Abstract
Endothelial cells play a pivotal role in the pathogenesis of systemic vasculitis. Endothelial cells have significant proinflammatory activities, amplifying and perpetuating the inflammatory process and contributing to vessel regeneration and repair. Significant contributions have improved the understanding of additional ways through which antineutrophil cytoplasmic antibodies (ANCA) may potentiate neutrophil- and monocyte-mediated endothelial cell activation and damage. Signaling pathways mediating ANCA effects have been delineated, and new animal models have demonstrated the pathogenic role of ANCA in the development of systemic vasculitis. Significant efforts have identified anti-endothelial cell antibody specificities and elucidated mechanisms through which these antibodies may promote endothelial cell activation and injury. New ways to assess in vivo endothelial cell damage and dysfunction also have been developed. In addition, besides being a relevant compensatory mechanism for ischemia, angiogenesis may have important proinflammatory functions in vasculitis. The potential relevance of bone-marrow-derived endothelial cell precursors in neovascularization has begun to be appreciated.
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References and Recommended Reading
Cid MC: Endothelial cell biology, perivascular inflammation and vasculitis. Cleve J Med 2002, 69(suppl):45–49.
Cohen Tervaert JW: Infections in primary systemic vasculitis. Cleve J Med 2002, 69(suppl):24–26.
Virgin HW: Host and viral genes that control herpes virus vasculitis. Cleve J Med 2002, 693.|:7–12.
Ferri C, Giuggioli M, Cazzato M, et al.: HCV-related cryoglobulinemic vasculitis: an update on its etiopathogenesis and therapeutic strategies. Clin Exp Rheumatol 2003, 213.|:78–84.
Day CJ, Hewins P, Savage COS: New developments in the pathogenesis of ANCA-associated vasculitis. Clin Exp Rheumatol 2003, 21:35–48.
Falk RJ, Terell RS, Charles LA, Jennette JC: Anti-neutrophil cytoplasmic antibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc Natl Acad Sci U S A 1990, 87:4115–4119.
van Rossum AP, Limburg PC, Kallenberg CGM: Membrane proteinase 3 expression on resting neutrophils as a pathogenic factor in PR3-ANCA-associated vasculitis. Clin Exp Rheumatol 2003, 21(suppl):64–68.
Henshaw TJ, Malone CC, Gabay JE, Williams RC: Elevations of neutrophil proteinase 3 in serum of patients with Wegener’s granulomatosis and polyarteritis nodosa. Arthritis Rheum 1994, 37:104–112.
Rutgers A, Heeringa P, Cohen-Tervaert JW: The role of myeloperoxidase in the pathogenesis of systemic vasculitis. Clin Exp Rheumatol 2003, 21(suppl):55–63.
Rarok AA, Stegeman CA, Limburg PC, Kallenberg CGM: Neutrophil membrane expression of proteinase 3 (PR3) is related to relapse in PR3-ANCA-associated vasculitis. J Am Soc Nephrol 2002, 13:2232–2238. A demonstration of the clinical relevance of PR3 membrane expression by circulating neutrophils as a prognostic indicator in patients with Wegener’s granulomatosis.
Schreiber A, Busiahn A, Luft FC, Kettritz R: Membrane expression of proteinase 3 is genetically determined. J Am Soc Nephrol 2003, 14:68–75.
Gencik M, Meller S, Borgmann S, Fricke H: Proteinase 3 gene polymorphisms and Wegener’s granulomatosis. Kidney Int 2000, 58:2473–2477. A polymorphism (-564 A/G) at the promoter region of the PR3 gene may be associated with higher PR3 production, and it is more prevalent in patients with Wegener’s granulomatosis than in healthy control subjects.
Preston GA, Yang JJ, Xiao H, Falk RJ: Understanding the pathogenesis of ANCA: where are we today? Cleve J Med 2002, 69(suppl):51–54.
Van der Geld Y, Simpelaar A, van der Zee R, et al.: Anti-neutrophil cytoplasmic antibodies to proteinase 3 in Wegener’s granulomatosis: epitope analysis using synthetic peptides. Kidney Int 2001, 59:147–159. These authors demonstrate that ANCA recognize a restricted number of epitopes in PR3 molecule that are close to the catalyic site.
