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1
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Lu L, He H, Feng J, Hu Z, Zhang S, Yang L, Liu Y, Wang T. Post-translational modification in the pathogenesis of vitiligo. Immunol Res 2024; 72:1229-1237. [PMID: 39320694 PMCID: PMC11618162 DOI: 10.1007/s12026-024-09545-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 09/13/2024] [Indexed: 09/26/2024]
Abstract
Vitiligo is a chronic dermatological condition marked by the loss of skin pigmentation. Its complex etiology involves multiple factors and has not been completely elucidated. Protein post-translational modification pathways have been proven to play a significant role in inflammatory skin diseases, yet research in the context of vitiligo remains limited. This review focuses on the role of post-translational modifications in vitiligo pathogenesis, especially their impact on cellular signaling pathways related to immune response and melanocyte survival. Current therapeutic strategies targeting these pathways are discussed, emphasizing the potential for novel treatments in vitiligo management.
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Affiliation(s)
- Lu Lu
- Department of Dermatology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, China
| | - Huimin He
- Department of Dermatology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, China
| | - Jindi Feng
- Department of Dermatology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, China
| | - Zhonghui Hu
- Department of Dermatology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, China
| | - Shiyu Zhang
- Department of Dermatology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, China
| | - Lu Yang
- Department of Dermatology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, China
| | - Yuehua Liu
- Department of Dermatology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, China.
| | - Tao Wang
- Department of Dermatology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, China.
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2
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Xiong H, Shen Z. Tissue-resident memory T cells in immunotherapy and immune-related adverse events by immune checkpoint inhibitor. Int J Cancer 2024; 155:193-202. [PMID: 38554117 DOI: 10.1002/ijc.34940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 03/05/2024] [Accepted: 03/07/2024] [Indexed: 04/01/2024]
Abstract
Tissue-resident memory T cells (TRM) are a specialized subset of T cells that reside in tissues and provide long-term protective immunity against pathogens that enter the body through that specific tissue. TRM cells have specific phenotype and reside preferentially in barrier tissues. Recent studies have revealed that TRM cells are the main target of immune checkpoint inhibitor immunotherapy since their role in cancer immunosurveillance. Furthermore, TRM cells also play a crucial part in pathogenesis of immune-related adverse events (irAEs). Here, we provide a concise review of biological characteristics of TRM cells, and the major advances and recent findings regarding their involvement in immune checkpoint inhibitor immunotherapy and the corresponding irAEs.
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Affiliation(s)
- Hao Xiong
- Department of Dermatology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
| | - Zhu Shen
- Department of Dermatology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
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3
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Nateghi-Rostami M, Sohrabi Y. Memory T cells: promising biomarkers for evaluating protection and vaccine efficacy against leishmaniasis. Front Immunol 2024; 15:1304696. [PMID: 38469319 PMCID: PMC10925770 DOI: 10.3389/fimmu.2024.1304696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Accepted: 02/08/2024] [Indexed: 03/13/2024] Open
Abstract
Understanding the immune response to Leishmania infection and identifying biomarkers that correlate with protection are crucial for developing effective vaccines. One intriguing aspect of Leishmania infection is the persistence of parasites, even after apparent lesion healing. Various host cells, including dendritic cells, fibroblasts, and Langerhans cells, may serve as safe sites for latent infection. Memory T cells, especially tissue-resident memory T cells (TRM), play a crucial role in concomitant immunity against cutaneous Leishmania infections. These TRM cells are long-lasting and can protect against reinfection in the absence of persistent parasites. CD4+ TRM cells, in particular, have been implicated in protection against Leishmania infections. These cells are characterized by their ability to reside in the skin and rapidly respond to secondary infections by producing cytokines such as IFN-γ, which activates macrophages to kill parasites. The induction of CD4+ TRM cells has shown promise in experimental immunization, leading to protection against Leishmania challenge infections. Identifying biomarkers of protection is a critical step in vaccine development and CD4+ TRM cells hold potential as biomarkers, as their presence and functions may correlate with protection. While recent studies have shown that Leishmania-specific memory CD4+ T-cell subsets are present in individuals with a history of cutaneous leishmaniasis, further studies are needed to characterize CD4+ TRM cell populations. Overall, this review highlights the importance of memory T cells, particularly skin-resident CD4+ TRM cells, as promising targets for developing effective vaccines against leishmaniasis and as biomarkers of immune protection to assess the efficacy of candidate vaccines against human leishmaniasis.
