The role of complement in mucous membrane pemphigoid

• Applicants: Professor Dr. Ralf Joachim Ludwig; Professor Dr. Enno Schmidt
• Subject Area: Dermatology
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 417348511

• Final Report Year: 2025

Final Report Abstract

This project focused on the role of the complement system in mucous membrane pemphigoid (MMP) and its potential use as a pharmacological target. We expanded the focus of the research to additional pemphigoid diseases, namely bullous pemphigoid (BP and epidermolysis bullosa acquisita (EBA). Across three experimental models of pemphigoid diseases (MMP, BP and EBA) disease developed independently of C3. This suggested that alternative C5 convertases drive complement activation, particularly C5 cleavage. Thrombin was identified as a potential alternative C5 convertase, particularly in EBA. In contrast, pharmacological thrombin blockade had no significant effect in MMP or BP. Furthermore, all three pemphigoid diseases developed independent of neutrophil elastase. Hence, neutrophil elastase does not act as an alternative C5 convertase in experimental pemphigoid disease. In addition, we identified a critical role of C5a receptor 1 (C5aR1) in MMP pathogenesis, with C5aR1-deficient mice showing resistance to disease induction. Therapeutic studies in antibody transfer-induced MMP demonstrated that intravenous immunoglobulin (IVIG) and dapsone mitigated disease severity by targeting neutrophil-mediated LTB4 release and complement activation. Furthermore, local (i.e., application as eye-drops) C5a inhibition significantly reduced conjunctival lesions in the MMP model, resulting in a patent application. Additionally, large-scale epidemiological studies using TriNetX identified an increased risk of blindness and esophageal strictures in MMP patients compared to controls.

Publications

• Comparison of Two Diagnostic Assays for Anti-Laminin 332 Mucous Membrane Pemphigoid. Frontiers in Immunology, 12.
  Goletz, Stephanie; Giurdanella, Federica; Holtsche, Maike M.; Nijenhuis, Miranda; Horvath, Barbara; Diercks, Gilles F. H.; Zillikens, Detlef; Hashimoto, Takashi; Schmidt, Enno & Pas, Hendri H.
  
• Dapsone Suppresses Disease in Preclinical Murine Models of Pemphigoid Diseases. Journal of Investigative Dermatology, 141(11), 2587-2595.e2.
  Murthy, Sripriya; Schilf, Paul; Patzelt, Sabrina; Thieme, Markus; Becker, Mareike; Kröger, Lasse; Bremer, Tabea; Derenda-Hell, Aleksandra; Knebel, Lea; Fagiani, Francesca; Ibrahim, Saleh M.; Schmidt, Enno; Zillikens, Detlef & Sadik, Christian D.
  
• European guidelines (S3) on diagnosis and management of mucous membrane pemphigoid, initiated by the European Academy of Dermatology and Venereology – Part I. Journal of the European Academy of Dermatology and Venereology, 35(9), 1750-1764.
  Rashid, H.; Lamberts, A.; Borradori, L.; Alberti‐Violetti, S.; Barry, R.J.; Caproni, M.; Carey, B.; Carrozzo, M.; Caux, F.; Cianchini, G.; Corrà, A.; Diercks, G.F.H.; Dikkers, F.G.; Di Zenzo, G.; Feliciani, C.; Geerling, G.; Genovese, G.; Hertl, M.; Joly, P. ... & Horváth, B.
  
• European Guidelines (S3) on diagnosis and management of mucous membrane pemphigoid, initiated by the European Academy of Dermatology and Venereology – Part II. Journal of the European Academy of Dermatology and Venereology, 35(10), 1926-1948.
  Schmidt, E.; Rashid, H.; Marzano, A.V.; Lamberts, A.; Di Zenzo, G.; Diercks, G.F.H.; Alberti‐Violetti, S.; Barry, R.J.; Borradori, L.; Caproni, M.; Carey, B.; Carrozzo, M.; Cianchini, G.; Corrà, A.; Dikkers, F.G.; Feliciani, C.; Geerling, G.; Genovese, G.; Hertl, M. ... & Caux, F.
  