Van der Geld YM, Tool AT, Videler J, et al.: Interference of PR3- ANCA with the enzymatic activity of PR3: Differences in patients during active disease or remission of Wegener’s granulomatosis. Clin Exp Immunol 2002, 129:562–570. Epitope recognition by ANCA varies along the course of the disease and may convey functional changes that may modify the biologic consequences of ANCA binding to their targets. According to the results generated in this study, PR3-ANCA from patients with Wegener’s during remission have greater inhibitory activity toward the enzymatic activity of PR3 than PR3-ANCA obtained from active patients.
Hess C, Sadallah S, Schifferli JA: Induction of neutrophil responsiveness to myeloperoxidase antibodies by their exposure to supernatant of degranulated autologous neutrophils. Blood 2000, 96:2822–2827.
Kettritz R, Schreiber A, Luft FC, Haller H: Role of mitogenactivated protein kinases in activation of human neutrophils by anti-neutrophil cytoplasmic antibodies. J Am Soc Nephrol 2001, 12:37–46. The signaling pathways activated by ANCA binding are investigated by different approaches. Signaling pathways mediated by specific recognition of ANCA targets by F(ab’)2 fragments are different than those triggered by the entire ANCA IgG, but converge in pathways involved in neutrophil degranulation.
Ben-Smith A, Dove SK, Martin A, et al.: Anti-neutrophil cytoplasm antibodies from patients with systemic vasculitis activate neutrophils through distinct signaling cascades: comparison with conventional Fc gamma receptor ligation. Blood 2001, 98:1448–1455. The signaling pathways activated by ANCA binding are investigated by different approaches. Signaling pathways mediated by specific recognition of ANCA targets by F(ab’)2 fragments are different than those triggered by the entire ANCA IgG, but converge in pathways involved in neutrophil degranulation.
Williams JM, Ben-Smith A, Hewins P, et al.: Activation of the G(i) heterotrimeric G proteins 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. The signaling pathways activated by ANCA binding are investigated by different approaches. Signaling pathways mediated by specific recognition of ANCA targets by F(ab’)2 fragments are different than those triggered by the entire ANCA IgG, but converge in pathways involved in neutrophil degranulation.
Kettritz R, Choi M, Butt W, et al.: Phosphatidylinositol 3-kinase controls anti-neutrophil cytoplasmic antibody-induced respiratory burst in human neutrophils. J Am Soc Nephrol 2002, 13:1740–1749. The signaling pathways activated by ANCA binding are investigated by different approaches. Signaling pathways mediated by specific recognition of ANCA targets by F(ab’)2 fragments are different than those triggered by the entire ANCA IgG, but converge in pathways involved in neutrophil degranulation.
Tanaka S, Edberg JC, Chatham W, et al.: Fc gamma RIIIb allelesensitive release of alpha-defensins: anti-neutrophil cytoplasmic antibody-induced release of chemotaxins. J Immunol 2003, 171:6090–6096.
Moosig F, Csernok E, Kumanovics G, Gross WL: Opsonization of apoptotic neutrophils by anti-neutrophil cytoplasmic antibodies leads to enhanced uptake by macrophages and increased release of tumor necrosis factor alpha. Clin Exp Immunol 2000, 122:499–503.
Tse WY, Williams J, Pall A, et al.: Antineutrophil cytoplasm antibody-induced neutrophil nitric oxide production is nitric oxide synthase independent. Kidney Int 2001, 59:593–600.
Radford D, Luu N, Hewins P, et al.: Anti-neutrophil cytoplasmic antibodies stabilize adhesion and promote migration of flowing neutrophils on endothelial cells. Arthritis Rheum 2001, 44:2851–2861.
Weidner S, Neupert W, Goppelt-Strube M, Rupprecht H: Antineutrophil cytoplasmic antibodies induce human monocytes to produce oxygen radicals in vitro. Arthritis Rheum 2001, 44:1698–1706. Many investigators have addressed the effects of ANCA on neutrophil functions. However, ANCA binding to monocytes also may be of great pathologic relevance. In this paper, it is demonstrated that, as with neutrophils, ANCA binding to monocytes also stimulates reactive oxygen species production.
Yang JJ, Preston GA, Alcorta DA, et al.: Expression profile of leukocyte genes activated by anti-neutrophil cytoplasmic autoantibodies (ANCA). Kidney Int 2002, 62:1638–1649. Using microarray technology, the authors explore changes in gene expression induced by ANCA on circulating leukocytes. Different and overlapping sets of genes are regulated by entire ANCA Ig or the F(ab’)2 fragment. Among them, inflammatory genes, such as cyclooxygenase- 2, as well as genes involved in monocyte differentiation, such as differentiation inducing factor-2, are upregulated.
