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A NCA disease : i mmunoserology and p athogenesis

A NCA disease : i mmunoserology and p athogenesis. A lenka Vizjak Institute of Pathology · Faculty of Medicine University of Ljubljana, Ljubljana, Slovenia. Antineutrophil cytoplasmic antibodies (ANCA).

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A NCA disease : i mmunoserology and p athogenesis

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  1. ANCAdisease: immunoserology and pathogenesis Alenka Vizjak Institute of Pathology · Faculty of Medicine University of Ljubljana, Ljubljana, Slovenia

  2. Antineutrophilcytoplasmicantibodies (ANCA) • Davies DJ etal. Necrotizingglomerulonephritiswith ANCA. Med J 1982; 285:606 • Van der Woude FJetal. Autoantibodies against neutrophils and monocytes: Tool for diagnosis and marker of disease activity in Wegener's granulomatosis. Lancet 1985; 1:425 • Jennette JCetal. ANCA-associated GN and vasculitis. Am J Pathol1989; 135: 921 Discoveryof ANCA – ofkeyimportancefortheclassificationofsmallvesselvasculitides(in thekidneynecrotizingcrescentic GN) and understandingoftheirpathogenesis(1. immunecomplex, 2. anti-GBM, 3. ANCA)

  3. ANCA disease Pathogenetically determinedgroup of small-vessel vasculitides including: • Wegener’s granulomatosis • Microscopic polyangiitis • Pauci-immune necrotizing crescentic GN= kidney-limited microscopic poliangiitis • Churg-Strauss syndrome

  4. ANCA antigens ANCA specific for various proteins, mostlyenzymes, 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 moleculein the azurophilic granules • Proteinase 3 (PR3) – 28 kDa serine proteinase, colocalized with MPO in the azurophilic granules

  5. 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)

  6. 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 orBPI, MPO, other, often multiple antigens)Atypical ANCA ( other, often multiple antigens) • Enzyme-linked immunosorbent assay (ELISA)Antigen specificity, quantitative value (relative)

  7. 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 granulomatosis80-98 % 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 %

  8. 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)

  9. Clinico-pathologic diagnosis in relation to ANCA antigen specificity in 423 ANCA positive patients (Institute of Pathology, Faculty of Medicine, Ljubljana)

  10. Patogenetic role of ANCA • Clinical evidenceCorrelation between ANCA values and activity of vasculitis, as well as relapsesDrug-induced ANCA vasculitis • In vitro studiesActivation 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 diseaseMPO-ANCA, PR3-ANCA, anti-LAMP-2 antibodies

  11. Falk RJ, Jennette JC. J Am Soc Nephrol 2010, 21: 745-752

  12. De Lind van Wijngaarden RAF et al, Clin JASN, 2008, 3: 237-252

  13. 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 vitrostudies and in vivoanimal models ANCA evidently have a key role in the pathogenesis of glomerular and vascular lesions in ANCAdisease.

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