• Differential expression of C5aR1 and C5aR2 in innate and adaptive immune cells located in early skin lesions of bullous pemphigoid patients. Frontiers in Immunology, 13.
  Emtenani, Shirin; Holtsche, Maike M.; Stahlkopf, Richard; Seiler, Daniel L.; Burn, Timothy; Liu, Huiqing; Parker, Melissa; Yilmaz, Kaan; Dikmen, Hasan O.; Lang, Markus Huber; Sadik, Christian D.; Karsten, Christian M.; van Beek, Nina; Ludwig, Ralf J.; Köhl, Jörg & Schmidt, Enno
  
• Evaluation of Site- and Autoantigen-Specific Characteristics of Mucous Membrane Pemphigoid. JAMA Dermatology, 158(1), 84.
  van Beek, Nina; Kridin, Khalaf; Bühler, Elena; Kochan, Anne S.; Ständer, Sascha; Ludwig, Ralf J.; Zillikens, Detlef; Schmidt, Enno & Günther, Claudia
  
• Increased Fibrosis in a Mouse Model of Anti-Laminin 332 Mucous Membrane Pemphigoid Remains Unaltered by Inhibition of Aldehyde Dehydrogenase. Frontiers in Immunology, 12.
  Patzelt, Sabrina; Pigors, Manuela; Steenbock, Heiko; Diel, Leonard; Boch, Katharina; Chakievska, Lenche; Künzel, Sven; Busch, Hauke; Fähnrich, Anke; Brinckmann, Jürgen & Schmidt, Enno
  
• Mucous membrane pemphigoid. Autoimmunity Reviews, 21(4), 103036.
  Du, Gefei; Patzelt, Sabrina; van Beek, Nina & Schmidt, Enno
  
• S2k Guideline for the diagnosis and treatment of mucous membrane pemphigoid. JDDG: Journal der Deutschen Dermatologischen Gesellschaft, 20(11), 1530-1550.
  Hofmann, Silke C.; Günther, Claudia; Böckle, Barbara C.; Didona, Dario; Ehrchen, Jan; Gaskins, Matthew; Geerling, Gerd; Gläser, Regine; Hadaschik, Eva; Hampl, Monika; Haßkamp, Pia; Jackowski, Jochen; Kiritsi, Dimitra; Nast, Alexander; Pleyer, Uwe; Reichel, Christoph; Roth, Mathias; Schumann, Michael; Sticherling, Michael ... & Schmidt, Enno
  
• Autoimmunity against laminin 332. Frontiers in Immunology, 14.
  Patzelt, Sabrina & Schmidt, Enno
  
• Bullous pemphigoid induced by IgG targeting type XVII collagen non‐NC16A / NC15A extracellular domains is driven by Fc gamma receptor‐ and complement‐mediated effector mechanisms and is ameliorated by neonatal Fc receptor blockade. The Journal of Pathology, 262(2), 161-174.
  Pigors, Manuela; Patzelt, Sabrina; Reichhelm, Niklas; Dworschak, Jenny; Khil'chenko, Stanislav; Emtenani, Shirin; Bieber, Katja; Hofrichter, Maxi; Kamaguchi, Mayumi; Goletz, Stephanie; Köhl, Gabriele; Köhl, Jörg; Komorowski, Lars; Probst, Christian; Vanderheyden, Katrien; Balbino, Bianca; Ludwig, Ralf J.; Verheesen, Peter & Schmidt, Enno
  
• Characteristics Associated With Refractory Course, Blindness, and Treatment Strategy–Related Outcomes in Patients With Mucous Membrane Pemphigoid. JAMA Dermatology, 159(2), 198.
  Kridin, Khalaf; van Beek, Nina; Bühler, Elena; Kochan, Anne S.; Ranjbar, Mahdy; Beissert, Stefan; Zillikens, Detlef; Günther, Claudia & Schmidt, Enno
  
• Evaluation of the Diagnostic Value of Oesophageal Biopsies for Direct Immunofluorescence Microscopy in Mucous Membrane Pemphigoid. Acta Dermato-Venereologica, 103, adv11947.
  Yilmaz, Kaan; Dikmen, Onur; Van Beek, Nina; Marquardt, Jens U.; Kirstein, Martha M.; Zillikens, Detlef & Schmidt, Enno
  
• IgM mucous membrane pemphigoid. J Dtsch Dermatol Ges 2023, 21: 285-87
  Yilmaz K., Hammers C.M., Boch K., Zillikens D., Shimanovich I. & Schmidt E.
  
• Immunpathogenese des Schleimhautpemphigoids. Die Ophthalmologie, 120(5), 462-471.
  Schmidt, Enno & Patzelt, Sabrina
  
• Intravenous Ig Ameliorates Disease in a Murine Model of Anti–Laminin 332 Mucous Membrane Pemphigoid. Journal of Investigative Dermatology, 144(12), 2671-2681.e1.
  Murthy, Sripriya; Patzelt, Sabrina; Künstner, Axel; Busch, Hauke; Schmidt, Enno & Sadik, Christian D.