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1
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Gonnin C, Leemans M, Canoui-Poitrine F, Lebraud M, Corneau A, Roquebert L, Caillet P, Gay P, Canovas J, Histe A, Blanc C, El-Sissy C, Larbi A, Poisson J, Ober P, Boudou-Rouquette P, Natella PA, Vallet H, Saadaoui B, Layese R, Tartour E, Paillaud E, Granier C. CD57 + EMRA CD8 + T cells in cancer patients over 70: associations with prior chemotherapy and response to anti-PD-1/PD-L1 therapy. Immun Ageing 2024; 21:89. [PMID: 39731117 DOI: 10.1186/s12979-024-00487-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 11/12/2024] [Indexed: 12/29/2024]
Abstract
BACKGROUND Immune ageing complicates cancer treatment in older individuals. While immunotherapy targeting the PD-1/PD-L1 pathway can reinvigorate T cells, these cells tend to become senescent with age. This study investigates different CD8+ T cell subsets usually associated with senescence, in cancer patients over 70 years old who are undergoing anti-PD-1/PD-L1 immunotherapy, and examines the relationship between these senescent cells and prior chemotherapy exposure. We analyzed data from the Elderly Cancer Patient (ELCAPA) cohort, which included 35 patients enrolled between March 2018 and March 2021. RESULTS Flow cytometry and unsupervised analysis were employed to characterize Effector Memory CD45RA+ (EMRA) and CD8+ T cell senescence at baseline, before initiating PD-1/PD-L1 therapy. EMRA cells were found to overexpress CD57 and KLRG1 compared to overall CD8+ T cells. Chemotherapy prior to anti-PD-1/PD-L1 was associated with an increased proportion of CD57+ EMRA CD8+ T cells (p = 0.009) and its granzyme B (GRZB) subset (p = 0.007). Using a 10% cut-off to define positivity, the six-month non-response tends to be associated with the CD57+ GRZB+ EMRA positivity (p = 0.097). Other CD8+ T cell subsets (EMRA, CD57+, or KLRG1+), usually associated with senescence, showed no significant association with previous chemotherapy or response to anti-PD-1/anti-PD-L1 therapy. CONCLUSIONS These findings underscore the impact of prior chemotherapy on expanding the pool of senescent T cells, particularly CD57+ EMRA CD8+ T and CD57+ GRZB+ EMRA CD8+ T cells, whose expansion could potentially affect the effectiveness of anti-PD-1/PD-L1 immunotherapy in elderly patients. This highlights the need for tailored approaches in this population.
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Affiliation(s)
- Cécile Gonnin
- Université Paris Cité, INSERM, PARCC, Paris, France
- Department of Immunology, APHP, Hôpital Européen Georges Pompidou (HEGP), Paris, France
| | - Michelle Leemans
- Université Paris-Est Créteil, INSERM, IMRB, Créteil, F-94010, France
| | - Florence Canoui-Poitrine
- Université Paris-Est Créteil, INSERM, IMRB, Créteil, F-94010, France
- AP-HP, Hopital Henri-Mondor, Public Health Department and Clinical Research Unit (URC Mondor), Créteil, F-94010, France
| | - Morgane Lebraud
- Department of Immunology, APHP, Hôpital Européen Georges Pompidou (HEGP), Paris, France
| | - Aurélien Corneau
- Sorbonne Université, Centre de recherche de Saint Antoine, CISA, Paris, F-75012, France
| | - Louise Roquebert
- Department of Immunology, APHP, Hôpital Européen Georges Pompidou (HEGP), Paris, France
| | - Philippe Caillet
- Department of Geriatric Medicine, Hôpital Europeen Georges Pompidou, AP-HP, Paris, France
| | - Pierre Gay
- Department of Geriatric Medicine, Hôpital Europeen Georges Pompidou, AP-HP, Paris, France
| | - Johanna Canovas
- Department of Geriatric Medicine, Hôpital Europeen Georges Pompidou, AP-HP, Paris, France
| | - Axelle Histe
- Université Paris-Est Créteil, INSERM, IMRB, Créteil, F-94010, France
- AP-HP, Hopital Henri-Mondor, Public Health Department and Clinical Research Unit (URC Mondor), Créteil, F-94010, France
| | - Catherine Blanc
- Plateforme de Cytométrie de la Pitié-Salpêtrière (CyPS) in Paris, Paris, France
| | - Carine El-Sissy
- Department of Immunology, APHP, Hôpital Européen Georges Pompidou (HEGP), Paris, France
- INSERM, Laboratory of Integrative Cancer Immunology, Paris, France
- Cordeliers Research Center, Sorbonne University, University Paris Cité, Paris, France
| | - Anis Larbi
- Medical and Scientific Affairs, Beckman Coulter Life Sciences, Paris, France
- Department of Medicine, Division of Geriatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Johanne Poisson
- Université Paris Cité, Department of Geriatrics, European Georges Pompidou Hospital, Paris Cancer Institute CARPEM, Assistance-Publique Hôpitaux de Paris (AP-HP), Paris, F-75015, France
- Université Paris-Cité, INSERM, Centre de recherche sur l'inflammation, UMR 1149, Paris, F-75018, France
| | - Pauline Ober
- Department of Immunology, APHP, Hôpital Européen Georges Pompidou (HEGP), Paris, France
| | - Pascaline Boudou-Rouquette
- Department of medical Oncology, Ariane program, Cochin hospital, Paris Cancer Institute CARPEM, Assistance-Publique Hôpitaux de Paris (AP-HP), Paris, F-75014, France
| | - Pierre-André Natella
- AP-HP, Hopital Henri-Mondor, Hopital Henri-Mondor, Public Health Department and Clinical Research Unit (URC Mondor), Créteil, F-94010, France
| | - Hélène Vallet
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), UMRS 1135, Centre d'immunologie et de Maladies Infectieuses (CIMI), Paris, France
- Department of Geriatrics, Saint Antoine hospital, Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France
| | - Besma Saadaoui
- Department of Geriatric Medicine, Hôpital Europeen Georges Pompidou, AP-HP, Paris, France
| | - Richard Layese
- Université Paris-Est Créteil, INSERM, IMRB, Créteil, F-94010, France
- AP-HP, Hopital Henri-Mondor, Public Health Department and Clinical Research Unit (URC Mondor), Créteil, F-94010, France
| | - Eric Tartour
- Université Paris Cité, INSERM, PARCC, Paris, France
- Department of Immunology, APHP, Hôpital Européen Georges Pompidou (HEGP), Paris, France
| | - Elena Paillaud
- Department of Geriatric Medicine, Hôpital Europeen Georges Pompidou, AP-HP, Paris, France.
- Université de Paris Cité, Paris, France.
- Univ. Paris Est Créteil, Inserm U955, IMRB, Créteil, France.
| | - Clémence Granier
- Université Paris Cité, INSERM, PARCC, Paris, France.