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Affiliation(s)
| | - Yahya Sohrabi
- Department of Cardiology I-Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital Münster, Westfälische Wilhelms-Universität, Münster, Germany
- Department of Medical Genetics, Third Faculty of Medicine, Charles University, Prague, Czechia
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4
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Shiu J, Lentsch G, Polleys CM, Mobasher P, Ericson M, Georgakoudi I, Ganesan AK, Balu M. Non-invasive Imaging Techniques for Monitoring Cellular Response to Treatment in Stable Vitiligo. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.15.553419. [PMID: 37645823 PMCID: PMC10462045 DOI: 10.1101/2023.08.15.553419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/31/2023]
Abstract
Punch grafting procedures, where small pieces of normal skin are transplanted into stable vitiligo patches, results in repigmentation in only half of patients treated, yet the factors that determine whether a patient responds to treatment or not are still unknown. Reflectance confocal microscopy (RCM) is adept at visualizing melanocyte migration and epidermal changes over large areas while multiphoton microscopy (MPM) can capture metabolic changes in keratinocytes. With the overall goal of identifying optical biomarkers for early treatment response, we followed 12 vitiligo lesions undergoing punch grafting. Dendritic melanocytes adjacent to the graft site were observed before clinical evidence of repigmentation in treatment responsive patients but not in treatment non-responsive patients, suggesting that the early visualization of melanocytes is indicative of a therapeutic response. Keratinocyte metabolic changes in vitiligo skin adjacent to the graft site also correlated with treatment response, indicating that a keratinocyte microenvironment that more closely resembles normal skin is more hospitable for migrating melanocytes. Taken together, these studies suggest that successful melanocyte transplantation requires both the introduction of new melanocytes and modulation of the local tissue microenvironment.
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Affiliation(s)
- Jessica Shiu
- Department of Dermatology, University of California, Irvine, Irvine, CA, USA
| | - Griffin Lentsch
- Beckman Laser Institute and Medical Clinic, University of California, Irvine, Irvine, CA, USA
| | | | - Pezhman Mobasher
- Department of Dermatology, University of California, Irvine, Irvine, CA, USA
| | - Marissa Ericson
- Biostatistics, Epidemiology and Research Design, University of California, Irvine, Irvine, CA, USA
| | - Irene Georgakoudi
- Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA
| | - Anand K Ganesan
- Department of Dermatology, University of California, Irvine, Irvine, CA, USA
- Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA
- Skin Biology Resource Center, University of California, Irvine, Irvine, CA, USA
| | - Mihaela Balu
- Beckman Laser Institute and Medical Clinic, University of California, Irvine, Irvine, CA, USA
- Skin Biology Resource Center, University of California, Irvine, Irvine, CA, USA
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5
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Chen Y, Griffiths CEM, Bulfone-Paus S. Exploring Mast Cell-CD8 T Cell Interactions in Inflammatory Skin Diseases. Int J Mol Sci 2023; 24:1564. [PMID: 36675078 PMCID: PMC9861959 DOI: 10.3390/ijms24021564] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/09/2023] [Accepted: 01/11/2023] [Indexed: 01/15/2023] Open
Abstract
The skin is exposed to environmental challenges and contains skin-resident immune cells, including mast cells (MCs) and CD8 T cells that act as sentinels for pathogens and environmental antigens. Human skin MCs and their mediators participate in the maintenance of tissue homeostasis and regulate the recruitment and activity of immune cells involved in the pathogenesis of skin diseases. The cutaneous CD8 T cell compartment is comprised of long-persisting resident memory T cells (TRM) and migratory or recirculating cells; both populations provide durable site immune surveillance. Several lines of evidence indicate that MC-derived products, such as CCL5 and TNF-α, modulate the migration and function of CD8 T cells. Conversely, activated CD8 T cells induce the upregulation of MC costimulatory molecules. Moreover, the close apposition of MCs and CD8 T cells has been recently identified in the skin of several dermatoses, such as alopecia areata. This review outlines the current knowledge about bidirectional interactions between human MCs and CD8 T cells, analyses the alteration of their communication in the context of three common skin disorders in which these cells have been found altered in number or function-psoriasis, atopic dermatitis, and vitiligo-and discusses the current unanswered questions.
