Pathogenesis of Pulmonary Vasculitis

Vasculitis is inflammation of blood vessels and can affect any type of vessel in any organ. Pulmonary vasculitis usually is a component of a systemic small vessel vasculitis. Three major forms of small vessel vasculitis that often affect the lungs are Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome. These forms of vasculitis are strongly associated with antineutrophil cytoplasmic autoantibodies (ANCA) directed against enzymes contained in the primary granules of neutrophils and peroxidase-positive lysosomes of monocytes. This review discusses the evidence for a pathogenic role of ANCA. In vitro, ANCAs can activate cytokine-primed neutrophils and monocytes resulting in oxygen radical formation and release of lysosomal enzymes. In vivo, antimyeloperoxidase ANCA has been shown to induce crescentic glomerulonephritis and systemic vasculitis. Overall, the available data suggest that ANCA are indeed a pathogenic factor in the development of small-vessel vasculitis. Antiglomerular basement membrane (anti-GBM) disease also causes pulmonary vasculitis through immune attack on alveolar capillaries and glomerulonephritis through antibody mediated injury to glomerular capillaries. Thus, there is evidence that antibodies are important pathogenic factors in both ANCA disease and anti-GBM disease, however, there are also indications that T cells may play important pathogenic roles in both categories of disease as well.

KEYWORDS

Vasculitis - antineutrophil cytoplasmic autoantibodies - neutrophil - myeloperoxidase - proteinase 3

REFERENCES

• 1 Jennette J C, Falk R J, Andrassy K et al.. Nomenclature of systemic vasculitides: the proposal of an international consensus conference.  Arthritis Rheum. 1994;  37 187-192
• 2 Franks T J, Koss M N. Pulmonary capillaritis.  Curr Opin Pulm Med. 2000;  6 430-435
• 3 Burns A. Pulmonary vasculitis.  Thorax. 1998;  53 220-227
• 4 Schwarz M I, Brown K K. Small vessel vasculitis of the lung.  Thorax . 2000;  55 502-510
• 5 Jennette J C, Falk R J. Small vessel vasculitis.  N Engl J Med. 1997;  337 1512-1523
• 6 Travis W D, Hoffman G S, Leavitt R Y, Pass H I, Fauci A S. Surgical pathology of the lung in Wegener's granulomatosis: review of 87 open lung biopsies from 67 patients.  Am J Surg Pathol . 1991;  15 315-333
• 7 Gaudin P B, Askin F B, Falk R J, Jennette J C. The pathologic spectrum of pulmonary lesions in patients with anti-neutrophil cytoplasmic autoantibodies specific for anti-proteinase 3 and anti-myeloperoxidase.  Am J Clin Pathol. 1995;  104 7-16
• 8 Vassilopoulos D, Niles J L, Villa-Forte A et al.. Prevalence of antineutrophil cytoplasmic antibodies in patients with various pulmonary diseases or multiorgan dysfunction.  Arthritis Rheum. 2003;  49 151-155
• 9 Davies D J, Moran J E, Niall J F, Ryan G B. Segmental necrotising glomerulonephritis with antineutrophil antibody: possible arbovirus aetiology?.  Br Med J (Clin Res Ed). 1982;  285 606
• 10 van der Woude F J, Rasmussen N, Lobatto S et al.. Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener's granulomatosis.  Lancet. 1985;  1 425-429
• 11 Goldschmeding R, van der Schoot C E, ten Bokkel Huinink D et al.. Wegener's granulomatosis autoantibodies identify a novel diisopropylfluorophosphate-binding protein in the lysosomes of normal human neutrophils.  J Clin Invest . 1989;  84 1577-1587
