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Gene Review

WG  -  Wegener granulomatosis

Homo sapiens



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Disease relevance of GPA

  • Autoantibodies to proteinase 3 (PR3) are involved in the pathogenesis of autoimmune-mediated vasculitis in granulomatosis with polyangiitis (GPA[1].
  • Anti-PR3 autoantigen interacts with a "gateway" receptor (PAR-2) on iDCs in vitro triggering their maturation and licenses them for a T helper 1 (Th1)-type response potentially favoring granuloma formation in GPA [1].
  • To address the question how the autoantigen PR3 becomes a target of adaptive immunity, we investigated the effect of PR3 on immature dendritic cells (iDCs) in patients with GPA, healthy blood donors, and patients with Crohn disease (CD), another granulomatous disease [1].
  • CONCLUSIONS: Selection and affinity maturation of potentially PR3-ANCA producing autoreactive B cells may start in granulomatous lesions, thereby contributing to disease progression from ANCA negative localised to PR3-ANCA positive generalised GPA [2].
  • We describe a case of hypertrophic cranial pachymeningitis (HCP) associated with granulomatosis with polyangiitis in a 60-year-old man presenting with chronic headache and multiple cranial nerve neuropathies [3].

Psychiatry related information on 

  • RESULTS: The incidence of 5/7 Id was significantly more frequent in GPA patients (43 of 86; 50%) [4].

High impact information on GPA

  • In granulomatosis with polyangiitis, inflammation begins in the airway but results in glomerulonephritis [5].
  • Bilateral uveitis was the initial manifestation of a limited form of granulomatosis with polyangiitis in a 47-year-old man [6].
  • Associated metabolic events and the loss of endothelial barrier properties suggest that anti-PR3-induced activation of endothelial cells may contribute to the pathogenetic sequelae of autoimmune vasculitis characterizing WG [7].
  • Anti-neutrophil cytoplasmic antibodies (ANCAs) targeting proteinase 3 (PR3) have a high specificity for granulomatosis with polyangiitis, and their role in activating leukocytes is well appreciated [7].
  • Employing a monoclonal antibody directed against human PR3 and ANCA-positive serum from GPA patients with specificity for PR3, we now investigated the role of free arachidonic acid (AA) in autoantibody-related human neutrophil activation [8].

Chemical compound and disease context of WG

  • Cytoplasmic antineutrophil cytoplasmic antibodies (cANCA) that accompany the neutrophilic vasculitis seen in granulomatosis with polyangiitis, are directed against proteinase-3 (PR-3), a serine proteinase which is located in azurophilic granules of neutrophils and monocytes [9].
  • This distinction is important because GPA requires cyclophosphamide therapy, whereas many other forms of vasculitis can be treated with corticosteroids alone [10].
  • METHODS: We analyzed the incidence of 5/7 Id in patients with ANCA-associated vasculitides (GPA, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitisin disease controls (systemic lupus erythematosus patients), and in healthy donors [4].
  • CONCLUSION: In this study, the use of MTX and prednisone as initial therapy for patients with WG-related glomerulonephritis and a normal or near-normal level of serum creatinine was not associated with a long-term decline in renal function [11].
  • OBJECTIVE: To determine the long-term renal outcome in patients with granulomatosis with polyangiitis and active glomerulonephritis who were treated with methotrexate (MTX) and glucocorticoids [11].

Biological context of GPA

  • HLA-DPB1 typing and fine mapping of the region with additional microsatellites and single-nucleotide polymorphisms (SNPs) revealed a strong association of GPA with the significantly over-represented DPB1*0401 ( P=1.51x10(-10), OR=3.91) allele compared with the control cohort [12].
  • Six microsatellite allele patterns were found significantly associated with GPA, three of which could be confirmed by individual genotyping [12].
  • In addition, an extended haplotype DPB1*0401/RXRB03 was identified showing an even stronger association with GPA ( P=7.13x10(-17), OR=6.41) [12].
  • Significantly more genes (55%, 45%, and 53%, respectively) from active GPA compared with the healthy repertoire carried mutations to negatively charged amino acids within the binding site coding regions, favouring affinity to the positively charged PR3 [2].
  • METHODS: Patients in our centre with GPA were selected according to both the Chapel Hill Consensus Conference (CHCC) definition and American College of Rheumatology classification criteria [13].

