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The role of CLA+T lymphocytes in the development of Atopic Dermatitis

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Universitat de Barcelona. Departament de Biologia Cel·lular, Fisiologia i Immunologia

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[eng] Atopic dermatitis is the most common chronic immune-mediated inflammatory skin disease affecting up to 20% of children and 10% of adults. The complex pathophysiology of the disease comprises genetic susceptibility, epidermal barrier dysfunction, cutaneous dysbiosis with abundance of S. aureus, an abnormal cutaneous immune system activation with a core Th2 response and pruritus. Cutaneous Lymphocyte-associated Antigen (CLA)+ T cells represent the subset of memory T cells that belong to the cutaneous immune system. CLA+ T cells recirculate between blood and skin through the thoracic duct, specifically respond to skin-related antigens, and represent over 90% of T cells infiltrating the skin. Therefore, CLA+ T cells constitute peripheral cellular biomarkers and, because they can be found in general circulation, they are a source of translational information on the immunological mechanisms taking place in the skin during disease. We have studied atopic dermatitis in the context of the cutaneous immune response through the effector function of CLA+ T cells. For this, we have stablished a novel ex vivo model of adult non- treated moderate-to-severe atopic dermatitis based on circulating CLA+ T cells cocultured with a suspension of autologous epidermal cells obtained from lesional biopsies in the same patients. Then, we have studied the T-cell effector function in response to relevant disease triggers such as S. aureus microorganism and house dust mite (HDM) allergen, as well as the association between cytokine response to the stimuli and patient’s clinical data. First, the study of IL-13 response to S. aureus enterotoxin B (SEB) by CLA+ T cells defined two groups of patients, Th2 high and Th2 low, within a clinically homogeneous population. In the Th2 high group, in contrast to the Th2 low group, the IL-13 response positively correlated with severity, in terms of EASI score, and levels of CCL17, sIL-2R and S. aureus-specific IgE in plasma. Additionally, in this group the IL-13 response directly correlated with CCL26 and indirectly correlated with LCN2 mRNA expression in cutaneous lesions. Conversely, in the Th2 low group, the CLA+ T-cell response to SEB skewed towards Th17, Th22 and Th1. Next, the role of the neuroimmune cytokine IL-31 was examined in our model by studying the CLA+ T-cell response to HDM, and a bimodal (present or absent) IL-31 response in relation with the HDM-specific IgE levels in plasma was observed. Patients producing IL-31 by HDM-activated CLA+ T cells showed increased HDM-specific and total IgE levels and reported an increased inflammatory profile compared to patients with no IL-31 response. Interestingly, the IL-31 response directly correlated with patient’s pruritus intensity and plasma levels of CCL27 and periostin. Of note, patients with no IL-31 response reported raised presence of HDM- specific and total IgE levels compared to control subjects, suggesting that the degree of IgE sensitization to HDM in this group was not enough for inducing IL-31 response. In summary, this novel ex vivo model of adult non-treated moderate-to-severe atopic dermatitis has allowed to functionally identify Th2 high and Th2 low responders from a clinically homogeneous population based on the SEB-CLA+-IL-13 axis, as well as stratifying patients into IL-31 producers and non-producers in relation with the degree of IgE sensitization to HDM by analyzing the CLA+ T-cell response to HDM and its association with clinical features. Altogether, this translational work expands the understanding of the heterogeneous inflammatory response of the disease and may contribute to improving the effectiveness of targeted therapies.

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cc by (c) Sans de San Nicolàs, Lídia, 2023

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Tesis Doctorals - Departament - Biologia Cel·lular, Fisiologia i Immunologia

# metadata.dc.title[].value
The role of CLA+T lymphocytes in the development of Atopic Dermatitis