• 12 Ludemann J, Utecht B, Gross W L. Anti-neutrophil cytoplasm antibodies in Wegener's granulomatosis recognize an elastinolytic enzyme.  J Exp Med. 1990;  171 357-362
• 13 Jennette J C, Hoidal J R, Falk R J. Specificity of anti-neutrophil cytoplasmic autoantibodies for proteinase 3.  Blood . 1990;  75 2263-2264
• 14 Falk R J, Jennette J C. Anti-neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis.  N Engl J Med. 1988;  318 1651-1657
• 15 Wucherpfennig K W. Mechanisms for the induction of autoimmunity by infectious agents.  J Clin Invest. 2001;  108 1097-1104
• 16 Raynauld J P, Bloch D A, Fries J F. Seasonal variation in the onset of Wegener's granulomatosis, polyarteritis nodosa and giant cell arteritis.  J Rheumatol. 1993;  20 1524-1526
• 17 Choi H K, Lamprecht P, Niles J L, Gross W L, Merkel P A. Subacute bacterial endocarditis with positive cytoplasmic antineutrophil cytoplasmic antibodies and anti-proteinase 3 antibodies.  Arthritis Rheum. 2000;  43 226-231
• 18 Stegeman C A, Tervaert J W, Sluiter W J, Manson W L, de Jong P E, Kallenberg C G. Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis.  Ann Intern Med. 1994;  120 12-17
• 19 Stegeman C A, Tervaert J W, de Jong P E, Kallenberg C G. Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's granulomatosis. Dutch Co-Trimoxazole Wegener Study Group.  N Engl J Med. 1996;  335 16-20
• 20 Pendergraft W F, Preston G A, Shah R R et al.. Autoimmunity is triggered by cPR-3(105-201), a protein complementary to human autoantigen proteinase-3.  Nat Med. 2004;  10 72-79
• 21 Jennette J C, Falk R J. Pathogenesis of the vascular and glomerular damage in ANCA-positive vasculitis.  Nephrol Dial Transplant. 1998;  13(suppl 1) 16-20
• 22 Weidner S, Neupert W, Goppelt-Struebe  M, Rupprecht H D. Antineutrophil cytoplasmic antibodies induce human monocytes to produce oxygen radicals in vitro.  Arthritis Rheum. 2001;  44 1698-1706
• 23 Savage C O, Pottinger B E, Gaskin G, Pusey C D, Pearson J D. Autoantibodies developing to myeloperoxidase and proteinase 3 in systemic vasculitis stimulate neutrophil cytotoxicity toward cultured endothelial cells.  Am J Pathol. 1992;  141 335-342
• 24 Ewert B H, Becker M E, Jennette J C, Falk R J. Antimyeloperoxidase antibodies induce neutrophil adherence to cultured human endothelial cells.  Ren Fail. 1995;  17 125-133
• 25 Brooks C J, King W J, Radford D J, Adu D, McGrath M, Savage C O. IL-1 beta production by human polymorphonuclear leucocytes stimulated by anti-neutrophil cytoplasmic autoantibodies: relevance to systemic vasculitis.  Clin Exp Immunol. 1996;  106 273-279
• 26 Hattar K, Bickenbach A, Csernok E et al.. Wegener's granulomatosis: antiproteinase 3 antibodies induce monocyte cytokine and prostanoid release-role of autocrine cell activation.  J Leukoc Biol . 2002;  71 996-1004
• 27 Grimminger F, Hattar K, Papavassilis C et al.. Neutrophil activation by anti-proteinase 3 antibodies in Wegener's granulomatosis: role of exogenous arachidonic acid and leukotriene B4 generation.  J Exp Med. 1996;  184 1567-1572
• 28 Ralston D R, Marsh C B, Lowe M P, Wewers M D. Antineutrophil cytoplasmic antibodies induce monocyte IL-8 release: role of surface proteinase-3, alpha1-antitrypsin, and Fcgamma receptors.  J Clin Invest. 1997;  100 1416-1424