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Affiliation(s)
| | | | - Silvia Bulfone-Paus
- Lydia Becker Institute of Immunology and Inflammation, Dermatology Research Centre, NIHR Manchester Biomedical Research Centre, University of Manchester, Manchester M13 9PL, UK
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6
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Hu Z, Wang T. Beyond skin white spots: Vitiligo and associated comorbidities. Front Med (Lausanne) 2023; 10:1072837. [PMID: 36910477 PMCID: PMC9995999 DOI: 10.3389/fmed.2023.1072837] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Accepted: 02/07/2023] [Indexed: 02/25/2023] Open
Abstract
Vitiligo is a common depigmentation disorder of an unknown origin characterized by the selective loss of melanocytes, resulting in typical white macules and patches. However, vitiligo is now recognized as more than just a skin disease, what a dermatologist observes as a white spot of skin is just the "tip of the iceberg" of the condition. We attempt to clarify the classification of comorbidities associated with vitiligo from various reviews and reports, and describe their possible pathogenesis. In conclusion, the literature provides evidence of an association between vitiligo and ocular and auditory abnormalities, autoimmune disorders, other dermatological diseases, metabolic syndrome and related disorders, and psychological diseases. These associations highlight the importance of a multidisciplinary approach in managing vitiligo patients.
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Affiliation(s)
- Zhonghui Hu
- Department of Dermatology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, China
| | - Tao Wang
- Department of Dermatology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, China
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7
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Zhao Y, Hu Y, Shen Q, Xiong R, Song X, Guan C. DCUN1D1, a new molecule involved in depigmentation via upregulating CXCL10. Exp Dermatol 2022; 32:457-468. [PMID: 36541112 DOI: 10.1111/exd.14732] [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: 09/30/2022] [Revised: 11/18/2022] [Accepted: 12/12/2022] [Indexed: 12/24/2022]
Abstract
CD8+ T cells in the lesioned site play a crucial role in the pathogenesis of vitiligo. The chemokine CXCL10 secreted by keratinocytes regulates the migration of CD8+ T cells into the skin. In our previous study, we found that DCUN1D1 expression in vitiligo lesions positively correlates with Cxcl10 expression. In this study, the regulatory effect of DCUN1D1 on CXCL10 and cell function was investigated. DCUN1D1 protein expression was significantly higher in the skin tissue from vitiligo lesions compared with samples from healthy controls. High expression of DCUN1D1 in keratinocytes caused local hair depigmentation in mice, reduced melanin content, high infiltration of CD8+ T cells and increased CXCL10 expression. This suggested that DCUN1D1 may regulate CD8+ T-cell infiltration and depigmentation through CXCL10. Inhibition of DCUN1D1 expression in HaCaT cells abolished the IFN-γ-induced upregulation of p-JAK1, p-STAT1 and CXCL10, suppressed the H2 O2 -induced ROS generation and apoptosis, and upregulated tyrosinase expression in melanocytes. Collectively, these results show that DCUN1D1 is an important regulator of CXCL10 and may be a new target for the treatment of vitiligo.
