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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 .