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Wegener’s Granulomatosis
Adrian Boucher, Adrian Bagarich, Sarah Moninhas, Fethi Sedik
PHM142 Fall 2014Coordinator: Dr. Jeffrey HendersonInstructor: Dr. David Hampson
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Introduction
• Part of a group of disorders that produce systemic vasculitis– Autoimmune disorder that involves attack
triggered by Anti-neutrophilic Cytoplasmic Autoantibody (ANCA)
• Systemic inflammation of small and medium blood vessels– Formation of granuloma
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Clinical Symptoms
• Most affected organs are those that are highly perfused– Respiratory
tract, kidneys – Also affects
skin, joints, nerves, ears, eyes
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Anti-neutrophilic Cytoplasmic Autoantibody (ANCA)
• IgG antibodies that primarily target PR3 in neutrophil– Attack endothelium
• Generated by B-cells in response to a stimulus
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Proteinase 3
• Found in the granules of neutrophils
• Serine protease that normally acts in combination with ROS to destroy pathogens
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Causes
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ANCA and Infection
Superantigen
Cell Wall Fragments
Neutrophil
B-cell
Neutrophil
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ANCA Production
B-cell
ANCA
Antigen
Blood
Antigen R
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Neutrophil
Priming of NeutrophilTNF-a
ANCA
PR3
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PR3/ANCA Complex
Neutrophil
TNF-a
ANCA
PR3
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Complex with Fc Receptor
Neutrophil
TNF-a
ANCA
PR3
FcR
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Localization and DegranulationTNF-a
ANCA
PR3
ROS
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Tissue NecrosisTNF-a
ANCA
PR3
ROS
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Positive Feedback
Properdin Complement Pathway
Neutrophil
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Typical Treatment Course• Immunosuppression therapy coupled with supportive treatments
– Hemodialysis in case of renal failure– Respiratory support in case of lung hemorrhage– Preventing infection
Lugmani, 2014
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Phases of immune suppression• Remission Induction
– Aggressive dosing of immunosuppressants• Coupled with high doses of corticosteroids to reduce inflammation further
– Goal: try to prevent as much irreversible tissue damage (kidneys, lungs) as you can, as quickly as possible
– Challenges: • Minimizing drug toxicity• Co-morbidity
• Remission Maintenance– Lower, continued doses of immunosuppressant to – Goal: prevent relapse going forward– Challenges:
• When is it safe to transition from induction to maintenance?• Issues with long-term drug exposure/accumulation
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Cyclophosphamide
• Cytotoxic alkylating agent, destroys T-cells and B-cells
• Followed up or coupled with maintenance agents
• Issues:– Considerable toxicity• Infertility, hair loss, nausea/vomiting
– Excessive compromise of immunity– High incidence of relapse
http://www.unilab.com.ph/files/1713/2323/4729/Cyclophosphamide_1_g_vial_powder_for_injection.JPG
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Summary• Wegener’s is autoimmune disease caused by Anti-
neutrophilic Cytoplasmic Autoantibody (ANCA)• ANCA are released by B-cells and target proteinase 3 (PR3)
released by neutrophils• Binding of ANCA/PR3 complex to Fc receptor
results in attack on endothelium by neutrophils• This damages the endothelium and results in tissue necrosis• The main treatment is immunosuppressant drugs such as
cyclophosphamide which destroy T and B cells• The goal of treatment is used to achieve remission as there
is no curing currently for Wegener’s
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References• http://www.moondragon.org/health/disorders/
wegenersgranulomatosis.html#symptoms• Woof, J. M., & Burton, D. R. (2004). Human antibody–Fc receptor interactions
illuminated by crystal structures. Nature Reviews Immunology, 4(2), 89-99.• Van der Geld, Y. M., Limburg, P. C., & Kallenberg, C. G. M. (2001). Proteinase 3,
Wegener’s autoantigen: from gene to antigen. Journal of leukocyte biology,69(2), 177-190.
• Chen, M., & Kallenberg, C. G. (2010). ANCA-associated vasculitides—advances in pathogenesis and treatment. Nature Reviews Rheumatology,6(11), 653-664.
• Lutalo, P. M., & D'Cruz, D. P. (2014). Diagnosis and classification of granulomatosis with polyangiitis (aka Wegener's granulomatosis). Journal of autoimmunity, 48, 94-98.
• Jennette, J. C., Falk, R. J., Hu, P., & Xiao, H. (2013). Pathogenesis of antineutrophil cytoplasmic autoantibody-associated small-vessel vasculitis.Annual Review of Pathology: Mechanisms of Disease, 8, 139-160.
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References• Tarzi RM, Pusey CD. Current and future prospects in the management of granulomatosis with
polyangiitis (Wegener's granulomatosis). Ther Clin Risk Manag. 2014;10:279-93.• Luqmani RA. State of the art in the treatment of systemic vasculitides. Front Immunol.
2014;5:471.• Walsh M, Flossmann O, Berden A, et al. Risk factors for relapse of antineutrophil cytoplasmic
antibody-associated vasculitis. Arthritis Rheum. 2012;64(2):542-8.• Walton EW. Giant-cell granuloma of the respiratory tract (Wegener's granulomatosis). Br
Med J. 1958;2(5091):265-70.• Flossmann O, Berden A, De groot K, et al. Long-term patient survival in ANCA-associated
vasculitis. Ann Rheum Dis. 2011;70(3):488-94.• Jayne D, Rasmussen N, Andrassy K, et al. A randomized trial of maintenance therapy for
vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. 2003;349(1):36-44.
• Harper L, Morgan MD, Walsh M, et al. Pulse versus daily oral cyclophosphamide for induction of remission in ANCA-associated vasculitis: long-term follow-up. Ann Rheum Dis. 2012;71(6):955-60.
• Little MA, Nightingale P, Verburgh CA, et al. Early mortality in systemic vasculitis: relative contribution of adverse events and active vasculitis. Ann Rheum Dis. 2010;69(6):1036-43.