43 results on '"Reali, Eva"'
Search Results
2. Integrated metabolomic analysis and cytokine profiling define clusters of immuno-metabolic correlation in new-onset psoriasis
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Tarentini, Elisabetta, Odorici, Giulia, Righi, Valeria, Paganelli, Alessia, Giacomelli, Luca, Mirisola, Valentina, Mucci, Adele, Benassi, Luisa, D’Aversa, Elisabetta, Lasagni, Claudia, Kaleci, Shaniko, Reali, Eva, and Magnoni, Cristina
- Published
- 2021
- Full Text
- View/download PDF
3. Blood to skin recirculation of CD4+ memory T cells associates with cutaneous and systemic manifestations of psoriatic disease
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Diani, Marco, Galasso, Marco, Cozzi, Chiara, Sgambelluri, Francesco, Altomare, Andrea, Cigni, Clara, Frigerio, Elena, Drago, Lorenzo, Volinia, Stefano, Granucci, Francesca, Altomare, Gianfranco, and Reali, Eva
- Published
- 2017
- Full Text
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4. The network of non-coding RNAs and their molecular targets in breast cancer
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Crudele, Francesca, Bianchi, Nicoletta, Reali, Eva, Galasso, Marco, Agnoletto, Chiara, and Volinia, Stefano
- Published
- 2020
- Full Text
- View/download PDF
5. From the Skin to Distant Sites: T Cells in Psoriatic Disease.
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Reali, Eva and Ferrari, Davide
- Subjects
- *
PSORIATIC arthritis , *T cells , *AUTOIMMUNE diseases , *SKIN inflammation , *CUTANEOUS manifestations of general diseases , *GENETIC disorders - Abstract
Human skin has long been known as a protective organ, acting as a mechanical barrier towards the external environment. More recent is the acquisition that in addition to this fundamental role, the complex architecture of the skin hosts a variety of immune and non-immune cells playing preeminent roles in immunological processes aimed at blocking infections, tumor progression and migration, and elimination of xenobiotics. On the other hand, dysregulated or excessive immunological response into the skin leads to autoimmune reactions culminating in a variety of skin pathological manifestations. Among them is psoriasis, a multifactorial, immune-mediated disease with a strong genetic basis. Psoriasis affects 2–3% of the population; it is associated with cardiovascular comorbidities, and in up to 30% of the cases, with psoriatic arthritis. The pathogenesis of psoriasis is due to the complex interplay between the genetic background of the patient, environmental factors, and both innate and adaptive responses. Moreover, an autoimmune component and the comprehension of the mechanisms linking chronic skin inflammation with systemic and joint manifestations in psoriatic patients is still a major challenge. The understanding of these mechanisms may offer a valuable chance to find targetable molecules to treat the disease and prevent its progression to severe systemic conditions. [ABSTRACT FROM AUTHOR]
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- 2023
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- View/download PDF
6. Increased frequency of activated CD8+ T cell effectors in patients with psoriatic arthritis
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Diani, Marco, Casciano, Fabio, Marongiu, Laura, Longhi, Matteo, Altomare, Andrea, Pigatto, Paolo D., Secchiero, Paola, Gambari, Roberto, Banfi, Giuseppe, Manfredi, Angelo A., Altomare, Gianfranco, Granucci, Francesca, and Reali, Eva
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- 2019
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7. Inhibition of CCR7/CCL19 Axis in Lesional Skin Is a Critical Event for Clinical Remission Induced by TNF Blockade in Patients with Psoriasis
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Bosè, Francesca, Petti, Luciana, Diani, Marco, Moscheni, Claudia, Molteni, Silvia, Altomare, Andrea, Rossi, Riccardo L., Talarico, Daniela, Fontana, Raffaella, Russo, Vincenzo, Altomare, Gianfranco, and Reali, Eva
- Published
- 2013
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8. CCR4+CD8+ T cells clonally expand to differentiated effectors in murine psoriasis and in human psoriatic arthritis.
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Montico, Guendalina, Mingozzi, Francesca, Casciano, Fabio, Protti, Giulia, Gornati, Laura, Marzola, Erika, Banfi, Giuseppe, Guerrini, Remo, Secchiero, Paola, Volinia, Stefano, Granucci, Francesca, and Reali, Eva
- Subjects
T cells ,PSORIATIC arthritis ,SYNOVIAL fluid ,PSORIASIS ,CHEMOKINE receptors ,SKIN diseases - Abstract
Psoriasis is a chronic inflammatory skin disease with an autoimmune component and associated with joint inflammation in up to 30% of cases. To investigate autoreactive T cells, we developed an imiquimod‐induced psoriasis‐like inflammation model in K5‐mOVA.tg C57BL/6 mice expressing ovalbumin (OVA) on the keratinocyte membrane, adoptively transferred with OT‐I OVA‐specific CD8+ T cells. We evaluated the expansion of OT‐I CD8+ T cells and their localization in skin, blood, and spleen. scRNA‐seq and TCR sequencing data from patients with psoriatic arthritis were also analyzed. In the imiquimod‐treated K5‐mOVA.tg mouse model, OT‐I T cells were markedly expanded in the skin and blood at early time points. OT‐I T cells in the skin showed mainly CXCR3+ effector memory phenotype, whereas in peripheral blood there was an expansion of CCR4+CXCR3+ OT‐I cells. At a later time point, expanded OVA‐specific T‐cell population was found in the spleen. In patients with psoriatic arthritis, scRNA‐seq and TCR sequencing data showed clonal expansion of CCR4+ TCM cells in the circulation and further expansion in the synovial fluid. Importantly, there was a clonotype overlap between CCR4+ TCM in the peripheral blood and CD8+ T‐cell effectors in the synovial fluid. This mechanism could play a role in the generation and spreading of autoreactive T cells to the synovioentheseal tissues in psoriasis patients at risk of developing psoriatic arthritis. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
9. Boosting NAD: An opportunity for metabolic reprogramming of Th17 cells in psoriatic disease
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Reali, Eva
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- 2023
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10. HIV-1 Tat affects the programming and functionality of human CD8+ T cells by modulating the expression of T-box transcription factors
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Sforza, Fabio, Nicoli, Francesco, Gallerani, Eleonora, Finessi, Valentina, Reali, Eva, Cafaro, Aurelio, Caputo, Antonella, Ensoli, Barbara, and Gavioli, Riccardo
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- 2014
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11. Editorial: The Interplay Between Immune Activation and Cardiovascular Disease During Infection, Autoimmunity and Aging: The Role of T Cells.
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Reali, Eva, Ferrando-Martinez, Sara, and Catalfamo, Marta
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AUTOIMMUNE diseases ,CARDIOVASCULAR diseases ,ATHEROSCLEROSIS ,T cells ,MONONUCLEAR leukocytes ,T helper cells ,COVID-19 - Abstract
Overall, this Research Topic highlights the role of T cell immune activation in cardiovascular disease suggesting an important role of T cells in the homeostasis of the vascular and cardiac system, and when dysregulated can contribute to the pathology of the disease. They point out that autoimmune diseases are often paralleled by the presence of autoreactive T cells opening the concept that self-reactive T cells may represent the link between autoimmune disease and the risk of CVD in patients with RA, SLE and psoriasis. Keywords: T cells; cardiovascular disease; infection; aging; autoimmunity EN T cells cardiovascular disease infection aging autoimmunity 1 5 5 06/28/21 20210624 NES 210624 Introduction Chronic activation of cells of the immune system including T cells and systemic inflammation are well known risk factors for cardiovascular disease (CVD). The proposed mechanisms by which T cells contribute to the pathology of the disease include dysregulated T helper and CD8 T cell function, expansion of terminally differentiated cytotoxic effectors CD4 SP + sp CD28 SP - sp T cells and impaired Tregs function. [Extracted from the article]
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- 2021
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12. CCR4+ Skin-Tropic Phenotype as a Feature of Central Memory CD8+ T Cells in Healthy Subjects and Psoriasis Patients.
