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

JCI Insight. 2019 Aug 8;4(15):e128239. doi: 10.1172/jci.insight.128239.


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 receptors, C5aR1 and BLT1, respectively, is increased in perilesional skin. Collectively, our results highlight Coversin and possibly L-Coversin as potential therapeutics for PDs.

Keywords: Autoimmune diseases; Autoimmunity; Complement; Dermatology; Eicosanoids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Products / pharmacology*
  • Biological Products / therapeutic use
  • Cells, Cultured
  • Chemotaxis / drug effects
  • Chemotaxis / immunology
  • Collagen Type VII / administration & dosage
  • Collagen Type VII / immunology
  • Complement C5 / antagonists & inhibitors*
  • Complement C5 / immunology
  • Complement C5 / metabolism
  • Complement Inactivating Agents / pharmacology*
  • Complement Inactivating Agents / therapeutic use
  • Disease Models, Animal
  • Granulocytes / immunology
  • Healthy Volunteers
  • Humans
  • Leukotriene B4 / antagonists & inhibitors*
  • Leukotriene B4 / immunology
  • Leukotriene B4 / metabolism
  • Male
  • Mice
  • Neutrophils
  • Pemphigoid, Bullous / drug therapy*
  • Pemphigoid, Bullous / immunology
  • Pemphigoid, Bullous / pathology
  • Primary Cell Culture
  • Rabbits
  • Skin / immunology
  • Skin / pathology


  • Biological Products
  • Collagen Type VII
  • Complement C5
  • Complement Inactivating Agents
  • Leukotriene B4