Anatomical context of GPA

  • PR3-maturated DCs derived from GPA patients induce a higher IFN-gamma response of PR3-specific CD4(+) T cells compared with patients with CD and healthy controls [1].
  • Here, we report on an extended association screen (EAS) with 202 microsatellite markers, representing apoptosis-related genes and further genes down-regulated in apoptotic neutrophils, using pooled DNA of 150 Northern German patients suffering from GPA and 100 healthy Northern German controls [12].
  • OBJECTIVES: To determine whether B cell selection and maturation take place in granulomatous lesions of GPA [2].
  • Although the neutrophil's pathogenic role in GPA has been studied, the role of the monocyte has not been explored [9].
  • Comparing various vasculitic and granulomatous tissues, WG granulomas contained more granulocytes [14].

Associations of GPA with chemical compounds

  • CONCLUSION: Data from the WGET, the first substantial reported experience of the combined use of etanercept and cyclophosphamide in the treatment of GPA, indicate that the combination of TNF inhibition and cyclophosphamide may heighten the risk of cancer beyond that observed with cyclophosphamide alone [15].
  • 15-Deoxyspergualin (DSG) is an alternative treatment modality for granulomatosis with polyangiitis (GPA) patients refractory to conventional treatment [16].
  • Autoantibodies directed against cytoplasmic antigens of neutrophils (ANCA), especially proteinase 3 (PR-3), have proved to be a useful clinical tool confirming the diagnosis or monitoring disease activity of GPA [17].
  • An open-label study of weekly low-dose MTX plus prednisone for the treatment of GPA was performed [18].
  • An open-label pilot study of weekly low-dose methotrexate (MTX) plus glucocorticoids (GC) for treatment of patients with GPA was performed [19].

Physical interactions of GPA

  • In the artery extract, serum IgG from 6/18 MPA patients bound to an 85 kDa antigen, whereas purified IgG from all GPA patients tested bound to a 28 kDa protein band and IgM from CSS patients bound to 2 main antigens of 38 and 60 kDa [20].

Regulatory relationships of GPA

  • IL-5 production was up-regulated in GPA TCL compared with CSS TCL (P = 0.014) [21].
  • The expression of CCR5 on NK cells was up-regulated in individuals with HIV viremia and in individuals with active GPA, indicating that expression of this receptor is modulated by states of immune activation associated with viral infection and inflammatory or immune-mediated diseases [22].
  • Leukocyte SLPI expression seems to be up-regulated in active GPA [23].
  • Finally, the in vitro IFN-gamma production by GPA PBMC is inhibited in a dose-dependent manner by exogenous IL-10 [24].
  • Although endothelial activation markers in GPA patients with inactive disease were not increased, the raised levels of hsCRP, MMPs, and TIMP-1 suggest that enhanced inflammation and excessive vascular remodelling are contributing factors in the development of accelerated atherosclerosis in GPA [25].

Other interactions of GPA

  • BACKGROUND: Proteinase-3 antineutrophil cytoplasmic antibody (PR3-ANCA) was the serological marker for GPA, while myeloperoxidase (MPO)-ANCA was the serological marker for microscopic polyangiitis (MPA) [13].
  • Using the geometric mean (+/- 2 standard deviations) in FM patients as the upper cutoff, 20% of SLE patients, 12% of RA patients, 4% of SS patients, and none of the GPA patients were positive for anti-alpha-actinin antibodies [26].
  • LEF has been also used in other autoimmune diseases, like Psoriatic Arthritis, granulomatosis with polyangiitis, Systemic Lupus Erythematosus, Sarcoidosis and others [27].
  • METHODS: A population-based study was performed for the PTPN22 polymorphism in 199 patients with GPA and in 399 healthy individuals [28].
  • Compared with HC, GPA TCL showed increased production of IFNgamma (P = 0.021), IL-5 (P = 0.043), and IL-13 (P = 0.021) [21].

