Relative importance of CCR5 and antineutrophil cytoplasmic antibodies in patients with Wegener's granulomatosis.
OBJECTIVE
Wegener's granulomatosis (WG) is an idiopathic inflammatory condition characterized by upper and lower airway involvement and often renal dysfunction. Sites of tissue injury include pleomorphic cell populations, and classically mononuclear cell infiltrates that may form granulomas. Vascular inflammation (i.e., vasculitis) is often but not always present. Because CCR5 and its ligands influence mononuclear cell trafficking, we sought to identify their expression in pulmonary lesions and to determine whether genetic variations in genes for CCR5 and its ligands influence susceptibility to WG.


METHODS
Lung biopsies from 4 patients that had classical features of WG were examined for protein expression of CCR5, RANTES, MIP-1alpha and MIP-1beta using immunohistochemistry. One hundred eighteen Caucasian patients with WG and 127 ethnically matched healthy controls were included in the genetic analysis. Genomic DNA samples were amplified by PCR. CCR5 Delta32 and RANTES -28 and -401 polymorphisms were determined by either specific primers or direct sequencing.


RESULTS
CCR5+ cells were enriched in lung lesions from patients with WG. Enhanced protein concentrations of RANTES, MIP-1alpha, and MIP-1beta were present in WG lung lesions, indicating redundancy of ligands for CCR5 in affected tissue. Genetic analyses revealed 3 subsets of patients with WG: (1) circulating antineutrophil cytoplasmic antibody (ANCA) positive and CCR5+/+ (58%); (2) CCR5+/+ and ANCA negative (22%); and (3) CCR5 Delta32 and ANCA positive (20%). Among patients in whom ANCA were repeatedly absent, none was found to carry the CCR5 Delta32 allele. Conversely, patients who possessed the CCR5 Delta32 allele were always ANCA positive.


CONCLUSIONS
CCR5 and its ligands are abundantly present in pulmonary lesions in WG. The absence of a genetic deletion for CCR5 (CCR5 Delta32) in WG patients lacking ANCA suggests that CCR5 may exert a particularly important pathogenetic role in those patients. Another subset of patients (approximately 20%) with WG possessed a genetic deletion for CCR5. That each of these patients was ANCA positive implies that an alternative pathway to CCR5 may exist, for which ANCA may be especially important.
Zhou
Yihua
Y
Department of Rheumatic and Immunologic Diseases, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Huang
Deren
D
Farver
Carol
C
Hoffman
Gary S
GS
D019268:Antibodies, Antineutrophil Cytoplasmic / Q000097:blood / Q000235:genetics*; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000032:analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D014890:Granulomatosis with Polyangiitis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D019713:Receptors, CCR5 / Q000235:genetics* / Q000378:metabolism
D019268:Antibodies, Antineutrophil Cytoplasmic; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019402:Macrophage Inflammatory Proteins; D019713:Receptors, CCR5; D004247:DNA