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 B ₄ (LTB ₄ ). C5a, a proteolytic fragment of C5, and LTB ₄ 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 LTB ₄ 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 LTB ₄ synergize in their suppressing effects in this model. Further supporting the therapeutic potential of Coversin in humans, we found that C5a and LTB ₄ 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.

Mucous membrane pemphigoid (MMP) is a mucocutaneous autoimmune blistering disease affecting diverse mucous membranes and the skin with inflammatory blisters and erosions. The pathogenesis of MMP is only poorly understood, but inflammation in MMP is triggered by specific binding of autoantibodies directed to different proteins of the dermal-epidermal/-epithelial junction, subsequently leading to the influx of inflammatory cells, particularly neutrophils, into the dermis. Using the anti-laminin 332 antibody transfer model of MMP, we addressed the molecular mechanisms of neutrophil infiltration and its significance for the eruption of mucocutaneous lesions. Mice deficient in 5-lipoxygenase ( Alox5 ^–/– ) or in the leukotriene B ₄ (LTB ₄ ) receptor BLT1 ( Ltb4r1 ^–/– ) were resistant to skin inflammation and exhibited substantially fewer mucosal lesions, with deficiency in either gene compromising the recruitment of neutrophils to the lesion. Furthermore, neutrophil-specific genetic deficiency in Ltb4r1 similarly protected from MMP. Hence, BLT1 was required on neutrophils, and neutrophil recruitment was indispensable for the eruption of lesions in MMP. In line with these findings, the BLT1 inhibitor CP-105,606 ameliorated MMP dose-dependently. Collectively, our results highlight neutrophils and LTB ₄ /BLT1 as key drivers of inflammation in MMP and as promising therapeutic targets.

Tamibarotene (AM80) is an agonist of retinoic acid receptor alpha. It is licensed in Japan for the treatment of acute promyelocytic leukemia. Results from preclinical models suggest that tamibarotene might also be effective in the treatment of diverse autoimmune diseases. The effect of tamibarotene on autoimmune diseases of the skin, however, has not been explored. We therefore examined the effect of tamibarotene on disease in the antibody-transfer mouse model of bullous pemphigoid (BP)-like epidermolysis bullosa acquisita (EBA), a prototypical example for pemphigoid diseases. Pemphigoid diseases are a group of autoimmune blistering skin diseases driven by autoantibodies and the recruitment and activity of granulocytes in the dermis. In sharp contrast to its effect in models of other autoimmune diseases, tamibarotene aggravated EBA pronouncedly. At the peak of disease, skin inflammation in tamibarotene-treated mice involved, on average, 1.6-fold more of the total body surface compared to vehicle-treated mice. Tamibarotene markedly reduced the recruitment of regulatory T cells (T_regs) into the dermis. This blunted the counterregulatory mechanisms that normally curb skin inflammation in this model. The effect aligns with previous reports describing tamibarotene-mediated downregulation of skin-homing receptors on T_regs. In addition, tamibarotene prolonged the responsiveness of aging neutrophils to immune complexes in vitro, providing another mechanism that may exacerbate EBA. Collectively, our results suggest that tamibarotene may elicit detrimental effects in patients with EBA by abolishing the recruitment of T_regs into skin. This warrants great caution when using tamibarotene in patients with EBA and possibly other pemphigoid diseases.