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Casciano, Fabio, Diani, Marco, Altomare, Andrea, Granucci, Francesca, Secchiero, Paola, Banfi, Giuseppe, and Reali, Eva
- Subjects
T cells ,T cell differentiation ,CHEMOKINE receptors ,CELL migration ,BLOOD cells - Abstract
The chemokine receptor CCR4 has emerged as a skin-homing molecule important for the migration of T cells from the blood to the dermis. From our previous data on psoriasis patients, CCR4
+ memory T cells emerged as a putative recirculating population between skin and blood. Here we focused our attention on the expression of CCR4 and skin-tropic molecules in the different stages of memory T cell differentiation. We analyzed the chemokine receptor profile in CD8+ and CD4+ CD45RA− CCR7+ (TCM ) and CD45RA− CCR7− (TEM ) cells. Subpopulations were further divided on the basis of CD62L expression, and the distribution among the subsets of the skin-homing molecule CLA (Cutaneous Lymphocyte Antigen) was evaluated. The characterization was performed on peripheral blood mononuclear cells isolated from 21 healthy subjects and 24 psoriasis patients. The results indicate that (i) the skin-homing CCR4 marker is mainly expressed in TCM cells, (ii) CCR4+ TCM cells also express high level of CLA and that (iii) the more differentiated phenotype TEM expresses CXCR3 and CCR5 but lower level of CCR4 and CLA. This indicates that progressive stages of memory T cell differentiation have profoundly different chemokine receptor patterns, with CD8+ TCM displaying a marked skin-tropic phenotype CLA+ CCR4+ . Differential skin-tropic phenotype between TCM and TEM cells was observed in both healthy subjects and psoriasis patients. However, patients showed an expanded circulating population of CD8+ TCM cells with phenotype CCR4+ CXCR3+ that could play a role in the pathophysiology of psoriasis and possibly in disease recurrence. [ABSTRACT FROM AUTHOR]- Published
- 2020
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13. T Helper Cell Subsets in Clinical Manifestations of Psoriasis
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Diani, Marco, Altomare, Gianfranco, and Reali, Eva
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Article Subject - Abstract
Psoriasis is a chronic inflammatory skin disease, which is associated with systemic inflammation and comorbidities, such as psoriatic arthritis and cardiovascular diseases. The autoimmune nature of psoriasis has been established only recently, conferring a central role to epidermal CD8 T cells recognizing self-epitopes in the initial phase of the disease. Different subsets of helper cells have also been reported as key players in the psoriasis pathogenesis. Here, we reviewed the knowledge on the role of each subset in the psoriatic cascade and in the different clinical manifestations of the disease. We will discuss the role of Th1 and Th17 cells in the initiation and in the amplification phase of cutaneous inflammation. Moreover, we will discuss the recently proposed role of tissue resident Th22 cells in disease memory in sites of recurrent psoriasis and the possible involvement of Th9 cells. Finally, we will discuss the hypothesis of a link between T helper cell subsets recirculating from the skin and the systemic manifestations of psoriasis.
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- 2016
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14. 48 - Hepatitis C vaccines
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Abrignani, Sergio, Reali, Eva, Houghton, Michael, and De Francesco, Raffaele
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- 2013
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15. T Cell Hierarchy in the Pathogenesis of Psoriasis and Associated Cardiovascular Comorbidities.
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Casciano, Fabio, Pigatto, Paolo D., Secchiero, Paola, Gambari, Roberto, and Reali, Eva
- Subjects
T cells ,SKIN diseases ,PSORIASIS ,PATIENTS - Abstract
The key role of T cells in the pathogenesis of cutaneous psoriasis has been well described in the last decade and the knowledge of the relative role of the different subsets of T cells in psoriasis pathogenesis has considerably evolved. Now, it is clear that IL-17A-producing T cells, including Th17/Tc17, have a central role in the pathogenesis of cutaneous psoriasis and therapies blocking the IL-17A pathway show high clinical efficacy. By contrast, the contribution of IFNγ-producing T cells has progressively become less clear because of the lack of efficacy of anti-IFNγ antibodies in clinical studies. In parallel, the role of CD8
+ T cells specific for self-antigens has been revived and increasing evidence now indicates that in psoriatic skin the majority CD8+ T cells are present in the form of epidermal tissue-resident memory T cells. In the last years it also emerged the possibility of a contribution of T cell recirculation in the pathogenesis of psoriasis and its systemic manifestations. The aim of this review is to define a hierarchy for the different subsets of T cells in the T cell-mediated inflammatory cascade in psoriatic skin. This analysis will possibly help to distinguish the subsets that initiate the disease, those involved in the establishment of the self-sustaining amplification loop that leads to the cutaneous clinical manifestations and finally the subsets that act as downstream players in established lesions. Specific T cell subpopulations finally will be considered for their possible role in propagating inflammation at distant sites and for representing a link with systemic inflammation and cardiovascular comorbidities. [ABSTRACT FROM AUTHOR]- Published
- 2018
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16. Biomarkers in the pathogenesis, diagnosis, and treatment of psoriasis
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Reali , Eva and Molteni
- Subjects
Targets and Therapy [Psoriasis] - Abstract
Silvia Molteni, Eva RealiLaboratory of Translational Immunology, Istituto Ortopedico Galeazzi, Milan, ItalyAbstract: Development of psoriasis results from a complex interplay between genetically predisposing factors and environmental triggers that give rise to a self-sustaining pathogenic cycle involving T cells, dendritic cells, connective tissue, and skin epithelium. From 5% to 40% of patients with psoriasis also develop psoriatic arthritis, and increasing evidence indicates an association with other systemic manifestations, including cardiovascular disease and the metabolic syndrome. In psoriatic disease, there is a need for development of biomarkers for assessment of disease severity, for prediction of the outcome of therapeutic interventions, and for distinction between the different clinical variants of the disease. A field of great importance is identification of biomarkers for prediction of development of comorbidities, such as arthritis, cardiovascular disease, and the metabolic syndrome. Genetic determinants of psoriasis and their products not only give an important insight into the pathogenesis of the disease, but may also function as markers of risk for developing cutaneous psoriasis or psoriatic arthritis. So far, there are limited validation data to support the use of candidate biomarkers in clinical practice. Here we review the data from several studies on some of the most promising candidate biomarkers for cutaneous psoriasis and psoriatic arthritis, for the detection of systemic inflammation, and for use as endpoints for therapeutic interventions. Attention is focused on the molecules that take part in the interplay giving rise to psoriasis and on gene products that may represent a link between predisposing genetic factors and the immune and inflammatory processes involved in pathogenesis of the disease. Finally, we provide an overview on how biomarkers can offer insights into the pathogenesis and natural history of psoriasis.Keywords: psoriatic disease, genetic markers, tissue-associated biomarkers, serum biomarkers, predictive factors, comorbidities
- Published
- 2012
17. Improving access to the outdoors for people with dementia
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Reali, Eva
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- 2021
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18. Editorial: Immunology of Psoriatic Disease.
