AUTHOR=Giusti Delphine , Bini Estela , Terryn Christine , Didier Kevin , Le Jan Sébastien , Gatouillat Grégory , Durlach Anne , Nesmond Stéphane , Muller Celine , Bernard Philippe , Antonicelli Frank , Pham Bach Nga 

TITLE=NET Formation in Bullous Pemphigoid Patients With Relapse Is Modulated by IL-17 and IL-23 Interplay

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.00701

DOI=10.3389/fimmu.2019.00701

ISSN=1664-3224

ABSTRACT=<p><bold>Background:</bold> DNA extracellular traps (ETs), released by neutrophils (NETs), or eosinophils (EETs), play a pathogenic role in several autoimmune disorders. However, to date, NETs have never been investigated in bullous pemphigoid (BP) with respect to clinical and immunological activities, both at baseline and at time of relapse which have been characterized with specific IL-17 and IL-23 patterns.</p><p><bold>Objective:</bold> We sought to assess whether ETs were associated with BP as well as the relative contribution of IL-17 axis cytokines to NET induction.</p><p><bold>Methods:</bold> Skin biopsy specimens were obtained from 11 patients with BP. Immuno-detection of neutrophils and eosinophils combined to DNA staining allowed us to investigate the <italic>in-situ</italic> presence of NETs and EETs using confocal scanning microscopy. NETs release was evaluated <italic>ex vivo</italic> by stimulating polymorphonuclear cells from BP patients with BP biological fluids in presence of IL-17A and IL-23 or of glucocorticoids.</p><p><bold>Results:</bold> At baseline, ETs were observed in BP lesions at the site of dermal-epidermal cleavage. Despite an important infiltrate of eosinophils, ETs were essentially associated with neutrophils <italic>in situ</italic> and were not related to BP clinical activity at diagnosis. <italic>In situ</italic> observation of NETs was associated in 6 among 8 patients with serum capacity of NET induction. Notably both blister fluid and sera from BP patients at diagnosis and at time of relapse could induce NET formation <italic>ex vivo</italic>. In contrast, a longitudinal investigation showed a decrease of NET formation with time of treatment in patients undergoing remission. Mimicking relapse, complementation of sera from BP patients with ongoing remission with either IL-17A or IL-23 increased NET formation. Conversely, IL-17A inhibited NET formation induced by serum from BP patients with relapse supplemented or not with IL-23. Finally, glucocorticoids also inhibited NET formation <italic>ex vivo</italic> in BP.</p><p><bold>Conclusion:</bold> NET formation is an associated phenomenon with BP. Furthermore, we showed that IL-23 favored NET formation, whereas the effects of IL-17A are environment dependent. Indeed, IL-17A displayed a protective effect on NET formation when associated with IL-23, showing for the first-time differential effects of these two cytokines in BP.</p>