- Department of Immunology, APHP, Hôpital Européen Georges Pompidou (HEGP), Paris, France.
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Hanna SJ, Thayer TC, Robinson EJS, Vinh NN, Williams N, Landry LG, Andrews R, Siah QZ, Leete P, Wyatt R, McAteer MA, Nakayama M, Wong FS, Yang JHM, Tree TIM, Ludvigsson J, Dayan CM, Tatovic D. Single-cell RNAseq identifies clonally expanded antigen-specific T-cells following intradermal injection of gold nanoparticles loaded with diabetes autoantigen in humans. Front Immunol 2023; 14:1276255. [PMID: 37908349 PMCID: PMC10613693 DOI: 10.3389/fimmu.2023.1276255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 10/02/2023] [Indexed: 11/02/2023] Open
Abstract
Gold nanoparticles (GNPs) have been used in the development of novel therapies as a way of delivery of both stimulatory and tolerogenic peptide cargoes. Here we report that intradermal injection of GNPs loaded with the proinsulin peptide C19-A3, in patients with type 1 diabetes, results in recruitment and retention of immune cells in the skin. These include large numbers of clonally expanded T-cells sharing the same paired T-cell receptors (TCRs) with activated phenotypes, half of which, when the TCRs were re-expressed in a cell-based system, were confirmed to be specific for either GNP or proinsulin. All the identified gold-specific clones were CD8+, whilst proinsulin-specific clones were both CD8+ and CD4+. Proinsulin-specific CD8+ clones had a distinctive cytotoxic phenotype with overexpression of granulysin (GNLY) and KIR receptors. Clonally expanded antigen-specific T cells remained in situ for months to years, with a spectrum of tissue resident memory and effector memory phenotypes. As the T-cell response is divided between targeting the gold core and the antigenic cargo, this offers a route to improving resident memory T-cells formation in response to vaccines. In addition, our scRNAseq data indicate that focusing on clonally expanded skin infiltrating T-cells recruited to intradermally injected antigen is a highly efficient method to enrich and identify antigen-specific cells. This approach has the potential to be used to monitor the intradermal delivery of antigens and nanoparticles for immune modulation in humans.
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Affiliation(s)
- Stephanie J. Hanna
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom
| | - Terri C. Thayer
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom
- Department of Biological and Chemical Sciences, Roberts Wesleyan University, Rochester, NY, United States
| | - Emma J. S. Robinson
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom
| | - Ngoc-Nga Vinh
- Division of Psychological Medicine and Clinical Neurosciences, Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom
| | - Nigel Williams
- Division of Psychological Medicine and Clinical Neurosciences, Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom
| | - Laurie G. Landry
- Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver, CO, United States
| | - Robert Andrews
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom
| | - Qi Zhuang Siah
- John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford, United Kingdom
| | - Pia Leete
- Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, United Kingdom
| | - Rebecca Wyatt
- Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, United Kingdom
| | | | - Maki Nakayama
- Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver, CO, United States
| | - F. Susan Wong
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom
| | - Jennie H. M. Yang
- Department of Immunobiology, School of Immunology & Microbial Sciences, King’s College London, Guy’s Hospital, London, United Kingdom
| | - Timothy I. M. Tree
- Department of Immunobiology, School of Immunology & Microbial Sciences, King’s College London, Guy’s Hospital, London, United Kingdom
| | - Johnny Ludvigsson
- Division of Pediatrics, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences and Crown Princess Victoria Children´s Hospital, Linköping University, Linköping, Sweden
| | - Colin M. Dayan
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom
| | - Danijela Tatovic
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom
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3
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La Manna MP, Shekarkar Azgomi M, Tamburini B, Badami GD, Mohammadnezhad L, Dieli F, Caccamo N. Phenotypic and Immunometabolic Aspects on Stem Cell Memory and Resident Memory CD8+ T Cells. Front Immunol 2022; 13:884148. [PMID: 35784300 PMCID: PMC9247337 DOI: 10.3389/fimmu.2022.884148] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 05/19/2022] [Indexed: 11/13/2022] Open
Abstract
The immune system, smartly and surprisingly, saves the exposure of a particular pathogen in its memory and reacts to the pathogen very rapidly, preventing serious diseases.Immunologists have long been fascinated by understanding the ability to recall and respond faster and more vigorously to a pathogen, known as “memory”.T-cell populations can be better described by using more sophisticated techniques to define phenotype, transcriptional and epigenetic signatures and metabolic pathways (single-cell resolution), which uncovered the heterogeneity of the memory T-compartment. Phenotype, effector functions, maintenance, and metabolic pathways help identify these different subsets. Here, we examine recent developments in the characterization of the heterogeneity of the memory T cell compartment. In particular, we focus on the emerging role of CD8+ TRM and TSCM cells, providing evidence on how their immunometabolism or modulation can play a vital role in their generation and maintenance in chronic conditions such as infections or autoimmune diseases.
