1 / 20

Wegener’s Granulomatosis

PHM142 Fall 2013 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson. Wegener’s Granulomatosis. By: Stephanie Dean Adam Joseph Foy Phillip Kim Timmy Lui Oct 23, 2013 PHM142. What is Wegener’s Granulomatosis ?.

faith
Télécharger la présentation

Wegener’s Granulomatosis

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. PHM142 Fall 2013 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson Wegener’s Granulomatosis By: Stephanie Dean Adam Joseph Foy Phillip Kim Timmy Lui Oct 23, 2013 PHM142

  2. What is Wegener’s Granulomatosis? • Wegener's granulomatosis (WG) is an auto-immune disease that causes inflammation of blood vessels (vasculitis) • WG commonly affects the upper respiratory tract, kidneys, and lungs. It can affect other organs also, but it isn't as common.

  3. Wegener’s Granulomatosis • It was first noticed by Klinger in 1931 and later by Wegener in 1936, whom this disease is named after. • The criteria for defining WG is: • necrotizing granulomas in the upper and lower respiratory tract • generalized necrotizing vasculitis of small arteries and veins • renal involvement.

  4. The cause of Wegener's granulomatosis • The exact cause of WG isn't definitively known but there is research that show a strong indication that anti-neutrophilcytoplasmicautoantibody (ANCA) plays a significant role in the progression of this disease. • ANCA bind to proteinase3 (PR-3) which are proteins found on the surface of cell membranes of neutrophils and this causes inflammation of blood vessels. • The attachment of ANCA are thought to activate neutrophils and cause them to attach to endothelium which causes the inflammation. • The cause of the elevated levels of ANCA are thought to be attributed to inhaled antigens, genetic predusposition, and host factors. • Environmental factors may include Staphylococcus aureus

  5. Proteinase 3 (PR3) • Mature PR3 has 222 amino acid residues • Serine protease, stored in azurophilic granules within neutrophils • Antigen of ANCA • Some expression on membrane of neutrophil • Genetically determined

  6. How is PR3 activated? • Post-translational modification occurs 1.) Amino-end peptide removed by signal peptidase 2.) Amino-end dipeptide removed by Dipeptidyl peptidase I (DPPI/cathepsin C) • Granules are excreted by neutrophil upon activation • Granular movement to surface caused by cytokines (TNF-alpha) and chemoattractants (IL-8) • ANCAs attack PR3 activating neutrophils, especially those signaled by TNF-alpha

  7. PR3 and WG • Binding of Cytoplasmic-ANCA (C-ANCA) to membrane-bound PR3 leads to overactive neutrophils • increased secretion of reactive oxygen species and proteinases (degranulation) • Ultimately damaging endothelial cells of blood vessels • higher densities of membrane-bound PR3 on neutrophils correlated with WG sensitivity • Likelihood of relapse higher

  8. Decreasing C-ANCA effect • Use of SerpinB1 • inhibits ANCAs by binding with the PR3 on membrane • Inhibit PR3 activity when bound together

  9. Decreasing Membrane Bound PR3 • Use of DPPI inhibitors • Lower DPPI resulted in lower PR3 content within neutrophils • Unprocessed protein produced • Degraded internally in cell or excreted (both in development of neutrophils)

  10. Symptoms • WG mostly affects the upper respiratory tract, kidneys, and lungs due to restricted blood flow • Patients commonly present with : • Chronic sinusitis (67%) • Pulmonary infiltrates (71%) • Chronic cough (34%) • Collapse of nasal support, causing saddle nose deformity (common) • Necrotizing glomerulonephritis (17%)

  11. Diagnosis • Cytoplasmic anti-neutrophilcytoplasmic autoantibody testing (c-ANCA) • fluorescence within cytoplasm suggests presence of PR3 auto-antibodies • Chest Radiography • Identifies pulmonary infiltrates • Renal/Pulmonary Biopsies • Identifies presence of necrotizing granulomas *Only conclusive test to diagnose WG*

  12. Treatment • Common treatment consists of cyclophosphamide (CYC) and corticosteroids • Prednisone • Initial phase is aggressive, second phase designed to prevent remission CYC Prednisone

  13. Problems • CYC has been a proposed carcinogen • After 10 years, relapse rate is about 67% • Survivability rate has not improved much since the 1970s

  14. Future treatments • Relapse may be prevented by maintaining the production of PR3-ANCA and primed neutrophils • Future treatments may target the Th1 response (ex: anti-Il-12)

  15. Summary • Wegener's granulomatosis (WG) is an auto-immune disease that causes inflammation of blood vessels (vasculitis) • Commonly affects the upper respiratory tract, kidneys, and lungs. • The exact cause isn’t known but it is believed anti-neutrophil cytoplasmic autoantibodies (ANCA) binds to its antigen, proteinase 3 • This causes neutrophil to over-release proteinases and reactive oxidative species, damaging endothelial walls • Renal/pulmonary biopsies are the only conclusive diagnostic test for WG • Treatment of WG is normally with cyclophosphamide (CYC) and corticosteroids (commonly prednisone)

