The Major Autoantibody Epitope on Factor H in Atypical Hemolytic Uremic Syndrome Is Structurally Different from Its Homologous Site in Factor H-related Protein 1, Supporting a Novel Model for Induction of Autoimmunity in This Disease

Bhattacharjee, Arnab; Reuter, Stefanie; Trojnár, Eszter; Kolodziejczyk, R.; Seeberger, Harald; Hyvärinen, Satu; Uzonyi, Barbara; Szilágyi, Ágnes; Prohászka, Zoltán; Goldman, Adrian; Józsi, Mihály; Jokiranta, T. Sakari

doi:10.1074/jbc.m114.630871

Cited by 65 publications

(68 citation statements)

References 48 publications

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“…Similarly, in a previous study (Bhattacharjee et al 2015) only 2 out of 17 studied patients had FH autoantibodies with both kappa and lambda light chains.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, most aHUS-associated FH autoantibodies have been shown to recognize and functionally block SCRs 19-20 of FH (Jozsi et al 2007), and cross-reactivity with FHR-1 has also been found (Moore et al 2010;Strobel et al 2011). A recent study shows that the autoantibody epitope is located on a loop of FH SCR20 that could take a different conformation upon ligand binding, and then adopting a similar structure to the homologous site in FHR-1; this may explain the association of FHR-1 deficiency with FH autoantibodies due to loss of tolerance (Bhattacharjee et al 2015).…”

Section: Introductionmentioning

confidence: 99%

“…These assays showed that mAb C18, which binds to the previously identified autoantibody loop on SCR20 (Bhattacharjee et al 2015), inhibited the interaction of all tested autoantibodies (n = 14) with FH, except in the case of P19. This finding, together with the variable inhibitory effect of other mAbs recognizing the C-terminal region (mAb A229, IXF9 and VIG8) confirmed the Cterminal specificity of all autoantibodies, and the microheterogeneity in the exact epitope and/or affinity of the individual autoantibodies (Fig.…”

Section: Inhibition Of Autoantibody Binding To Fh Using Monoclonal Anmentioning

confidence: 99%

“…Autoantibody binding to FH SCRs 19-20 was studied in detail by ELISA using recombinant FH SCR19-20 fragments with 13 different single amino acid substitutions (Bhattacharjee et al 2015). For that purpose, plates were coated with recombinant wild type or mutant FH SCR19-20…”

Section: Binding Of Autoantibodies To Recombinant Fh19-20 Mutantsmentioning

confidence: 99%

“…Costar High Binding ELISA plates were coated overnight at 4°C with 50 ng/well of either purified (Bhattacharjee et al 2015).…”

Section: Binding Of Autoantibodies To Recombinant Fh Fragmentsmentioning

confidence: 99%

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Heterogeneity but individual constancy of epitopes, isotypes and avidity of factor H autoantibodies in atypical hemolytic uremic syndrome

Nozal

Bernabeu-Herrero

Uzonyi

et al. 2016

Molecular Immunology

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Factor H (FH) autoantibodies are present in 6-10% of atypical hemolytic uremic syndrome (aHUS) patients, most of whom have homozygous deficiency of the FH-related protein FHR-1.Although the pathogenic role of the autoantibodies is established, little is known about their molecular characteristics and changes over time. Here, we describe the specificity and other immunological features of anti-FH autoantibodies in the Spanish and Hungarian aHUS cohorts.A total of 19 patients were included and serial samples of 14 of them were available. FH autoantibodies from FHR-1 deficient patients (n=13) mainly recognized FH, its SCR19-20 fragment and FHR-1, but autoantibody specificity in patients who are homo-or heterozygous for the CFHR1 gene (n=6)

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“…Similarly, in a previous study (Bhattacharjee et al 2015) only 2 out of 17 studied patients had FH autoantibodies with both kappa and lambda light chains.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Inhibition Of Autoantibody Binding To Fh Using Monoclonal Anmentioning

confidence: 99%

Section: Binding Of Autoantibodies To Recombinant Fh19-20 Mutantsmentioning

confidence: 99%

“…Costar High Binding ELISA plates were coated overnight at 4°C with 50 ng/well of either purified (Bhattacharjee et al 2015).…”

Section: Binding Of Autoantibodies To Recombinant Fh Fragmentsmentioning

confidence: 99%

See 3 more Smart Citations

Heterogeneity but individual constancy of epitopes, isotypes and avidity of factor H autoantibodies in atypical hemolytic uremic syndrome

Nozal

Bernabeu-Herrero

Uzonyi

et al. 2016

Molecular Immunology

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Self‐nonself discrimination by the complement system

Meri

2016

FEBS Letters

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The alternative pathway (AP) of complement can recognize nonself structures by only two molecules, C3b and factor H. The AP deposits C3b covalently on nonself structures via an amplification system. The actual discrimination is performed by factor H, which has binding sites for polyanions (sialic acids, glycosaminoglycans, phospholipids). This robust recognition of ‘self’ protects our own intact viable cells and tissues, while activating structures are recognized by default. Foreign targets are opsonized for phagocytosis or killed. Mutations in factor H predispose to severe diseases. In hemolytic uremic syndrome, they promote complement attack against blood cells and vascular endothelial cells and lead, for example, to kidney and brain damage. Even pathogens can exploit factor H. In fact, the ability to bind factor H discriminates most pathogenic microbes from nonpathogenic ones.

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