Wegener’s Granulomatosis Adrian Boucher, Adrian Bagarich, Sarah Moninhas, Fethi Sedik PHM142 Fall 2014 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson 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 Clinical Symptoms • Most affected organs are those that are highly perfused – Respiratory tract, kidneys – Also affects skin, joints, nerves, ears, eyes Anti-neutrophilic Cytoplasmic Autoantibody (ANCA) • IgG antibodies that primarily target PR3 in neutrophil – Attack endothelium • Generated by B-cells in response to a stimulus Proteinase 3 • Found in the granules of neutrophils • Serine protease that normally acts in combination with ROS to destroy pathogens Causes ANCA and Infection Superantigen B-cell Cell Wall Fragments Neutrophil Neutrophil ANCA Production Blood B-cell Antigen R Antigen ANCA Priming of Neutrophil TNF-a ANCA PR3 Neutrophil PR3/ANCA Complex TNF-a ANCA PR3 Neutrophil Complex with Fc Receptor TNF-a ANCA PR3 FcR Neutrophil Localization and Degranulation TNF-a ANCA PR3 ROS Tissue Necrosis TNF-a ANCA PR3 ROS Positive Feedback Neutrophil Properdin Complement Pathway 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 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 Cyclophosphamide • Cytotoxic alkylating agent, destroys T-cells and B-cells • Followed up or coupled with maintenance agents • Issues: http://www.unilab.com.ph/files/1713/2323/4729/Cycl ophosphamide_1_g_vial_powder_for_injection.JPG – Considerable toxicity • Infertility, hair loss, nausea/vomiting – Excessive compromise of immunity – High incidence of relapse Summary • Wegener’s is autoimmune disease caused by Antineutrophilic 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 References • • • • • • http://www.moondragon.org/health/disorders/wegenersgranulomatosis.html#sy mptoms Woof, J. 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