Human Translational Research in Psoriasis Using CLA+ T Cells

Focusing on the study of human memory CLA+ T cells to understand psoriasis pathology constitutes an innovative approach to explore the pathological mechanism of this chronic cutaneous inflammatory disease. CLA+ T cells can be considered peripheral cell biomarkers in the study of T-cell mediated human skin diseases. During the last few years, new evidences have been found that link streptococcal infection with IL-17 response in psoriasis by studying the interaction between Streptococcus pyogenes with CLA+ T cells and autologous epidermal cells. S. pyogenes constitutes the best clinically characterized trigger of psoriasis and by exploring its effect on CLA+ T cells and epidermal cells in psoriasis may allow understanding psoriasis by using patient’s clinical samples ex vivo

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-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.[spa] La mayoría de los avances en psoriasis han tenido lugar a través de investigación traslacional. Los linfocitos T circulantes con tropismo cutáneo (CLA+) constituyen biomarcadores celulares para el estudio de enfermedades cutáneas mediadas por células T. El estudio de dichas células periféricas puede aportar información traslacional relevante, por ejemplo, a través del análisis de sus respuestas al ser activadas con desencadenantes asociados a la enfermedad, como el Streptococcus pypogenes, la faringitis por el cual está asociada a la aparición de psoriasis en gotas, y al empeoramiento de la psoriasis en placa. Las células T circulantes CLA+ de pacientes con psoriasis en gotas, en presencia de células epidérmicas autólogas y de un extracto de S. pyogenes (SE), producen una respuesta efectora predominante de tipo Th17 (IL-17A). Otros mediadores relevantes, como el IFN-gamma y la IL-9, también son producidos en este modelo. Curiosamente, se ha observado un pico temporal común entre los niveles de ASO en sangre, de PASI (severidad), y la cantidad de citoquinas producidas por los linfocitos T CLA+. El cocultivo de células T CLA+ y células epidérmicas (CLA+/Epi), provenientes de pacientes con psoriasis en placa, también responden al SE, y producen IL-17A, IFN-gamma e IL-9, ésta última siendo necesaria para la producción óptima de los niveles de IL-17A, tanto en gotas como en placas. Sin embargo, todavía queda por dilucidar qué tipo de relación existe entre la respuesta efectora ex vivo y los aspectos clínicos de estos pacientes. Finalmente, debido a que la IL-17A en psoriasis constituye la citoquina clave responsable de la severidad en la enfermedad, es importante estudiar genes en células cutáneas cuya expresión esté regulada por IL-17A. Así mismo, hemos determinado que la expresión del gen ZC3H12A es inducida en queratinocitos por la IL-17A, y que su producto proteico, la ribonucleasa MCPIP1, se localiza de forma anormal en la epidermis de las lesiones psoriáticas, donde probablemente podría afectar la expresión de otros genes. En conjunto, se han podido estudiar diferentes aspectos de la psoriasis a través del estudio de las células T CLA+ circulantes en respuesta a un estímulo asociado a la enfermedad

CLA+ T cell response to microbes in psoriasis

Streptococcus pyogenes throat infection is a clinically relevant trigger of both guttate and chronic plaque psoriasis, and it provides an ideal context in which to study the pathogenesis of these diseases using an antigen-dependent approach. Circulating cutaneous lymphocyte-associated antigen (CLA) positive (+) memory T cells are a subset of peripheral lymphocytes whose phenotype and function are related to immunological mechanisms in the skin. These cells are considered peripheral biomarkers of T-cell-mediated skin diseases. The coculture of autologous epidermal cells with CLA+ T cells from psoriasis patients activated by S. pyogenes allows the reproduction of the ex vivo initial molecular events that occur during psoriatic lesion formation. With cooperation of autologous epidermal cells, S. pyogenes selectively activates CLA+ T cells both in guttate and plaque psoriasis, inducing key mediators, including an IL-17 response. Here, we explore potential new mechanisms of psoriasis development including the influence of HLA-Cw6 on S. pyogenes CLA+ T cell activation in guttate psoriasis, the relevance of IL-9 on microbe induced IL-17 response in guttate and plaque psoriasis, and novel effector functions of Candida albicans. This review will summarize recent knowledge of psoriatic mechanisms elicited by microbes that have been studied through an innovative translational perspective based on CLA+ T cell-mediated cutaneous immune response

CLA+ T cell response to microbes in psoriasis

Streptococcus pyogenes throat infection is a clinically relevant trigger of both guttate and chronic plaque psoriasis, and it provides an ideal context in which to study the pathogenesis of these diseases using an antigen-dependent approach. Circulating cutaneous lymphocyte-associated antigen (CLA) positive (+) memory T cells are a subset of peripheral lymphocytes whose phenotype and function are related to immunological mechanisms in the skin. These cells are considered peripheral biomarkers of T-cell-mediated skin diseases. The coculture of autologous epidermal cells with CLA+ T cells from psoriasis patients activated by S. pyogenes allows the reproduction of the ex vivo initial molecular events that occur during psoriatic lesion formation. With cooperation of autologous epidermal cells, S. pyogenes selectively activates CLA+ T cells both in guttate and plaque psoriasis, inducing key mediators, including an IL-17 response. Here, we explore potential new mechanisms of psoriasis development including the influence of HLA-Cw6 on S. pyogenes CLA+ T cell activation in guttate psoriasis, the relevance of IL-9 on microbe induced IL-17 response in guttate and plaque psoriasis, and novel effector functions of Candida albicans. This review will summarize recent knowledge of psoriatic mechanisms elicited by microbes that have been studied through an innovative translational perspective based on CLA+ T cell-mediated cutaneous immune response