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Reali, Eva and Brembilla, Nicolò Costantino
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PSORIATIC arthritis ,ARTHRITIS -- Immunological aspects ,INFLAMMATION ,METABOLIC syndrome ,SKIN physiology - Published
- 2019
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19. Chapter 47 - Hepatitis C virus vaccines
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Reali, Eva, Houghton, Michael, and Abrignani, Sergio
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- 2008
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20. The latest advances on CD8 T cell biology in health and disease
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Catalfamo, Marta and Reali, Eva
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- 2020
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21. List of Contributors
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Abrignani, Sergio, Ahmed, Sohail, Anderson, Teresa A., Arlett, Peter R., Atkinson, William L., Aylward, R. Bruce, Bachmann, Martin F., Baker, Carol J., Ballou, W. Ripley, Barnett, Elizabeth D., Barrett, Alan D.T., Barrett, P. Noel, Barry, Eileen M., Baylor, Norman W., Belgharbi, Lahouari, Bell, Beth P., Belshe, Robert B., Berinstein, Jeffrey A., Berinstein, Neil L., Bethony, Jeffrey M., Black, Steven, Bock, Hans L., Bogaerts, Hugues H., Brachman, Philip S., Bridges, Carolyn B., Caplan, Arthur L., Cavaleri, Marco, Chandran, Aruna, Clark, H. Fred, Clemens, John D., Cochi, Stephen L., Cohen, Joe, Cox, Nancy J., Cutts, Felicity T., Dagan, Ron, Daum, Robert S., Decker, Michael D., De Francesco, Raffaele, Dellepiane, Nora, DeStefano, Frank, Dietz, Vance J., Douglas, R. Gordon, Dubischar-Kastner, Katrin, Edwards, Kathryn M., Egan, William, Ehmann, Falk, Ehrlich, Hartmut J., Ellis, Ronald W., Emerson, Suzanne U., Evans, Geoffrey, Fausther-Bovendo, Hugues F., Feinstone, Stephen M., Fine, Paul E.M., Finn, Theresa M., Fiore, Anthony E., Friede, Martin, Friedlander, Arthur M., Garçon, Nathalie, Gershman, Mark D., Gershon, Anne A., Girard, Marc P., Gomez, Phillip L., Grabenstein, John D., Granoff, Dan M., Gray, Gregory C., Halsey, Neal A., Halstead, Scott B., Harrison, Lee H., Healy, C. Mary, Hem, Stanley, Henderson, Donald A., Hinman, Alan R., Hotez, Peter J., Houghton, Michael, Jackson, Lisa A., Jacobs, Anna L., Jacobson, Julie, Karron, Ruth A., Katz, Jacqueline M., Keller, Margaret A., Kennedy, Richard B., Kew, Olen M., Klugman, Keith P., Koff, Wayne C., Kotloff, Karen L., Kozarsky, Phyllis E., Kroger, Andrew T., Kurz, Xavier, Lakdawala, Seema S., Lane, J. Michael, Levin, Myron J., Levine, Emily Marcus, Levine, Myron M., Livey, Ian, Ljungman, Per, Lopalco, Pier Luigi, Lowy, Douglas R., Luke, Catherine J., Lutzky, Viviana P., Malley, Richard, Markowitz, Lauri E., Marshall, Valerie B., Martin, Rebecca M., Miller, Mark A., Mitchell, Violaine, Monath, Thomas P., Moss, Denis J., Moss, William J., Mulholland, Kim, Murphy, Trudy V., Nabel, Gary J., Nataro, James P., Offit, Paul A., Okwo-Bele, Jean Marie, Orenstein, Walter A., Orme, Ian M., Oyston, Petra C.F., Papania, Mark J., Parashar, Umesh D., Fiebelkorn, Amy Parker, Pelton, Stephen, Pickering, Larry K., Pittman, Phillip R., Plotkin, Stanley A., Plotkin, Susan L., Poland, Gregory A., Portsmouth, Daniel, Purcell, Robert H., Quirk, Mary R., Rappuoli, Rino, Reali, Eva, Reef, Susan E., Robinson, James M., Rodewald, Lance E., Rogalewicz, Joseph A., Roper, Martha H., Rubin, Steven A., Rupprecht, Charles E., Rutala, William A., Sack, David A., Sah, Binod K., Salisbury, David M., Samant, Vijay B., Santosham, Mathuram, Saudan, Philippe, Schiller, John T., Schleiss, Mark R., Schuchat, Anne, Schwartz, Jason L., Seward, Jane F., Shin, Sunheang, Shouval, Daniel, Siegrist, Claire-Anne, Smith, Kim Connelly, Stanberry, Lawrence R., Staples, J. Erin, Starke, Jeffrey R., Steere, Allen C., Steffen, Robert, Stiehm, E. Richard, Strebel, Peter M., Subbarao, Kanta, Sullivan, Nancy J., Sutcliffe, Catherine G., Sutter, Roland W., Takahashi, Michiaki, Thomas, Stephen J., Tiwari, Tejpratap S.P., Tsai, Theodore F., Van Damme, Pierre, Vidor, Emmanuel, Ward, John W., Wassilak, Steven G.F., Watt, James P., Weber, David J., Weiner, David B., Weniger, Bruce G., Wexler, Deborah L., Wharton, Melinda, Whitney, Cynthia G., Wiersma, Steven, Williamson, E. Diane, Wood, David J., Xu, Zhi Yi, and Zanetti, Alessandro
- Published
- 2013
- Full Text
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22. Biomarkers in the pathogenesis, diagnosis, and treatment of psoriasis.
- Author
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Molteni, Silvia and Reali, Eva
- Subjects
PSORIASIS ,SKIN diseases ,T cells ,NATURAL history ,NATURAL history libraries ,BIOMARKERS - Abstract
Development of psoriasis results from a complex interplay between genetically predisposing factors and environmental triggers that give rise to a self-sustaining pathogenic cycle involving T cells, dendritic cells, connective tissue, and skin epithelium. From 5% to 40% of patients with psoriasis also develop psoriatic arthritis, and increasing evidence indicates an association with other systemic manifestations, including cardiovascular disease and the metabolic syndrome. In psoriatic disease, there is a need for development of biomarkers for assessment of disease severity, for prediction of the outcome of therapeutic interventions, and for distinction between the different clinical variants of the disease. A field of great importance is identification of biomarkers for prediction of development of comorbidities, such as arthritis, cardiovascular disease, and the metabolic syndrome. Genetic determinants of psoriasis and their products not only give an important insight into the pathogenesis of the disease, but may also function as markers of risk for developing cutaneous psoriasis or psoriatic arthritis. So far, there are limited validation data to support the use of candidate biomarkers in clinical practice. Here we review the data from several studies on some of the most promising candidate biomarkers for cutaneous psoriasis and psoriatic arthritis, for the detection of systemic inflammation, and for use as endpoints for therapeutic interventions. Attention is focused on the molecules that take part in the interplay giving rise to psoriasis and on gene products that may represent a link between predisposing genetic factors and the immune and inflammatory processes involved in pathogenesis of the disease. Finally, we provide an overview on how biomarkers can offer insights into the pathogenesis and natural history of psoriasis. [ABSTRACT FROM AUTHOR]
- Published
- 2012
23. UC.183, UC.110, and UC.84 Ultra-Conserved RNAs Are Mutually Exclusive with miR-221 and Are Engaged in the Cell Cycle Circuitry in Breast Cancer Cell Lines.
