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• W2750668670 abstract "Chronic skin inflammation, subepidermal blistering, and severe itching are the clinical hallmarks of bullous pemphigoid (BP). The disease is caused by autoantibodies against type XVII collagen (COL17, BP180), more specifically, the extracellular fraction of the 16th noncollagenous domain of the protein (NC16A) (Schmidt and Zillikens, 2013Schmidt E. Zillikens D. Pemphigoid diseases.Lancet. 2013; 381: 320-332Abstract Full Text Full Text PDF PubMed Scopus (671) Google Scholar). Two pathways are thought to drive BP pathogenesis. First, autoantibody binding to COL17 leads to activation of the complement cascade, evidenced by the detection of complement deposits along the dermal-epidermal junction in patients with BP (Jordon et al., 1967Jordon R.E. Beutner E.H. Witebsky E. Blumental G. Hale W.L. Lever W.F. Basement zone antibodies in bullous pemphigoid.JAMA. 1967; 200: 751-756Crossref PubMed Scopus (399) Google Scholar, Jordon et al., 1975Jordon R.E. Schroeter A.L. Good R.A. Day N.K. The complement system in bullous pemphigoid: II. Immunofluorescent evidence for both classical and alternate-pathway activation.Clin Immunol Immunopathol. 1975; 3: 307-314Crossref PubMed Scopus (66) Google Scholar) and in mouse models of the disease (Iwata et al., 2015Iwata H. Bieber K. Hirose M. Ludwig R.J. Animal models to investigate pathomechanisms and evaluate novel treatments for autoimmune bullous dermatoses.Curr Pharm Des. 2015; 21: 2422-2439Crossref PubMed Scopus (20) Google Scholar). For example, blockade of C1q or use of noncomplement activating mutant IgG as well as C4- and C5-deficient mice (Nelson et al., 2006Nelson K.C. Zhao M. Schroeder P.R. Li N. Wetsel R.A. Diaz L.A. et al.Role of different pathways of the complement cascade in experimental bullous pemphigoid.J Clin Invest. 2006; 116: 2892-2900Crossref PubMed Scopus (87) Google Scholar) protected from anti-COL17 IgG transfer-induced blistering, thus underscoring the key relevance of the classical pathway of complement in BP pathogenesis (Li et al., 2010Li Q. Ujiie H. Shibaki A. Wang G. Moriuchi R. Qiao H. et al.Human IgG1 monoclonal antibody against human collagen 17 noncollagenous 16A domain induces blisters via complement activation in experimental bullous pemphigoid model.J Immunol. 2010; 185: 7746-7755Crossref PubMed Scopus (52) Google Scholar, Nelson et al., 2006Nelson K.C. Zhao M. Schroeder P.R. Li N. Wetsel R.A. Diaz L.A. et al.Role of different pathways of the complement cascade in experimental bullous pemphigoid.J Clin Invest. 2006; 116: 2892-2900Crossref PubMed Scopus (87) Google Scholar). Second, noncomplement-dependent pathways lead to a depletion of COL17 (Ujiie et al., 2014Ujiie H. Sasaoka T. Izumi K. Nishie W. Shinkuma S. Natsuga K. et al.Bullous pemphigoid autoantibodies directly induce blister formation without complement activation.J Immunol. 2014; 193: 4415-4428Crossref PubMed Scopus (78) Google Scholar), facilitated by protein kinase C-regulated micropinocytosis (Iwata et al., 2016Iwata H. Kamaguchi M. Ujiie H. Nishimura M. Izumi K. Natsuga K. et al.Macropinocytosis of type XVII collagen induced by bullous pemphigoid IgG is regulated via protein kinase C.Lab Invest. 2016; 96: 1301-1310Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar). It is currently unclear which of these two mechanisms drives inflammation and blistering in patients with BP. Yet, the clinical description of an inflammatory and a noninflammatory BP phenotype (Izumi et al., 2016Izumi K. Nishie W. Mai Y. Wada M. Natsuga K. Ujiie H. et al.Autoantibody profile differentiates between inflammatory and noninflammatory bullous pemphigoid.J Invest Dermatol. 2016; 136: 2201-2210Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar) provokes the assumption that complement-mediated blistering may be one of the driving disease pathways in patients with inflammatory BP. Despite these detailed insights into BP pathogenesis (Ludwig et al., 2013Ludwig R.J. Kalies K. Köhl J. Zillikens D. Schmidt E. Emerging treatments for pemphigoid diseases.Trends Mol Med. 2013; 19: 501-512Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar), corticosteroids are still the mainstay of treatment. Although inducing a rapid and complete clinical remission in almost all patients (Joly et al., 2002Joly P. Roujeau J.