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Affiliation(s)
- Yan Zhao
- School of Basic Med ical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yebei Hu
- Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, China.,Department of Dermatology, Affiliated Hangzhou Dermatology Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qingmei Shen
- School of Basic Med ical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Renxue Xiong
- Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, China.,Department of Dermatology, Affiliated Hangzhou Dermatology Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiuzu Song
- Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, China.,Department of Dermatology, Affiliated Hangzhou Dermatology Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang Chinese Medical University, Hangzhou, China
| | - Cuiping Guan
- Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, China.,Department of Dermatology, Affiliated Hangzhou Dermatology Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang Chinese Medical University, Hangzhou, China
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8
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Chopra A, Gupta A. Skin as an immune organ and the site of biomimetic, non-invasive vaccination. MEDICINE IN NOVEL TECHNOLOGY AND DEVICES 2022. [DOI: 10.1016/j.medntd.2022.100196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
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Abstract
RATIONALE The purpose of this report was to describe resident memory cluster of differentiation 8 (CD8) + T cells may contribute to the progression of inflammatory vitiligo. PATIENT CONCERNS A 32-year-old male has a stable vitiligo for 1 year, then some patches present inflammatory erythema. Two years later, the inflammatory patches enlarged and joined together, and the remaining 2 common patches shows repigmentation and no change respectively. Both CD69 + CD8 + T cells and CD103 + CD8 + T cells showed marked increase in inflammatory vitiligo than common vitiligo. DIAGNOSIS Histological findings show that the numbers of lymphocytes are increased in inflammatory vitiligo than common vitiligo. Immunofluorescence staining show that the numbers of CD69 + CD8 + T cells demonstrated a marked increase in inflammatory vitiligo than common vitiligo. INTERVENTIONS Without any intervention. OUTCOMES The previous upper 2 patches on the abdomen with erythematous rim were enlarged and joined together. However the lowest lesion with uninflamed common rim on the abdomen remained static, the one on the right groin showed spot-like repigmentation. LESSONS This case report demonstrates that resident memory CD8 + T cells may contribute to the progression of inflammatory vitiligo.
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Affiliation(s)
- YanLi Xu
- School of Clinical Medicine, Weifang Medical University, Weifang, Shandong Province, P.R. China
- Department of Dermatology, Yidu Central Hospital, Weifang, Shandong Province, P.R. China
| | - Bao-Xiang Zhang
- Department of Dermatology, Yidu Central Hospital, Weifang, Shandong Province, P.R. China
- * Correspondence: Bao-Xiang Zhang, Department of Dermatology, Yidu Central Hospital, Weifang, Shandong Province, 262500, P.R. China (e-mail: )
| | - Mao Lin
- Department of Dermatology, Chongqing Chinese Medicine Hospital, Yuzhong District, Chongqing, P.R. China
| | - Lu Zhang
- Department of Dermatology, Yidu Central Hospital, Weifang, Shandong Province, P.R. China
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10
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Cook CP, Taylor M, Liu Y, Schmidt R, Sedgewick A, Kim E, Hailer A, North JP, Harirchian P, Wang H, Kashem SW, Shou Y, McCalmont TC, Benz SC, Choi J, Purdom E, Marson A, Ramos SBV, Cheng JB, Cho RJ. A single-cell transcriptional gradient in human cutaneous memory T cells restricts Th17/Tc17 identity. Cell Rep Med 2022; 3:100715. [PMID: 35977472 PMCID: PMC9418858 DOI: 10.1016/j.xcrm.2022.100715] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 05/21/2022] [Accepted: 07/14/2022] [Indexed: 11/29/2022]
Abstract
The homeostatic mechanisms that fail to restrain chronic tissue inflammation in diseases, such as psoriasis vulgaris, remain incompletely understood. We profiled transcriptomes and epitopes of single psoriatic and normal skin-resident T cells, revealing a gradated transcriptional program of coordinately regulated inflammation-suppressive genes. This program, which is sharply suppressed in lesional skin, strikingly restricts Th17/Tc17 cytokine and other inflammatory mediators on the single-cell level. CRISPR-based deactivation of two core components of this inflammation-suppressive program, ZFP36L2 and ZFP36, replicates the interleukin-17A (IL-17A), granulocyte macrophage-colony-stimulating factor (GM-CSF), and interferon gamma (IFNγ) elevation in psoriatic memory T cells deficient in these transcripts, functionally validating their influence. Combinatoric expression analysis indicates the suppression of specific inflammatory mediators by individual program members. Finally, we find that therapeutic IL-23 blockade reduces Th17/Tc17 cell frequency in lesional skin but fails to normalize this inflammatory-suppressive program, suggesting how treated lesions may be primed for recurrence after withdrawal of treatment.