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Corrà, Fabio, Crudele, Francesca, Baldassari, Federica, Bianchi, Nicoletta, Galasso, Marco, Minotti, Linda, Agnoletto, Chiara, Di Leva, Gianpiero, Brugnoli, Federica, Reali, Eva, Bertagnolo, Valeria, Vecchione, Andrea, and Volinia, Stefano
- Subjects
MICRORNA ,CELL cycle ,CELL lines ,BREAST cancer ,NON-coding RNA ,CANCER cells - Abstract
In the human genome, there are about 600 ultra-conserved regions (UCRs), long DNA sequences extremely conserved in vertebrates. We performed a large-scale study to quantify transcribed UCR (T-UCR) and miRNA levels in over 6000 cancer and normal tissue samples to find possible correlation between these kinds of regulatory molecules. Our analysis evidenced several non-coding RNAs showing negative co-regulation with miRNAs; among them, we focused on miR-221 to investigate any relationship with its pivotal role in the cell cycle. We have chosen breast cancer as model, using two cell lines with different phenotypes to carry out in vitro treatments with siRNAs against T-UCRs. Our results demonstrate that the expression of uc.183, uc.110, and uc.84 T-UCRs is mutually exclusive with miR-221 and is engaged in the regulation of CDKN1B expression. In addition, tests with a set of anticancer drugs, including BYL719, AZD5363, AZD8055, AZD7762, and XL765, revealed the modulation of specific T-UCRs without alteration of miR-221 levels. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
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24. Infliximab Modulates Il23-TH17 Axis in Patients With Inflammatory Bowel Diseases
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Caprioli, Flavio, Bosè, Francesca, Vigano', Chiara, Palazzo, Marco, Basilisco, Guido, Conte, Dario, Abrignani, Sergio, and Reali, Eva
- Published
- 2011
- Full Text
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25. Purinergic Signaling and Inflammasome Activation in Psoriasis Pathogenesis.
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Ferrari, Davide, Casciano, Fabio, Secchiero, Paola, and Reali, Eva
- Subjects
INFLAMMASOMES ,PATHOGENESIS ,SYMPTOMS ,CARDIOVASCULAR diseases ,PSORIASIS ,T cells - Abstract
Psoriasis is a chronic inflammatory disease of the skin associated with systemic and joint manifestations and accompanied by comorbidities, such as metabolic syndrome and increased risk of cardiovascular disease. Psoriasis has a strong genetic basis, but exacerbation requires additional signals that are still largely unknown. The clinical manifestations involve the interplay between dendritic and T cells in the dermis to generate a self-sustaining inflammatory loop around the TNFα/IL-23/IL-17 axis that forms the psoriatic plaque. In addition, in recent years, a critical role of keratinocytes in establishing the interplay that leads to psoriatic plaques' formation has re-emerged. In this review, we analyze the most recent evidence of the role of keratinocytes and danger associates molecular patterns, such as extracellular ATP in the generation of psoriatic skin lesions. Particular attention will be given to purinergic signaling in inflammasome activation and in the initiation of psoriasis. In this phase, keratinocytes' inflammasome may trigger early inflammatory pathways involving IL-1β production, to elicit the subsequent cascade of events that leads to dendritic and T cell activation. Since psoriasis is likely triggered by skin-damaging events and trauma, we can envisage that intracellular ATP, released by damaged cells, may play a role in triggering the inflammatory response underlying the pathogenesis of the disease by activating the inflammasome. Therefore, purinergic signaling in the skin could represent a new and early step of psoriasis; thus, opening the possibility to target single molecular actors of the purinome to develop new psoriasis treatments. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
26. PS1-31 TNF-blockade enhances T cell responses to TCR stimulation in peripheral blood while it inhibits inflammatory gene expression in target tissues
- Author
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Bosè, F., Raeli, L., Garutti, C., Frigerio, E., Caprioli, Flavio, Altomare, Gianfranco, Geginat, Jens, Abrignani, Sergio, and Reali, Eva
- Published
- 2010
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27. The Importance of the Peptide Bond at Position 2 in HCO-Met-Leu-Phe-OMe Analogues as shown by Studies on Human Neutrophils.
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Cavicchioni, Giorgio, Breveglieri, Angela, Boggian, Marisa, Vertuani, Gianni, Reali, Eva, and Spisani, Susanna
- Published
- 1996
- Full Text
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28. IL-8 enhances antibody-dependent cellular cytotoxicity in human neutrophils.
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Reali, Eva, Spisani, Susanna, Gavioli, Riccardo, Lanza, Francesco, Moretti, Sabrina, and Traniello, Serena
- Subjects
ANTIBODY-dependent cell cytotoxicity ,CELLULAR immunity ,PROTEIN kinase C ,PROTEIN kinases ,NEUTROPHIL immunology ,CYTOLOGICAL research - Abstract
Human neutrophils are able to kill in vitro colorectal carcinoma cell line SW11-16 coated with mAb 17-1A, but they are not cytotoxic towards a non-immunized tumour target. Neutrophil exposure to the inflammatory cytokine, lL-8, produces a significant increase in antibody-dependent cellular cytotoxicity, which is related to IL-8 concentration. Oxyradical production is one of the lytic mechanisms used by phagocytes, and IL-8 is shown to activate this function, which does not occur if neutrophils are pretreated with the protein kinase C inhibitor, staurosporine. but is increased by R59022, a dyacylglycerol kinase inhibitor. The IL-8 effect is mediated by protein kinase C, which is potentiated by the calcium flux induced by the interaction between antibody coating tumour target and FcγRIII on effector cells, as previously demonstrated. Data suggest a possible new role for IL-8 in tumour surveillance [ABSTRACT FROM AUTHOR]
- Published
- 1995
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29. A Peptide Nucleic Acid (PNA) Masking the miR-145-5p Binding Site of the 3′UTR of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mRNA Enhances CFTR Expression in Calu-3 Cells.
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Sultan, Shaiq, Rozzi, Andrea, Gasparello, Jessica, Manicardi, Alex, Corradini, Roberto, Papi, Chiara, Finotti, Alessia, Lampronti, Ilaria, Reali, Eva, Cabrini, Giulio, Gambari, Roberto, Borgatti, Monica, and Yavin, Eylon
- Subjects
CYSTIC fibrosis transmembrane conductance regulator ,PEPTIDE nucleic acids ,BINDING sites ,MESSENGER RNA - Abstract
Peptide nucleic acids (PNAs) have been demonstrated to be very useful tools for gene regulation at different levels and with different mechanisms of action. In the last few years the use of PNAs for targeting microRNAs (anti-miRNA PNAs) has provided impressive advancements. In particular, targeting of microRNAs involved in the repression of the expression of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which is defective in cystic fibrosis (CF), is a key step in the development of new types of treatment protocols. In addition to the anti-miRNA therapeutic strategy, inhibition of miRNA functions can be reached by masking the miRNA binding sites present within the 3′UTR region of the target mRNAs. The objective of this study was to design a PNA masking the binding site of the microRNA miR-145-5p present within the 3′UTR of the CFTR mRNA and to determine its activity in inhibiting miR-145-5p function, with particular focus on the expression of both CFTR mRNA and CFTR protein in Calu-3 cells. The results obtained support the concept that the PNA masking the miR-145-5p binding site of the CFTR mRNA is able to interfere with miR-145-5p biological functions, leading to both an increase of CFTR mRNA and CFTR protein content. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
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30. T Cell Subpopulations in the Physiopathology of Fibromyalgia: Evidence and Perspectives.
