Increased expression of in situ IL‐31RA and circulating CXCL8 and CCL2 in pemphigus herpetiformis suggests participation of the IL‐31 family in the pathogenesis of the disease

Abstract

Background Pemphigus herpetiformis (PH) is a rare clinical subtype of pemphigus with the presence of urticarial plaques, severe pruritus, rare acantholysis and eosinophilic spongiosis. Objectives The aim of this study was to investigate the influence of IL-31 and pro-inflammatory cytokines/chemokines in the pathogenesis of PH. Methods Twenty-five patients with PH and three groups: pemphigus foliaceus (PF = 14), pemphigus vulgaris (PV = 15) and healthy controls (HC = 20) were selected for this study. The groups were analysed by immunohistochemistry utilizing IL-31, IL-31RA, IL-4, IL-17 and TNF-a antibodies. Serum levels of IL-4, IL-13, TNF, CXCL8, CCL5 and CCL2 were evaluated by cytometric bead array. Results Analysis of IL-31 family of PH patients revealed the following findings: (i) Enhanced in situ expression of IL-31 in PH samples, compared to PF and to PV (epidermis); (ii) Cutaneous IL-31RA expression in PH samples was higher than in PF, PV and HC groups (epidermis and dermis); (iii) PF patients that evolved to PH showed significant increased IL-31RA epidermal expression during the PH phase. Profile of pro-inflammatory cytokines (IL-4, IL-17 and TNF-a) in PH patients' skin exhibited: (i) Enhanced IL-4 expression, when compared to patients with PF (epidermis and dermis) and with PV (epidermis); (ii) Augmented IL-17 expression than PF and PV patients (epidermis); (iii) Augmented expression of TNF-a when compared to PF at the epidermal level. Evaluation of circulating cytokines and chemokines showed higher levels of CXCL8 and CCL2 in PH sera compared to HC group. Conclusions IL-31 and IL-31RA, cytokines related to pruritus, and pro-inflammatory chemokines (CXCL8 and CCL2) seem to exert a role in the pathogenesis of PH. These findings support future studies to clarify the role of IL-31 pathway as a potential therapeutic target for patients with PH.

IL‐31 and IL‐31 receptor alpha in pemphigus: Contributors to more than just itch?

“…These features might reflect its immune status as type 2‐skewed inflammation 1,9 . Consistent with these observations, type‐2 cytokine IL‐31 and its receptor subunit IL‐31RA increased in the lesional skin of PH, as was also demonstrated in a prior report, 4 although expression levels of TSLP and periostin were not increased. In contrast, in PF, another pruritic subtype of pemphigus, IL‐31/IL‐31RA signaling was not increased.…”

“…Pemphigus‐associated itch not only impairs patients' quality of life, but also evokes scratching behavior, which might exacerbate skin erosions and promote secondary bacterial infections 3 . However, pathogenic mechanisms underlying the pruritis of PH and PF are still uncertain 1,4 …”

Interleukin-31 as a Clinical Target for Pruritus Treatment

“…In bullous pemphigoid, it is eosinophils that appear to be the major source of IL-31 (72,73). Another, related, condition in which IL-31 has been implicated is pemphigus herpetiformis (dermatitis herpetiformis) (74,75).…”

Interleukin‐31: The “itchy” cytokine in inflammation and therapy

“…82,83 As a major product of CD4 + T cells in DOCK8 deficient mice, IL-31 appears to be involved in the DOCK8 mutation-driven hyper IgE syndrome, characterized by a combined immunodeficiency, eczematous skin lesion, and high serum IgE levels. 84 Finally, initial, yet mostly descriptive or non-controlled and small scale human studies/trials suggest an involvement of IL-31 in various cutaneous disorders beyond AD including pemphigus herpetiformis, 85 chronic spontaneous urticaria, 86,87 cutaneous T-cell lymphoma, [88][89][90][91][92] systemic lupus erythematosus, 93,94 bullous pemphigoid, [95][96][97] dermatomyositis, 98 and psoriasis. 70,[99][100][101][102] This needs to be further explored, especially given the potential beneficial effect of new anti-IL-31 strategies in these sometimes hard-to-treat skin diseases.…”

“…Finally, initial, yet mostly descriptive or non‐controlled and small scale human studies/trials suggest an involvement of IL‐31 in various cutaneous disorders beyond AD including pemphigus herpetiformis, 85 chronic spontaneous urticaria, 86,87 cutaneous T‐cell lymphoma, 88–92 systemic lupus erythematosus, 93,94 bullous pemphigoid, 95–97 dermatomyositis, 98 and psoriasis 70,99–102 . This needs to be further explored, especially given the potential beneficial effect of new anti‐IL‐31 strategies in these sometimes hard‐to‐treat skin diseases.…”