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Affiliation(s)
- Christopher P Cook
- Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA; Dermatology, Veterans Affairs Medical Center, San Francisco, CA, USA
| | - Mark Taylor
- Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA; Clinical Research Centre, Medical University of Białystok, Białystok, Poland
| | - Yale Liu
- Dermatology, Veterans Affairs Medical Center, San Francisco, CA, USA; Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, ShaanXi 710004, P.R. China
| | - Ralf Schmidt
- Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA
| | | | - Esther Kim
- Division of Plastic Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Ashley Hailer
- Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA
| | - Jeffrey P North
- Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA
| | - Paymann Harirchian
- Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA; Dermatology, Veterans Affairs Medical Center, San Francisco, CA, USA
| | - Hao Wang
- Department of Statistics, University of California, Berkeley, Berkeley, CA, USA
| | - Sakeen W Kashem
- Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA; Dermatology, Veterans Affairs Medical Center, San Francisco, CA, USA
| | - Yanhong Shou
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, P.R. China
| | - Timothy C McCalmont
- Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA, USA; Golden State Dermatology Associates, Walnut Creek, CA, USA
| | | | - Jaehyuk Choi
- Department of Dermatology, Northwestern University, Evanston, IL, USA
| | - Elizabeth Purdom
- Department of Statistics, University of California, Berkeley, Berkeley, CA, USA
| | - Alexander Marson
- Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA
| | - Silvia B V Ramos
- Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Jeffrey B Cheng
- Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA; Dermatology, Veterans Affairs Medical Center, San Francisco, CA, USA.
| | - Raymond J Cho
- Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA.
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11
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Cheng B, Veerabagu S, Miller CJ, Sobanko JF, Shin TM, Higgins HW, Giordano CN, Etzkorn JR. A comparison of invasive squamous cell carcinoma greater than 1 year after treatment with 5-Fluourouracil, Imiquimod, or Photodynamic Therapy with Aminolevulinic Acid. J Am Acad Dermatol 2022; 87:592-596. [PMID: 35661760 DOI: 10.1016/j.jaad.2022.05.051] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 05/19/2022] [Accepted: 05/24/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND Studies comparing 5-Fluorouracil (5-FU), imiquimod, and photodynamic therapy with aminolevulinic acid (PDT-ALA) have evaluated the relative efficacy of destroying actinic keratoses. However, this endpoint may not directly translate to cutaneous squamous cell carcinoma (cSCC) prevention, and no study has evaluated these field therapies for cSCC prevention long term, defined as greater than 1 year post treatment. OBJECTIVE Determine the time to surgically treated invasive cSCC development after treatment with 5-FU, imiquimod, or PDT-ALA beginning 1 year post treatment. METHODS Retrospective cohort study using the Optum Clinformatics Data Mart database from 2012-2019 RESULTS: Rate of cSCC development in patients treated with 5-FU showed no significant difference compared to imiquimod (0.99, 95% CI: 0.90 - 1.08). PDT-ALA was worse than 5-FU (1.27, 95% CI: 1.19 - 1.36) and imiquimod (HR 1.29, 95% CI: 1.17 - 1.43). Other known predictors of cSCC were consistent with previous literature. LIMITATIONS Location of field therapy could not be determined with a claims database. CONCLUSIONS 5-FU is not superior to imiquimod beginning 1 year post treatment, despite previously demonstrated superior AK destruction efficacy, but was superior to PDT-ALA. Conflating AK destruction and cSCC prevention efficacy may not be appropriate. Future prospective studies should aim to use an endpoint of cSCC development.