• 29 Casselman B L, Kilgore K S, Miller B F, Warren J S. Antibodies to neutrophil cytoplasmic antigens induce monocyte chemoattractant protein-1 secretion from human monocytes.  J Lab Clin Med. 1995;  126 495-502
• 30 Condliffe A M, Chilvers E R, Haslett C, Dransfield I. Priming differentially regulates neutrophil adhesion molecule expression/function.  Immunology . 1996;  89 105-111
• 31 Ward R A, Nakamura M, McLeish K R. Priming of the neutrophil respiratory burst involves p38 mitogen-activated protein kinase-dependent exocytosis of flavocytochrome b558-containing granules.  J Biol Chem . 2000;  275 36713-36719
• 32 Falk R J, Terrell R S, Charles L A, Jennette J C. Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro.  Proc Natl Acad Sci U S A . 1990;  87 4115-4119
• 33 Csernok E, Ernst M, Schmitt W, Bainton D F, Gross W L. Activated neutrophils express proteinase 3 on their plasma membrane in vitro and in vivo.  Clin Exp Immunol. 1994;  95 244-250
• 34 Rarok A A, Limburg P C, Kallenberg C G. Neutrophil-activating potential of antineutrophil cytoplasm autoantibodies.  J Leukoc Biol . 2003;  74 3-15
• 35 Porges A J, Redecha P B, Kimberly W T, Csernok E, Gross W L, Kimberly R P. Anti-neutrophil cytoplasmic antibodies engage and activate human neutrophils via Fc gamma RIIa.  J Immunol. 1994;  153 1271-1280
• 36 Mulder A H, Heeringa P, Brouwer E, Limburg P C, Kallenberg C G. Activation of granulocytes by anti-neutrophil cytoplasmic antibodies (ANCA): a Fc gamma RII-dependent process.  Clin Exp Immunol. 1994;  98 270-278
• 37 Kettritz R, Jennette J C, Falk R J. Crosslinking of ANCA-antigens stimulates superoxide release by human neutrophils.  J Am Soc Nephrol . 1997;  8 386-394
• 38 Ben-Smith A, Dove S K, Martin A, Wakelam M J, Savage C O. Antineutrophil cytoplasm autoantibodies from patients with systemic vasculitis activate neutrophils through distinct signaling cascades: comparison with conventional Fcgamma receptor ligation.  Blood . 2001;  98 1448-1455
• 39 Williams J M, Ben-Smith A, Hewins P et al.. Activation of the G(i) heterotrimeric G protein by ANCA IgG F(ab')(2) fragments is necessary but not sufficient to stimulate the recruitment of those downstream mediators used by intact ANCA IgG.  J Am Soc Nephrol. 2003;  14 661-669
• 40 Yang J J, Preston G A, Alcorta D A et al.. Expression profile of leukocyte genes activated by anti-neutrophil cytoplasmic autoantibodies (ANCA).  Kidney Int. 2002;  62 1638-1649
• 41 Johansson M W, Patarroyo M, Oberg F, Siegbahn A, Nilsson K. Myeloperoxidase mediates cell adhesion via the alpha M beta 2 integrin (Mac-1, CD11b/CD18).  J Cell Sci. 1997;  110 1133-1139
• 42 Cai T Q, Wright S D. Human leukocyte elastase is an endogenous ligand for the integrin CR3 (CD11b/CD18, Mac-1, alpha M beta 2) and modulates polymorphonuclear leukocyte adhesion.  J Exp Med. 1996;  184 1213-1223
• 43 Brouwer E, Tervaert J W, Horst G et al.. Predominance of IgG1 and IgG4 subclasses of anti-neutrophil cytoplasmic autoantibodies (ANCA) in patients with Wegener's granulomatosis and clinically related disorders.  Clin Exp Immunol. 1991;  83 379-386
• 44 Jayne D R, Weetman A P, Lockwood C M. IgG subclass distribution of autoantibodies to neutrophil cytoplasmic antigens in systemic vasculitis.  Clin Exp Immunol. 1991;  84 476-481
• 45 Stegeman C A, Tervaert J W, Huitema M G, Kallenberg C G. Serum markers of T-cell activation in relapses of Wegener's granulomatosis.  Adv Exp Med Biol. 1993;  336 389-392