  16. References • Faurschou, M. et al. Malignancies in Wegener's granulomatosis: incidence and relation to cyclophosphamide therapy in a cohort of 293 patients. The Journal of Reheumatology. 2008. 35. 100 • Reinhold-Keller, E. et al. An interdisciplinary approach to the care of patients with Wegenerʼs granulomatosis: Long‐term outcome in 155 patients. Arthritis and Rheumatism. 2000. 43. 1021 • Khan, A. R. et al. Wegener's granulomatosis: treatment and survival characteristics in a high‐prevalence southern hemisphere region. Internal Medicine Journal. 2012. 42. 23 • Schinlder, A. M. Wegener's Granulomatosis vasculitis and granuloma. Autoimmune Review. 2010. 9. 483 Images Cyclophosphamide. Drugs Information Online. Accessed October 7, 2013 from http://www.drugs.com/pro/cyclophosphamide.html Deltasone. RxList. Accessed October 7, 2013 from http://www.rxlist.com/deltasone-drug.htm

  17. References • Weeda, L.W. and Coffery, S.A.. Wegener's Granulomatosis. Oral Maxillofacial Surgery. (2008). 643-649 • Seo, P. and Stone, J.H.. The AntineutrophilCytoplasmic Antibody - Associated Vasculitides. The American Journal of Medicine. (2004). 117: 39-50 • Langford, C.A.. Wegener Granulomatosis. The American Journal of the Medical Sciences. (2001). 321: 76-82 • Images • The potential role of ANCAs and cytokines in neutrophil-mediated vascular injury. expert reviews in molecular medicine. Accessed October 16, 2013. http://journals.cambridge.org/fulltext_content/ERM/ERM7_08/S146239940500921Xsup005.htm • Wegener's Granulotosis. Vasculitis Foundation. Accessed October 16, 2013. http://elms.readyhosting.com/Classes/Web%20Design/JosephGay/ABOUT.HTML

  18. References • Lynch, Joseph P., and Henry Tazelaar. "Wegener Granulomatosis (Granulomatosis with Polyangiitis): Evolving Concepts in Treatment." Seminar in Respiratory and Critical Care Medicine. 32.3 (2011): 274-97. • Marzano, A.V., Y. Balice, M. Papini, R. Testa, E. Berti, and C. Crosti. "Localized Wegener's granulomatosis." Journal of the European Academy of Dermatology and Venereology. 25.12 (2011): 1466-70. • Millet, Arnaud, MagaliPederzoli-Ribeil, LoicGuillevin, et al. "Antineutrophilcytoplasmic antibody-associated vasculitides: is it time to split up the group?." Ann Rheum Dis. 72. (2013): 1273-79. • Korkmaz, Brice, Adam Lesner, Stephanie Letast, et al. "Neutrophilproteinase 3 and dipeptidyl peptidase I (cathepsin C) as pharmacological targets in granulomatosis with polyangiitis (Wegener granulomatosis)." Seminars in Immunopathology. 35.4 (2013): 411-21. • Images • van der Geld, Y.M., P.C. Limburg, and G.M. Kallenberg. "Proteinase 3, Wegener's autoantigen: from gene to antigen." Journal of Leukocyte Biology. 69.2 (2001): 177-90. Print.

  19. References • Papadopoulos, Particia J. "Wegener Granulomatosis ." Wegener Granulomatosis. Medscape, 12 Aug. 2013. Web. 15 Oct. 2013. <http://emedicine.medscape.com/article/332622-overview>. • Schriber, Andrew, MD. "Wegener's Granulomatosis: MedlinePlus Medical Encyclopedia." U.S National Library of Medicine. U.S. National Library of Medicine, 22 Mar. 2013. Web. 15 Oct. 2013. <http://www.nlm.nih.gov/medlineplus/ency/article/000135.htm>. • Langford, Carol A., MD. "Granulomatosis with Polyangiitis (Wegener's)." Granulomatosis with Polyangiitis (Wegener's). American College of Rheumatology, June 2012. Web. 15 Oct. 2013. <https://www.rheumatology.org/Practice/Clinical/Patients/Diseases_And_Conditions/Granulomatosis_with_Polyangiitis_%28Wegener_s%29/>. • "ANCA/MPO/PR3 Antibodies." Lab Tests Online. American Association for Clinical Chemistry, 21 Dec. 2011. Web. 15 Oct. 2013. <http://labtestsonline.org/understanding/analytes/anca/tab/test>. Images: • http://bestpractice.bmj.com/best-practice/monograph/1094/resources/image/bp/10.html • http://www.facedoctornyc.com/procedures/saddle-nose-deformity.php

More Related