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Banfi, Giuseppe, Diani, Marco, Pigatto, Paolo D., and Reali, Eva
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T cells ,FIBROMYALGIA ,PATHOLOGICAL physiology ,ETIOLOGY of diseases ,ENVIRONMENTALLY induced diseases ,EMOTIONAL conditioning - Abstract
Fibromyalgia is one of the most important "rheumatic" disorders, after osteoarthritis. The etiology of the disease is still not clear. At the moment, the most defined pathological mechanism is the alteration of central pain pathways, and emotional conditions can trigger or worsen symptoms. Increasing evidence supports the role of mast cells in maintaining pain conditions such as musculoskeletal pain and central sensitization. Importantly, mast cells can mediate microglia activation through the production of proinflammatory cytokines such as IL-1β, IL-6, and TNFα. In addition, levels of chemokines and proinflammatory cytokines are enhanced in serum and could contribute to inflammation at systemic level. Despite the well-characterized relationship between the nervous system and inflammation, the mechanism that links the different pathological features of fibromyalgia, including stress-related manifestations, central sensitization, and dysregulation of the innate and adaptive immune responses is largely unknown. This review aims to provide an overview of the current understanding of the role of adaptive immune cells, in particular T cells, in the physiopathology of fibromyalgia. It also aims at linking the latest advances emerging from basic science to envisage new perspectives to explain the role of T cells in interconnecting the psychological, neurological, and inflammatory symptoms of fibromyalgia. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
31. Increased frequency of activated CD8+ T cell effectors in patients with psoriatic arthritis.
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Diani, Marco, Casciano, Fabio, Marongiu, Laura, Longhi, Matteo, Altomare, Andrea, Pigatto, Paolo D., Secchiero, Paola, Gambari, Roberto, Banfi, Giuseppe, Manfredi, Angelo A., Altomare, Gianfranco, Granucci, Francesca, and Reali, Eva
- Abstract
The aim of this study is to identify subsets of T cells differentially represented in the circulation of patients with psoriatic arthritis and to evaluate the possibility that they can recirculate between peripheral blood and the inflamed joints. We analyzed the phenotype and cytokine expression in circulating CD8
+ and CD4+ T cells in 69 subjects: 28 with cutaneous psoriasis, 15 patients with psoriatic arthritis, and 26 healthy subjects. In the circulation, the percentage of each subset was compared among the groups and correlation was calculated with the serum concentration of C-reactive protein. To investigate the migration of T cells towards the inflamed joints, we performed a transwell migration assay towards patient serum and synovial fluid. In selected patients we analyzed in parallel T cells from peripheral blood and from synovial fluid. In the circulation, we found increased percentage of CD8+ CCR6+ T cell effectors expressing CD69 and of IL-17-producing T cells in patients with psoriatic arthritis. CD8+ effector/effector memory T cells showed increased migration towards synovial fluid. Finally, in synovial fluid we found accumulation of CXCR3+ CD8+ T cells and CD69+ cells. CD4+ T cells in the two compartments shared many similarities with CD8+ T cells. The results indicate a role for memory T cell effectors in systemic and joint manifestations of psoriatic arthritis. [ABSTRACT FROM AUTHOR]- Published
- 2019
- Full Text
- View/download PDF
32. W1282 Infliximab Modulates Mucosal Cytokine Profile in Patients With Inflammatory Bowel Diseases.
- Author
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Caprioli, Flavio, Bosè, Francesca, Raeli, Lorenzo, Viganò, Chiara, Basilisco, Guido, Conte, Dario, Abrignani, Sergio, and Reali, Eva
- Published
- 2010
- Full Text
- View/download PDF
33. T cell responses in psoriasis and psoriatic arthritis.
- Author
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Diani, Marco, Altomare, Gianfranco, and Reali, Eva
- Subjects
- *
PSORIATIC arthritis , *T cells , *PSORIASIS , *INTERLEUKIN-21 , *CD8 antigen , *AUTOANTIGENS , *IMMUNOLOGY - Abstract
According to the current view the histological features of psoriasis arise as a consequence of the interplay between T cells, dendritic cells and keratinocytes giving rise to a self-perpetuating loop that amplifies and sustains inflammation in lesional skin. In particular, myeloid dendritic cell secretion of IL-23 and IL-12 activates IL-17-producing T cells, Th22 and Th1 cells, leading to the production of inflammatory cytokines such as IL-17, IFN-γ, TNF and IL-22. These cytokines mediate effects on keratinocytes thus establishing the inflammatory loop. Unlike psoriasis the immunopathogenic features of psoriatic arthritis are poorly characterized and there is a gap in the knowledge of the pathogenic link between inflammatory T cell responses arising in the skin and the development of joint inflammation. Here we review the knowledge accumulated over the years from the early evidence of autoreactive CD8 T cells that was studied mainly in the years 1990s and 2000s to the recent findings of the role of Th17, Tc17 cells and γδ T cells in psoriatic disease pathogenesis. The review will also focus on common and distinguishing features of T cell responses in psoriatic plaques and in synovial fluid of patients with psoriatic arthritis. The integration of this information could help to distinguish the role played by T cells in the initiation phase of the disease from the role of T cells as downstream effectors sustaining inflammation in psoriatic plaques and potentially leading to disease manifestation in distant joints. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
34. A role for CCR5+CD4 T cells in cutaneous psoriasis and for CD103+ CCR4+ CD8 Teff cells in the associated systemic inflammation.