• 46 Schmitt W H, Heesen C, Csernok E, Rautmann A, Gross W L. Elevated serum levels of soluble interleukin-2 receptor in patients with Wegener's granulomatosis: association with disease activity.  Arthritis Rheum. 1992;  35 1088-1096
• 47 Schmitt W H, Csernok E, Kobayashi S, Klinkenborg A, Reinhold-Keller E, Gross W L. Churg-Strauss syndrome: serum markers of lymphocyte activation and endothelial damage.  Arthritis Rheum. 1998;  41 445-452
• 48 Popa E R, Stegeman C A, Bos N A, Kallenberg C G, Tervaert J W. Differential B- and T-cell activation in Wegener's granulomatosis.  J Allergy Clin Immunol. 1999;  103 885-894
• 49 Schlesier M, Kaspar T, Gutfleisch J, Wolff-Vorbeck G, Peter H H. Activated CD4+ and CD8+ T-cell subsets in Wegener's granulomatosis.  Rheumatol Int. 1995;  14 213-219
• 50 Brouwer E, Stegeman C A, Huitema M G, Limburg P C, Kallenberg C G. T cell reactivity to proteinase 3 and myeloperoxidase in patients with Wegener's granulomatosis (WG).  Clin Exp Immunol. 1994;  98 448-453
• 51 Griffith M E, Coulthart A, Pusey C D. T cell responses to myeloperoxidase (MPO) and proteinase 3 (PR3) in patients with systemic vasculitis.  Clin Exp Immunol. 1996;  103 253-258
• 52 King W J, Brooks C J, Holder R, Hughes P, Adu D, Savage C O. T lymphocyte responses to anti-neutrophil cytoplasmic autoantibody (ANCA) antigens are present in patients with ANCA-associated systemic vasculitis and persist during disease remission.  Clin Exp Immunol. 1998;  112 539-546
• 53 Popa E R, Franssen C F, Limburg P C, Huitema M G, Kallenberg C G, Cohen Tervaert J W. In vitro cytokine production and proliferation of T cells from patients with anti-proteinase 3- and antimyeloperoxidase-associated vasculitis, in response to proteinase 3 and myeloperoxidase.  Arthritis Rheum. 2002;  46 1894-1904
• 54 Gephardt G N, Ahmad M, Tubbs R R. Pulmonary vasculitis (Wegener's granulomatosis): immunohistochemical study of T and B cell markers.  Am J Med. 1983;  74 700-704
• 55 Cunningham M A, Huang X R, Dowling J P, Tipping P G, Holdsworth S R. Prominence of cell-mediated immunity effectors in “pauci-immune” glomerulonephritis.  J Am Soc Nephrol. 1999;  10 499-506
• 56 Csernok E, Trabandt A, Muller A et al.. Cytokine profiles in Wegener's granulomatosis: predominance of type 1 (Th1) in the granulomatous inflammation.  Arthritis Rheum. 1999;  42 742-750
• 57 Muller A, Trabandt A, Gloeckner-Hofmann K et al.. Localized Wegener's granulomatosis: predominance of CD26 and IFN-gamma expression.  J Pathol. 2000;  192 113-120
• 58 Moosig F, Csernok E, Wang G, Gross W L. Costimulatory molecules in Wegener's granulomatosis (WG): lack of expression of CD28 and preferential up-regulation of its ligands B7-1 (CD80) and B7-2 (CD86) on T cells.  Clin Exp Immunol. 1998;  114 113-118
• 59 Komocsi A, Lamprecht P, Csernok E et al.. Peripheral blood and granuloma CD4(+)CD28(-) T cells are a major source of interferon-gamma and tumor necrosis factor-alpha in Wegener's granulomatosis.  Am J Pathol. 2002;  160 1717-1724
• 60 Esnault V L, Mathieson P W, Thiru S, Oliveira D B, Martin-Lockwood C. Autoantibodies to myeloperoxidase in Brown Norway rats treated with mercuric chloride.  Lab Invest . 1992;  67 114-120
