H D de Koning1,2,3,4, I M J J van Vlijmen-Willems1, D Rodijk-Olthuis1, J W M van der Meer2,4, P L J M Zeeuwen1,3,4, A Simon2,4, J Schalkwijk1,3,4. 1. Department of Dermatology, Radboud University Medical Center, 6500 HB, Nijmegen, the Netherlands. 2. Department of Internal Medicine, Radboud University Medical Center, 6500 HB, Nijmegen, the Netherlands. 3. Radboud Institute for Molecular Life Sciences (RIMLS), Nijmegen, the Netherlands. 4. Nijmegen Center for Immunodeficiency and Autoinflammation, Nijmegen, the Netherlands.
Abstract
BACKGROUND: Schnitzler's syndrome (SchS) is an autoinflammatory disease characterized by a chronic urticarial rash, a monoclonal component and signs of systemic inflammation. Interleukin (IL)-1β is pivotal in the pathophysiology. OBJECTIVES: Here we investigated the cellular source of proinflammatory mediators in the skin of patients with SchS. METHODS: Skin biopsies of lesional and nonlesional skin from eight patients with SchS and healthy controls, and patients with cryopyrin-associated periodic syndrome (CAPS), delayed-pressure urticaria (DPU) and cold-contact urticaria (CCU) were studied. We studied in vivoIL-1β, IL-17 and antimicrobial protein (AMP) expression in resident skin cells and infiltrating cells. In addition we investigated the in vitro effect of IL-1β, IL-17 and polyinosinic-polycytidylic acid (poly:IC) stimulation on cultured epidermal keratinocytes. RESULTS: Remarkably, we found IL-1β-positive dermal mast cells in both lesional and nonlesional skin of patients with SchS, but not in healthy control skin and CCU, and fewer in CAPS. IL-17-positive neutrophils were observed only in lesional SchS and DPU skin. In lesional SchS epidermis, mRNA and protein expression levels of AMPs were strongly increased compared with nonlesional skin and that of healthy controls. When exposed to IL-1β, poly:IC or IL-17, patient and control primary human keratinocytes produced AMPs in similar amounts. CONCLUSIONS: Dermal mast cells of patients with SchS produce IL-1β. This presumably leads to activation of keratinocytes and neutrophil influx, and further amplification of inflammation by IL-17 (from neutrophils and mast cells) and epidermal AMP production leading to chronic histamine-independent neutrophilic urticarial dermatosis.
BACKGROUND:Schnitzler's syndrome (SchS) is an autoinflammatory disease characterized by a chronic urticarial rash, a monoclonal component and signs of systemic inflammation. Interleukin (IL)-1β is pivotal in the pathophysiology. OBJECTIVES: Here we investigated the cellular source of proinflammatory mediators in the skin of patients with SchS. METHODS: Skin biopsies of lesional and nonlesional skin from eight patients with SchS and healthy controls, and patients with cryopyrin-associated periodic syndrome (CAPS), delayed-pressure urticaria (DPU) and cold-contact urticaria (CCU) were studied. We studied in vivoIL-1β, IL-17 and antimicrobial protein (AMP) expression in resident skin cells and infiltrating cells. In addition we investigated the in vitro effect of IL-1β, IL-17 and polyinosinic-polycytidylic acid (poly:IC) stimulation on cultured epidermal keratinocytes. RESULTS: Remarkably, we found IL-1β-positive dermal mast cells in both lesional and nonlesional skin of patients with SchS, but not in healthy control skin and CCU, and fewer in CAPS. IL-17-positive neutrophils were observed only in lesional SchS and DPU skin. In lesional SchS epidermis, mRNA and protein expression levels of AMPs were strongly increased compared with nonlesional skin and that of healthy controls. When exposed to IL-1β, poly:IC or IL-17, patient and control primary human keratinocytes produced AMPs in similar amounts. CONCLUSIONS: Dermal mast cells of patients with SchS produce IL-1β. This presumably leads to activation of keratinocytes and neutrophil influx, and further amplification of inflammation by IL-17 (from neutrophils and mast cells) and epidermal AMP production leading to chronic histamine-independent neutrophilic urticarial dermatosis.
Authors: B Dyring-Andersen; T V Honoré; A Madelung; M Bzorek; S Simonsen; S N Clemmensen; R A Clark; N Borregaard; L Skov Journal: Br J Dermatol Date: 2017-10-08 Impact factor: 9.302