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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 5

Coversin ablates the progression of ongoing skin inflammation.

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Coversin ablates the progression of ongoing skin inflammation.
Therapeut...
Therapeutic effect of treatment with Coversin initiated on day 5. (A) Representative clinical presentation on day 6, one day after the initiation of Coversin therapy, and at the end of the experiment on day 12. White arrows indicate BP-like EBA skin lesions. (B) Progression of disease determined by the percentage of the total ABSA as mean ± SEM. Data were analyzed by 2-way ANOVA with Holm-Šídák’s multiple-comparisons test. *P < 0.05, **P < 0.01, and ***P < 0.001 compared with control. #P < 0.05 compared with 0.125 mg/kg Coversin. (C) Peak value of the ABSA determined for each mouse individually and (D) C5a serum levels (ng/mL) on day 12 presented as mean ± SEM with dots representing individual mice (n = 9–11 mice/group). In D, data were analyzed using 1-way ANOVA with Holm-Šídák’s multiple-comparisons test. All results shown were pooled from 2 independent experiments.

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