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INVESTIGATIVE REPORT ActaDV ActaDV Advances in dermatology and venereology Acta Dermato-Venereologica
Eosinophils are a Major Source of Interleukin-31 in Bullous Pemphigoid
Urda RÜDRICH 1, Manuela GEHRING 1, Eleni PAPAKONSTANTINOU 1, Anja ILLERHAUS 2, Judith ENGMANN 1, Alexander KAPP 1, Karin HARTMANN 3, N. Helge MEYER 4, Bernhard F. GIBBS 4 and Ulrike RAAP 1, 4
1
Department of Dermatology and Allergology, Hannover Medical School, Hannover, 2 Department of Dermatology, University of Cologne, Köln, 3 Department of Dermatology and Allergology, Medical University of Lübeck, Lübeck, and 4 Dermatology and Allergology, Department of Human Medicine, Carl von Ossietzky University of Oldenburg, Oldenburg, Germany
Bullous pemphigoid( BP) is characterized by substantial skin and blood eosinophilia as well as intensive pruritus. Since the pruritogenic cytokine interleukin( IL)- 31 is increased in inflammatory skin diseases the aim of this study was to determine whether IL-31 plays a role in BP. Using immunofluorescence, IL-31 expression was analysed in eosinophils derived from blister fluids and skin from patients with BP and IL-31 levels in blister fluids, serum and culture supernatants were determined by enzyme-linked immunoassay( ELISA). High levels of IL-31 expression were observed in BP blister fluids, but they were only marginally elevated in BP serum compared with healthy controls. Eosinophils from either BP blister fluids or skin biopsies showed strong expression of IL-31. Furthermore, peripheral blood eosinophils from patients with BP, but not healthy controls, released high levels of IL-31, reflecting those in blister fluids. In conclusion, eosinophils are a major source of IL-31 in BP and this cytokine may contribute to itch in patients with BP.
Key words: bullous pemphigoid; IL-31; itch; pruritus; eosinophils. Accepted Apr 24, 2018; Epub ahead of print Apr 24, 2018 Acta Derm Venereol 2018; 98: 766 – 771.
Corr: Ulrike Raap, Dermatology and Allergology, Department of Human Medicine Klinikum Oldenburg AöR, Rahel-Straus-Straße 10, DE-26133 Oldenburg, Germany. E-mail: ulrike. raap @ klinikum-oldenburg. de
Bullous pemphigoid( BP) is one of the most common autoimmune blistering skin diseases, with a high prevalence in the elderly population. BP is characterized by circulating IgG and IgE autoantibodies against the hemidesmosomal proteins BP180 and BP230. In most patients with BP autoantibodies recognize the non-collagenous 16A domain( NC16A), located at the membraneproximal region of BP180. It has been suggested that the disease activity in patients with BP can be determined based on the serum level of these autoantibodies( 1). ELISAs, highly specific and sensitive for detecting circulating autoantibodies against the BP180 NC16A region, have been established for the diagnosis of BP( 2, 3). It is usually distinguished from other pemphigoid diseases by a combination of direct and indirect immunofluorescence, which show in situ deposits of IgG and C3 at the epidermal basement membrane, together with the clinical appearance of blisters( 4). Histopathological
SIGNIFICANCE
Bullous pemphigoid is an autoimmune disease of the skin and is associated with severe itch and blister formation. In this study we show that eosinophils are a major source of IL- 31, a factor that is known to cause itch in other skin diseases, and that IL-31 levels were highly expressed in blister fluids from patients with bullous pemphigoid. We also revealed that eosinophils from patients with bullous pemphigoid released higher levels of IL-31 than eosinophils from healthy donors. These observations indicate that targeting IL-31 may have a therapeutic potential in bullous pemphigoid.
examination of lesional skin from patients with BP shows that the majority of sub-epidermal blisters are filled with an eosinophil-rich leukocyte infiltrate( 5). Elevated levels of various cytokines and chemokines, including tumour necrosis factor alpha( TNFα), interleukin( IL)-6, IL-8, IL-15, and CC chemokine ligand CCL18 have also been measured in sera and blister fluids of patients with BP, which also correlate with disease activity( 6 – 9). Clinically, erythematous patches or urticarial lesions may precede bullae formation by several days to months. Itch is one of the major symptoms; it presents as mild or severe in almost all patients( 10, 11).
IL-31 is a cytokine that plays an important role in itchassociated inflammation. In a transgenic mouse model overexpressing IL-31, mice developed severe itch with skin lesions accompanied by inflammatory cell infiltration and increased numbers of mast cells( 12). The phenotype described in IL-31 transgenic mice shows similarity with the clinical picture of patients with atopic dermatitis( AD)( 12). In patients with AD, IL-31 serum levels are increased and correlate with disease severity( 13 – 15). Meanwhile, several studies have reported increased IL- 31 concentrations in various inflammatory skin diseases, such as chronic spontaneous urticaria, allergic contact dermatitis and mastocytosis( 14 – 19).
IL-31 signalling requires the input of a heterodimeric receptor composed of the IL-31 receptor A( IL-31RA) and the oncostatin M receptor( OSMR)( 20). These IL-31 receptors are expressed on several immune cells, including T cells, keratinocytes, dendritic cells, eosinophils, basophils, macrophages and dorsal root ganglia( 16, 21 – 25). Functionally, IL-31 leads to the release of doi: 10.2340 / 00015555-2951 Acta Derm Venereol 2018; 98: 766 – 771
This is an open access article under the CC BY-NC license. www. medicaljournals. se / acta Journal Compilation © 2018 Acta Dermato-Venereologica.