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. I have consulted for all 5 and have received grants in aid from 2, CSL Behring and Lev. I Chair the DSMB for Dyax

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)

Discovering HAE Pathophysiology

Mechanism of Action of C1 Inhibitor Serpin: Serine Protease Inhibitor

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

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

The Complement Pathways Lectin Pathway Classical Pathway Alternative Pathway C1q C4 C2 C3 C5 to C9 Lysis MBL C3 (H 2 O) Factors B, D, Properdin MASP 1,2,3 C1r,C1s C1 Inh // C3 regulatory molecules

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

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

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

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

Actin Stress FibersVE-Cadherin Nonstimulated Stimulated Sandoval R, et al. J Physiol. 2001;533: Impact of Bradykinin on Permeability

Surface Factor XII HMW Kininogen-Prekallikrein Assembly on Initiating Surfaces HMW=high-molecular-weight. Mandle R, et al. Proc Natl Acad Sci. 1976;73:

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

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

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

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

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

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

B2 Receptor + Bradykinin ‘NO’ PGE 2 TPA Plasminogen Plasmin Endothelial cell Vasodilatation Increased Vascular Permeability ANGIOEDEMA Activation of Endothelial Cells by Bradykinin Zhao Y, et al. Am J Physiol. 2001;280: NO=nitric oxide; PGE 2 =prostaglandin E 2 ; TPA=tissue plasminogen activator.

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

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

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