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Affiliation(s)
- Marco Pio La Manna
- Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR) Azienda Ospedaliera Universitaria Policlinico (A.O.U.P.) Paolo Giaccone, University of Palermo, Palermo, Italy
- Department of Biomedicine, Neurosciences and Advanced Diagnostic (Bi.N.D.), University of Palermo, Palermo, Italy
| | - Mojtaba Shekarkar Azgomi
- Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR) Azienda Ospedaliera Universitaria Policlinico (A.O.U.P.) Paolo Giaccone, University of Palermo, Palermo, Italy
- Department of Biomedicine, Neurosciences and Advanced Diagnostic (Bi.N.D.), University of Palermo, Palermo, Italy
| | - Bartolo Tamburini
- Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR) Azienda Ospedaliera Universitaria Policlinico (A.O.U.P.) Paolo Giaccone, University of Palermo, Palermo, Italy
- Department of Biomedicine, Neurosciences and Advanced Diagnostic (Bi.N.D.), University of Palermo, Palermo, Italy
| | - Giusto Davide Badami
- Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR) Azienda Ospedaliera Universitaria Policlinico (A.O.U.P.) Paolo Giaccone, University of Palermo, Palermo, Italy
- Department of Biomedicine, Neurosciences and Advanced Diagnostic (Bi.N.D.), University of Palermo, Palermo, Italy
| | - Leila Mohammadnezhad
- Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR) Azienda Ospedaliera Universitaria Policlinico (A.O.U.P.) Paolo Giaccone, University of Palermo, Palermo, Italy
- Department of Biomedicine, Neurosciences and Advanced Diagnostic (Bi.N.D.), University of Palermo, Palermo, Italy
| | - Francesco Dieli
- Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR) Azienda Ospedaliera Universitaria Policlinico (A.O.U.P.) Paolo Giaccone, University of Palermo, Palermo, Italy
- Department of Biomedicine, Neurosciences and Advanced Diagnostic (Bi.N.D.), University of Palermo, Palermo, Italy
| | - Nadia Caccamo
- Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR) Azienda Ospedaliera Universitaria Policlinico (A.O.U.P.) Paolo Giaccone, University of Palermo, Palermo, Italy
- Department of Biomedicine, Neurosciences and Advanced Diagnostic (Bi.N.D.), University of Palermo, Palermo, Italy
- *Correspondence: Nadia Caccamo,
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4
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Presence of Skin Tissue-Resident Memory T Cells in Human Nonmalignant and Premalignant Melanocytic Skin Lesions and in Melanoma. Am J Dermatopathol 2022; 44:416-423. [PMID: 35311751 DOI: 10.1097/dad.0000000000002184] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
ABSTRACT The infiltration of tissue-resident memory (TRM) cells in melanoma correlates with improved survival, suggesting an important role for TRM cells in immunity against melanoma. However, little is known about the presence of TRM cells in nonmalignant and premalignant melanocytic lesions. This study aimed to evaluate the presence of TRM cells in human skin melanocytic lesions, representing the spectrum from healthy skin to metastatic melanoma. FFPE sections from healthy skin, sun-exposed skin, benign nevi, lentigo maligna (LM), primary LM melanoma, and primary cutaneous and metastatic melanoma were analyzed by immunohistochemistry. The number of infiltrating cells expressing TRM-associated markers, CD3, CD4, CD8, CD69, CD103, and CD49a, was quantified by digital analyses. Multiplex immunofluorescence was performed to analyze coexpression of TRM cell markers. More T cells and CD69+ cells were found in melanoma lesions, as compared with healthy skin and nevi. CD103+ and CD49a+ cell numbers did not significantly differ. More importantly, no differences were seen in expression of all markers between healthy skin and benign nevi. Similar results, except for CD69, were observed in LM melanoma, as compared with LM and sun-exposed skin. Interestingly, multiplex immunofluorescence showed that nevi tissues have comparable CD103+ T cell numbers with healthy skin but comprise more CD103+ CD8+ cells. Expression of TRM cell markers is significantly increased in melanoma, as compared with nonmalignant skin. Our data also show that TRM cells are not abundantly present already in premalignant tissues. Further studies on the specificity of TRM cells for melanocyte/melanoma antigens may reveal their significance in cancer immunosurveillance.
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5
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Levin MJ, Weinberg A. Immune Responses to Varicella-Zoster Virus Vaccines. Curr Top Microbiol Immunol 2022; 438:223-246. [PMID: 35102438 DOI: 10.1007/82_2021_245] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
The live attenuated varicella vaccine is intended to mimic the tempo and nature of the humoral and cell-mediated immune responses to varicella infection. To date, two doses of varicella vaccine administered in childhood have been very effective in generating varicella-zoster virus (VZV) immune responses that prevent natural infection for at least several decades. After primary infection, the infecting VZV establishes latency in sensory and cranial nerve ganglia with the potential to reactivate and cause herpes zoster. Although, the immune responses developed during varicella are important for preventing herpes zoster they wane with increasing age (immune senescence) or with the advent of immune suppression. Protection can be restored by increasing cell-mediated immune responses with two doses of an adjuvanted recombinant VZV glycoprotein E vaccine that stimulates both VZV-and gE-specific immunity. This vaccine provides ~85-90% protection against herpes zoster for 7-8 years (to date).
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Affiliation(s)
- Myron J Levin
- Departments of Pediatrics and Medicine, University of Colorado Denver School of Medicine, Anschutz Medical Campus, Aurora, CO, USA
| | - Adriana Weinberg
- Departments of Pediatrics, Medicine, and Pathology, University of Colorado Denver School of Medicine, Anschutz Medical Campus, Aurora, CO, USA.
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Faraj S, Kemp EH, Gawkrodger DJ. Patho-immunological mechanisms of vitiligo: the role of the innate and adaptive immunities and environmental stress factors. Clin Exp Immunol 2022; 207:27-43. [PMID: 35020865 PMCID: PMC8802175 DOI: 10.1093/cei/uxab002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 10/04/2021] [Accepted: 10/15/2021] [Indexed: 12/17/2022] Open
Abstract
Epidermal melanocyte loss in vitiligo, triggered by stresses ranging from trauma to emotional stress, chemical exposure or metabolite imbalance, to the unknown, can stimulate oxidative stress in pigment cells, which secrete damage-associated molecular patterns that then initiate innate immune responses. Antigen presentation to melanocytes leads to stimulation of autoreactive T-cell responses, with further targeting of pigment cells. Studies show a pathogenic basis for cellular stress, innate immune responses and adaptive immunity in vitiligo. Improved understanding of the aetiological mechanisms in vitiligo has already resulted in successful use of the Jak inhibitors in vitiligo. In this review, we outline the current understanding of the pathological mechanisms in vitiligo and locate loci to which therapeutic attack might be directed.
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Affiliation(s)
- Safa Faraj
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
| | | | - David John Gawkrodger
- Department of Infection, Immunology and Cardiovascular Disease, University of Sheffield, Sheffield, UK
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7
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Wu Y, Wang GJ, He HQ, Qin HH, Shen WT, Yu Y, Zhang X, Zhou ML, Fei JB. Low-dose intralesional injection of 5-fluorouracil and triamcinolone reduces tissue resident memory T cells in chronic eczema. World J Clin Cases 2022; 10:166-176. [PMID: 35071516 PMCID: PMC8727240 DOI: 10.12998/wjcc.v10.i1.166] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 10/29/2021] [Accepted: 11/28/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Tissue resident memory T (TRM) cells have been reported to play a significant role in the pathogenesis and relapse of chronic eczema.
AIM To compare the efficacy and safety of the intralesional injection of 5-fluorouracil (5-FU) and triamcinolone (TA) with those associated with TA alone for the treatment of chronic eczema.
METHODS A total of 168 patients were randomized to 5-FU+TA or TA groups and received a one-time intralesional injection of 5-FU+TA or TA only. Biopsies were collected before and 2 wk after treatment for evaluation of histopathological changes. All patients were followed up monthly for up to 1 year.
RESULTS No serious adverse event was observed in either group. Although the mean atopic dermatitis severity index scores and effective rates were comparable between the two groups after 2 wk of treatment, the relapse rate was significantly lower in the 5-FU+TA group than in the TA group. Histological examination showed significantly fewer CD8+ and CD103+ T cells but not CD4+ T cells in the 5-FU+TA group.
CONCLUSION One-time intralesional injection of 5-FU+TA is effective and safe for chronic eczema treatment and can further reduce the retention of TRM cells in the lesional skin and the relapse rate of chronic eczema.
