Abstract
Background: 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.Objective: We sought to assess whether ETs were associated with BP as well as the relative contribution of IL-17 axis cytokines to NET induction.Methods: 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 in-situ presence of NETs and EETs using confocal scanning microscopy. NETs release was evaluated ex vivo by stimulating polymorphonuclear cells from BP patients with BP biological fluids in presence of IL-17A and IL-23 or of glucocorticoids.Results: 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 in situ and were not related to BP clinical activity at diagnosis. In situ 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 ex vivo. 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 ex vivo in BP.Conclusion: 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.
Highlights
Bullous pemphigoid (BP) is an invalidating autoimmune subepidermal blistering disease affecting preferentially the elderly
To investigate the presence of either neutrophil extracellular trap (NET) or extracellular traps (EET) or even both in BP at site of lesion, immune-detection of neutrophils and eosinophils along with DNA staining was performed on paraffinembedded skin biopsy specimens from 11 BP patients
A 3-dimensional reconstruction picture corresponding to Figure 1E allowed defining NETs as shapes of DNA extruding from neutrophils stained by MPO (Supplementary Video S1; Figure 1F)
Summary
Bullous pemphigoid (BP) is an invalidating autoimmune subepidermal blistering disease affecting preferentially the elderly. Eosinophils and neutrophils are the most represented cells in the skin inflammatory infiltrate of BP patients [1] Both cells have the capacity to form DNA traps [2,3,4,5] which play a pathogenic role in several autoimmune diseases [6, 7]. DNA trap formation has never been investigated in BP with respect to the clinical features of the disease i.e., activity and outcome. DNA extracellular traps (ETs), released by neutrophils (NETs), or eosinophils (EETs), play a pathogenic role in several autoimmune disorders. 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
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