Analytical, diagnostic and therapeutic context of WG

  • After fractionation of these antigens by size, with gel filtration high performance liquid chromatography, sera from patients with clinically different forms of systemic vasculitis, granulomatosis with polyangiitis,  and microscopic polyangiitis (MPA), showed contrasting specificities of binding [29].
  • ANCA by both IIF and ELISA were detected in 78% (12/14) of control patients with GPA [30].
  • A prior history of allergy was also associated with GPA as compared with either control group [31].
  • METHODS: An open-label, prospective, standardized trial for the treatment of GPA was performed using CYC and glucocorticoids for remission induction and MTX for remission maintenance [32].
  • Based on these observations, we conclude that 5/7 anti-Id is a promising tool for the development of a specific immunotherapy for GPA [4].


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  2. B lymphocyte maturation in Wegener's granulomatosis: a comparative analysis of VH genes from endonasal lesions. Voswinkel, J., Mueller, A., Kraemer, J.A., Lamprecht, P., Herlyn, K., Holl-Ulrich, K., Feller, A.C., Pitann, S., Gause, A., Gross, W.L. Ann. Rheum. Dis. (2006) [Pubmed]
  3. MPO-ANCA-positive Wegener's granulomatosis presenting with hypertrophic cranial pachymeningitis: case report and review of the literature. Akahoshi, M., Yoshimoto, G., Nakashima, H., Miyake, K., Inoue, Y., Tanaka, Y., Tsukamoto, H., Horiuchi, T., Otsuka, T., Harada, M. Modern rheumatology / the Japan Rheumatism Association (2004) [Pubmed]
  4. Incidence and disease associations of a proteinase 3-antineutrophil cytoplasmic antibody idiotype (5/7 Id) whose antiidiotype inhibits proteinase 3-antineutrophil cytoplasmic antibody antigen binding activity. Strunz, H.P., Csernok, E., Gross, W.L. Arthritis Rheum. (1997) [Pubmed]
  5. Immunologic aspects of renal disease. Ambrus, J.L., Sridhar, N.R. JAMA (1997) [Pubmed]
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  12. New genomic region for Wegener's granulomatosis as revealed by an extended association screen with 202 apoptosis-related genes. Jagiello, P., Gencik, M., Arning, L., Wieczorek, S., Kunstmann, E., Csernok, E., Gross, W.L., Epplen, J.T. Hum. Genet. (2004) [Pubmed]
  13. Renal histology in Chinese patients with anti-myeloperoxidase autoantibody-positive Wegener's granulomatosis. Chen, M., Yu, F., Wang, S.X., Zou, W.Z., Zhang, Y., Zhao, M.H., Wang, H.Y. Nephrol. Dial. Transplant. (2007) [Pubmed]
  14. Proteinase 3, the target antigen of anticytoplasmic antibodies circulating in Wegener's granulomatosis. Immunolocalization in normal and pathologic tissues. Braun, M.G., Csernok, E., Gross, W.L., Müller-Hermelink, H.K. Am. J. Pathol. (1991) [Pubmed]
  15. Solid malignancies among patients in the Wegener's Granulomatosis Etanercept Trial. Stone, J.H., Holbrook, J.T., Marriott, M.A., Tibbs, A.K., Sejismundo, L.P., Min, Y.I., Specks, U., Merkel, P.A., Spiera, R., Davis, J.C., St Clair, E.W., McCune, W.J., Ytterberg, S.R., Allen, N.B., Hoffman, G.S. Arthritis Rheum. (2006) [Pubmed]
  16. In vivo effects of cyclic administration of 15-deoxyspergualin on leucocyte function in patients with Wegener's granulomatosis. K??lsch, A.I., Schmitt, W.H., Breedijk, A., Marinaki, S., Weigerding, S., Nebe, T.C., Nemoto, K., van der Woude, F.J., Yard, B.A., Birck, R. Clin. Exp. Immunol. (2006) [Pubmed]