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Affiliation(s)
- Yun Wu
- Department of Dermatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China
| | - Guo-Jiang Wang
- Department of Dermatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China
| | - Hui-Qiong He
- Department of Dermatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China
| | - Hai-Hong Qin
- Department of Dermatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China
| | - Wen-Tong Shen
- Department of Dermatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China
| | - Yue Yu
- Department of Dermatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China
| | - Xun Zhang
- Department of Dermatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China
| | - Mao-Lin Zhou
- Department of Dermatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China
| | - Jian-Biao Fei
- Department of Dermatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China
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Branisteanu D, Cojocaru C, Diaconu R, Porumb E, Alexa A, Nicolescu A, Brihan I, Bogdanici C, Branisteanu G, Dimitriu A, Zemba M, Anton N, Toader M, Grechin A, Branisteanu D. Update on the etiopathogenesis of psoriasis (Review). Exp Ther Med 2022; 23:201. [PMID: 35126704 PMCID: PMC8794554 DOI: 10.3892/etm.2022.11124] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 11/22/2021] [Indexed: 11/05/2022] Open
Affiliation(s)
- Daciana Branisteanu
- Department of Dermatology, ‘Grigore T. Popa’ University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Catalina Cojocaru
- Department of Dermatology, Railway Clinical Hospital, 700506 Iasi, Romania
| | - Roxana Diaconu
- Department of Dermatology, Railway Clinical Hospital, 700506 Iasi, Romania
| | - Elena Porumb
- Department of Dermatology, ‘Sf. Spiridon’ Clinical Emergency County Hospital, 700111 Iasi, Romania
| | - Anisia Alexa
- Department of Ophthalmology, ‘Grigore T. Popa’ University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Alin Nicolescu
- Department of Dermatology, ‘Roma’ Medical Center for Diagnosis and Treatment, 011773 Bucharest, Romania
| | - Ilarie Brihan
- Department of Dermatology, Dermatology Clinic, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
| | - Camelia Bogdanici
- Department of Ophthalmology, ‘Grigore T. Popa’ University of Medicine and Pharmacy, 700115 Iași, Romania
| | - George Branisteanu
- Faculty of Medicine, ‘Grigore T. Popa’ University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Andreea Dimitriu
- Department of Dermatology, ‘Arcadia’ Hospitals and Medical Centers, 700620 Iasi, Romania
| | - Mihail Zemba
- Department of Ophthalmology, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Nicoleta Anton
- Department of Ophthalmology, ‘Grigore T. Popa’ University of Medicine and Pharmacy, 700115 Iași, Romania
| | - Mihaela Toader
- Department of Oral Dermatology, ‘Grigore T. Popa’ University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Adrian Grechin
- Department of Ophthalmology, ‘Sf. Spiridon’ Clinical Emergency County Hospital, 700111 Iasi, Romania
| | - Daniel Branisteanu
- Department of Ophthalmology, ‘Grigore T. Popa’ University of Medicine and Pharmacy, 700115 Iași, Romania
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Kok L, Masopust D, Schumacher TN. The precursors of CD8 + tissue resident memory T cells: from lymphoid organs to infected tissues. Nat Rev Immunol 2022; 22:283-293. [PMID: 34480118 PMCID: PMC8415193 DOI: 10.1038/s41577-021-00590-3] [Citation(s) in RCA: 118] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/05/2021] [Indexed: 02/08/2023]
Abstract
CD8+ tissue resident memory T cells (TRM cells) are essential for immune defence against pathogens and malignancies, and the molecular processes that lead to TRM cell formation are therefore of substantial biomedical interest. Prior work has demonstrated that signals present in the inflamed tissue micro-environment can promote the differentiation of memory precursor cells into mature TRM cells, and it was therefore long assumed that TRM cell formation adheres to a 'local divergence' model, in which TRM cell lineage decisions are exclusively made within the tissue. However, a growing body of work provides evidence for a 'systemic divergence' model, in which circulating T cells already become preconditioned to preferentially give rise to the TRM cell lineage, resulting in the generation of a pool of TRM cell-poised T cells within the lymphoid compartment. Here, we review the emerging evidence that supports the existence of such a population of circulating TRM cell progenitors, discuss current insights into their formation and highlight open questions in the field.
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Affiliation(s)
- Lianne Kok
- grid.430814.a0000 0001 0674 1393Division of Molecular Oncology & Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - David Masopust
- grid.17635.360000000419368657Department of Microbiology and Immunology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN USA
| | - Ton N. Schumacher
- grid.430814.a0000 0001 0674 1393Division of Molecular Oncology & Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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10
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Willemsen M, Krebbers G, Tjin EPM, Willemsen KJ, Louis A, Konijn VAL, Narayan VS, Post NF, Bakker WJ, Melief CJM, Bekkenk MW, Luiten RM. IFN-γ-induced PD-L1 expression on human melanocytes is impaired in vitiligo. Exp Dermatol 2021; 31:556-566. [PMID: 34758170 DOI: 10.1111/exd.14500] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 10/17/2021] [Accepted: 11/08/2021] [Indexed: 12/16/2022]
Abstract
Mounting evidence shows that the PD-1/PD-L1 axis is involved in tumor immune evasion. This is demonstrated by anti-PD-1 antibodies that can reverse tumor-associated PD-L1 to functionally suppress anti-tumor T-cell responses. Since type I and II interferons are key regulators of PD-L1 expression in melanoma cells and IFN-γ-producing CD8+ T cells and IFN-α-producing dendritic cells are abundant in vitiligo skin, we aimed to study the role of PD-1/PD-L1 signalling in melanocyte destruction in vitiligo. Moreover, impaired PD-1/PD-L1 function is observed in a variety of autoimmune diseases. It is, therefore, hypothesized that manipulating PD-1/PD-L1 signalling might have therapeutic potential in vitiligo. The PD-1+ T cells were abundantly present in situ in perilesional vitiligo skin, but expression of PD-L1 was limited and confined exclusively to dermal T cells. More specifically, neither melanocytes nor other epidermal skin cells expressed PD-L1. Exposure to IFN-γ, but also type I interferons, increased PD-L1 expression in primary melanocytes and fibroblasts, derived from healthy donors. Primary human keratinocytes only showed increased PD-L1 expression upon stimulation with IFN-γ. More interestingly, melanocytes derived from non-lesional vitiligo skin showed no PD-L1 upregulation upon IFN-γ exposure, while other skin cells displayed significant PD-L1 expression after exposure. In a vitiligo skin explant model, incubation of non-lesional vitiligo skin with activated (IFN-γ-producing) T cells from vitiligo lesions was previously described to induce melanocyte apoptosis. Although PD-L1 expression was induced in epidermal cells in these explants, this induction was completely absent in melanocytes. The lack of PD-L1 upregulation by melanocytes in the presence of IFN-γ-producing T cells shows that melanocytes lack protection against T-cell attack during vitiligo pathogenesis. Manipulating PD-1/PD-L1 signalling may, therefore, be a therapeutic option for vitiligo patients.
