ANCA disease: immunoserology and pathogenesis (PPT / 4418 KB)
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ANCA disease: immunoserology and pathogenesis Alenka Vizjak Institute of Pathology · Faculty of Medicine University of Ljubljana, Ljubljana, Slovenia
Antineutrophil cytoplasmic antibodies (ANCA) Discovery of ANCA – of key importance for the classification of small vessel vasculitides (in the kidney necrotizing crescentic GN) and understanding of their pathogenesis (1. immune complex, 2. anti-GBM, 3. ANCA) • Davies DJ et al. Necrotizing glomerulonephritis with ANCA. Med J 1982; 285:606 • Van der Woude FJ et al. Autoantibodies against neutrophils and monocytes: Tool for diagnosis and marker of disease activity in Wegener's granulomatosis. Lancet 1985; 1:425 • Jennette JC et al. ANCA-associated GN and vasculitis. Am J Pathol 1989; 135: 921
ANCA disease Pathogenetically determined group of smallvessel vasculitides including: • Wegener’s granulomatosis • Microscopic polyangiitis • Pauci-immune necrotizing crescentic GN = kidney-limited microscopic poliangiitis • Churg-Strauss syndrome
ANCA antigens ANCA specific for various proteins, mostly enzymes, localized in the cytoplasmic lyzosomes of neutrophils and monocytes. Major target antigens for ANCA in patients with pauci-immune small vessel vasculitides : • Myeloperoxidase (MPO) – epitope expressed by 130 kDa native molecule in the azurophilic granules • Proteinase 3 (PR3) – 28 kDa serine proteinase, colocalized with MPO in the azurophilic granules
ANCA antigens Other ANCA antigens: lactoferrin, elastase, lysozyme, cathepsin G, azurocidin, bactericidal permeability increasing protein (BPI), alpha-enolase, defensin, unknown human lysosomal-associated membrane protein 2 (h-lamp-2) - homologous to bacterial protein FimH (Kain R et al. Nat Med 2008)
ANCA testing • Indirect immunofluorescence (IIF) C-ANCA ( PR3) P-ANCA, with nuclear extension ( MPO) P-ANCA, without nuclear extension ( mostly unknown antigens) Atypical C-ANCA ( PR3 after treatment or BPI, MPO, other, often multiple antigens) Atypical ANCA ( other, often multiple antigens) • Enzyme-linked immunosorbent assay (ELISA) Antigen specificity, quantitative value (relative)
Sensitivity and specificity of ANCA (IIF + ELISA for PR3, MPO) from different studies in the literature Disease Sensitivity of ANCA ___________________________________________________ Limited Wegener's granulomatosis 50-66 % Generalized Wegener's granulomatosis 80-98 % Microscopic polyangiitis 82-90 % Pauci-immune necrotizing extracap GN 90-95 % Churg-Strauss syndrome 60-70 % Control group Specificity of ANCA ____________________________________________________ Patients with various other diseases 76-91 % Healthy subjects 94-99 %
Selected demographic features and serologic findings in 423 ANCA positive patients grouped according to their clinico-pathologic settings (Institute of Pathology, Faculty of Medicine, Ljubljana) Features
Pauci-immune vasculitis (n=153)
Suspected vasculitis (n=59)
IBD, AHBD (n=83)
Other diseases (n=128)
59.614.2
60.717.0
40.117.5
53.718.2
93/60
38/21
52/21
80/48
PR3-ANCA
22951.0
51.17.8
24.11.9
33.84.4
MPO-ANCA
570.871.3
65.89.9
31.54.4
34.52.5
Age Female/male
IBD = inflammatory bowel diseases, AHBD = autoimmune hepato-biliary disorders
Vizjak A et al. Wien Klin Wochenschr 2000, 112: 665-670
Clinico-pathologic diagnosis in relation to ANCA antigen specificity in 423 ANCA positive patients (Institute of Pathology, Faculty of Medicine, Ljubljana) No of pts
PR3
MPO
PR3+ MPO
Other ags
56 54 28
45 3 2
6 45 24
2 2 0
3 4 0
Skin vasculitis
2 8
0 1
1 3
0 0
1 4
Goodpasture sy + ANCA
5
0
5
0
0
59 211
12 20
26 76
6 22
15 93
Diagnosis Wegener’s granulomatosis Microscopic polyangiitis Pauci-immune necr GN Churg-Strauss syndrome
Suspected vasculitis IBD, AHBD, other diseases
Vizjak A et al. Wien Klin Wochenschr 2000, 112: 665-670
Pathogenetic role of ANCA • Clinical evidence Correlation between ANCA values and activity of vasculitis, as well as relapses Drug-induced ANCA vasculitis • In vitro studies Activation of neutrophils by binding of ANCAs release of destructive enzymes and toxic reactive oxygen radicals, as well as neutrophil extracellular traps; factors released by activated neutrophils activate the alternative complement pathway; ANCAs bind also to ANCA antigens adsorbed to anionic endothelium and GBM, enhancing complement dependent cytotoxicity; ANCAs disregulate neutrophil apoptosis necrosis; specific T lymphocytes for PR3 • Several animal models of ANCA disease MPO-ANCA, PR3-ANCA, anti-LAMP-2 antibodies
Falk RJ, Jennette JC. J Am Soc Nephrol 2010, 21: 745-752
De Lind van Wijngaarden RAF et al, Clin JASN, 2008, 3: 237-252
Conclusions • PR3- and MPO-ANCA are highly specific diagnostic marker for pauci-immune small vessel vasculitides determined as ANCA disease. Rarely, ANCA specific for other antigens are involved in ANCA disease. • ANCA can be not rarely positive in various other diseases, mostly with an atypical IIF pattern, in low values, and specificities for rare and unknown ANCA antigens. • In view of clinical serologic correlations, as well as in vitro studies and in vivo animal models ANCA evidently have a key role in the pathogenesis of glomerular and vascular lesions in ANCA disease.
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