Dual inhibition of complement factor 5 and leukotriene B4 synergistically suppresses murine pemphigoid disease

JCI Insight
Tanya SezinChristian D Sadik

Abstract

The treatment of most autoimmune diseases still relies on systemic immunosuppression and is associated with severe side effects. The development of drugs that more specifically abrogate pathogenic pathways is therefore most desirable. In nature, such specificity is exemplified, e.g., by the soft tick-derived biotherapeutic Coversin, which locally suppresses immune responses by inhibiting complement factor 5 (C5) and leukotriene B4 (LTB4). C5a, a proteolytic fragment of C5, and LTB4 are critical drivers of skin inflammation in pemphigoid diseases (PDs), a group of autoimmune blistering skin diseases. Here, we demonstrate that both Coversin and its mutated form L-Coversin, which inhibits LTB4 only, dose dependently attenuate disease in a model of bullous pemphigoid-like epidermolysis bullosa acquisita (BP-like EBA). Coversin, however, reduces disease more effectively than L-Coversin, indicating that inhibition of C5 and LTB4 synergize in their suppressing effects in this model. Further supporting the therapeutic potential of Coversin in humans, we found that C5a and LTB4 are both present in the blister fluid of patients with BP in quantities inducing the recruitment of granulocytes and that the number of cells expressing their re...Continue Reading

References

Mar 1, 1993·Journal of Leukocyte Biology·S D TennenbergM J Lieser
Feb 3, 2005·Nature Reviews. Drug Discovery·Curtis T KeithBrent R Stockwell
Feb 9, 2005·The Journal of Immunology : Official Journal of the American Association of Immunologists·Miles A NunnPatricia A Nuttall
Apr 21, 2005·The Journal of Clinical Investigation·Cassian SitaruDetlef Zillikens
May 23, 2006·International Immunopharmacology·Richard G DiScipioP Sriramarao
Jan 12, 2007·The Journal of Biological Chemistry·Natalie J HepburnClaire L Harris
Mar 24, 2007·The Journal of Pathology·M T ChiriacC Sitaru
Oct 22, 2008·Nature Chemical Biology·Andrew L Hopkins
Feb 6, 2009·Annals of Neurology·Jindrich SoltysHenry J Kaminski
Jul 8, 2009·Nature Biotechnology·Joseph LehárAlexis A Borisy
Aug 16, 2011·Trends in Immunology·Christian D SadikAndrew D Luster
Oct 4, 2011·The Journal of Immunology : Official Journal of the American Association of Immunologists·Andreas Barratt-DueTom Eirik Mollnes
Nov 8, 2011·Journal of Leukocyte Biology·Christian D Sadik, Andrew D Luster
Nov 1, 2012·Proceedings of the National Academy of Sciences of the United States of America·Christian D SadikAndrew D Luster
Dec 15, 2012·Lancet·Enno Schmidt, Detlef Zillikens
Apr 30, 2013·The Journal of Biological Chemistry·Pietro RoversiMiles A Nunn
Jun 14, 2013·The Journal of Immunology : Official Journal of the American Association of Immunologists·Andreas Barratt-DueTom E Mollnes
May 3, 2014·The Journal of Immunology : Official Journal of the American Association of Immunologists·Markus Huber-LangTom E Mollnes
Nov 28, 2015·Critical Care : the Official Journal of the Critical Care Forum·Espen W SkjefloTom E Mollnes
Mar 29, 2016·Nature Structural & Molecular Biology·Matthijs M JoreSusan M Lea
Jan 4, 2018·Blood Advances·Timothy H J GoodshipPaul Veys
Mar 31, 2018·Frontiers in Immunology·Christian M KarstenEnno Schmidt
Jun 16, 2018·The Journal of Dermatology·Khalaf KridinShira Zelber-Sagi

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Citations

Nov 17, 2019·Seminars in Immunopathology·Christian D Sadik, Enno Schmidt
Sep 15, 2020·Frontiers in Immunology·Lina JegodzinskiChristian D Sadik
Dec 29, 2020·Frontiers in Immunology·Marion OrtPriska Kaufmann
Jan 29, 2021·Frontiers in Immunology·Katja BieberRalf J Ludwig
Aug 10, 2020·Journal of Autoimmunity·Tanya SezinChristian D Sadik
Feb 21, 2021·The Journal of Investigative Dermatology·Paul SchilfChristian D Sadik
May 26, 2021·The Journal of Investigative Dermatology·Sripriya MurthyChristian D Sadik
Jun 17, 2020·The Journal of Dermatological Treatment·Pedro Miguel GarridoPaulo Filipe
Nov 24, 2020·The Journal of Investigative Dermatology·Roberto MaglieMichael Hertl

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Methods Mentioned

BETA
ELISA

Clinical Trials Mentioned

NCT03588026

Software Mentioned

BZ II Analyzer
GraphPad Prism

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