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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 2

Effect of preventative treatment with varying doses of Coversin on skin inflammation at the histopathological level.

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Effect of preventative treatment with varying doses of Coversin on skin ...
Histopathological analysis and comparison of skin from mice treated with varying doses of Coversin in a preventative treatment regimen and harvested on day 10 of the antibody transfer BP-like EBA model. (A) Representative direct immunofluorescence microscopy pictures of staining for IgG (upper) and C3 (lower) in perilesional skin. The arrows indicate the linear deposition of IgG and C3, respectively, at the DEJ. (B) Representative pictures of H&E staining (upper) and immunofluorescence staining for Ly-6G (middle) and Siglec-F (lower). Asterisks in the upper images indicate subepidermal clefts; arrows in the middle and lower images indicate examples for Ly-6G+ (neutrophils) and Siglec-F+ (eosinophils) cells, respectively. (C) Percentage of lesional skin sections exhibiting (red) or not exhibiting (blue) subepidermal clefts. (D) Ly-6G+ area and (E) number of Siglec-F+ cells per high-power magnification field (HPF; original magnification, ×200). Scale bars: 100 μm. Results were pooled from 2 independent experiments and are presented as mean ± SEM with dots representing individual mice (n = 9–11 mice/group). Data in C were analyzed by χ2 test followed by Fisher’s exact test. *P < 0.05.

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