Memory T Cell subpopulations as early predictors of remission to vedolizumab in ulcerative colitis

Background: vedolizumab is a humanized monoclonal antibody targeting the α4β7 integrin used for the treatment of ulcerative colitis. Few biomarkers related to vedolizumab response have been identified. The aim of this work was to assess whether baseline circulating CD4+ and CD8+ memory T-lymphocyte subpopulations could help to identify patients with response to vedolizumab treatment in ulcerative colitis. Methods: prospective pilot study in 15 patients with active ulcerative colitis and previous failure to anti-TNFα starting vedolizumab treatment. Peripheral blood samples were obtained before the first dose of vedolizumab and at week 6 and 14 of treatment. Clinical remission was defined as a Mayo Clinic partial score of ≤2 points without any concomitant dose of steroids. Biochemical remission or endoscopic improvement was defined as fecal calprotectin <250 mcg/g or Mayo endoscopic subscore ≤1. Results: at week 14, nine patients achieved clinical remission and eight patients achieved biochemical remission or endoscopic improvement. Patients in clinical remission presented higher baseline CD8 α4β7 + memory T cells concentration when compared with patients with no remission. In addition, patients with biochemical remission or endoscopic improvement at week 14 presented higher baseline concentration of CD8 α4β7 + memory T cells. No differences were identified according to flare severity, extent of disease or type of anti-TNFα failure. There were no significant differences regarding changes in T cell subsets during vedolizumab induction. Conclusion: CD8+ α4β7 + memory T cells before starting vedolizumab therapy could be an early predictor of remission in ulcerative colitis patients and therefore help to select a subset of responders

MCPIP1 RNase is aberrantly distributed in psoriatic epidermis and rapidly induced by IL-17A.

ZC3H12A, which encodes the RNase monocyte chemotactic protein-induced protein 1 (MCPIP1), is up-regulated in psoriatic skin and reduced to normal levels after clinical treatments with anti-IL-17A/IL-17R neutralizing antibodies. In IL-17A-stimulated keratinocytes, MCPIP1 is rapidly increased at the transcript and protein levels. Also, IL-17A was found to be the main inducer of ZC3H12A expression in keratinocytes treated with supernatants derived from a Streptococcus pyogenes-activated psoriatic ex vivo model based on the co-culture of psoriatic cutaneous lymphocyte-associated antigen (CLA(+)) T cells and lesional epidermal cells. Moreover, MCPIP1 was aberrantly distributed in the suprabasal layers of psoriatic epidermis. In psoriatic samples, IL-17A-stimulated epidermal cell suspensions showed an increased MCPIP1 expression, especially in the mid-differentiated cellular compartment. The knockdown of ZC3H12A showed that this RNase participates in the regulation of the mRNAs present in suprabasal differentiated keratinocytes. Furthermore, JAK/STAT3 inhibition prevented the IL-17A-dependent induction of MCPIP1. In the mouse model of imiquimod-induced psoriasis, Zc3h12a expression was abrogated in Il17ra(-/-) mice. These results support the notion that IL-17A-mediated induction of MCPIP1 is involved in the regulation of local altered gene expression in suprabasal epidermal layers in psoriasis

Interplay between Humoral and CLA + T Cell Response against Candida albicans in Psoriasis

Candida albicans (CA) infections have been associated with psoriasis onset or disease flares. However, the integrated immune response against this fungus is still poorly characterized in psoriasis. We studied specific immunoglobulins in plasma and the CA response in cocultures of circulating memory CD45RA- cutaneous lymphocyte antigen (CLA)+/- T cell with autologous epidermal cells from plaque and guttate psoriasis patients (cohort 1, n = 52), and also healthy individuals (n = 17). A complete proteomic profile was also evaluated in plaque psoriasis patients (cohort 2, n = 114) regarding their anti-CA IgA levels. Increased anti-CA IgA and IgG levels are present in the plasma from plaque but not guttate psoriasis compared to healthy controls. CA cellular response is confined to CLA+ T cells and is primarily Th17. The levels of anti-CA IgA are directly associated with CLA+ Th17 response in plaque psoriasis. Proteomic analysis revealed distinct profiles in psoriasis patients with high anti-CA IgA. C-C motif chemokine ligand 18, chitinase-3-like protein 1 and azurocidin were significantly elevated in the plasma from plaque psoriasis patients with high anti-CA levels and severe disease. Our results indicate a mechanism by which Candida albicans exposure can trigger a clinically relevant IL-17 response in psoriasis. Assessing anti-CA IgA levels may be useful in order to evaluate chronic psoriasis patients

Global variation in postoperative mortality and complications after cancer surgery: a multicentre, prospective cohort study in 82 countries

© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 licenseBackground: 80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality. Methods: This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov, NCT03471494. Findings: Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70–8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39–8·80) and upper-middle-income countries (2·06, 1·11–3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26–11·59) and upper-middle-income countries (3·89, 2·08–7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications. Interpretation: Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications. Funding: National Institute for Health Research Global Health Research Unit

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide. Methods: A multimethods analysis was performed as part of the GlobalSurg 3 study—a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital. Findings: Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3·85 [95% CI 2·58–5·75]; p<0·0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63·0% vs 82·7%; OR 0·35 [0·23–0·53]; p<0·0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer. Interpretation: Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised. Funding: National Institute for Health and Care Research