Beatrice Dyring-Andersen

Increased number and frequency of group 3 innate lymphoid cells in nonlesional psoriatic skin

Psoriasis is a common immune‐mediated inflammatory disease that affects the skin and joints. The interleukin (IL)‐23/IL‐17A axis and IL‐22 play key roles in the pathogenesis of psoriasis. IL‐23‐responsive innate lymphoid cells (ILCs) with a high capacity to produce IL‐17 and/or IL‐22 have recently been identified and associated with inflammatory bowel diseases. The occurrence and role of ILCs in human skin are poorly understood.

CD4+ T cells producing interleukin (IL)‐17, IL‐22 and interferon‐γ are major effector T cells in nickel allergy

Background It has been suggested that interleukin (IL)‐17 and IL‐22 play important roles in the elicitation of human allergic contact dermatitis; however, the frequencies of T cell subtypes producing IL‐17 and IL‐22 in human allergic contact dermatitis are unknown.

IL-1β–Dependent Activation of Dendritic Epidermal T Cells in Contact Hypersensitivity

Substances that penetrate the skin surface can act as allergens and induce a T cell–mediated inflammatory skin disease called contact hypersensitivity (CHS). IL-17 is a key cytokine in CHS and was originally thought to be produced solely by CD4+ T cells. However, it is now known that several cell types, including γδ T cells, can produce IL-17. In this study, we determine the role of γδ T cells, especially dendritic epidermal T cells (DETCs), in CHS. Using a well-established model for CHS in which 2,4-dinitrofluorobenzene (DNFB) is used as allergen, we found that γδ T cells are important players in CHS. Thus, more IL-17–producing DETCs appear in the skin following exposure to DNFB in wild-type mice, and DNFB-induced ear swelling is reduced by ∼50% in TCRδ−/− mice compared with wild-type mice. In accordance, DNFB-induced ear swelling was reduced by ∼50% in IL-17−/− mice. We show that DNFB triggers DETC activation and IL-1β production in the skin and that keratinocytes produce IL-1β when stimulated with DNFB. We find that DETCs activated in vitro by incubation with anti-CD3 and IL-1β produce IL-17. Importantly, we demonstrate that the IL-1R antagonist anakinra significantly reduces CHS responses, as measured by decreased ear swelling, inhibition of local DETC activation, and a reduction in the number of IL-17+ γδ T cells and DETCs in the draining lymph nodes. Taken together, we show that DETCs become activated and produce IL-17 in an IL-1β–dependent manner during CHS, suggesting a key role for DETCs in CHS.

Laser capture microdissection followed by next‐generation sequencing identifies disease‐related microRNAs in psoriatic skin that reflect systemic microRNA changes in psoriasis

Psoriasis is a systemic disease with cutaneous manifestations. MicroRNAs (miRNAs) are small non‐coding RNA molecules that are differentially expressed in psoriatic skin; however, only few cell‐ and region‐specific miRNAs have been identified in psoriatic lesions. We used laser capture microdissection (LCM) and next‐generation sequencing (NGS) to study the specific miRNA expression profiles in the epidermis (Epi) and dermal inflammatory infiltrates (RD) of psoriatic skin (N = 6). We identified 24 deregulated miRNAs in the Epi and 37 deregulated miRNAs in the RD of psoriatic plaque compared with normal psoriatic skin (FCH > 2, FDR < 0.05). Interestingly, 9 of the 37 miRNAs in RD, including miR‐193b and miR‐223, were recently described as deregulated in circulating peripheral blood mononuclear cells (PBMCs) from patients with psoriasis. Using flow cytometry and qRT‐PCR, we found that miR‐193b and miR‐223 were expressed in Th17 cells. In conclusion, we demonstrate that LCM combined with NGS provides a robust approach to explore the global miRNA expression in the epidermal and dermal compartments of psoriatic skin. Furthermore, our results indicate that the altered local miRNA changes seen in the RD are reflected in the circulating immune cells, suggesting that miRNAs may contribute to the pathogenesis of psoriasis.

The Vitamin D Analogue Calcipotriol Reduces the Frequency of CD8+IL-17+ T Cells in Psoriasis Lesions

The vitamin D analogue calcipotriol is an immunomodulatory drug widely used to treat psoriasis; however, how calcipotriol affects the immune cells in psoriasis lesions is not fully understood. The aim of this atudy was to investigate the effect of calcipotriol on the frequency of CD4+ and CD8+ T cells and innate lymphoid cells (ILC) and their production of IL‐17A, IFN‐γ and IL‐22 in psoriasis lesions in patients with chronic plaque psoriasis. Eighteen patients with psoriasis were included, and two similar psoriasis lesions were chosen for each patient. One lesion was treated with calcipotriol (50 μg/g) and the other with vehicle twice a day for 14 days. The clinical effect was measured by degree of erythema, scaling and induration in each lesion (SUM score). Skin biopsies were collected for histological and immunohistochemical analyses. Skin‐derived cells were isolated and analysed by flow cytometry. After 14 days of treatment with calcipotriol, a significant clinical and histological effect was seen; however, we found no differences in the frequency of CD4+ and CD8+ T cells or ILC between calcipotriol‐ and vehicle‐treated skin. The main finding was a significant decrease in CD8+IL‐17+ T cells in skin‐derived cells from calcipotriol‐treated skin, which was further supported by the absence of CD8+IL‐17+ T cells in immunohistochemical staining of calcipotriol‐treated skin. No changes in the frequency of IL‐22+ or IFN‐γ+ cells were observed. Our findings show that the vitamin D analogue calcipotriol reduces the frequency of CD8+IL‐17+ T cells in psoriasis lesions concomitant with clinical improvement.