• 61 Harper J M, Thiru S, Lockwood C M, Cooke A. Myeloperoxidase autoantibodies distinguish vasculitis mediated by anti-neutrophil cytoplasm antibodies from immune complex disease in MRL/Mp-lpr/lpr mice: a spontaneous model for human microscopic angiitis.  Eur J Immunol . 1998;  28 2217-2226
• 62 Kinjoh K, Kyogoku M, Good R A. Genetic selection for crescent formation yields mouse strain with rapidly progressive glomerulonephritis and small vessel vasculitis.  Proc Natl Acad Sci U S A . 1993;  90 3413-3417
• 63 Neumann I, Birck R, Newman M et al.. SCG/Kinjoh mice: a model of ANCA-associated crescentic glomerulonephritis with immune deposits.  Kidney Int. 2003;  64 140-148
• 64 Mathieson P W, Thiru S, Oliveira D B. Mercuric chloride-treated brown Norway rats develop widespread tissue injury including necrotizing vasculitis.  Lab Invest. 1992;  67 121-129
• 65 Harper J M, Healey D G, Thiru S, Gordon C, Cook A. Factors involved in the pathogenesis of neutrophilic vasculitis in MRL/Mp-lpr/lpr mice: a model for human microscopic angiitis.  Autoimmunity . 1999;  31 133-145
• 66 Brouwer E, Huitema M G, Klok P A et al.. Antimyeloperoxidase-associated proliferative glomerulonephritis: an animal model.  J Exp Med. 1993;  177 905-914
• 67 Yang J J, Jennette J C, Falk R J. Immune complex glomerulonephritis is induced in rats immunized with heterologous myeloperoxidase.  Clin Exp Immunol. 1994;  97 466-473
• 68 Foucher P, Heeringa P, Petersen A H et al.. Antimyeloperoxidase-associated lung disease: an experimental model.  Am J Respir Crit Care Med. 1999;  160 987-994
• 69 Heeringa P, Foucher P, Klok P A et al.. Systemic injection of products of activated neutrophils and H2O2 in myeloperoxidase-immunized rats leads to necrotizing vasculitis in the lungs and gut.  Am J Pathol. 1997;  151 131-140
• 70 Heeringa P, Brouwer E, Klok P A et al.. Autoantibodies to myeloperoxidase aggravate mild antiglomerular basement membrane-mediated glomerular injury in the rat.  Am J Pathol. 1996;  149 1695-1706
• 71 Smyth C L, Little M A, Cook T, Smith J, Haskard D, Pusey C D. Time course of development of vasculitisin a rat model of ANCA-associated experimental autoimmune vasculitis.  Kidney Blood Press Res. 2003;  26 263
• 72 Smyth C L, Smith J, Cook T et al.. Immunisation with MPO directly induces small vessel vasculitis with pauci-immune focal segmental glomerulonephritis and alveolar haemorrhage in rats.  J Am Soc Nephrol. 2002;  13 170A
• 73 Xiao H, Heeringa P, Hu P et al.. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice.  J Clin Invest. 2002;  110 955-963
• 74 Merkel F, Pullig O, Marx M, Netzer K O, Weber M. Course and prognosis of anti-basement membrane antibody (anti-BM-Ab)-mediated disease: report of 35 cases.  Nephrol Dial Transplant . 1994;  9 372-376
• 75 Kluth D C, Rees A J. Anti-glomerular basement membrane disease.  J Am Soc Nephrol. 1999;  10 2446-2453
• 76 Segelmark M, Butkowski R, Wieslander J. Antigen restriction and IgG subclasses among anti-GBM autoantibodies.  Nephrol Dial Transplant . 1990;  5 991-996
• 77 Bombassei G J, Kaplan A A. The association between hydrocarbon exposure and anti-glomerular basement membrane antibody-mediated disease (Goodpasture's syndrome).  Am J Ind Med. 1992;  21 141-153
• 78 Donaghy M, Rees A J. Cigarette smoking and lung haemorrhage in glomerulonephritis caused by autoantibodies to glomerular basement membrane.  Lancet. 1983;  2 1390-1393
