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Hereditary Angioedema: Pathogenesis of Attacks

Hereditary Angioedema: Pathogenesis of Attacks. Michael M. Frank, MD Samuel Katz Professor of Pediatrics, Medicine and Immunology Duke University Medical Center. Conflict of interest. 5 companies (Lev, CSL Behring, Jerini, Pharming, Dyax) have completed trials of therapy for HAE.

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Hereditary Angioedema: Pathogenesis of Attacks

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  1. Hereditary Angioedema: Pathogenesis of Attacks Michael M. Frank, MD Samuel Katz Professor of Pediatrics, Medicine and Immunology Duke University Medical Center

  2. Conflict of interest • 5 companies (Lev, CSL Behring, Jerini, Pharming, Dyax) have completed trials of therapy for HAE. • I have consulted for all 5 and have received grants in aid from 2, CSL Behring and Lev. • I Chair the DSMB for Dyax

  3. Angioedema vs Urticaria Angioedema: swelling involving the deep dermis; generally localized; mildly pruritic, rarely burning or painful; lasts hours to several days Urticaria: circumscribed raised erythematous lesions involving the superficial dermis; often generalized usually pruritic; lesions usually vary in size and stage; individual lesions last minutes to hours (usually ≤ 24 hr)

  4. Discovering HAE Pathophysiology

  5. Mechanism of Action of C1 Inhibitor Serpin: Serine Protease Inhibitor

  6. Functions of C1 Inhibitor C1r, C1s, MASP1,2,3, Alternative Pathway Complement Contact Activation Systems Factor XII (Hageman Factor) XIIa, XIIf Clotting Kinin Generating Fibrinolytic Plasmin Tissue plasminogen activator (t-PA) Kallikrein Factor XIa

  7. C1r-C1INH C1s-C1INH ¯ ¯ Activated C1 (C1) = C1q C1r2 C1s2 ¯ C1q + 2 C1 + C1 INH HAE Pathophysiology Activated C1 Binds Four C1INH Molecules C1 = C1q C1r2 C1s2 ¯ Ziccardi RJ. J Immunol. 1982;128:2500-2504.

  8. Lectin Pathway MBL The Complement Pathways MASP 1,2,3 C3 regulatory molecules C1 Inh // Classical Pathway C1q C4C2 C3 C5 to C9 Lysis C1r,C1s C3 (H2O) Alternative Pathway Factors B, D, Properdin

  9. Contact System Is Activated in HAE Patients Curd JG, et al. J Exp Med. 1980;152:742-747. Curd JG, et al. Mol Immunol. 1982;19:1365.

  10. C1INH gene +/+ +/+ −/ − − / − − / − B2BKR gene +/+ +/+ +/+ +/+ − / − Evans blue No Yes Yes Yes Yes C1-INH therapy No No No Yes No C1-INH Null Mice and Vascular Permeability Han ED, et al. J Clin Invest. 2002;109:1057-1063;.

  11. In Vivo Generation of Kinins in HAE Nussberger J, et al. J Allergy Clin Immunol. 1999;104:1321-1322; with permission.

  12. C1 Inhibitor and the Kinin System Factor XII Factor XIIa Factor XIIf Prekallikrein KALLIKREIN HMW Kininogen BRADYKININ B2 Receptor - C1 inhibitor ANGIOEDEMA

  13. Impact of Bradykinin on Permeability VE-Cadherin Actin Stress Fibers Nonstimulated Stimulated Sandoval R, et al. J Physiol. 2001;533:433-445

  14. Assembly on Initiating Surfaces FactorXII Surface HMWKininogen-Prekallikrein HMW=high-molecular-weight. Mandle R, et al. Proc Natl Acad Sci. 1976;73:4179-4183.

  15. Immunoperoxidase Staining of Endothelial Cells Antibody to Factor XII Normal plasma Factor XII–deficient plasma Antibody to HMW-Kininogen Normal plasma HMW-kininogen–deficient plasma Joseph K, et al. Clin Immunol. 1999;92:246-255.

  16. Factor XII–Dependent Bradykinin Formation HMW=high-molecular-weight. Kaplan AP, et al. J Allergy Clin Immunol. 2002;109:195-209.

  17. C1-INH Inhibition of Factor XII Autoactivation HF=Hageman factor. Weiss R, et al. Blood. 1986;68:239-243.

  18. Kallikrein “Feedback” Activation of Factor XII Factor XII Surface Factor XIIa Prekallikrein Kallikrein HMW Kininogen HMW=high-molecular-weight. Cochrane CG, et al. J Exp Med. 1973;138:1564-1583.

  19. C1 Inhibitor and the Kinin System Clot Factor XII Factor XIIa Factor XIIf C1 + C4 C4a+C4b Prekallikrein KALLIKREIN HMW Kininogen BRADYKININ B2 Receptor - C1 inhibitor ANGIOEDEMA

  20. Reduction of Serum Complement by Factor XIIf Factor XIIf (mg/mL) Ghebrehiwet B, et al. J Clin Invest. 1983;71:1450-1456.

  21. Activation of Endothelial Cells by Bradykinin B2 Receptor Vasodilatation Increased Vascular Permeability + Bradykinin ‘NO’ PGE2 ANGIOEDEMA Endothelial cell Plasminogen TPA Plasmin NO=nitric oxide; PGE2=prostaglandin E2; TPA=tissue plasminogen activator. Zhao Y, et al. Am J Physiol. 2001;280:1821-1829.

  22. Ex Vivo Generation of Bradykinin Fields T, et al. J Allergy Clin Immunol. 1983;72:54-60; with permission. Ghebrehiwet B, et al. J Clin Invest. 1983;71:1450-1456.

  23. Endothelial Cell u-PAR Cytokeratin 1 Bradykinin B2 Receptor gC1qR Zn++ Zn++ HMWK Bradykinin Factor XII Prekallikrein Factor XIIa Kallikrein Bradykinin B2 Receptor Joseph K, et al. Thromb Haemostasis. 2004;91:61-70.

  24. Autoactivation of Factor XII Surface * Factor XII Factor XIIa *Amount of factor XIIa in plasma is <0.01% of factor XII Silverberg M, et al. J Biol Chem. 1980;255:7281-7286.

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