Abstract
Epidermolysis bullosa acquisita (EBA) is a rare, but prototypical, organ-specific autoimmune disease, characterized and caused by autoantibodies against type VII collagen (COL7). Mucocutaneous inflammation, blistering, and scarring are the clinical hallmarks of the disease. Treatment of EBA is difficult and mainly relies on general immunosuppression. Hence, novel treatment options are urgently needed. The phosphatidylinositol-3-kinase (PI3K) pathway is a putative target for the treatment of inflammatory diseases, including EBA. We recently discovered LAS191954, an orally available, selective PI3Kδ inhibitor. PI3Kδ has been shown to be involved in B cell and neutrophil cellular functions. Both cell types critically contribute to EBA pathogenesis, rendering LAS191954 a potential drug candidate for EBA treatment. We, here, demonstrate that LAS191954, when administered chronically, dose-dependently improved the clinical phenotype of mice harboring widespread skin lesions secondary to immunization-induced EBA. Direct comparison with high-dose corticosteroid treatment indicated superiority of LAS191954. Interestingly, levels of circulating autoantibodies were unaltered in all groups, indicating a mode of action independent of the inhibition of B cell function. In line with this, LAS191954 also hindered disease progression in antibody transfer-induced EBA, where disease develops dependent on myeloid, but independent of B cells. We further show that, in vitro, LAS191954 dose-dependently impaired activation of human myeloid cells by relevant disease stimuli. Specifically, immune complex-mediated and C5a-mediated ROS release were inhibited in a PI3Kδ-dependent manner. Accordingly, LAS191954 also modulated the dermal–epidermal separation induced in vitro by co-incubation of immune complexes with polymorph nuclear cells, thus pointing to an important role of PI3Kδ in EBA effector functions. Altogether, these results suggest a new potential mechanism for the treatment of EBA and potentially also other autoimmune bullous diseases.
Highlights
Pemphigoid diseases comprise a group of autoimmune disorders with a high, and so far, unmet medical need
A similar selectivity profile as in the enzymatic assays has been observed in PI3Kδ-dependent or PI3Kβ-dependent (S1Pactivated HUVEC) cellular assays, with reported IC50 of 4.6 nM and 295 nM, respectively
The aim of this study was to test whether pharmacological inhibition of PI3Kδ with a novel selective inhibitor can modulate the progression of experimental epidermolysis bullosa acquisita (EBA) in mice
Summary
Pemphigoid diseases comprise a group of autoimmune disorders with a high, and so far, unmet medical need. They are clinically characterized by chronic (muco)-cutaneous inflammation and subepidermal blistering, and are caused by autoantibodies targeting structural proteins of the dermal–epidermal junction [1,2,3,4]. PI3Kδ in EBA by autoantibodies targeting type XVII collagen (COL17) respond well to corticosteroid treatment, but after stopping treatment, the disease frequently relapses [6]. This requires prolonged, and often systemic, corticosteroid treatment. There is a yet high unmet medical need for the development of novel treatments for pemphigoid diseases, especially EBA [3]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