• 79 Kalluri R, Meyers K, Mogyorosis A, Madaio M P, Neilsen E G. Goodpasture syndrome involving overlap with Wegener's granulomatosis and anti-glomerular basement membrane disease.  J Am Soc Nephrol. 1997;  8 1795-1800
• 80 Fisher M, Pusey C D, Vaughan R W, Rees A J. Susceptibility to antiglomerular basement membrane disease is strongly associated with HLA-DRB1 genes.  Kidney Int. 1997;  51 222-229
• 81 Lerner R A, Glassock R J, Dixon F J. The role of antiglomerular basement membrane antibody in the pathogenesis of human glomerulonephritis.  J Exp Med. 1967;  126 989-1004
• 82 Wieslander J, Barr J F, Butkowski R J et al.. Goodpasture antigen of the glomerular basement membrane: localization to noncollagenous regions of type IV collagen.  Proc Natl Acad Sci U S A . 1984;  81 3838-3842
• 83 Kalluri R, Sun M J, Hudson B G, Neilson E G. The Goodpasture autoantigen: structural delineation of two immunologically privileged epitopes on alpha3(IV) chain of type IV collagen.  J Biol Chem. 1996;  271 9062-9068
• 84 Hellmark T, Segelmark M, Unger C, Burkhardt H, Saus J, Wieslander J. Identification of a clinically relevant immunodominant region of collagen IV in Goodpasture disease.  Kidney Int. 1999;  55 936-944
• 85 Byrne M C, Budisavljevic M N, Fan Z, Self S E, Ploth D W. Renal transplant in patients with Alport's syndrome.  Am J Kidney Dis. 2002;  39 769-775
• 86 Cochrane C G, Unanue E R, Dixon F J. A role of polymorphonuclear leukocytes and complement in nephrotoxic nephritis.  J Exp Med. 1965;  122 99-119
• 87 Unanue E R, Dixon F J. Experimental glomerulonephritis, V: Studies on the interaction of nephrotoxic antibodies with tissues of the rat.  J Exp Med. 1965;  121 697-714
• 88 Assmann K J, Tangelder M M, Lange W P et al.. Anti-GBM nephritis in the mouse: severe proteinuria in the heterologous phase.  Virchows Arch A Pathol Anat HistoPathol. 1985;  406 285-299
• 89 Sheerin N S, Springall T, Carroll M C, Hartley B, Sacks S H. Protection against anti-glomerular basement membrane (GBM)-mediated nephritis in C3- and C4-deficient mice.  Clin Exp Immunol. 1997;  110 403-409
• 90 Suzuki Y, Shirato I, Okumura K et al.. Distinct contribution of Fc receptors and angiotensin II-dependent pathways in anti-GBM glomerulonephritis.  Kidney Int. 1998;  54 1166-1174
• 91 Radeke H H, Janssen-Graalfs I, Sowa E N et al.. Opposite regulation of type II and III receptors for immunoglobulin G in mouse glomerular mesangial cells and in the induction of anti-glomerular basement membrane (GBM) nephritis.  J Biol Chem. 2002;  277 27535-27544
• 92 Kalluri R, Danoff T M, Okada H, Neilson E G. Susceptibility to anti-glomerular basement membrane disease and Goodpasture syndrome is linked to MHC class II genes and the emergence of T cell-mediated immunity in mice.  J Clin Invest. 1997;  100 2263-2275
• 93 Hopfer H, Maron R, Butzmann U, Helmchen U, Weiner H L, Kalluri R. The importance of cell-mediated immunity in the course and severity of autoimmune anti-glomerular basement membrane disease in mice.  FASEB J. 2003;  17 860-868
• 94 Wu J, Hicks J, Borillo J, Glass W F, Lou Y H. CD4(+) T cells specific to a glomerular basement membrane antigen mediate glomerulonephritis.  J Clin Invest. 2002;  109 517-524
• 95 Wu J, Borillo J, Glass W F, Hicks J, Ou C N, Lou Y H. T-cell epitope of alpha3 chain of type IV collagen induces severe glomerulonephritis.  Kidney Int. 2003;  64 1292-1301