Characterization of a New Ex Vivo Model for the Study of Psoriasis Immunopathology
[eng] Psoriasis is an inflammatory immune-mediated skin disease that usually occurs in individuals with genetic susceptibility in conjunction with environmental triggers. Circulating effector memory skin-tropic CLA+ T cells have been shown to participate in the development of several immune cell-med...
| Autor: | |
|---|---|
| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2017 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/110929 |
| Acceso en línea: | https://hdl.handle.net/2445/110929 http://hdl.handle.net/10803/402829 |
| Access Level: | acceso abierto |
| Palabra clave: | Psoriasi Immunopatologia Psoriasis Immunopathology |
| Sumario: | [eng] Psoriasis is an inflammatory immune-mediated skin disease that usually occurs in individuals with genetic susceptibility in conjunction with environmental triggers. Circulating effector memory skin-tropic CLA+ T cells have been shown to participate in the development of several immune cell-mediated cutaneous diseases, due to its selective recruitment into the skin and the subsequent rapid effector response upon cognate antigen recognition. Several studies point to the capacity of recirculation of CLA+ T cells between skin and blood, which suggests that in skin diseases implying chronicity, such as psoriasis, the study of circulating CLA+ T cells could constitute peripheral cellular biomarkers and thus providing a tool for translational evaluation of current pathology status. In this regard, we proposed an ex vivo model that uses isolated memory CLA+ T cells from patient’s blood and then are cultured together with autologous epidermal cells, in order to match more accurately a proper intercellular interaction in the cutaneous context of skin lesions. Once established the cellular basis, this experimental approach is completed by the activation with a clinical relevant trigger, the Streptococcus pyogenes. Based on this antigen-specific innate stimulus, the study of the circulating memory CLA+ T-cell subset as a potential carrier of disease-associated information, has allowed the characterization of different aspects of psoriasis disease. Such activation induces, among others, high levels of IL-17 response by CLA+ T cells, which is predominant in case of guttate psoriasis, and correlates with IL-17-regulated transcripts levels in keratinocytes as well, resembling a psoriatic-associated gene expression pattern. Interestingly, IL-17A have been shown to be the key disease-associated cytokine responsible of psoriasis severity in patients. Therefore, the finding of a CLA+ T-cell-selective production of IL-9, which in turn is necessary for optimal production of IL-17A from CLA+ T cells, upon activation with S. pyogenes, suggests a significant Th17-supportive role from other less-characterized skin-homing T-cell lineages in psoriasis. Additionally, we have found a synchronicity in guttate psoriasis-derived CLA+T-cell ex vivo responses to S. pyogenes, the rate of streptococcal exposure (ASO) and disease severity (PASI), thereby supporting that clinical outcomes can be reflected by peripheral CLA+ T cells following encounter of an antigen that initially triggered the disease. However, the assessment of the relation of S. pyogenes-exerted effector function in plaque psoriasis-derived samples with their clinic status, has still to be elucidated. Finally, the early determination of the IL-17-targeted gene ZC3H12A, which encodes for the ribonuclease MCPIP1, in keratinocytes, through strep-induced production of IL-17A by the CLA+/Epi coculture, led to the succeeding characterization of its aberrant, and rapid IL-17A-induced, expression in psoriatic lesions and epidermal cells, respectively, where its ribonuclease activity could be modulating other altered-expressed genes. Overall, psoriatic-associated events can be reproduced ex vivo in a CLA- and SE-dependent manner and provides a tool to expand knowledge and understanding of immune responses in psoriasis. |
|---|