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Affiliation(s)
- Marcella Willemsen
- Department of Dermatology and Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam, The Netherlands
| | - Gabrielle Krebbers
- Department of Dermatology and Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam, The Netherlands
| | - Esther P M Tjin
- Department of Dermatology and Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam, The Netherlands
| | - Karin J Willemsen
- Department of Dermatology and Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam, The Netherlands
| | - Alesha Louis
- Department of Dermatology and Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam, The Netherlands
| | - Veronique A L Konijn
- Department of Dermatology and Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam, The Netherlands
| | - Vidhya S Narayan
- Department of Dermatology and Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam, The Netherlands
| | - Nicoline F Post
- Department of Dermatology and Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam, The Netherlands
| | - Walbert J Bakker
- Department of Dermatology and Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam, The Netherlands
| | | | - Marcel W Bekkenk
- Department of Dermatology and Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam, The Netherlands
| | - Rosalie M Luiten
- Department of Dermatology and Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam, The Netherlands
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11
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Park JM, Han YM, Oh JY, Lee DY, Choi SH, Hahm KB. Transcriptome profiling implicated in beneficiary actions of kimchi extracts against Helicobacter pylori infection. J Clin Biochem Nutr 2021; 69:171-187. [PMID: 34616109 PMCID: PMC8482382 DOI: 10.3164/jcbn.20-116] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 11/15/2020] [Indexed: 12/12/2022] Open
Abstract
Dietary intervention to prevent Helicobacter pylori (H. pylori)-gastric cancer might be ideal because of no risk of bacterial resistance, safety, and rejuvenating action of atrophic gastritis. We have published data about the potential of fermented kimchi as nutritional approach for H. pylori. Hence recent advances in RNAseq analysis lead us to investigate the transcriptome analysis to explain these beneficiary actions of kimchi. gastric cells were infected with either H. pylori or H. pylori plus kimchi. 943 genes were identified as significantly increased or decreased genes according to H. pylori infection and 68 genes as significantly changed between H. pylori infection and H. pylori plus kimchi (p<0.05). Gene classification and Medline database showed DLL4, FGF18, PTPRN, SLC7A11, CHAC1, FGF21, ASAN, CTH, and CREBRF were identified as significantly increased after H. pylori, but significantly decreased with kimchi and NEO1, CLDN8, KLRG1, and IGFBP1 were identified as significantly decreased after H. pylori, but increased with kimchi. After KEGG and STRING-GO analysis, oxidative stress, ER stress, cell adhesion, and apoptosis genes were up-regulated with H. pylori infection but down-regulated with kimchi, whereas tissue regeneration, cellular anti-oxidative response, and anti-inflammation genes were reversely regulated with kimchi (p<0.01). Conclusively, transcriptomes of H. pylori plus kimchi showed significant biological actions.
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Affiliation(s)
- Jong Min Park
- Daejeon University School of Oriental Medicine, Daejeon, 34520, Korea
| | - Young Min Han
- Seoul Center, Korea Basic Science Institute, Seoul, 02456, Korea
| | - Ji Young Oh
- CJ Food Research Center, Suwon, 16471, Korea
| | | | | | - Ki Baik Hahm
- CHA Cancer Preventive Research Center, CHA Bio Complex, Pangyo, 13497, Korea
- Medpacto Research Institute, Medpacto, Seoul, 06668, Korea
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12
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Schunkert EM, Shah PN, Divito SJ. Skin Resident Memory T Cells May Play Critical Role in Delayed-Type Drug Hypersensitivity Reactions. Front Immunol 2021; 12:654190. [PMID: 34497600 PMCID: PMC8419326 DOI: 10.3389/fimmu.2021.654190] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 08/06/2021] [Indexed: 12/31/2022] Open
Abstract
Delayed-type drug hypersensitivity reactions (dtDHR) are immune-mediated reactions with skin and visceral manifestations ranging from mild to severe. Clinical care is negatively impacted by a limited understanding of disease pathogenesis. Though T cells are believed to orchestrate disease, the type of T cell and the location and mechanism of T cell activation remain unknown. Resident memory T cells (TRM) are a unique T cell population potentially well situated to act as key mediators in disease pathogenesis, but significant obstacles to defining, identifying, and testing TRM in dtDHR preclude definitive conclusions at this time. Deeper mechanistic interrogation to address these unanswered questions is necessary, as involvement of TRM in disease has significant implications for prediction, diagnosis, and treatment of disease.
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Abstract
PURPOSE OF REVIEW The clinical overlap between spondyloarthritis (SpA) and inflammation of barrier tissues such as the intestine and skin indicates a role of barrier tissue immunity in the development of SpA. Herein, we review the recent advances in understanding lymphocyte populations and functions within the intestine and skin implicated in the pathophysiology of SpA. RECENT FINDINGS A number of unique lymphocyte populations have been identified to be expanded within the gut and skin of patients with SpA, including γδ T cells, mucosa-associated invariant T (MAIT) cells, innate lymphoid cells (ILCs) and T resident memory (TRM) cells. These cells respond to microbial cues at their barrier surface causing cellular activation and generation of interleukin (IL)-17, which is hypothesized to be the mechanism by which they contribute to SpA pathogenesis. SUMMARY Understanding how unique lymphocyte populations expand and produce IL-17 in the development of SpA provides insights into the pathophysiology of this disease as well as potential future therapeutic avenues.
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14
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Hendriks A, Mnich ME, Clemente B, Cruz AR, Tavarini S, Bagnoli F, Soldaini E. Staphylococcus aureus-Specific Tissue-Resident Memory CD4 + T Cells Are Abundant in Healthy Human Skin. Front Immunol 2021; 12:642711. [PMID: 33796109 PMCID: PMC8008074 DOI: 10.3389/fimmu.2021.642711] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 02/18/2021] [Indexed: 12/12/2022] Open
Abstract
The skin is an immunocompetent tissue that harbors several kinds of immune cells and a plethora of commensal microbes constituting the skin microbiome. Staphylococcus aureus is a prominent skin pathogen that colonizes a large proportion of the human population. We currently have an incomplete understanding of the correlates of protection against S. aureus infection, however genetic and experimental evidence has shown that CD4+ T cells play a key role in orchestrating a protective anti-S. aureus immune response. A high S. aureus-specific memory CD4+ T cell response has been reported in the blood of healthy subjects. Since T cells are more abundant in the skin than in blood, we hypothesized that S. aureus-specific CD4+ T cells could be present in the skin of healthy individuals. Indeed, we observed proliferation of tissue-resident memory CD4+ T cells and production of IL-17A, IL-22, IFN-γ and TNF-β by cells isolated from abdominal skin explants in response to heat-killed S. aureus. Remarkably, these cytokines were produced also during an ex vivo epicutaneous S. aureus infection of human skin explants. These findings highlight the importance of tissue-resident memory CD4+ T cells present at barrier sites such as the skin, a primary entry site for S. aureus. Further phenotypical and functional characterization of these cells will ultimately aid in the development of novel vaccine strategies against this elusive pathogen.
