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. 2019 Sep 11:10:2107.
doi: 10.3389/fimmu.2019.02107. eCollection 2019.

Characteristic Pattern of IL-17RA, IL-17RB, and IL-17RC in Monocytes/Macrophages and Mast Cells From Patients With Bullous Pemphigoid

Stéphane Nesmond  1 , Céline Muller  1 , Richard Le Naour  1   2 , Manuelle Viguier  3 , Philippe Bernard  1   3 , Frank Antonicelli  1   4 , Sébastien Le Jan  1
Affiliations

Characteristic Pattern of IL-17RA, IL-17RB, and IL-17RC in Monocytes/Macrophages and Mast Cells From Patients With Bullous Pemphigoid

Stéphane Nesmond et al. Front Immunol. .

Abstract

Inflammation is largely implicated in bullous pemphigoid (BP), the most frequent skin auto-immune blistering disease. IL-17, essentially IL-17A/F, has been involved in blister formation through regulation of protease production, and its specific serum profile within BP was related to disease outcome. However, relationships between IL-17 family ligands and receptors are quite complex with six different IL-17 isoforms, and five different receptors. We here aimed at clarifying the contribution of the IL-17 axis in BP by characterizing not only the expression of IL-17 receptor (IL-17R) members within immune cells isolated from BP patients (PMNs, n = 9; T-lymphocytes, n = 10; and monocytes, n = 10) but also the expression of IL-17 isoforms in sera (n = 83), and blister fluid (n = 31) of BP patients. We showed that at diagnosis, IL-17RA and IL-17RC expression were significantly increased in monocytes isolated from BP patients as compared to those from control subjects (p = 0.006 and p = 0.016, respectively). Notably, both IL-17RA and IL-17RC mRNA expression remained elevated in BP monocytes at time of relapse. We further demonstrated a significant increase of all IL-17 isoforms tested in BP blister fluid compared with BP serum (IL-17A, p < 0.0001; IL-17A/F, p < 0.0001; IL-17B, p = 0.0023; IL-17C, p = 0.0022; IL-17E, p < 0.0001). Among all, IL-17B was the only cytokine for which a significant decreased concentration within blister fluid was observed in BP patients with severe disease compared to patients with moderate disease (p = 0.012). We further evidenced a significant negative correlation between IL-17B levels and blister/erosion BPDAI subscore (r = -0.52, p = 0.003). We finally identified mast cells as a potential target of IL-17B in lesional skin of BP patients. In conclusion, we showed here that IL-17RA and IL-17RC expression in monocyte was associated with disease activity and evidenced in situ a negative correlation between BP disease activity and IL-17B, whose effects could be mediated by IL-17RB expressed by mast cell in BP lesional skin.

Keywords: IL-17 isoforms; IL-17 receptors; autoimmunity; bullous pemphigoid; inflammation.

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Figures

Figure 1
Figure 1
IL-17RA and IL-17RC mRNA expressions were increased in monocytes isolated from blood of patients with BP. The mRNA expression of IL-17RA, IL-17RB, IL-17RC, and IL-17RE were analyzed by real-time quantitative PCR in polymorphonuclear cells (PMNs) (A), in lymphocytes (B), and in monocytes (C) isolated from blood of control subjects (CTR), and of patients with BP at diagnosis (BP). Lines represent the mean, and non-parametric Mann–Whitney's test was used for statistical analysis (*p < 0.05; **p < 0.01). (D) Monocytes from BP patients and control subjects were stained for IL-17RA or IL-17RC. Negative control: primary antibodies were not added. Nuclei were counterstained with Hoechst (blue). Scale bar = 10 μm.
Figure 2
Figure 2
Analysis of IL-17RA and IL-17RC expression in monocytes issued from patients with BP according to disease outcome. IL-17RA and IL-17RC mRNA expressions were analyzed in monocytes of BP patients with ongoing remission (A) and of BP patients who relapsed (B), at diagnosis (D0), and at day 360 (D360), or at the time of relapse (DRelapse), respectively. Non-parametric paired Wilcoxon's test was used for statistical analysis (*p < 0.05; ns = non-significant).
Figure 3
Figure 3
The expression of each IL-17 isoform tested was increased in blister fluid of BP patients. The concentrations of IL-17A, IL-17A/F, IL-17B, IL-17C, and IL-17E were measured at the time of diagnosis in serum (BP sera), and blister fluid (BF) of BP patients, and in serum of control subjects (CTR sera) using U-PLEX cytokine multiplex assay. Lines represent the mean, and non-parametric Mann–Whitney's test was used for statistical analysis (**p < 0.01; ***p < 0.001).
Figure 4
Figure 4
IL-17B levels were decreased in BP patients with severe disease extent and negatively correlated with blisters/erosions BPDAI subscore. (A) IL-17A, IL-17A/F, IL-17B, IL-17C, and IL-17E concentrations measured at the time of diagnosis in BF were analyzed according to the disease extent. “Moderate” stands for BP patients with a BPDAI <56 and “Severe” for BP patients with a BPDAI ≥56. Non-parametric Mann–Whitney's test was used for statistical analysis (*p < 0.05). (B) Correlations between total, skin, blisters/erosions, or erythema/urticaria BPDAI scores, and IL-17B levels in BF were analyzed using the Pearson's correlation test.
Figure 5
Figure 5
IL-17RA, IL-17RB, and IL-17RC showed differential pattern of expression in immune cells associated to lesional skin of patients with BP. Paraffin-embedded skin biopsy specimen of blistering skin from BP patients (n = 3) were subjected to double immunofluorescence staining for IL-17RA, IL-17RB, and IL-17RC (in red), and either Tryptase, CD163, or myeloperoxidase (MPO) (in green) with Hoechst counterstain. Negative control: primary antibodies were not added. Scale bar = 10 μm.
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