Yang JJ, Preston GA, Pendergraft WF, et al.: Internalization of proteinase 3 is concomitant with endothelial cell apoptosis and internalization of myeloperoxidase with generation of intercellular oxidants. Am J Pathol 2001, 158:581–592.
Taekema-Roelvink ME, Kooten C, Koou SV, et al.: Proteinase 3 enhances endothelial monocyte chemoattractant protein-1 production and induces increased adhesion of neutrophils to endothelial cells by up-regulating intercellular cell adhesion molecule-1. J Am Soc Nephrol 2001, 12:932–940.
Xiao H, Heeringa P, Hu P, et al.: Anti-neutrophil cytoplasmic antibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest 2002, 110:955–963. This is the first animal model demonstrating the full potential of ANCA to trigger lesions similar to those found in human ANCA-associated vasculitis. The authors generate ANCA-MPO in MPO knockout mice by immunization with human MPO. By transferring splenocytes of these animals into immunodeficient mice, they develop crescentic glomerulonephritis and vasculitis. Similar lesions can be observed with infusion of purified ANCA-MPO, but these are less severe than those achieved by transferring splenocytes.
Weidebach W, Viana VS, Leon EP, et al.: C-ANCA positive IgG fraction from patients with Wegener’s granulomatosis induces lung vasculitis in rats. Clin Exp Immunol 2002, 129:54–60. Another animal model that demonstrates the ability of purified cytoplasmic ANCA IgG to induce pulmonary vasculitis.
Shoenfeld Y: Classification of anti-endothelial cell antibodies into antibodies against microvascular and macrovascular endothelial cells. the pathogenic and diagnostic implications. Cleve J Med 2002, 69(suppl):65–68.
Chanseaud Y, de la Peña-Lefèvre G, Guilpain P, et al.: IgM and IgG autoantibodies from microscopic polyangiitis patients but not those with other small and medium-sized vessel vasculitis recognize multiple endothelial cell antigens. Clin Immunol 2003, 109:165–178. Using Western blot analysis, these authors were able to confirm the striking heterogeneity of antigens recognized by AECA.
Lee KH, Chung H, Kim HS, et al.: Human alpha-enolase from endothelial cells as a target antigen of anti-endothelial cell antibody in Behçet’s disease. Arthritis Rheum 2003, 48:2025–2035. By proteomic analysis, alpha-enolase, an enzyme also expressed by neutrophils and recognized by ANCA detected in several chronic inflammatory disorders, is identified as one of the endothelial antigens recognized by AECA in Behçet’s disease.
Coll-Vinent B, Cebrián M, Cid MC, et al.: Dynamic pattern of endothelial cell adhesion molecule expression in muscle and perineural vessels from patients with classical polyarteritis nodosa. Arthritis Rheum 1998, 41:435–444.
Woywodt A, Streiber F, de Groot K, et al.: Circulating endothelial cells as markers for ANCA-associated small-vessel vasculitis. Lancet 2003, 361:206–210. Increased numbers of circulating mature endothelial cells are detected in patients with active systemic necrotizing vasculitis. The majority of these cells display a necrotic and prothrombotic phenotype.
Raza K, Thambyrajah J, Townend IN, et al.: Suppression of inflammation in primary systemic vasculitis restores vascular endothelial function: lessons for atherosclerotic disease?. Circulation 2000, 102:1470–1472. Impaired endothelium-dependent relaxation indicating endothelial cell dysfunction is demonstrated in patients with systemic vasculitis and improves with treatment.
Filer AD, Gardner-Medwin JM, Thambyrajah J, et al.: Diffuse endothelial dysfunction is common to ANCA associated systemic vasculitis and polyarteritis nodosa. Ann Rheum Dis 2003, 62:162–167.
Hernández-Rodríguez J, Segarra M, Vilardell C, et al.: Tissue production of pro-inflammatory cytokines (IL-1b, TNFa and IL-6) correlates with the intensity of the systemic inflammatory response and with corticosteroid requirements in giantcell arteritis. Rheumatology 2004, 43:294–301.
Hellmich B, Ehlers S, Csernok E, Gross WL: Update on the pathogenesis of Churg-Strauss syndrome. Clin Exp Rheumatol 2003, 21(suppl):69–77.
