title: CC Chemokine Ligand 18 in ANCA-Associated Crescentic GN.
abstract: ANCA-associated vasculitis is the most frequent cause of crescentic GN. To define new molecular and/or cellular biomarkers of this disease in the kidney, we performed microarray analyses of renal biopsy samples from patients with ANCA-associated crescentic GN. Expression profiles were correlated with clinical data in a prospective study of patients with renal ANCA disease. CC chemokine ligand 18 (CCL18), acting through CC chemokine receptor 8 (CCR8) on mononuclear cells, was identified as the most upregulated chemotactic cytokine in patients with newly diagnosed ANCA-associated crescentic GN. Macrophages and myeloid dendritic cells in the kidney were detected as CCL18-producing cells. The density of CCL18(+) cells correlated with crescent formation, interstitial inflammation, and impairment of renal function. CCL18 protein levels were higher in sera of patients with renal ANCA disease compared with those in sera of patients with other forms of crescentic GN. CCL18 serum levels were higher in patients who suffered from ANCA-associated renal relapses compared with those in patients who remained in remission. Using a murine model of crescentic GN, we explored the effects of the CCL18 murine functional analog CCL8 and its receptor CCR8 on kidney function and morphology. Compared with wild-type mice, Ccr8(-/-) mice had significantly less infiltration of pathogenic mononuclear phagocytes. Furthermore, Ccr8(-/-) mice maintained renal function better and had reduced renal tissue injury. In summary, our data indicate that CCL18 drives renal inflammation through CCR8-expressing cells and could serve as a biomarker for disease activity and renal relapse in ANCA-associated crescentic GN.
authors.affiliation: III. Medizinische Klinik and.
authors.forename: Silke R
authors.initials: SR
authors.lastname: Brix
authors.affiliation: III. Medizinische Klinik and.
authors.forename: Gesa
authors.initials: G
authors.lastname: Stege
authors.affiliation: III. Medizinische Klinik and.
authors.forename: Erik
authors.initials: E
authors.lastname: Disteldorf
authors.affiliation: III. Medizinische Klinik and.
authors.forename: Elion
authors.initials: E
authors.lastname: Hoxha
authors.affiliation: III. Medizinische Klinik and.
authors.forename: Christian
authors.initials: C
authors.lastname: Krebs
authors.affiliation: III. Medizinische Klinik and.
authors.forename: Sonja
authors.initials: S
authors.lastname: Krohn
authors.affiliation: Institut für Klinische Chemie and Institut für.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Otto
authors.affiliation: Institut für Klinische Chemie and Institut für.
authors.forename: Kristin
authors.initials: K
authors.lastname: Klätschke
authors.affiliation: III. Medizinische Klinik and.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Herden
authors.affiliation: Medizinische Klinik III, Uniklinik Rheinisch Westfälische Technische Hochschule, Aachen, Germany;
authors.forename: Felix
authors.initials: F
authors.lastname: Heymann
authors.affiliation: Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York;
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Lira
authors.affiliation: Medizinische Klinik III, Uniklinik Rheinisch Westfälische Technische Hochschule, Aachen, Germany;
authors.forename: Frank
authors.initials: F
authors.lastname: Tacke
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum Jena, Jena, Germany;
authors.forename: Gunter
authors.initials: G
authors.lastname: Wolf
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum Jena, Jena, Germany;
authors.forename: Martin
authors.initials: M
authors.lastname: Busch
authors.affiliation: Klinik für Innere Medizin, Vivantes Klinikum im Friedrichshain, Berlin, Germany;
authors.forename: Wolfram J
authors.initials: WJ
authors.lastname: Jabs
authors.affiliation: Klinik für Nephrologie und Notfallmedizin, Klinikum Dortmund, Dortmund, Germany;
authors.forename: Fedai
authors.initials: F
authors.lastname: Özcan
authors.affiliation: Abteilung Innere Medizin I, Universitätsklinikum Ulm, Ulm, Germany;
authors.forename: Frieder
authors.initials: F
authors.lastname: Keller
authors.affiliation: Abteilung Nephrologie, Klinikum St. Georg, Leipzig, Germany; and.
authors.forename: Joachim
authors.initials: J
authors.lastname: Beige
authors.affiliation: IV Medizinische Abteilung, Asklepios Klinik Barmbek, Hamburg, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Wagner
authors.affiliation: Pathologie, Universitätsklinikum Hamburg Eppendorf, Hamburg, Germany;
authors.forename: Udo
authors.initials: U
authors.lastname: Helmchen
authors.affiliation: Pathologie, Universitätsklinikum Hamburg Eppendorf, Hamburg, Germany;
authors.forename: Mercedes
authors.initials: M
authors.lastname: Noriega
authors.affiliation: Pathologie, Universitätsklinikum Hamburg Eppendorf, Hamburg, Germany;
authors.forename: Thorsten
authors.initials: T
authors.lastname: Wiech
authors.affiliation: III. Medizinische Klinik and.
authors.forename: Ulf
authors.initials: U
authors.lastname: Panzer
authors.affiliation: III. Medizinische Klinik and rstahl@uke.de.
authors.forename: Rolf A K
authors.initials: RA
authors.lastname: Stahl
mesh_terms: D000368:Aged; D000818:Animals; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000150:complications*; D015415:Biomarkers / Q000097:blood; D054412:Chemokine CCL8 / Q000235:genetics / Q000378:metabolism; D019742:Chemokines, CC / Q000032:analysis / Q000097:blood*; D003713:Dendritic Cells / Q000737:chemistry; D005260:Female; D005921:Glomerulonephritis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008264:Macrophages / Q000737:chemistry; D008297:Male; D051379:Mice; D008875:Middle Aged; D011446:Prospective Studies; D040081:Protein Array Analysis; D054401:Receptors, CCR8 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; C111792:CCL18 protein, human; C515454:Ccl8 protein, mouse; C489319:Ccr8 protein, mouse; D054412:Chemokine CCL8; D019742:Chemokines, CC; D054401:Receptors, CCR8
keywords: ANCA; CCL18; CCR8; GN