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Affiliation(s)
- Astrid Hendriks
- GSK, Siena, Italy.,Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Malgorzata Ewa Mnich
- GSK, Siena, Italy.,Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | | | - Ana Rita Cruz
- GSK, Siena, Italy.,Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
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15
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Wang T, Li K, Xiao S, Xia Y. A Plausible Role for Collectins in Skin Immune Homeostasis. Front Immunol 2021; 12:594858. [PMID: 33790889 PMCID: PMC8006919 DOI: 10.3389/fimmu.2021.594858] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 02/25/2021] [Indexed: 12/13/2022] Open
Abstract
The skin is a complex organ that faces the external environment and participates in the innate immune system. Skin immune homeostasis is necessary to defend against external microorganisms and to recover from stress to the skin. This homeostasis depends on interactions among a variety of cells, cytokines, and the complement system. Collectins belong to the lectin pathway of the complement system, and have various roles in innate immune responses. Mannose-binding lectin (MBL), collectin kidney 1, and liver (CL-K1, CL-L1) activate the lectin pathway, while all have multiple functions, including recognition of pathogens, opsonization of phagocytosis, and modulation of cytokine-mediated inflammatory responses. Certain collectins are localized in the skin, and their expressions change during skin diseases. In this review, we summarize important advances in our understanding of how MBL, surfactant proteins A and D, CL-L1, and CL-K1 function in skin immune homeostasis. Based on the potential roles of collectins in skin diseases, we suggest therapeutic strategies for skin diseases through the targeting of collectins and relevant regulators.
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Affiliation(s)
- Tian Wang
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ke Li
- Core Research Laboratory, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Shengxiang Xiao
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yumin Xia
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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16
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Liu B, Xie Y, Wu Z. Identification of Candidate Genes and Pathways in Nonsegmental Vitiligo Using Integrated Bioinformatics Methods. Dermatology 2020; 237:464-472. [PMID: 33302271 DOI: 10.1159/000511893] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 09/25/2020] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Nonsegmental vitiligo (NSV) is an acquired depigmentation disorder of unknown origin. Enormous interests focus on finding novel biomarkers and pathways responsible for NSV. METHODS The gene expression level was obtained by integrating microarray datasets (GSE65127 and GSE75819) from the Gene Expression Omnibus database using the sva R package. Differentially expressed genes (DEGs) between each group were identified by the limma R package. The interaction network was constructed using STRING, and significant modules coupled with hub genes were identified by cytoHubba and molecular complex detection. Pathway analyses were conducted using generally applicable gene set enrichment and further visualized in R environment. RESULTS A total of 102 DEGs between vitiligo lesional skin and healthy skin, 14 lesion-specific genes, and 29 predisposing genes were identified from the integrated dataset. Except for the anticipated decrease in melanogenesis, three major functional changes were identified, including oxidative phosphorylation, p53, and peroxisome proliferator-activated receptor (PPAR) signaling in lesional skin. PPARG, MUC1, S100A8, and S100A9 were identified as key hub genes involved in the pathogenesis of vitiligo. Besides, upregulation of the T cell receptor signaling pathway was considered to be associated with susceptibility of the skin in NSV patients. CONCLUSION Our study reveals several potential pathways and related genes involved in NSV using integrated bioinformatics methods. It might provide references for targeted strategies for NSV.
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Affiliation(s)
- Baoyi Liu
- Department of Dermatology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yongyi Xie
- Department of Dermatology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhouwei Wu
- Department of Dermatology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China,
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17
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Granier C, Gey A, Roncelin S, Weiss L, Paillaud E, Tartour E. Immunotherapy in older patients with cancer. Biomed J 2020; 44:260-271. [PMID: 33041248 PMCID: PMC8358190 DOI: 10.1016/j.bj.2020.07.009] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 07/17/2020] [Accepted: 07/22/2020] [Indexed: 12/19/2022] Open
Abstract
Ageing implicates a remodeling of our immune system, which is a consequence of the physiological senescence of our cells and tissues coupled with environmental factors and chronic antigen exposure. An immune system that senesces includes more differentiated cells with accumulation of highly differentiated CD4 and CD8 T cells. The pool of naive T cells decreases with the exponential thymic involution induced by age. Differentiated T cells have similar, if not higher, functional capacities but scarce studies are looking at the impact of senescence among specific T cells. After a stimulation, other immune cells (monocytes, dendritic cells and NK) are functionally altered during ageing. It is as if the immune system was more efficient at the basal level, but less efficient after a stimulation in the old compared to young people, likely due to less reserve. Concerning the clinical impact, older people are more prone to certain pathogens and their clinical manifestations differ from the younger people. Severe flu and VZV reactivation are more frequent with an altered cellular response to vaccination. Vaccination failure can have detrimental consequences in people presenting frailty criteria. Old people frailty is majored by their comorbidities and diseases like cancer. Thus, chemotherapies are employed with circumspection in older patients. The use of anti-PD-1/PD-L1 immunotherapies is therefore attractive, because of less side effects with a better response compared to chemotherapy. Old persons inclusion is lacking in current studies and clinical trials. Some subgroups or pooled analyses confirm the gain in response without increased toxicities in older patients but their inclusion criteria differ from the real-life practice. Specific studies focusing on this population are needed because of the increasing cancer incidence with age and the overall ageing of the population.
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Affiliation(s)
- C Granier
- Biological Immunology Department, APHP, Georges Pompidou European Hospital, Paris, France; University of Paris, PARCC, INSERM, APHP, Paris, France; Ligue Contre le Cancer Labeled Team, France.
| | - A Gey
- Biological Immunology Department, APHP, Georges Pompidou European Hospital, Paris, France; University of Paris, PARCC, INSERM, APHP, Paris, France; Ligue Contre le Cancer Labeled Team, France
| | - S Roncelin
- Biological Immunology Department, APHP, Georges Pompidou European Hospital, Paris, France
| | - L Weiss
- Clinical Immunology Department, APHP, Paris, France; INSERM U976 HIPI, Paris, France; Paris Descartes Medical School, University of Paris, Paris, France
| | - E Paillaud
- Department of Geriatric, APHP, Paris Cancer Institute CARPEM, Europeen Georges Pompidou Hospital, Paris, France; Paris Est Creteil University, INSERM, IMRB, Creteil, France
| | - E Tartour
- Biological Immunology Department, APHP, Georges Pompidou European Hospital, Paris, France; University of Paris, PARCC, INSERM, APHP, Paris, France; Ligue Contre le Cancer Labeled Team, France
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18
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Abstract
Vitiligo is an autoimmune disease of the skin that targets pigment-producing melanocytes and results in patches of depigmentation that are visible as white spots. Recent research studies have yielded a strong mechanistic understanding of this disease. Autoreactive cytotoxic CD8+ T cells engage melanocytes and promote disease progression through the local production of IFN-γ, and IFN-γ-induced chemokines are then secreted from surrounding keratinocytes to further recruit T cells to the skin through a positive-feedback loop. Both topical and systemic treatments that block IFN-γ signaling can effectively reverse vitiligo in humans; however, disease relapse is common after stopping treatments. Autoreactive resident memory T cells are responsible for relapse, and new treatment strategies focus on eliminating these cells to promote long-lasting benefit. Here, we discuss basic, translational, and clinical research studies that provide insight into the pathogenesis of vitiligo, and how this insight has been utilized to create new targeted treatment strategies.