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Affiliation(s)
- Brian Cheng
- University of South Carolina School of Medicine; Columbia, SC, USA
| | | | - Christopher J Miller
- Department of Dermatology; Hospital of the University of Pennsylvania; Philadelphia, PA, USA
| | - Joseph F Sobanko
- Department of Dermatology; Hospital of the University of Pennsylvania; Philadelphia, PA, USA
| | - Thuzar M Shin
- Department of Dermatology; Hospital of the University of Pennsylvania; Philadelphia, PA, USA
| | - H William Higgins
- Department of Dermatology; Hospital of the University of Pennsylvania; Philadelphia, PA, USA
| | - Cerrene N Giordano
- Department of Dermatology; Hospital of the University of Pennsylvania; Philadelphia, PA, USA
| | - Jeremy R Etzkorn
- Department of Dermatology; Hospital of the University of Pennsylvania; Philadelphia, PA, USA
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12
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Liu Y, Wang H, Taylor M, Cook C, Martínez-Berdeja A, North JP, Harirchian P, Hailer AA, Zhao Z, Ghadially R, Ricardo-Gonzalez RR, Grekin RC, Mauro TM, Kim E, Choi J, Purdom E, Cho RJ, Cheng JB. Classification of human chronic inflammatory skin disease based on single-cell immune profiling. Sci Immunol 2022; 7:eabl9165. [PMID: 35427179 PMCID: PMC9301819 DOI: 10.1126/sciimmunol.abl9165] [Citation(s) in RCA: 85] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Inflammatory conditions represent the largest class of chronic skin disease, but the molecular dysregulation underlying many individual cases remains unclear. Single-cell RNA sequencing (scRNA-seq) has increased precision in dissecting the complex mixture of immune and stromal cell perturbations in inflammatory skin disease states. We single-cell-profiled CD45+ immune cell transcriptomes from skin samples of 31 patients (7 atopic dermatitis, 8 psoriasis vulgaris, 2 lichen planus (LP), 1 bullous pemphigoid (BP), 6 clinical/histopathologically indeterminate rashes, and 7 healthy controls). Our data revealed active proliferative expansion of the Treg and Trm components and universal T cell exhaustion in human rashes, with a relative attenuation of antigen-presenting cells. Skin-resident memory T cells showed the greatest transcriptional dysregulation in both atopic dermatitis and psoriasis, whereas atopic dermatitis also demonstrated recurrent abnormalities in ILC and CD8+ cytotoxic lymphocytes. Transcript signatures differentiating these rash types included genes previously implicated in T helper cell (TH2)/TH17 diatheses, segregated in unbiased functional networks, and accurately identified disease class in untrained validation data sets. These gene signatures were able to classify clinicopathologically ambiguous rashes with diagnoses consistent with therapeutic response. Thus, we have defined major classes of human inflammatory skin disease at the molecular level and described a quantitative method to classify indeterminate instances of pathologic inflammation. To make this approach accessible to the scientific community, we created a proof-of-principle web interface (RashX), where scientists and clinicians can visualize their patient-level rash scRNA-seq-derived data in the context of our TH2/TH17 transcriptional framework.
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Affiliation(s)
- Yale Liu
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, ShaanXi 710004, P. R. China
- Department of Dermatology, University of California, San Francisco, San Francisco, CA 94107, USA
- Dermatology, Veterans Affairs Medical Center, San Francisco, CA 94121, USA
| | - Hao Wang
- Department of Statistics, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Mark Taylor
- Department of Dermatology, University of California, San Francisco, San Francisco, CA 94107, USA
| | - Christopher Cook
- Department of Dermatology, University of California, San Francisco, San Francisco, CA 94107, USA
- Dermatology, Veterans Affairs Medical Center, San Francisco, CA 94121, USA
| | | | - Jeffrey P North