  17. Human endothelial cells express proteinase 3, the target antigen of anticytoplasmic antibodies in Wegener's granulomatosis. Mayet, W.J., Csernok, E., Szymkowiak, C., Gross, W.L., Meyer zum Büschenfelde, K.H. Blood (1993) [Pubmed]
  18. An analysis of forty-two Wegener's granulomatosis patients treated with methotrexate and prednisone. Sneller, M.C., Hoffman, G.S., Talar-Williams, C., Kerr, G.S., Hallahan, C.W., Fauci, A.S. Arthritis Rheum. (1995) [Pubmed]
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  20. Analysis of autoantibody repertoires in small- and medium-sized vessels vasculitides. Evidence for specific perturbations in polyarteritis nodosa, microscopic polyangiitis, Churg-Strauss syndrome and Wegener's granulomatosis. Chanseaud, Y., Tamby, M.C., Guilpain, P., Reinbolt, J., Kambouchner, M., Boyer, N., Noël, L.H., Guillevin, L., Boissier, M.C., Mouthon, L. J. Autoimmun. (2005) [Pubmed]
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  22. Expression of chemokine and inhibitory receptors on natural killer cells: effect of immune activation and HIV viremia. Kottilil, S., Shin, K., Planta, M., McLaughlin, M., Hallahan, C.W., Ghany, M., Chun, T.W., Sneller, M.C., Fauci, A.S. J. Infect. Dis. (2004) [Pubmed]
  23. Increased expression of the secretory leukocyte proteinase inhibitor in Wegener's granulomatosis. Ohlsson, S., Falk, R., Yang, J.J., Ohlsson, K., Segelmark, M., Wieslander, J. Clin. Exp. Immunol. (2003) [Pubmed]
  24. Active Wegener's granulomatosis is associated with HLA-DR+ CD4+ T cells exhibiting an unbalanced Th1-type T cell cytokine pattern: reversal with IL-10. Lúdvíksson, B.R., Sneller, M.C., Chua, K.S., Talar-Williams, C., Langford, C.A., Ehrhardt, R.O., Fauci, A.S., Strober, W. J. Immunol. (1998) [Pubmed]
  25. Accelerated atherosclerosis in patients with Wegener's granulomatosis. de Leeuw, K., Sanders, J.S., Stegeman, C., Smit, A., Kallenberg, C.G., Bijl, M. Ann. Rheum. Dis. (2005) [Pubmed]
  26. Alpha-actinin-binding antibodies in relation to systemic lupus erythematosus and lupus nephritis. Becker-Merok, A., Kalaaji, M., Haugbro, K., Nikolaisen, C., Nilsen, K., Rekvig, O.P., Nossent, J.C. Arthritis Res. Ther. (2006) [Pubmed]
  27. Leflunomide in clinical practice. Pinto, P., Dougados, M. Acta reumatol??gica portuguesa (2006) [Pubmed]
  28. The PTPN22 620W allele is a risk factor for Wegener's granulomatosis. Jagiello, P., Aries, P., Arning, L., Wagenleiter, S.E., Csernok, E., Hellmich, B., Gross, W.L., Epplen, J.T. Arthritis Rheum. (2005) [Pubmed]
  29. Association of alkaline phosphatase with an autoantigen recognised by circulating anti-neutrophil antibodies in systemic vasculitis. Lockwood, C.M., Bakes, D., Jones, S., Whitaker, K.B., Moss, D.W., Savage, C.O. Lancet (1987) [Pubmed]
  30. Prevalence of antineutrophil cytoplasmic antibodies in patients with various pulmonary diseases or multiorgan dysfunction. Vassilopoulos, D., Niles, J.L., Villa-Forte, A., Arroliga, A.C., Sullivan, E.J., Merkel, P.A., Hoffman, G.S. Arthritis Rheum. (2003) [Pubmed]
  31. Wegener's granulomatosis: Possible role of environmental agents in its pathogenesis. Albert, D., Clarkin, C., Komoroski, J., Brensinger, C.M., Berlin, J.A. Arthritis Rheum. (2004) [Pubmed]
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