Role of CLA+T lymphocytes in the mechanisms triggering psoriasis

Abstract

[eng] Psoriasis is a common immune-mediated inflammatory skin condition affecting around 2% of the population worldwide. Different disease subtypes have been described regarding their specific clinical phenotype: chronic plaques, inverse, guttate, pustular and erythrodermic. Disease onset occurs from a complex interaction between the immune system (mostly T cells) and environmental factors (like microbes), along with a susceptible genetic background, resulting in increased secretion of cytokines, governed by the IL-17/IL-23 axis, that enhance the inflammatory loop leading to the appearance of cutaneous lesions. The skin, besides being an effective physical barrier that protects us from external agents, accommodates diverse types of immune cells. Importantly, the extravasation of T cells from blood to cutaneous tissue is tightly regulated by the expression of specific adhesion molecules and their ligands on both T cells and dermal blood vessels respectively. The Cutaneous Lymphocyte-associated Antigen (CLA) identifies the subset of effector memory T cells with cutaneous tropism. CLA-expressing cells represent more than 90% of skin infiltrating T cells but, since these cells are able to recirculate between blood and tissue, a proportion of them can be found in circulation, thus being a useful tool with translational value for the study of T cell-mediated skin conditions. Our group has developed an ex vivo model of psoriasis based on the coculture of circulating CLA+ T cells with autologous epidermal cells obtained from lesional biopsies in the same patient. In this thesis, this model is used to discuss how circulating CLA+ T cells respond to relevant disease triggers such as microorganisms (Streptococcus pyogenes and Candida albicans) and lesional pro-inflammatory cytokines (IL-15 and IL-23) in plaque and guttate forms of psoriasis, as well as the association between cytokine response to microbes in vitro and patients exposure to the same microorganism, measured by the presence of specific antibodies in plasma. First, the study of S. pyogenes (SE)-specific antibodies revealed increased IgA response in both plaque and guttate psoriasis compared to healthy controls and atopic dermatitis patients. Interestingly, increased anti-SE IgA levels were reported in patients despite no history of streptococcal infection. Of note, anti-SE IgA levels positively correlated with CLA+ T cell dependent IL-17 response in vitro. Next, humoral response against C. Albicans (CA) was assessed and plaque psoriasis patients showed increased anti-CA IgA and IgG compared with guttate psoriasis and controls. T cell cytokines induced after stimulation with CA were evaluated in supernatants revealing raised Th17 and Th9 responses in psoriasis, specifically in the CLA+ T cell subset. Interestingly, anti-CA IgA levels and IL-17F/A responses were directly associated in CLA+ and CLA- T cells cocultures from plaque psoriasis only. Because patients with increased anti-CA IgA may carry pathological peculiarities, a broad proteomic profile was evaluated in plasma samples of plaque psoriasis patients reporting raised presence of proteins associated to anti-microbial humoral response that could link psoriasis and periodontitis. Finally, the influence of lesional pro-inflammatory cytokines IL-15 and IL-23 was examined in our model and revealed the synergistic induction of IL-17F and IL-17A cytokines by CLA+ T cells in cocultures from psoriasis but not healthy controls. This synergy required the presence of autologous epidermal cells, although it did not depend on skin-resident memory T cells, and was mainly mediated by activated CD4+ CLA+ T cells. In summary, this work has characterized novel mechanisms related to triggering factors of psoriasis and confirms that the subset of skin-tropic CLA+ memory T cells particularly are key inducers of IL-17 cytokines upon activation by these triggers, which may contribute to the feedforward inflammatory loop and perpetuate psoriasis pathogenesis.