- Department of Dermatology, University of California, San Francisco, San Francisco, CA 94107, USA
| | - Paymann Harirchian
- Department of Dermatology, University of California, San Francisco, San Francisco, CA 94107, USA
- Dermatology, Veterans Affairs Medical Center, San Francisco, CA 94121, USA
| | - Ashley A Hailer
- Department of Dermatology, University of California, San Francisco, San Francisco, CA 94107, USA
- Dermatology, Veterans Affairs Medical Center, San Francisco, CA 94121, USA
| | - Zijun Zhao
- Santa Clara Valley Medical Center, Santa Clara, CA 95128, USA
| | - Ruby Ghadially
- Department of Dermatology, University of California, San Francisco, San Francisco, CA 94107, USA
- Dermatology, Veterans Affairs Medical Center, San Francisco, CA 94121, USA
| | - Roberto R Ricardo-Gonzalez
- Department of Dermatology, University of California, San Francisco, San Francisco, CA 94107, USA
- Department of Immunology and Microbiology, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Roy C Grekin
- Department of Dermatology, University of California, San Francisco, San Francisco, CA 94107, USA
| | - Theodora M Mauro
- Department of Dermatology, University of California, San Francisco, San Francisco, CA 94107, USA
- Dermatology, Veterans Affairs Medical Center, San Francisco, CA 94121, USA
| | - Esther Kim
- Department of Plastic Surgery, University of California, San Francisco, San Francisco, CA 94107, USA
| | - Jaehyuk Choi
- Department of Dermatology, Northwestern School of Medicine, Chicago, IL 60611, USA
| | - Elizabeth Purdom
- Department of Statistics, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Raymond J Cho
- Department of Dermatology, University of California, San Francisco, San Francisco, CA 94107, USA
| | - Jeffrey B Cheng
- Department of Dermatology, University of California, San Francisco, San Francisco, CA 94107, USA
- Dermatology, Veterans Affairs Medical Center, San Francisco, CA 94121, USA
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13
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Xiao H, Dong Y, Xiao L, Liang X, Zheng J. Identification of key gene contributing to vitiligo by immune infiltration. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2022; 15:157-167. [PMID: 35535201 PMCID: PMC9077110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 02/26/2022] [Indexed: 06/14/2023]
Abstract
BACKGROUND A deeper understanding of new prognostic and diagnostic biomarkers for vitiligo, an autoimmune disease, is needed. The purpose of this study is to identify the underlying long noncoding RNAs (lncRNAs) and immune infiltration related to the cause of vitiligo. METHODS The microarray data (GSE75819) were available to be downloaded from NCBI-GEO. Eight hub genes were identified from the Protein-protein interaction (PPI) network by the dissection of differentially expressed genes (DEG), Kyoto Gene and Genomic Encyclopedia (KEGG) expansion pathway, and Gene Ontology (GO). Further analysis based on the immune infiltration as well as the correlation between DEGs and immune cells was performed. Our conclusions were verified by using the GSE534 eventually. RESULTS According to our analysis, we obtained a total of 666 DEGs and 8 hub genes that include ECT2, CCT8, VRK1, UQCRH, EBNA1BP2, CRY2, IFIH1, and BCCIP, which may play an important role in vitiligo. Moreover, the immune infiltration profiles varied significantly between normal and vitiligo tissues. Compared with normal tissues, vitiligo tissues contained a greater proportion of mast cells (P<0.05). The analysis revealed that T cells regulatory (Tregs) have a negative correlation with the VRK1 expression (R=-0:77, P<0.001), whereas the mast cells resting have a positive correlation with the VRK1 expression (R=0:72, P<0.001) in vitiligo. CONCLUSION The gene expression profile of vitiligo was realized by a bioinformatics method. The expressions of 8 hub genes and 22 immune cells were found, as the same as CRY2 and VRK1 have a special correlation with immune cells, which may be a significant cause of the pathogenesis of vitiligo. This provides a new idea for the diagnosis and treatment of vitiligo.
