Relative Importance of CCR5 and Antineutrophil Cytoplasmic Antibodies in Patients with Wegener's Granulomatosis

YIHUA ZHOU, DEREN HUANG, CAROL FARVER, and GARY S. HOFFMAN

ABSTRACT.

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-1a and MIP-1ß 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 D32 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-1a, and MIP-1ß 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 D32 and ANCA positive (20%). Among patients in whom ANCA were repeatedly absent, none was found to carry the CCR5 D32 allele. Conversely, patients who possessed the CCR5 D32 allele were always ANCA positive.

Conclusion. CCR5 and its ligands are abundantly present in pulmonary lesions in WG. The absence of a genetic deletion for CCR5 (CCR5 D32) in WG patients lacking ANCA suggests that CCR5 may exert a particularly important pathogenetic role in those patients. Another subset of patients (~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. (J Rheumatol 2003;30:1541-7)

Key Indexing Terms:

WEGENER'S GRANULOMATOSIS
CHEMOKINES
RECEPTORS/CHEMOKINES
POLYMORPHISMS
CCR5

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From the Department of Rheumatic and Immunologic Diseases, the Department of Pathology, and the Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA.

Supported in part by grants from The Harold C. Schott Foundation, The George B. Storer Foundation, and The Irving and Elsa Konigsberg Fund for Vasculitis Research.

Y. Zhou, MD; G.S. Hoffman, MD, Professor, Harold C. Schott Chair, Department of Rheumatic and Immunologic Diseases; D. Huang, MD, PhD, Lerner Research Institute; C. Farver, MD, Professor, Department of Pathology.

Address reprint requests to Dr. G.S. Hoffman, Department of Rheumatic and Immunologic Diseases and Center for Vasculitis Care and Research, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail: hoffman@ccf.org

Submitted May 7, 2002; revision accepted December 1, 2002.

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