Distinct molecular signatures of mild extrinsic and intrinsic atopic dermatitis

Atopic dermatitis (AD) is a common inflammatory skin disease with underlying defects in epidermal function and immune responses. In this study, we used microarray analysis to investigate differences in gene expression in lesional skin from patients with mild extrinsic or intrinsic AD compared to skin from healthy controls and from lesional psoriasis skin. The primary aim was to identify differentially expressed genes involved in skin barrier formation and inflammation, and to compare our results with those reported for patients with moderate and severe AD. In contrast to severe AD, expression of the majority of genes associated with skin barrier formation was unchanged or upregulated in patients with mild AD compared to normal healthy skin. Among these, no significant differences in the expression of filaggrin (FLG) and loricrin at both mRNA and protein level were found in lesional skin from patients with mild AD, despite the presence of heterozygous FLG mutations in the majority of patients with mild extrinsic AD. Several inflammation‐associated genes such as S100A9, MMP12, CXCL10 and CCL18 were highly expressed in lesional skin from patients with mild psoriasis and were also increased in patients with mild extrinsic and intrinsic AD similar to previous reports for severe AD. Interestingly, expression of genes involved in inflammatory responses in intrinsic AD resembled that of psoriasis more than that of extrinsic AD. Overall, differences in expression of inflammation‐associated genes found among patients with mild intrinsic and extrinsic AD correlated with previous findings for patients with severe intrinsic and extrinsic AD.

NKG2D-dependent activation of dendritic epidermal T cells in contact hypersensitivity.

The interaction between keratinocytes (KC) and skin-resident immune cells plays an important role in induction of contact hypersensitivity (CHS). A specific subset of γδ T cells termed dendritic epidermal T cells (DETC) are located in mouse epidermis, and we have recently shown that DETC become activated and produce IL-17 in an IL-1β-dependent manner during CHS. Various receptors on DETC, including NKG2D, are involved in DETC responses against tumors and during wound healing. The ligands for NKG2D (NKG2DL) are stress-induced proteins such as Mult-1, H60, Rae-1 in mice and MICA, MICB and ULBP in humans. Here, we show that allergens up-regulate expression of the NKG2DL Mult-1, H60 and Rae-1 in cultured mouse KC and of MICA in primary human KC. We demonstrate that Mult-1 is expressed in mouse skin exposed to allergen. Furthermore, we find that the vast majority of DETC in murine epidermis and skin-homing cutaneous lymphocyte-associated antigen (CLA) positive γδ T cells in humans express NKG2D. Finally, we demonstrate that blocking of NKG2D partially inhibits allergen-induced DETC activation. These findings demonstrate that NKG2D and NKG2DL are involved in allergen-induced activation of DETC and indicate that the NKG2D/NKG2DL pathway might be a potential target for treatment of CHS.

Rapid allergen‐induced interleukin‐17 and interferon‐γ secretion by skin‐resident memory CD8+ T cells

Skin‐resident memory T (TRM) cells are associated with immunological memory in the skin. Whether immunological memory responses to allergens in the skin are solely localized to previously allergen‐exposed sites or are present globally in the skin is not clear. Furthermore, the mechanisms whereby TRM cells induce rapid recall responses need further investigation.

Epicutaneous exposure to nickel induces nickel allergy in mice via a MyD88-dependent and interleukin-1-dependent pathway

Several attempts to establish a model in mice that reflects nickel allergy in humans have been made. Most models use intradermal injection of nickel in combination with adjuvant to induce nickel allergy. However, such models poorly reflect induction of nickel allergy following long‐lasting epicutaneous exposure to nickel.

Increased prevalence of lymphoid tissue inducer cells in the cerebrospinal fluid of patients with early multiple sclerosis

Background: Inflammatory cytokines produced by cells of the immune system are believed to play a central role in the pathogenesis of multiple sclerosis (MS). Innate lymphoid cells (ILCs) have been shown to produce and secrete a wide range of the cytokines involved in MS pathogenesis; however, a possible implication of ILCs in MS development and disease progression has not been investigated. Objective: With this study, we aimed to clarify a potential role of ILCs in the early stages of MS. Methods and Results: Using flow cytometry, we analysed the prevalence and phenotype of ILCs in the cerebrospinal fluid (CSF) of patients experiencing their first or second demyelinating event. We found a substantial increase in both frequency and number of ILCs, in particular the LTi subset, as compared to healthy controls. We also found an association between CSF pleocytosis and an increased frequency of LTi cells in the CSF, suggesting a favoured recruitment of blood derived LTi cells. Conclusion: Our data suggests a role for ILCs, and in particular the LTi subset, in the early stages of MS. This finding represents an important contribution to the understanding of early inflammation in MS, and adds new knowledge beneficial for future MS therapies.