Publication

Mechanisms of Disease: pathogenesis and treatment of ANCA-associated vasculitides

Kallenberg, C. G. M., Heeringa, P. & Stegeman, C. A., Dec-2006, In : Nature clinical practice rheumatology. 2, 12, p. 661-670 10 p.

Research output: Contribution to journalReview articleAcademicpeer-review

Wegener's granulomatosis and microscopic polyangiitis are idiopathic systemic vasculitides strongly associated with antineutrophil cytoplasmic autoantibodies (ANCA). In Wegener's granulomatosis, ANCA are mostly directed against proteinase 3 (PR3), whereas in microscopic polyangiitis ANCA are directed against myeloperoxidase; increases in levels of these autoantibodies precede or coincide with clinical relapses in many cases. In vitro, ANCA can further activate primed neutrophils to release reactive oxygen species and lytic enzymes, and, in conjunction with neutrophils, can damage and lyse endothelial cells. Patients with Wegener's granulomatosis or microscopic polyangiitis have an increased percentage of neutrophils that constitutively express PR3 on their membrane. These neutrophils can be stimulated by ANCA, without priming. In vivo, transfer of splenocytes from myeloperoxidase-deficient mice immunized with mouse mycloperoxidase into wild-type mice resulted in pauci-immune systemic vasculitis. A similar experiment in PR3-deficient mice did not cause significant vasculitic lesions. Together, clinical, in vitro and in vivo experimental data support a pathogenic role for ANCA in Wegener's gramilomatosis and microscopic polyangiitis, although this role is more evident for myeloperoxidase-specific ANCA than for PR3-specific ANCA. Several controlled trials have led to an evidence-based approach for the treatment of ANCA-associated vasculitis, and further studies, based on new insights into pathogenesis, are in progress.

Original languageEnglish
Pages (from-to)661-670
Number of pages10
JournalNature clinical practice rheumatology
Volume2
Issue number12
Publication statusPublished - Dec-2006

    Keywords

  • ANCA-associated vasculitis, MPO-ANCA, pathogenesis, PR3-ANCA, Wegener's granulomatosis, ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES, CHURG-STRAUSS-SYNDROME, WEGENERS-GRANULOMATOSIS, ENDOTHELIAL-CELLS, HUMAN NEUTROPHILS, SYSTEMIC VASCULITIS, MEMBRANE EXPRESSION, ANTIMYELOPEROXIDASE ANTIBODIES, MICROSCOPIC POLYANGIITIS, MAINTENANCE THERAPY

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