Atypical hemolytic uremic syndrome-associated variants and autoantibodies impair binding of factor h and factor h-related protein 1 to pentraxin 3.
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.
Junior Research Group Cellular Immunobiology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, 07745 Jena, Germany.
Anne
A
Kopp
Stefanie
S
Strobel
Agustín
A
Tortajada
Santiago
S
Rodríguez de Córdoba
Pilar
P
Sánchez-Corral
Zoltán
Z
Prohászka
Margarita
M
López-Trascasa
Mihály
M
Józsi
D065766:Atypical Hemolytic Uremic Syndrome; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D002097:C-Reactive Protein / Q000276:immunology / Q000378:metabolism*; D003180:Complement C3b Inactivator Proteins / Q000276:immunology / Q000378:metabolism*; D017242:Complement Factor H / Q000276:immunology / Q000378:metabolism*; D005109:Extracellular Matrix / Q000276:immunology / Q000378:metabolism; D006463:Hemolytic-Uremic Syndrome / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D000683:Serum Amyloid P-Component / Q000276:immunology / Q000378:metabolism*; D000099153:Pentraxins
D001323:Autoantibodies; D001324:Autoantigens; D002097:C-Reactive Protein; D003180:Complement C3b Inactivator Proteins; D017242:Complement Factor H; D000683:Serum Amyloid P-Component; D000099153:Pentraxins; C517621:CFHR1 protein, human