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Affiliation(s)
- Michael L. Frisoli
- University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA;, ,
| | - Kingsley Essien
- University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA;, ,
| | - John E. Harris
- University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA;, ,
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19
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Orlik C, Deibel D, Küblbeck J, Balta E, Ganskih S, Habicht J, Niesler B, Schröder-Braunstein J, Schäkel K, Wabnitz G, Samstag Y. Keratinocytes costimulate naive human T cells via CD2: a potential target to prevent the development of proinflammatory Th1 cells in the skin. Cell Mol Immunol 2020; 17:380-394. [PMID: 31324882 PMCID: PMC7109061 DOI: 10.1038/s41423-019-0261-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Accepted: 06/27/2019] [Indexed: 12/01/2022] Open
Abstract
The interplay between keratinocytes and immune cells, especially T cells, plays an important role in the pathogenesis of chronic inflammatory skin diseases. During psoriasis, keratinocytes attract T cells by releasing chemokines, while skin-infiltrating self-reactive T cells secrete proinflammatory cytokines, e.g., IFNγ and IL-17A, that cause epidermal hyperplasia. Similarly, in chronic graft-versus-host disease, allogenic IFNγ-producing Th1/Tc1 and IL-17-producing Th17/Tc17 cells are recruited by keratinocyte-derived chemokines and accumulate in the skin. However, whether keratinocytes act as nonprofessional antigen-presenting cells to directly activate naive human T cells in the epidermis remains unknown. Here, we demonstrate that under proinflammatory conditions, primary human keratinocytes indeed activate naive human T cells. This activation required cell contact and costimulatory signaling via CD58/CD2 and CD54/LFA-1. Naive T cells costimulated by keratinocytes selectively differentiated into Th1 and Th17 cells. In particular, keratinocyte-initiated Th1 differentiation was dependent on costimulation through CD58/CD2. The latter molecule initiated STAT1 signaling and IFNγ production in T cells. Costimulation of T cells by keratinocytes resulting in Th1 and Th17 differentiation represents a new explanation for the local enrichment of Th1 and Th17 cells in the skin of patients with a chronic inflammatory skin disease. Consequently, local interference with T cell-keratinocyte interactions may represent a novel strategy for the treatment of Th1 and Th17 cell-driven skin diseases.
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Affiliation(s)
- Christian Orlik
- Institute of Immunology, Section Molecular Immunology, Heidelberg University, Im Neuenheimer Feld 305, 69120, Heidelberg, Germany
| | - Daniel Deibel
- Institute of Immunology, Section Molecular Immunology, Heidelberg University, Im Neuenheimer Feld 305, 69120, Heidelberg, Germany
| | - Johanna Küblbeck
- Institute of Immunology, Section Molecular Immunology, Heidelberg University, Im Neuenheimer Feld 305, 69120, Heidelberg, Germany
| | - Emre Balta
- Institute of Immunology, Section Molecular Immunology, Heidelberg University, Im Neuenheimer Feld 305, 69120, Heidelberg, Germany
| | - Sabina Ganskih
- Institute of Immunology, Section Molecular Immunology, Heidelberg University, Im Neuenheimer Feld 305, 69120, Heidelberg, Germany
| | - Jüri Habicht
- Institute of Immunology, Section Molecular Immunology, Heidelberg University, Im Neuenheimer Feld 305, 69120, Heidelberg, Germany
| | - Beate Niesler
- Institute of Human Genetics, Department of Human Molecular Genetics, and nCounter Core Facility, Heidelberg University, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany
| | - Jutta Schröder-Braunstein
- Institute of Immunology, Section Molecular Immunology, Heidelberg University, Im Neuenheimer Feld 305, 69120, Heidelberg, Germany
| | - Knut Schäkel
- Department of Dermatology, Heidelberg University, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany
| | - Guido Wabnitz
- Institute of Immunology, Section Molecular Immunology, Heidelberg University, Im Neuenheimer Feld 305, 69120, Heidelberg, Germany
| | - Yvonne Samstag
- Institute of Immunology, Section Molecular Immunology, Heidelberg University, Im Neuenheimer Feld 305, 69120, Heidelberg, Germany.
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20
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Khalil S, Bardawil T, Kurban M, Abbas O. Tissue-resident memory T cells in the skin. Inflamm Res 2020; 69:245-254. [PMID: 31989191 DOI: 10.1007/s00011-020-01320-6] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 12/20/2019] [Accepted: 01/12/2020] [Indexed: 12/16/2022] Open
Abstract
PURPOSE Tissue-resident memory T (TRM) cells are a newly described subset of memory T cells. The best characterized TRM cells are CD8+ and express CD103 and CD69. These cells are non-recirculating and persist long term in tissues, providing immediate protection against invading pathogens. However, their inappropriate activation might contribute to the pathogenesis of autoimmune and inflammatory disorders. In the skin, these cells have been described in psoriasis, vitiligo, and melanoma among other diseases. METHODS Literature review was done to highlight what is currently known on the phenotype and function of TRM cells and summarizes the available data describing their role in various cutaneous conditions. RESULTS Resolved psoriatic skin and disease-naïve non-lesional skin contain a population of IL-17-producing TRM cells with shared receptor sequences that recognize common antigens and likely contribute to disease recurrence after cessation of therapy. In vitiligo, TRM cells produce perforin, granzyme B, and interferon-γ following stimulation by interleukin-15 and collaborate with recirculating memory T cells to maintain disease. In melanoma, increased accumulation of TRM cells was recently shown to correlate with improved survival in patients undergoing therapy with immune checkpoint inhibitors.
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Affiliation(s)
- Samar Khalil
- Department of Dermatology, American University of Beirut Medical Center, Beirut, Lebanon
| | - Tara Bardawil
- Department of Dermatology, American University of Beirut Medical Center, Beirut, Lebanon
| | - Mazen Kurban
- Department of Dermatology, American University of Beirut Medical Center, Beirut, Lebanon.,Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon
| | - Ossama Abbas
- Department of Dermatology, American University of Beirut Medical Center, Beirut, Lebanon.
