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Dual inhibition of complement factor 5 and leukotriene B4 synergistically suppresses murine pemphigoid disease
Tanya Sezin, … , Miles A. Nunn, Christian D. Sadik
Tanya Sezin, … , Miles A. Nunn, Christian D. Sadik
Published August 8, 2019
Citation Information: JCI Insight. 2019;4(15):e128239. https://doi.org/10.1172/jci.insight.128239.
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Research Article Dermatology

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

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

Authors

Tanya Sezin, Sripriya Murthy, Claudia Attah, Malte Seutter, Maike M. Holtsche, Christoph M. Hammers, Enno Schmidt, Fibi Meshrkey, Sadegh Mousavi, Detlef Zillikens, Miles A. Nunn, Christian D. Sadik

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Figure 1

Coversin dose dependently suppresses skin inflammation in a preventative setting.

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Coversin dose dependently suppresses skin inflammation in a preventative...
Effect of varying doses of Coversin administered twice daily starting 4 days before the first application of anti-COL7c IgG. (A) Representative clinical presentation at the end of the experiment on day 10. White arrows indicate BP-like EBA skin lesions. (B) Progression of disease benchmarked as percentage of the total body surface area affected by skin lesions (ABSA). Results were pooled from 2 independent experiments and are presented as mean ± SEM (n = 10–11 mice per group). Data were analyzed using 2-way ANOVA with Holm-Šídák’s multiple-comparisons test. ##P < 0.01, and ###P < 0.001 compared with 2.5 mg/kg body weight Coversin. ***P < 0.001 compared with 0.25 mg/kg Coversin. §P < 0.05, and §§§P < 0.001 for 2.5 mg/kg Coversin vs. 0.025 mg/kg Coversin. +P < 0.05, and ++P < 0.01 for 0.25 mg/kg Coversin vs. 0.025 mg/kg Coversin. (C) Peak value of ABSA determined individually for each mouse. (D) C5a serum levels on day 10. Results presented in C and D were pooled from 2 independent experiments (n = 9–11 mice/group) and are shown as mean ± SEM with dots representing individual mice. Data were analyzed using 1-way ANOVA with Holm-Šídák’s multiple-comparisons test. *P < 0.05, **P < 0.01, ***P < 0.001 for the comparisons indicated by dashed lines.

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