- Author
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Sgambelluri, Francesco, Diani, Marco, Altomare, Andrea, Frigerio, Elena, Drago, Lorenzo, Granucci, Francesca, Banfi, Giuseppe, Altomare, Gianfranco, and Reali, Eva
- Subjects
- *
T cells , *PSORIASIS , *INFLAMMATION , *MOLECULES , *TISSUE wounds - Abstract
Recent results have identified critical components of the T cell response involved in the initiation and amplification phases of psoriasis. However the link between T cell responses arising in the skin and the systemic inflammation associated with severe psoriasis is largely unknown. We hypothesized that specific subsets of memory T cells recirculating from the skin could play a role. We therefore dissected the circulating memory T cell compartment in patients by analyzing the T CM , T EM and T eff phenotype, the pattern of CCR4 and CCR5 chemokine receptor expression and the expression of the tissue homing molecule CD103. For each subset we calculated the correlation with the Psoriasis Area and Severity Index (PASI) and with the extent of systemic inflammation measured as serum level of the prototypic short pentraxin, C reactive protein (CRP). Validation was performed by comparison with gene expression data in psoriatic plaques. We found that circulating CD103 + CCR4 + CCR5 + and CCR4 + CCR6 - CD8 + T eff cells, were highly correlated with CRP levels as well as with the validated index PASI, reflecting a link between skin involvement and systemic inflammation in patients with severe psoriasis. In addition we observed a contraction of circulating CCR5 + T cells in psoriasis patients, with a highly significant inverse correlation between CCR5 + CD4 T cells and the PASI score. Increased expression of CCR5 and CCL5 genes in psoriatic skin lesions was consistent with an accumulation of CCR5 + cells in psoriatic plaques indicating a role for CCR5/CCL5 axis in disease pathogenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
35. Dual role of anti-TNF therapy: Enhancement of TCR-mediated T cell activation in peripheral blood and inhibition of inflammation in target tissues
- Author
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Bosè, Francesca, Raeli, Lorenzo, Garutti, Cecilia, Frigerio, Elena, Cozzi, Alessandra, Crimi, Marco, Caprioli, Flavio, Scavelli, Rossana, Altomare, Gianfranco, Geginat, Jens, Abrignani, Sergio, and Reali, Eva
- Subjects
- *
TUMOR necrosis factors , *T cell receptors , *PERIPHERAL circulation , *INFLAMMATION , *CYTOKINES , *PSORIASIS , *INFLAMMATORY bowel diseases , *IMMUNOTHERAPY - Abstract
Abstract: The impact of anti-TNF therapy on systemic immune responses in patients has not been clearly defined. Here, we examined Th1/Th2/Th17 cytokine expression, activation and proliferation of peripheral T cells from patients with psoriasis and inflammatory bowel disease before and during anti-TNF therapy. In parallel, we calculated the correlation with the clinical response and we monitored cytokine expression in biopsies from inflamed tissues. We evidenced a dual role of TNF-blockade. In peripheral blood, it increased the expression of cytokines such as IL-17, IL-10, and IFN-γ, and enhanced the expression of activation markers and the proliferative response of CD4 T cells to TCR stimulation. By contrast, in biopsies from target tissues, TNF-blockade diminished the expression of Th17/Th1 cytokine and early inflammatory genes. Importantly, the enhanced T cell responses to TCR-stimulation did not impair the clinical response to the therapy and, in responder patients, occurred with the concomitant down-regulation of inflammatory genes in the target tissues. [Copyright &y& Elsevier]
- Published
- 2011
- Full Text
- View/download PDF
36. Priming with a very low dose of DNA complexed with cationic block copolymers followed by protein boost elicits broad and long-lasting antigen-specific humoral and cellular responses in mice
- Author
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Voltan, Rebecca, Castaldello, Arianna, Brocca-Cofano, Egidio, De Michele, Rita, Triulzi, Chiara, Altavilla, Giuseppe, Tondelli, Luisa, Laus, Michele, Sparnacci, Katia, Reali, Eva, Gavioli, Riccardo, Ensoli, Barbara, and Caputo, Antonella
- Subjects
- *
DRUG dosage , *DNA vaccines , *BLOCK copolymers , *PROTEINS , *ANTIGENS , *LABORATORY mice , *ENZYMES , *MEDICAL protocols , *T cells - Abstract
Abstract: Cationic block copolymers spontaneously assemble via electrostatic interactions with DNA molecules in aqueous solution giving rise to micellar structures that protect the DNA from enzymatic degradation both in vitro and in vivo. In addition, we have previously shown that they are safe, not immunogenic and greatly increased antigen-specific CTL responses following six intramuscular inoculations of a very low dose (1μg) of the vaccine DNA as compared to naked DNA. Nevertheless, they failed to elicit detectable humoral responses against the antigen. To gain further insight in the potential application of this technology, here we show that a shorter immunization protocol based on two DNA intramuscular inoculations of 1μg of DNA delivered by these copolymers and a protein boost elicits in mice broad (both humoral and cellular) and long-lasting responses and increases the antigen-specific Th1-type T cell responses and CTLs as compared to priming with naked DNA. These results indicate that cationic block copolymers represent a promising adjuvant and delivery technology for DNA vaccination strategies aimed at combating intracellular pathogens. [Copyright &y& Elsevier]
- Published
- 2009
- Full Text
- View/download PDF
37. CCR4 + CD8 + T cells clonally expand to differentiated effectors in murine psoriasis and in human psoriatic arthritis.
- Author
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Montico G, Mingozzi F, Casciano F, Protti G, Gornati L, Marzola E, Banfi G, Guerrini R, Secchiero P, Volinia S, Granucci F, and Reali E
- Subjects
- Humans, Mice, Animals, CD8-Positive T-Lymphocytes, Imiquimod, Mice, Inbred C57BL, Inflammation, Receptors, Antigen, T-Cell genetics, Receptors, CCR4, Arthritis, Psoriatic, Psoriasis, Skin Diseases
- Abstract
Psoriasis is a chronic inflammatory skin disease with an autoimmune component and associated with joint inflammation in up to 30% of cases. To investigate autoreactive T cells, we developed an imiquimod-induced psoriasis-like inflammation model in K5-mOVA.tg C57BL/6 mice expressing ovalbumin (OVA) on the keratinocyte membrane, adoptively transferred with OT-I OVA-specific CD8
+ T cells. We evaluated the expansion of OT-I CD8+ T cells and their localization in skin, blood, and spleen. scRNA-seq and TCR sequencing data from patients with psoriatic arthritis were also analyzed. In the imiquimod-treated K5-mOVA.tg mouse model, OT-I T cells were markedly expanded in the skin and blood at early time points. OT-I T cells in the skin showed mainly CXCR3+ effector memory phenotype, whereas in peripheral blood there was an expansion of CCR4+ CXCR3+ OT-I cells. At a later time point, expanded OVA-specific T-cell population was found in the spleen. In patients with psoriatic arthritis, scRNA-seq and TCR sequencing data showed clonal expansion of CCR4+ TCM cells in the circulation and further expansion in the synovial fluid. Importantly, there was a clonotype overlap between CCR4+ TCM in the peripheral blood and CD8+ T-cell effectors in the synovial fluid. This mechanism could play a role in the generation and spreading of autoreactive T cells to the synovioentheseal tissues in psoriasis patients at risk of developing psoriatic arthritis., (© 2023 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)- Published
- 2023
- Full Text
- View/download PDF
38. CCR4 + Skin-Tropic Phenotype as a Feature of Central Memory CD8 + T Cells in Healthy Subjects and Psoriasis Patients.
- Author
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Casciano F, Diani M, Altomare A, Granucci F, Secchiero P, Banfi G, and Reali E
- Subjects
- Adult, Cell Differentiation, Female, Humans, Immunologic Memory, Immunophenotyping, Male, Middle Aged, Oligosaccharides, Organ Specificity, Sialyl Lewis X Antigen analogs & derivatives, CD8-Positive T-Lymphocytes immunology, Psoriasis immunology, Receptors, CCR4 metabolism, Receptors, Lymphocyte Homing metabolism, Skin immunology
- Abstract
The chemokine receptor CCR4 has emerged as a skin-homing molecule important for the migration of T cells from the blood to the dermis. From our previous data on psoriasis patients, CCR4
+ memory T cells emerged as a putative recirculating population between skin and blood. Here we focused our attention on the expression of CCR4 and skin-tropic molecules in the different stages of memory T cell differentiation. We analyzed the chemokine receptor profile in CD8+ and CD4+ CD45RA- CCR7+ (TCM ) and CD45RA- CCR7- (TEM ) cells. Subpopulations were further divided on the basis of CD62L expression, and the distribution among the subsets of the skin-homing molecule CLA (Cutaneous Lymphocyte Antigen) was evaluated. The characterization was performed on peripheral blood mononuclear cells isolated from 21 healthy subjects and 24 psoriasis patients. The results indicate that (i) the skin-homing CCR4 marker is mainly expressed in TCM cells, (ii) CCR4+ TCM cells also express high level of CLA and that (iii) the more differentiated phenotype TEM expresses CXCR3 and CCR5 but lower level of CCR4 and CLA. This indicates that progressive stages of memory T cell differentiation have profoundly different chemokine receptor patterns, with CD8+ TCM displaying a marked skin-tropic phenotype CLA+ CCR4+ . Differential skin-tropic phenotype between TCM and TEM cells was observed in both healthy subjects and psoriasis patients. However, patients showed an expanded circulating population of CD8+ TCM cells with phenotype CCR4+ CXCR3+ that could play a role in the pathophysiology of psoriasis and possibly in disease recurrence., (Copyright © 2020 Casciano, Diani, Altomare, Granucci, Secchiero, Banfi and Reali.)- Published
- 2020
- Full Text
- View/download PDF
39. Reduction of CD68+ macrophages and decreased IL-17 expression in intestinal mucosa of patients with inflammatory bowel disease strongly correlate with endoscopic response and mucosal healing following infliximab therapy.