-C. Benichou J. Picard C. Dreno B. Delaporte E. et al.A comparison of oral and topical corticosteroids in patients with bullous pemphigoid.N Engl J Med. 2002; 346: 321-327Crossref PubMed Scopus (477) Google Scholar), frequently occurring relapses require (Bernard et al., 2009Bernard P. Reguiai Z. Tancrède-Bohin E. Cordel N. Plantin P. Pauwels C. et al.Risk factors for relapse in patients with bullous pemphigoid in clinical remission: a multicenter, prospective, cohort study.Arch Dermatol. 2009; 145: 537-542Crossref PubMed Scopus (94) Google Scholar) prolonged corticosteroid treatment (Joly et al., 2002Joly P. Roujeau J.-C. Benichou J. Picard C. Dreno B. Delaporte E. et al.A comparison of oral and topical corticosteroids in patients with bullous pemphigoid.N Engl J Med. 2002; 346: 321-327Crossref PubMed Scopus (477) Google Scholar). Therefore, treatments maintaining the initial therapeutic response, or at least reducing the steroid dose, are urgently needed. Yet, with the exception of the anti-C5 antibody eculizumab, no complement-targeting biologicals have been approved for clinical use. In addition, eculizumab inhibits the activation of the terminal cascade driven by all three complement pathways. As BP pathology has been linked specifically to classical complement pathway (CP) activity, its selective blockade would maintain full functionality of the alternative and lectin complement pathways to mediate innate humoral immunity. Furthermore, targeting upstream of C5 in the CP would also prevent the production of upstream anaphylatoxins such as C4a and C3a that may induce migration and activation of effector immune cells to the site of complement activation. To assess the role of the CP in driving BP autoantibody-mediated complement activation, we used TNT003, a mouse monoclonal IgG2a antibody that inhibits activation of C1s, a CP-specific serine protease (Shi et al., 2014Shi J. Rose E.L. Singh A. Hussain S. Stagliano N.E. Parry G.C. et al.TNT003, an inhibitor of the serine protease C1s, prevents complement activation induced by cold agglutinin disease patient autoantibodies.Blood. 2014; 123: 4015-4022Crossref PubMed Scopus (102) Google Scholar). Here, we aimed to evaluate the impact of TNT003 on complement activation driven by anti-COL17 autoantibodies from patients with BP in the indirect complement activation assay (Jankásková et al., 2016Jankásková J. Horváth O.N. Varga R. Ruzicka T. Sárdy M. Complement fixation test: an update of an old method for diagnosis of bullous pemphigoid.Acta Derm Venereol. 2016; 96: 197-201Crossref PubMed Scopus (9) Google Scholar) using human biomaterial as approved by the Institutional Review Board at the University of Lübeck and after written informed consent. In this assay, cryosections of human skin are incubated with the serum of patients with BP and a complement source, leading to the deposition of complement along the dermal-epidermal junction of the skin section. We selected this model based on previous data in animal models of BP, hinting toward a prominent role of CP activation in BP pathogenesis (Nelson et al., 2006Nelson K.C. Zhao M. Schroeder P.R. Li N. Wetsel R.A. Diaz L.A. et al.Role of different pathways of the complement cascade in experimental bullous pemphigoid.J Clin Invest. 2006; 116: 2892-2900Crossref PubMed Scopus (87) Google Scholar), and so far missing data on the role of complement activation in human models of the disease. Although the deposition of complement at the dermal-epidermal junction is well established, no data on the concentration of complement components in the serum of patients with BP are available. To test if the complement activation in BP is restricted to the skin or (as reported for certain cytokines) is also “systemically” present, we first analyzed the concentration of several complement components (C1s, C1q, C1s-C1INH, C3a, C4, C4a, and C5) (Supplementary Figure S1 online and Figure 1) in the plasma of patients with BP (Supplementary Table S1 online). The concentrations of all above-mentioned anaphylatoxins (C3a, C4a, C5a) were similar between newly diagnosed patients with BP and age-and sex-matched controls (Figure 1a). Furthermore, all anaphylatoxin concentrations did not change after treatment (Figure 1b) and did not correlate with the concentration of BP180-NC16A serum autoantibodies (Figure 1c). Hence, in BP, complement activation seems to be locally restricted to the skin compartment, as the anaphylatoxins in the plasma were at similar levels compared with controls. To investigate the effect of TNT003 on complement activation, we next evaluated if TNT003 can modulate C3 deposition at the dermal-epidermal junction and anaphylatoxin formation in the complement activation assay (Jankásková et al., 2016Jankásková J. Horváth O.N. Varga R. Ruzicka T. Sárdy M. Complement fixation test: an update of an old method for diagnosis of bullous pemphigoid.Acta Derm Venereol. 