Abstract
Many autoimmune skin diseases, such as bullous pemphigoid (BP), psoriasis and certain types of chronic urticaria, are associated with intensive pruritus. While histamine and neuropeptides have previously been ascribed to play a role in itch that accompanies these diseases, recent evidence suggests that the pruritogenic cytokine interleukin (IL)-31 is a major driver of pruritic responses. IL-31 was originally shown to be produced by activated helper T cells, particularly Th2 cells, mast cells, macrophages and dendritic cells. However, more recent evidence demonstrated that eosinophils are a major source of this cytokine too, particularly in bullous pemphigoid. Basophils have also been shown to express the cytokine which, through autocrine action, strongly supports the production of other Th2-type cytokines from these cells. These investigations suggest that the dynamic recruitment of eosinophils and basophils in some autoimmune skin diseases could play an important role in the severity of IL-31-mediated itch. Furthermore, these studies suggest that IL-31, in addition to its pruritic actions, also has potential immunomodulatory roles in terms of supporting Th2-type immunity, which often underpins IgE-associated autoimmune diseases (such as bullous pemphigoid and urticaria) as well as allergies. While the role of IL-31 in psoriasis remains to be clarified, current evidence shows that this cytokine plays a major role in BP, chronic spontaneous urticaria and dermatomyositis. This suggests potential use of IL-31 receptor-blocking therapeutic approaches (e.g., Nemolizumab) for the treatment of IL-31-associated disorders.
Highlights
IL-31 was first described by Dillon et al as a T cell-derived cytokine that was predominantly produced by The cells [1]
IL-31 is a member of the gp130/IL-6 family of cytokines and is a four helix bundle cytokine that acts as a ligand for the heterodimeric IL-31 receptor A (IL-31RA), a novel type I cytokine receptor, and the oncostatin M receptor (OSMR), the latter of which increases IL-31 binding affinity to IL-31RA
IL-31 in Autoimmune Skin Diseases appears to depend on the expression of both the IL-31RA and OSMR since, in basophils, we recently demonstrated that blocking of either receptor type decreases IL-31-induced IL-4 and IL-13 release [7]
Summary
IL-31 was first described by Dillon et al as a T cell-derived cytokine that was predominantly produced by The cells [1]. Before the discovery of IL-31, histamine was widely considered to be the most important pruritic mediator and the relative lack of therapeutic control of itch by H1antihistamines was ascribed following the discovery of additional H4-receptor input in pruritus [reviewed in [17]] This is partly supported by a recent successful clinical trial using an H4receptor antagonist in atopic dermatitis [18], indicating potential future combinational H1- and H4-receptor antagonist/inverse agonist approaches. In an animal model of atopic dermatitis anti-IL-31 treatment significantly reduced scratching in mice [16], underlining the important role of IL-31 in mediating pruritus This seems to apply to humans too, where IL-31 levels were shown to correlate with disease severity in atopic dermatitis [27, 28]. Since pruritus is a major feature in bullous pemphigoid, chronic spontaneous urticaria (CsU) and other autoimmune diseases there is a potential role for IL-31 in some of these diseases too
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