- Author
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Caprioli F, Bosè F, Rossi RL, Petti L, Viganò C, Ciafardini C, Raeli L, Basilisco G, Ferrero S, Pagani M, Conte D, Altomare G, Monteleone G, Abrignani S, and Reali E
- Subjects
- Adult, Antigens, CD genetics, Antigens, Differentiation, Myelomonocytic genetics, Apoptosis drug effects, Case-Control Studies, Cell Differentiation drug effects, Cell Proliferation drug effects, Colitis, Ulcerative immunology, Colitis, Ulcerative metabolism, Crohn Disease immunology, Crohn Disease metabolism, Down-Regulation, Endoscopy, Female, Gastrointestinal Agents adverse effects, Granulocyte-Macrophage Colony-Stimulating Factor genetics, Granulocyte-Macrophage Colony-Stimulating Factor metabolism, Humans, Infliximab, Interleukin-17 genetics, Intestinal Mucosa drug effects, Intestinal Mucosa metabolism, Macrophages drug effects, Macrophages metabolism, Male, Microscopy, Fluorescence, Middle Aged, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Tumor Necrosis Factor-alpha antagonists & inhibitors, Antibodies, Monoclonal adverse effects, Antigens, CD metabolism, Antigens, Differentiation, Myelomonocytic metabolism, Colitis, Ulcerative drug therapy, Crohn Disease drug therapy, Interleukin-17 metabolism, Intestinal Mucosa pathology, Macrophages pathology, Wound Healing
- Abstract
Background: Antibodies against tumor necrosis factor represent an effective therapy for patients with inflammatory bowel disease. Despite their successful results, the exact mechanism by which infliximab suppresses intestinal inflammation is still a matter of debate. In this study, we used a translational approach to identify the key mechanisms associated with resolution of mucosal inflammation induced by infliximab., Methods: A total of 16 patients with active inflammatory bowel disease (9 with Crohn's disease and 7 with ulcerative colitis) and 16 controls were enrolled in the study. Patients received infliximab infusions at 0, 2, and 6 weeks. At enrollment and at week 6, patients underwent flexible sigmoidoscopy, and biopsies were taken from the sigmoid colon. RNA was extracted, and mucosal expression of 96 immune-related genes was evaluated by qRT-PCR and confirmed by immunofluorescence microscopy on tissue. Correlation between infliximab-induced gene expression modulation and endoscopic response to therapy was calculated. Lamina propria mononuclear cell apoptosis induced by infliximab was evaluated on tissue sections by the terminal deoxynucleotidyl transferase dUTP nick end labeling assay., Results: We found that infliximab-induced downregulation of macrophage and Th17 pathway genes was significantly associated with both endoscopic response to the therapy and achievement of mucosal healing. Importantly, the observed reduction of lamina propria CD68 macrophages was associated with an increased rate of macrophage apoptosis., Conclusions: The 2 mechanisms associated with infliximab-induced resolution of intestinal inflammation are the reduction of lamina propria infiltrating CD68 macrophages and the downregulation of interleukin 17A. Moreover, the data suggest that infliximab-induced macrophage apoptosis may represent a key mechanism for the therapeutic success of anti-tumor necrosis factor antibodies.
- Published
- 2013
- Full Text
- View/download PDF
40. Defective erythroid maturation in gelsolin mutant mice.
- Author
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Cantù C, Bosè F, Bianchi P, Reali E, Colzani MT, Cantù I, Barbarani G, Ottolenghi S, Witke W, Spinardi L, and Ronchi AE
- Subjects
- Actins antagonists & inhibitors, Actins metabolism, Anemia chemically induced, Animals, Biomarkers metabolism, Cell Differentiation drug effects, Cytochalasin D pharmacology, Depsipeptides pharmacology, Embryo, Mammalian, Embryonic Stem Cells drug effects, Embryonic Stem Cells metabolism, Erythrocytes drug effects, Erythrocytes metabolism, Fetus, Gelsolin deficiency, Gene Expression Regulation, Developmental drug effects, Liver drug effects, Liver metabolism, Mice, Mice, Inbred BALB C, Mice, Knockout, Phenylhydrazines toxicity, Embryonic Stem Cells pathology, Erythrocytes pathology, Erythropoiesis genetics, Gelsolin genetics, Liver pathology
- Abstract
Background: During late differentiation, erythroid cells undergo profound changes involving actin filament remodeling. One of the proteins controlling actin dynamics is gelsolin, a calcium-activated actin filament severing and capping protein. Gelsolin-null (Gsn(-/-)) mice generated in a C57BL/6 background are viable and fertile.1, Design and Methods: We analyzed the functional roles of gelsolin in erythropoiesis by: (i) evaluating gelsolin expression in murine fetal liver cells at different stages of erythroid differentiation (using reverse transcription polymerase chain reaction analysis and immunohistochemistry), and (ii) characterizing embryonic and adult erythropoiesis in Gsn(-/-) BALB/c mice (morphology and erythroid cultures)., Results: In the context of a BALB/c background, the Gsn(-/-) mutation causes embryonic death. Gsn(-/-) embryos show defective erythroid maturation with persistence of circulating nucleated cells. The few Gsn(-/-) mice reaching adulthood fail to recover from phenylhydrazine-induced acute anemia, revealing an impaired response to stress erythropoiesis. In in vitro differentiation assays, E13.5 fetal liver Gsn(-/-) cells failed to undergo terminal maturation, a defect partially rescued by Cytochalasin D, and mimicked by administration of Jasplakinolide to the wild-type control samples., Conclusions: In BALB/c mice, gelsolin deficiency alters the equilibrium between erythrocyte actin polymerization and depolymerization, causing impaired terminal maturation. We suggest a non-redundant role for gelsolin in terminal erythroid differentiation, possibly contributing to the Gsn(-/-) mice lethality observed in mid-gestation.