Mueller A, Holl-Ulrich K, Feller AC, et al.: Immune phenomena in localized and generalized Wegener’s granulomatosis. Clin Exp Rheumatol 2003, 21(suppl):49–54.
Cid MC, Vilardell C: Tissue targeting and disease expression patterns in systemic vasculitis. Best Pract Res Clin Rheumatol 2001, 15:259–279.
Bielsa I, Carrascosa JM, Hausmann G, Ferrandiz C: An immunohistopathologic study in cutaneous necrotizing vasculitis. J Cutan Pathol 2000, 27:130–135.
Cid MC, Cebrián M, Font C, et al.: Cell adhesion molecules in the development of inflammatory infiltrates in giant-cell arteritis: inflammation-induced angiogenesis as the preferential site of leukocyte-endothelial cell interactions. Arthritis Rheum 2000, 43:184–194. Preferential expression of endothelial adhesion molecules for leukocytes in neovessels supports a proinflammatory role of angiogenesis in giant cell arteritis.
Cid MC, Hernández-Rodríguez J, Esteban MJ, et al.: Tissue and serum angiogenic activity is associated with low prevalence of ischemic complications in patients with giant-cell arteritis. Circulation 2002, 106:1664–1671. In this study, angiogenesis measured in inflammatory lesions, as well as serum angiogenic activity assessed in in vitro and in vivo assays, is associated with a low prevalence of ischemic events in giant cell arteritis, indicating that angiogenesis may have a compensatory function for ischemia in this disease.
Cid MC, Hernández-Rodríguez J, Robert J, et al.: Interferonalpha may exacerbate cryoglobulinemia-related ischemic manifestations: an adverse effect potentially related to its anti-angiogenic activity. Arthritis Rheum 1999, 42:1051–1055.
Hernández-Rodríguez J, Segarra M, Vilardell C, et al.: Elevated production of interleukin-6 is associated with a lower incidence of ischemic events in patients with GCA: angiogenic activity of IL-6 as a potential protective mechanism. Circulation 2003, 107:2428–2434. In a large series of patients with giant cell arteritis, the authors demonstrate that tissue IL-6 messenger RNA measured by real-time polymerase chain reaction, tissue IL-6 protein, assessed by immunostaining, as well as circulating levels of IL-6, are lower in patients with disease-related ischemic events. Through a series of experiments, the authors show that IL-6 has angiogenic activity and suggest that this can be one of the mechanisms through which IL-6 may be negatively associated with the development of ischemic events. These findings are in accordance with previous publications by the authors showing that ischemic events are less frequent in patients with a strong acute-phase response.
García-Porrua C, Pego-Reigosa R, Armesto V, González-Gay MA: Neovascularization around the optic nerve in giant-cell arteritis. Arthritis Rheum 2003, 49:737–738.
Tepper OM, Sealove BA, Murayama T, Asahara T: Newly emerging concepts in blood vessel growth: recent discovery of endothelial progenitor cells and their function in tissue regeneration. J Investigative Med 2003, 51:353–359.
Nakatani K, Takeshita S, Tsujimoto H, et al.: Circulating endothelial cells in Kawasaki disease. Clin Exp Immunol 2003, 131:536–540. These authors show that patients with active Kawasaki’s disease have elevated numbers of circulating mature endothelial cells suggesting endothelial cell damage and also an increased numbers of circulating endothelial cell progenitors, probably involved in reparative vasculogenesis. This is the first demonstration of increased bone marrow- derived circulating endothelial cell precursors in vasculitis.
de Groot K, Goldberg C, WoyWodt F, et al.: Circulating stem cells in patients with ANCA-associated vasculitis (AAV). Paper presented at the 11th International Vasculitis and ANCA Workshop. Prague, Czech Republic; October 2003. These authors show increased numbers of circulating bone marrow- derived endothelial cell progenitors in patients with systemic necrotizing vasculitis, particularly in patients in early remission after corticosteroid treatment, supporting the potential participation of these cells in vessel and tissue repair.
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Cid, M.C., Segarra, M., Martínez, A.G. et al. Endothelial cells, antineutrophil cytoplasmic antibodies, and cytokines in the pathogenesis of systemic vasculitis. Curr Rheumatol Rep 6, 184–194 (2004). https://doi.org/10.1007/s11926-004-0067-3
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DOI: https://doi.org/10.1007/s11926-004-0067-3