related region of FH, although greater epitope diversity has also been reported . FH is a negative regulator of complement activation, and there is evidence from mouse models that specific abrogation of FH functions at cell surfaces by inhibiting its cell‐binding, with preservation of its fluid‐phase functions, leading to the typical histopathology of HUS …”

Section: Introductionmentioning

confidence: 99%

Characterization of genetic predisposition and autoantibody profile in atypical haemolytic–uraemic syndrome

et al. 2018

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We previously reported that Indian paediatric patients with atypical haemolytic-uraemic syndrome (aHUS) showed high frequencies of anti-complement factor H (FH) autoantibodies that are correlated with homozygous deletion of the genes for FH-related proteins 1 and 3 (FHR1 and FHR3) (FHR1/3 ). We now report that Indian paediatric aHUS patients without anti-FH autoantibodies also showed modestly higher frequencies of the FHR1/3 genotype. Further, when we characterized epitope specificities and binding avidities of anti-FH autoantibodies in aHUS patients, most anti-FH autoantibodies were directed towards the FH cell-surface anchoring polyanionic binding site-containing C-terminal short conservative regions (SCRs) 17-20 with higher binding avidities than for native FH. FH SCR17-20-binding anti-FH autoantibodies also bound the other cell-surface anchoring polyanionic binding site-containing region FH SCR5-8, at lower binding avidities. Anti-FH autoantibody avidities correlated with antibody titres. These anti-FH autoantibody characteristics did not differ between aHUS patients with or without the FHR1/3 genotype. Our data suggest a complex matrix of interactions between FHR1-FHR3 deletion, immunomodulation and anti-FH autoantibodies in the aetiopathogenesis of aHUS.

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“…CFHR1 is a complement modulator that regulates complement by blocking complement C5 convertase activity and interfering with C5b surface binding (28). In autoimmune atypical hemolytic uremic syndrome (aHUS), CFH is blocked by FH autoantibodies, and 90% of patients carry homozygous deletions of CFHR1 (29). However, heterozygous CFHR1/CFH hybrid genes were also identified in 4.5% of patients with aHUS.…”

Section: Discussionmentioning

confidence: 99%

CFHR1 is a potentially downregulated gene in lung adenocarcinoma

Yan

Wang

et al. 2019

Mol Med Report

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There is increasing evidence that human complement factor H-related protein 1 (CFHR1) plays a crucial role in the development of malignant diseases. However, few studies have identified the roles of CFHR1 in the occurrence and prognosis of lung adenocarcinoma (LADC). In the present study, comprehensive bioinformatic analyses of data obtained from the Oncomine platform, UALCAN and Gene Expression Profiling Interactive Analysis (GEPIA) demonstrated that CFHR1 expression is significantly reduced in both LADC tissues and cancer cells. The patients presenting with downregulation of CFHR1 had significantly lower overall survival (OS) and post progression survival (PPS) times. Through analysis of the datasets from Gene Expression Omnibus database, we found that the compound actinomycin D promoted CFHR1 expression, further displaying the cytotoxic effect in the LADC cell line A549. In addition, the expression level of CFHR1 in the cisplatin-resistant LADC cell line CDDP-R (derived from H460) was also significantly reduced. Our research demonstrated that low levels of CFHR1 are specifically found in LADC samples, and CFHR1 could serve as a potential therapeutic target for this subset of lung cancers. Determination of the detailed roles of CFHR1 in LADC biology could provide insightful information for further investigations.

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Analysis of Linear Antibody Epitopes on Factor H and CFHR1 Using Sera of Patients with Autoimmune Atypical Hemolytic Uremic Syndrome

Cited by 11 publications

References 37 publications

Assessment of the Role of C3(H2O) in the Alternative Pathway

Assessment of the Role of C3(H2O) in the Alternative Pathway

Characterization of genetic predisposition and autoantibody profile in atypical haemolytic–uraemic syndrome

CFHR1 is a potentially downregulated gene in lung adenocarcinoma

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