- Published
- 2012
- Full Text
- View/download PDF
41. Melanocortin peptides inhibit urate crystal-induced activation of phagocytic cells.
- Author
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Capsoni F, Ongari AM, Reali E, and Catania A
- Subjects
- Crystallization, Cytokines biosynthesis, Gout metabolism, Humans, Melanocortins metabolism, Monocytes metabolism, Neutrophils metabolism, Uric Acid metabolism, Gout immunology, Melanocortins immunology, Monocytes immunology, Neutrophil Activation immunology, Neutrophils immunology, Uric Acid immunology
- Abstract
Introduction: The melanocortin peptides have marked anti-inflammatory potential, primarily through inhibition of proinflammatory cytokine production and action on phagocytic cell functions. Gout is an acute form of arthritis caused by the deposition of urate crystals, in which phagocytic cells and cytokines play a major pathogenic role. We examined whether alpha-melanocyte-stimulating hormone (alpha-MSH) and its synthetic derivative (CKPV)2 influence urate crystal-induced monocyte (Mo) activation and neutrophil responses in vitro., Methods: Purified Mos were stimulated with monosodium urate (MSU) crystals in the presence or absence of melanocortin peptides. The supernatants were tested for their ability to induce neutrophil activation in terms of chemotaxis, production of reactive oxygen intermediates (ROIs), and membrane expression of CD11b, Toll-like receptor-2 (TLR2) and TLR4. The proinflammatory cytokines interleukin (IL)-1beta, IL-8, and tumor necrosis factor-alpha (TNF-alpha) and caspase-1 were determined in the cell-free supernatants. In parallel experiments, purified neutrophils were preincubated overnight with or without melanocortin peptides before the functional assays., Results: The supernatants from MSU crystal-stimulated Mos exerted chemoattractant and priming activity on neutrophils, estimated as ROI production and CD11b membrane expression. The supernatants of Mos stimulated with MSU in the presence of melanocortin peptides had less chemoattractant activity for neutrophils and less ability to prime neutrophils for CD11b membrane expression and oxidative burst. MSU crystal-stimulated Mos produced significant levels of IL-1beta, IL-8, TNF-alpha, and caspase-1. The concentrations of proinflammatory cytokines, but not of caspase-1, were reduced in the supernatants from Mos stimulated by MSU crystals in the presence of melanocortin peptides. Overnight incubation of neutrophils with the peptides significantly inhibited their ability to migrate toward chemotactic supernatants and their capacity to be primed in terms of ROI production., Conclusions: Alpha-MSH and (CKPV)2 have a dual effect on MSU crystal-induced inflammation, inhibiting the Mos' ability to produce neutrophil chemoattractants and activating compounds and preventing the neutrophil responses to these proinflammatory substances. These findings reinforce previous observations on the potential role of alpha-MSH and related peptides as a new class of drugs for treatment of inflammatory arthritis.
- Published
- 2009
- Full Text
- View/download PDF
42. Targeted delivery of murine IFN-gamma using a recombinant fowlpox virus: NK cell recruitment to regional lymph nodes and priming of tumor-specific host immunity.
- Author
-
Zeytin H, Reali E, Zaharoff DA, Rogers CJ, Schlom J, and Greiner JW
- Subjects
- Animals, Cancer Vaccines administration & dosage, Cell Line, Tumor, Cell Movement, Cytotoxicity, Immunologic, DNA, Recombinant administration & dosage, Female, Genetic Vectors, Immunologic Factors administration & dosage, Injections, Interferon-gamma biosynthesis, Interferon-gamma blood, Mice, Mice, Inbred C57BL, Neoplasms, Experimental immunology, Neoplasms, Experimental prevention & control, Recombinant Proteins administration & dosage, T-Lymphocytes, Cytotoxic immunology, Cancer Vaccines immunology, Fowlpox virus genetics, Immunologic Factors genetics, Interferon-gamma genetics, Killer Cells, Natural immunology, Lymph Nodes immunology
- Abstract
Interferon-gamma (IFN-gamma) is a proinflammatory cytokine that also acts as a potent immunomodulatory agent. In this study, a replication-deficient recombinant avian (fowlpox) virus was engineered to express the murine IFN-gamma gene (rF-MuIFN-gamma) with the rationale of delivering concentrated levels of the cytokine to a local tissue microenvironment. Subcutaneous (s.c.) rF-MuIFN-gamma administration resulted in IFN-gamma production that (1) was restricted to the tissue microenvironment of the injection site and (2) was biologically active, as evidenced by a significant increase of class I MHC expression levels in s.c. growing tumors following rF-MuIFN-gamma administration. Infection of a highly tumorigenic murine cell line, MC38, with rF-MuIFN-gamma functioned as an effective tumor cell-based vaccine by protecting mice from the formation of primary tumors and from subsequent tumor challenge. The cell-based vaccine was completely ineffective if mice were vaccinated with MC38 cells either pretreated with rIFN-gamma or infected with the wild-type fowlpox virus (FP-WT). Analysis of the regional lymph nodes draining the site of injection of the rF-MuIFN-gamma-based tumor cell vaccine revealed the presence of tumor-specific cell lysis (CTL) as well as a significant amount of lysis directed at natural killer (NK)-sensitive YAC-1 cells. Flow cytometric analyses coupled with functional assays confirmed the sustained presence of NK1.1(+) cells within those draining lymph nodes for up to 5 days after rF-MuIFN-gamma injection. Mice treated with NK cell-depleting antibodies prior to the injection of the rF-MuIFN-gamma-infected MC38 tumor cells were not protected from primary tumor growth; analysis of the lymph nodes draining the injection site in NK-depleted mice revealed an accompanying loss of the tumor-specific CTL activity. The findings provide evidence that NK cells, known for their contributions to host innate immunity, also provide immunoregulatory signals required for the development of an adaptive immune response, which, in turn, protected vaccinated mice against tumor growth.
- Published
- 2008
- Full Text
- View/download PDF
43. Identification of an interferon-gamma-inducible carcinoembryonic antigen (CEA) CD8(+) T-cell epitope, which mediates tumor killing in CEA transgenic mice.
- Author
-
Schmitz J, Reali E, Hodge JW, Patel A, Davis G, Schlom J, and Greiner JW
- Subjects
- Adenocarcinoma therapy, Animals, Cytotoxicity, Immunologic immunology, Humans, Interferon-gamma immunology, Mice, Mice, Transgenic, Neoplasms, Experimental therapy, Adenocarcinoma immunology, Carcinoembryonic Antigen immunology, Epitopes, T-Lymphocyte immunology, Immunotherapy, Adoptive methods, Interferon-gamma pharmacology, Neoplasms, Experimental immunology, T-Lymphocytes, Cytotoxic immunology
- Abstract
This study describes a CD8(+) T-cell line specific for a MHC class I-restricted carcinoembryonic antigen (CEA) epitope, residues 526-533, isolated from CEA transgenic (CEA.Tg) mice immunized with a recombinant vaccinia-CEA vaccine. Incubation of splenocytes from the immune CEA.Tg mice with the CEA(526-533) peptide resulted in the outgrowth of low-avidity CD8(+) T cells, which produced IFN-gamma and mediated perforin-dependent tumor cell lysis. However, the CEA peptide-specific T cells killed CEA-expressing murine colorectal tumor cells only after pretreatment of the targets with murine IFN-gamma (muIFN-gamma), and lysis was H-2D(b)-restricted and involved the Fas-FasL-mediated cytotoxic pathway. When the CEA peptide-specific T cells were used as in vivo effectors in adoptive T-cell transfer studies, muIFN-gamma treatment of the CEA.Tg mice was again required for T-cell-dependent growth suppression of CEA-expressing metastatic tumors. The results indicate that (a) vaccination of mice carrying the human CEA gene with recombinant vaccinia-CEA generates a CEA epitope-specific, CD8-dependent CTL response, (b) CEA, a normal, tissue-specific antigen, can also serve as a target for antitumor immunity after the adoptive transfer of CEA peptide-specific T cells, and (c) muIFN-gamma might be an effective cancer vaccine adjuvant by virtue of its ability to augment the susceptibility of tumor targets to cell-mediated lysis.
- Published
- 2002
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