Vasculitis EIA

Anti-PR3 (c-ANCA) Autoimmune EIA

Clinical Utility

The systemic vasculitides are inflammatory diseases of blood vessels and comprise a heterogeneous group of disorders, the causes of which are generally unknown. The diseases have diverse presentations, and are often rapidly progressive, causing irreversible damage to kidney and lung blood vessels. Davies¹ first observed antineutrophil cytoplasmic antibodies (ANCA) in vasculitis patients in 1982. ANCA are autoantibodies specific for proteins located in the primary and secondary granules of neutrophils and in the peroxidase-positive lysosomes of peripheral blood monocytes. They were originally detected by indirect immunofluorescence on ethanol-fixed neutrophils, producing characteristic staining patterns with accentuation of the fluorescent activity within the nuclear lobes. Two major patterns of immunofluorescent staining have been observed: a classical or cytoplasmic staining designated c-ANCA, and a perinuclear pattern designated p-ANCA, which was described in association with renal systemic vasculitis.² Other staining patterns have been described and are generally noted as atypical or snowdrift patterns.^3,4 The nature of the antigens and clinical significance of the antibodies responsible for these atypical fluorescent patterns is currently unclear.

The association between ANCA and Wegener's granulomatosis (WG), a systemic necrotising vasculitis was formally described by Woude in 1985, and confirmed by other workers.^5,6 The target autoantigen associated with c-ANCA was identified in 1990 as proteinase 3,⁷ a 29 kD neutrophil serine protease of azurophil granules, previously characterized by Kao.⁸ Proteinase 3 has been confirmed as the major autoantigen in WG.^9,10

The presence of c-ANCA denotes a spectrum of disease varying from idiopathic pauci-immune necrotizing glomerulonephritis to extended WG. Extended WG is characterized by granulomatomous inflammation of the respiratory tract, systemic vasculitis and necrotising crescentric glomerulonephritis; c-ANCA are present in over 90% of WG patients.^11–13 It is also detected in 67–86% of patients with so-called limited WG without renal involvement, and in 40–50% of patients with pauci-immune necrotizing glomerulonephritis.

Not all c-ANCA-positive sera react with the PR3 antigen; reported sensitivity of anti-PR3 antibodies is 70–100%.^14–16 c-ANCA-positive serum may contain antibodies against antigens other that PR3 but the role of these antibodies is unclear. Prognostically, antibody titer rises are thought to predict relapse and to help differentiate relapse from opportunistic infection.^17,18 Recent evidence suggests that in a large minority of patients, c-ANCA/anti-PR3 titers do not follow disease activity.¹⁹

As the clinical spectrum of ANCA-related diseases increases and further target antigens are identified and characterized, the introduction of antigen-specific ELISAs using highly purified antigen extracts may play a valuable role in the identification of disease subtypes.

References

1. Davies DJ, et al. Br Med J. 285:606, 1982.
2. Falk RJ, et al. N Engl J Med. 318:1651–1657, 1988.
3. Rump JA, et al. Immunobiology. 181:406–413, 1990.
4. Hagen EC, et al. Blood. 81:1996–2002, 1993.
5. Gross WL, et al. Lancet. 5:806, 1986.
6. Parlevliet KJ, et al. Q J Med. 66:55–63, 1988.
7. Ludemann J, et al. J Exp Med. 171:357–362, 1990.
8. Kao RC, et al. J Clin Invest. 82:1963–1973, 1988.
9. Jennette JC, et al. Blood. 75:2263–2264, 1990.
10. Lesavre P, et al. Klin Wochenschr. 69:552–557, 1991.
11. Cohen Tervaert JW, et al. Arch Int Med. 149:2461–2465, 1989
12. Andrassy K, et al. Clin Nephrol. 32:159–167, 1989.
13. Gross WH, et al. Clin Exp Immunol. 91:1–12, 1993.
14. Kallenberg CG, et al. Amer J Med. 93:675–682, 1992.
15. Falk RJ and Jennette JC. Am J Kidney Dis. 18:145–147, 1991.
16. Gross WL, et al. 5th International ANCA Workshop,Cambridge, UK, September 1993.
17. Nolle B, et al. Ann Intern Med. 111 28–40, 1989.
18. Cohen Tervaert JW, et al. Lancet. 336:709–711, 1990.
19. Kerr GS, et al. Arthritis Rheum36:365–371, 1993.

Anti-PR3 (c-ANCA) Autoimmune EIA

Result Interpretation