title: Eotaxin/CCL11 in idiopathic retroperitoneal fibrosis.
abstract: BACKGROUND
  Idiopathic retroperitoneal fibrosis (IRF) is a rare fibro-inflammatory disorder characterized by a periaortic tissue which often encases the ureters causing acute renal failure. IRF histology shows fibrosis and a chronic inflammatory infiltrate with frequent tissue eosinophilia. We assessed a panel of molecules promoting eosinophilia and fibrosis in IRF patients and performed an immunogenetic study.
  
  
  METHODS
  Serum levels of eotaxin/CCL11, regulated and normal T-cell expressed and secreted (RANTES), granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-5, platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) were measured using a multiplex assay in 24 newly diagnosed, untreated IRF patients and 14 healthy controls. Retroperitoneal biopsies (available in 8/24 patients) were histologically evaluated to assess eosinophil infiltration, whereas mast cells (MCs) were identified by immunohistochemical analysis for human tryptase. Immunohistochemistry for eotaxin/CCL11 and its receptor CCR3 was also performed. Six single nucleotide polymorphisms (SNPs) within the CCL11 gene (rs6505403, rs1860184, rs4795896, rs17735961, rs16969415 and rs17809012) were investigated in 142 IRF patients and 214 healthy controls.
  
  
  RESULTS
  Serum levels of eotaxin/CCL11 were higher in IRF patients than in controls (P = 0.009). Eotaxin/CCL11 drives tissue infiltration of eosinophils and MCs, which can promote fibrosis. Eosinophilic infiltration was prominent (>5 cells/hpf) in five (62.5%) cases, and abundant tryptase-positive MCs were found in all cases; notably, MCs were in a degranulating state. Immunohistochemistry showed that CCL11 was highly produced by infiltrating mononuclear cells and that its receptor CCR3 was expressed by infiltrating eosinophils, MCs, lymphocytes and fibroblasts. None of the tested CCL11 SNPs showed disease association, but the TTCCAT haplotype was significantly associated with IRF (P = 0.0005).
  
  
  CONCLUSIONS
  These findings suggest that the eotaxin/CCL11-CCR3 axis is active in IRF and may contribute to its pathogenesis; the TTCCAT haplotype within the CCL11 gene is significantly associated with IRF.
authors.affiliation: Department of Clinical Medicine, University of Parma, Parma, Italy.
authors.forename: Domenica
authors.initials: D
authors.lastname: Mangieri
authors.forename: Domenico
authors.initials: D
authors.lastname: Corradi
authors.forename: Davide
authors.initials: D
authors.lastname: Martorana
authors.forename: Giovanni
authors.initials: G
authors.lastname: Malerba
authors.forename: Alessandra
authors.initials: A
authors.lastname: Palmisano
authors.forename: Irene
authors.initials: I
authors.lastname: Libri
authors.forename: Veronica
authors.initials: V
authors.lastname: Bartoli
authors.forename: Maria L
authors.initials: ML
authors.lastname: Carnevali
authors.forename: Matteo
authors.initials: M
authors.lastname: Goldoni
authors.forename: Paolo
authors.initials: P
authors.lastname: Govoni
authors.forename: Rossella
authors.initials: R
authors.lastname: Alinovi
authors.forename: Carlo
authors.initials: C
authors.lastname: Buzio
authors.forename: Augusto
authors.initials: A
authors.lastname: Vaglio
mesh_terms: D000077214:Becaplermin; D016022:Case-Control Studies; D054413:Chemokine CCL11 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D018946:Chemokine CCL5 / Q000097:blood; D004804:Eosinophils / Q000473:pathology; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000097:blood; D056726:Genetic Association Studies; D016179:Granulocyte Colony-Stimulating Factor / Q000097:blood; D006239:Haplotypes; D006801:Humans; D055261:Immunogenetic Phenomena; D015848:Interleukin-5 / Q000097:blood; D008297:Male; D008407:Mast Cells / Q000473:pathology; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D020574:Proto-Oncogene Proteins c-sis / Q000097:blood; D054397:Receptors, CCR3 / Q000378:metabolism; D012185:Retroperitoneal Fibrosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology
chemical_list: C515456:CCL11 protein, human; C483024:CCL5 protein, human; C515350:CCR3 protein, human; D054413:Chemokine CCL11; D018946:Chemokine CCL5; C508599:IL5 protein, human; D015848:Interleukin-5; D020574:Proto-Oncogene Proteins c-sis; D054397:Receptors, CCR3; D016222:Fibroblast Growth Factor 2; D016179:Granulocyte Colony-Stimulating Factor; D000077214:Becaplermin