2016; 96: 197-201Crossref PubMed Scopus (9) Google Scholar). For this, complement-inactivated serum from patients with BP (Supplementary Table S2 online) was first incubated on skin cryosections from healthy donors followed by the addition of normal human plasma as a complement source in the absence or presence of TNT003. Interestingly, we observed only C3 deposits in 32 of 91 tested sera from patients with BP, despite the presence of C3 deposits in many of the patients at diagnosis (Supplementary Table S2). This significantly lower number of patients with complement-fixing BP might result from differences in the assay protocols. For example, in this study patient sera were more diluted and unspecific complement activation in patient sera was inhibited by the addition of EDTA. When examining 18 of these 32 complement-fixing samples, blockade of C1s by TNT003 dose-dependently (≥10 μg/ml) alleviated C3 deposition at the dermal-epidermal junction in all 18 tested samples that had C3 deposits (Figure 2a). In addition, TNT003, but not TNT001 (isotype control), reduced C4a and C5a concentrations to baseline levels (defined as concentrations in the presence of EDTA) in the assay supernatants. Levels of C3a were unaffected by TNT003 or TNT001 (Figure 2b), which could be caused by the nonclassical pathway C3c deposition observed at the stratum corneum. We also observed a similar degree of inhibition of anaphylatoxin generation when sections were incubated with normal human serum that might be due to unspecific complement activation mechanisms like binding of naturally occurring autoantibodies (Prüßmann et al., 2014Prüßmann J. Prüßmann W. Recke A. Rentzsch K. Juhl D. Henschler R. et al.Co-occurrence of autoantibodies in healthy blood donors.Exp Dermatol. 2014; 23: 519-521Crossref PubMed Scopus (26) Google Scholar) to intracellular antigens. Furthermore, because C1s blockade hampered anaphylatoxin formation, we also investigated its relevance on neutrophil functionality. For this, a chemotaxis assay was employed, using supernatants of the complement activation assay as chemoattractant. In line with the previous results, neutrophil chemoattraction is reduced by TNT003-dependent complement inhibition (Supplementary Figure S2). Collectively, TNT003 is capable of completely blocking CP pathway activation, evidenced by the reduction of C4a and C5a production induced by incubation of sera from patients with BP on cryosections of human skin, and the reduction of C3 deposition in the complement activation test. Although only one-third of our patients demonstrated complement-fixing capacity, all 91 patients had C3 deposits at the dermal-epidermal junction. Thus, serum titers of complement-fixing antibodies do not reflect the local situation in skin, which is also supported by unchanged levels of complement factors in patient plasma. Consequently, the impact of complement inhibitor TNT003 on inflammation and blistering in BP needs to be evaluated in a clinical study. TNT009, the recently developed humanized IgG4 mAb version of TNT003, is currently being tested in a phase I clinical trial in patients with CP-mediated diseases, including BP (NCT02502903). Given favorable data from this phase I study, phase II clinical trials using TNT009 would be warranted in patients with BP. SP, ELR, and SH are employees and shareholders of the company True North Therapeutics that also financed parts of this study. We thank Claudia Kauderer and Cindy Hass for excellent technical assistance as well as Ana Luiza Lima and Vanessa Krull for the management of human material. Download .pdf (.18 MB) Help with pdf files Supplementary Data Increasing the Complement of Therapeutic Options in Bullous PemphigoidJournal of Investigative DermatologyVol. 138Issue 2PreviewBullous pemphigoid is a potentially life-threatening autoantibody-mediated dermatosis characterized by blister formation. Experimental mouse models of bullous pemphigoid feature complement-induced inflammation and tissue damage. Kasprick et al. now provide preclinical data that utilize ex vivo human skin assays and support testing of complement inhibition as a therapeutic strategy in human bullous pemphigoid. Full-Text PDF Open Archive" @default.
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• W2750668670 title "The Anti-C1s Antibody TNT003 Prevents Complement Activation in the Skin Induced by Bullous Pemphigoid Autoantibodies" @default.
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