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21
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Gilhar A, Laufer-Britva R, Keren A, Paus R. Frontiers in alopecia areata pathobiology research. J Allergy Clin Immunol 2019; 144:1478-1489. [PMID: 31606262 DOI: 10.1016/j.jaci.2019.08.035] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 08/26/2019] [Accepted: 08/27/2019] [Indexed: 12/11/2022]
Abstract
This current review explores selected and as yet insufficiently investigated frontiers in current alopecia areata (AA) pathobiology research, with an emphasis on potential "new" players in AA pathobiology that deserve more systematic exploration and therapeutic targeting. Indeed, new evidence suggests that CD8+ T cells, which have long been thought to be the central players in AA pathobiology, are not the only drivers of disease. Instead, subsets of natural killer (NK) and so-called "unconventional" T cells (invariant NK T cells, γδ T cells, classic NK cells, and type 1 innate lymphoid cells), all of which can produce large amounts of IFN-γ, might also drive AA pathobiology independent of classical, autoantigen-dependent CD8+ T-cell functions. Another important new frontier is the role of regulatory lymphocyte subsets, such as regulatory T cells, γδ regulatory T cells, NKT10 cells, and perifollicular mast cells, in maintaining physiologic hair follicle immune privilege (IP); the extent to which these functions are defective in patients with AA; and how this IP-protective role could be restored therapeutically in patients with established AA. Broadening our AA research horizon along the lines suggested above promises not only to open the door to innovative and even more effective immunotherapy strategies for AA but will also likely be relevant for other autoimmune disorders in which pathobiology, ectopic MHC class I expression, and IP collapse play an important role.
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Affiliation(s)
- Amos Gilhar
- Skin Research Laboratory, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
| | | | - Aviad Keren
- Skin Research Laboratory, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Ralf Paus
- Dr Philipp Frost Department of Dermatology & Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, Fla; Dermatology Research Centre, University of Manchester and NIHR Manchester Biomedical Research Centre, Manchester, United Kingdom
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22
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The Dynamics of the Skin's Immune System. Int J Mol Sci 2019; 20:ijms20081811. [PMID: 31013709 PMCID: PMC6515324 DOI: 10.3390/ijms20081811] [Citation(s) in RCA: 369] [Impact Index Per Article: 61.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 04/09/2019] [Accepted: 04/09/2019] [Indexed: 12/12/2022] Open
Abstract
The skin is a complex organ that has devised numerous strategies, such as physical, chemical, and microbiological barriers, to protect the host from external insults. In addition, the skin contains an intricate network of immune cells resident to the tissue, crucial for host defense as well as tissue homeostasis. In the event of an insult, the skin-resident immune cells are crucial not only for prevention of infection but also for tissue reconstruction. Deregulation of immune responses often leads to impaired healing and poor tissue restoration and function. In this review, we will discuss the defensive components of the skin and focus on the function of skin-resident immune cells in homeostasis and their role in wound healing.
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Characterization of donor and recipient CD8+ tissue-resident memory T cells in transplant nephrectomies. Sci Rep 2019; 9:5984. [PMID: 30979940 PMCID: PMC6461670 DOI: 10.1038/s41598-019-42401-9] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Accepted: 03/29/2019] [Indexed: 12/12/2022] Open
Abstract
Tissue-resident memory T (TRM) cells are characterized by their surface expression of CD69 and can be subdivided in CD103+ and CD103− TRM cells. The origin and functional characteristics of TRM cells in the renal allograft are largely unknown. To determine these features we studied TRM cells in transplant nephrectomies. TRM cells with a CD103+ and CD103− phenotype were present in all samples (n = 13) and were mainly CD8+ T cells. Of note, donor-derived TRM cells were only detectable in renal allografts that failed in the first month after transplantation. Grafts, which failed later, mainly contained recipient derived TRM cells. The gene expression profiles of the recipient derived CD8+ TRM cells were studied in more detail and showed a previously described signature of tissue residence within both CD103+ and CD103− TRM cells. All CD8+ TRM cells had strong effector abilities through the production of IFNγ and TNFα, and harboured high levels of intracellular granzyme B and low levels of perforin. In conclusion, our results demonstrate that donor and recipient TRM cells reside in the rejected renal allograft. Over time, the donor-derived TRM cells are replaced by recipient TRM cells which have features that enables these cells to aggressively respond to the allograft.
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Richmond JM, Strassner JP, Rashighi M, Agarwal P, Garg M, Essien KI, Pell LS, Harris JE. Resident Memory and Recirculating Memory T Cells Cooperate to Maintain Disease in a Mouse Model of Vitiligo. J Invest Dermatol 2019; 139:769-778. [PMID: 30423329 PMCID: PMC6431571 DOI: 10.1016/j.jid.2018.10.032] [Citation(s) in RCA: 97] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 10/24/2018] [Accepted: 10/28/2018] [Indexed: 10/27/2022]
Abstract
Tissue resident memory T cells (Trm) form in the skin in vitiligo and persist to maintain disease, as white spots often recur rapidly after discontinuing therapy. We and others have recently described melanocyte-specific autoreactive Trm in vitiligo lesions. Here, we characterize the functional relationship between Trm and recirculating memory T cells (Tcm) in our vitiligo mouse model. We found that both Trm and Tcm sensed autoantigen in the skin long after stabilization of disease, producing IFN-γ, CXCL9, and CXCL10. Blockade of Tcm recruitment to the skin with FTY720 or depletion of Tcm with low-dose Thy1.1 antibody reversed disease, indicating that Trm cooperate with Tcm to maintain disease. Taken together, our data provide characterization of skin memory T cells in vitiligo, demonstrate that Trm and Tcm work together during disease, and indicate that targeting their survival or function may provide novel, durable treatment options for patients.
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Affiliation(s)
- Jillian M Richmond
- Department of Dermatology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - James P Strassner
- Department of Dermatology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Mehdi Rashighi
- Department of Dermatology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Priti Agarwal
- Department of Dermatology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Madhuri Garg
- Department of Dermatology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Kingsley I Essien
- Department of Dermatology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Lila S Pell
- Department of Dermatology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - John E Harris
- Department of Dermatology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
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Kalia V, Sarkar S. Regulation of Effector and Memory CD8 T Cell Differentiation by IL-2-A Balancing Act. Front Immunol 2018; 9:2987. [PMID: 30619342 PMCID: PMC6306427 DOI: 10.3389/fimmu.2018.02987] [Citation(s) in RCA: 137] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 12/04/2018] [Indexed: 01/07/2023] Open
Abstract
Interleukin-2 (IL-2) regulates key aspects of CD8 T cell biology–signaling through distinct pathways IL-2 triggers critical metabolic and transcriptional changes that lead to a spectrum of physiological outcomes such as cell survival, proliferation, and effector differentiation. In addition to driving effector differentiation, IL-2 signals are also critical for formation of long-lived CD8 T cell memory. This review discusses a model of rheostatic control of CD8 T cell effector and memory differentiation by IL-2, wherein the timing, duration, dose, and source of IL-2 signals are considered in fine-tuning the balance of key transcriptional regulators of cell fate.
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Affiliation(s)
- Vandana Kalia
- Division of Hematology and Oncology, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, United States.,Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA, United States
| | - Surojit Sarkar
- Division of Hematology and Oncology, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, United States.,Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA, United States.,M3D Graduate Program, University of Washington School of Medicine, Seattle, WA, United States.,Department of Pathology, University of Washington School of Medicine, Seattle, WA, United States
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