title: Autoantibodies to endothelial cell surface ATP synthase, the endogenous receptor for hsp60, might play a pathogenic role in vasculatides.
abstract: BACKGROUND
  Heat shock protein (hsp) 60 that provides "danger signal" binds to the surface of resting endothelial cells (EC) but its receptor has not yet been characterized. In mitochondria, hsp60 specifically associates with adenosine triphosphate (ATP) synthase. We therefore examined the possible interaction between hsp60 and ATP synthase on EC surface.
  
  
  RESULTS
  Using Far Western blot approach, co-immunoprecipitation studies and surface plasmon resonance analyses, we demonstrated that hsp60 binds to the β-subunit of ATP synthase. As a cell surface-expressed molecule, ATP synthase is potentially targeted by anti-EC-antibodies (AECAs) found in the sera of patients suffering vasculitides. Based on enzyme-linked immunosorbent assay and Western blotting techniques with F1-ATP synthase as substrate, we established the presence of anti-ATP synthase antibodies at higher frequency in patients with primary vasculitides (group I) compared with secondary vasculitides (group II). Anti-ATP synthase reactivity from group I patients was restricted to the β-subunit of ATP synthase, whereas those from group II was directed to the α-, β- and γ-subunits. Cell surface ATP synthase regulates intracellular pH (pHi). In low extracellular pH medium, we detected abnormal decreased of EC pHi in the presence of anti-ATP synthase antibodies, irrespective of their fine reactivities. Interestingly, soluble hsp60 abrogated the anti-ATP synthase-induced pHi down-regulation.
  
  
  CONCLUSIONS
  Our results indicate that ATP synthase is targeted by AECAs on the surface of EC that induce intracellular acidification. Such pathogenic effect in vasculitides can be modulated by hsp60 binding on ATP synthase which preserves ATP synthase activity.
authors.affiliation: EA2216 "Immunology and Pathology" and IFR 148 ScInBioS, Université de Brest and Université Européenne de Bretagne, Brest, France.
authors.forename: Jean-Eric
authors.initials: JE
authors.lastname: Alard
authors.forename: Sophie
authors.initials: S
authors.lastname: Hillion
authors.forename: Loïc
authors.initials: L
authors.lastname: Guillevin
authors.forename: Alain
authors.initials: A
authors.lastname: Saraux
authors.forename: Jacques-Olivier
authors.initials: JO
authors.lastname: Pers
authors.forename: Pierre
authors.initials: P
authors.lastname: Youinou
authors.forename: Christophe
authors.initials: C
authors.lastname: Jamin
mesh_terms: D000328:Adult; D000368:Aged; D000954:Antigens, Surface / Q000276:immunology / Q000378:metabolism; D001323:Autoantibodies / Q000009:adverse effects / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D001327:Autoimmune Diseases / Q000097:blood / Q000150:complications; D016022:Case-Control Studies; D002478:Cells, Cultured; D018834:Chaperonin 60 / Q000378:metabolism; D042783:Endothelial Cells / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D025261:Mitochondrial Proton-Translocating ATPases / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D014657:Vasculitis / Q000097:blood / Q000209:etiology* / Q000276:immunology / Q000378:metabolism; D055815:Young Adult
chemical_list: D000954:Antigens, Surface; D001323:Autoantibodies; D018834:Chaperonin 60; C087589:anti-endothelial cell antibody; D025261:Mitochondrial Proton-Translocating ATPases