Atypical hemolytic uremic syndrome-associated variants and autoantibodies impair binding of factor H and factor H-related protein 1 to pentraxin 3

Anne Kopp, Stefanie Strobel, Agustín Tortajada, Santiago Rodríguez De Córdoba, Pilar Sánchez-Corral, Z. Prohászka, Margarita López-Trascasa, Mihály Józsi

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Abstract

Atypical hemolytic uremic syndrome (aHUS) is a renal disease associated with complement alternative pathway dysregulation and is characterized by endothelial injury. Pentraxin 3 (PTX3) is a soluble pattern recognition molecule expressed by endothelial cells and upregulated under inflammatory conditions. PTX3 activates complement, but it also binds the complement inhibitor factor H. In this study, we show that native factor H, factor H-like protein 1, and factor H-related protein 1 (CFHR1) bind to PTX3 and that PTX3-bound factor H and factor H-like protein 1 maintain their complement regulatory activities. PTX3, when bound to extracellular matrix, recruited functionally active factor H. Residues within short consensus repeat 20 of factor H that are relevant for PTX3 binding were identified using a peptide array. aHUS-associated factor H mutations within this binding site caused a reduced factor H binding to PTX3. Similarly, seven of nine analyzed anti-factor H autoantibodies isolated from aHUS patients inhibited the interaction between factor H and PTX3, and five autoantibodies also inhibited PTX3 binding to CFHR1. Moreover, the aHUS-associated CFHR1*B variant showed reduced binding to PTX3 in comparison with CFHR1*A. Thus, the interactions of PTX3 with complement regulators are impaired by certain mutations and autoantibodies affecting factor H and CFHR1, which could result in an enhanced local complement-mediated inflammation, endothelial cell activation, and damage in aHUS.

Original languageEnglish
Pages (from-to)1858-1867
Number of pages10
JournalJournal of Immunology
Volume189
Issue number4
DOIs
Publication statusPublished - Aug 15 2012

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Complement Factor H
Autoantibodies
Complement Inactivating Agents
Atypical Hemolytic Uremic Syndrome
PTX3 protein
factor H-related protein 1
Endothelial Cells
Alternative Complement Pathway
Mutation
Extracellular Matrix
Proteins

ASJC Scopus subject areas

  • Immunology

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Atypical hemolytic uremic syndrome-associated variants and autoantibodies impair binding of factor H and factor H-related protein 1 to pentraxin 3. / Kopp, Anne; Strobel, Stefanie; Tortajada, Agustín; De Córdoba, Santiago Rodríguez; Sánchez-Corral, Pilar; Prohászka, Z.; López-Trascasa, Margarita; Józsi, Mihály.

In: Journal of Immunology, Vol. 189, No. 4, 15.08.2012, p. 1858-1867.

Research output: Contribution to journalArticle

Kopp, Anne ; Strobel, Stefanie ; Tortajada, Agustín ; De Córdoba, Santiago Rodríguez ; Sánchez-Corral, Pilar ; Prohászka, Z. ; López-Trascasa, Margarita ; Józsi, Mihály. / Atypical hemolytic uremic syndrome-associated variants and autoantibodies impair binding of factor H and factor H-related protein 1 to pentraxin 3. In: Journal of Immunology. 2012 ; Vol. 189, No. 4. pp. 1858-1867.
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