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Affiliation(s)
- Hefang Xiao
- Department of Orthopedics, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, School of Clinical Medicine, Zhengzhou UniversityNo. 7 Weiwu Road, Jinshui District, Zhengzhou, Henan, China
| | - Yonghui Dong
- Department of Orthopedics, Henan Provincial People’s HospitalZhengzhou, Henan, China
| | - Likang Xiao
- Department of Orthopedics, Henan Provincial People’s HospitalZhengzhou, Henan, China
| | - Xiaming Liang
- Department of Orthopedics, Henan Provincial People’s HospitalZhengzhou, Henan, China
| | - Jia Zheng
- Department of Orthopedics, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, School of Clinical Medicine, Zhengzhou UniversityNo. 7 Weiwu Road, Jinshui District, Zhengzhou, Henan, China
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14
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Saluzzo S, Pandey RV, Gail LM, Dingelmaier-Hovorka R, Kleissl L, Shaw L, Reininger B, Atzmüller D, Strobl J, Touzeau-Römer V, Beer A, Staud C, Rieger A, Farlik M, Weninger W, Stingl G, Stary G. Delayed antiretroviral therapy in HIV-infected individuals leads to irreversible depletion of skin- and mucosa-resident memory T cells. Immunity 2021; 54:2842-2858.e5. [PMID: 34813775 DOI: 10.1016/j.immuni.2021.10.021] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 07/20/2021] [Accepted: 10/27/2021] [Indexed: 02/07/2023]
Abstract
People living with HIV (PLWH) are at increased risk for developing skin and mucosal malignancies despite systemic reconstitution of CD4+ T cells upon antiretroviral therapy (ART). The underlying mechanism of chronic tissue-related immunodeficiency in HIV is unclear. We found that skin CD4+ tissue-resident memory T (Trm) cells were depleted after HIV infection and replenished only upon early ART initiation. TCR clonal analysis following early ART suggested a systemic origin for reconstituting CD4+ Trm cells. Single-cell RNA sequencing in PLWH that received late ART treatment revealed a loss of CXCR3+ Trm cells and a tolerogenic skin immune environment. Human papilloma virus-induced precancerous lesion biopsies showed reduced CXCR3+ Trm cell frequencies in the mucosa in PLWH versus HIV- individuals. These results reveal an irreversible loss of CXCR3+ Trm cells confined to skin and mucosa in PLWH who received late ART treatment, which may be a precipitating factor in the development of HPV-related cancer.
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Affiliation(s)
- Simona Saluzzo
- Department of Dermatology, Medical University of Vienna, Vienna 1090, Austria.
| | - Ram Vinay Pandey
- Department of Dermatology, Medical University of Vienna, Vienna 1090, Austria
| | - Laura Marie Gail
- Department of Dermatology, Medical University of Vienna, Vienna 1090, Austria; LBI-RUD - Ludwig-Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna 1090, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria
| | | | - Lisa Kleissl
- Department of Dermatology, Medical University of Vienna, Vienna 1090, Austria; LBI-RUD - Ludwig-Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna 1090, Austria
| | - Lisa Shaw
- Department of Dermatology, Medical University of Vienna, Vienna 1090, Austria
| | - Bärbel Reininger
- Department of Dermatology, Medical University of Vienna, Vienna 1090, Austria
| | - Denise Atzmüller
- Department of Dermatology, Medical University of Vienna, Vienna 1090, Austria; LBI-RUD - Ludwig-Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna 1090, Austria
| | - Johanna Strobl
- Department of Dermatology, Medical University of Vienna, Vienna 1090, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria
| | | | - Andrea Beer
- Department of Pathology, Medical University of Vienna, Vienna 1090, Austria
| | - Clement Staud
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Vienna 1090, Austria
| | - Armin Rieger
- Department of Dermatology, Medical University of Vienna, Vienna 1090, Austria
| | - Matthias Farlik
- Department of Dermatology, Medical University of Vienna, Vienna 1090, Austria
| | - Wolfgang Weninger
- Department of Dermatology, Medical University of Vienna, Vienna 1090, Austria
| | - Georg Stingl
- Department of Dermatology, Medical University of Vienna, Vienna 1090, Austria
| | - Georg Stary
- Department of Dermatology, Medical University of Vienna, Vienna 1090, Austria; LBI-RUD - Ludwig-Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna 1090, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.
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15
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Assessment of the Tissue Resident Memory Cells in Lesional Skin of Patients with Psoriasis and in Healthy Skin of Healthy Volunteers. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph182111251. [PMID: 34769769 PMCID: PMC8582754 DOI: 10.3390/ijerph182111251] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/22/2021] [Accepted: 10/24/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND In the course of plaque psoriasis, tissue resident memory cells (TRM) are responsible for the phenomenon of "immune memory" of lesions, i.e., the appearance of recurrences of lesions in the same location, as well as Koebner phenomenon. We present results determining the location and amount of TRM in psoriatic lesions in patients suffering from plaque psoriasis, as well as an analysis of the relationship between TRM markers expression and the duration and severity of the disease. METHODS TRM markers (CD4, CD8, CD103, CD69, CD49, CXCR6) and tissue expression of cytokines (IL-17, IL-22) in the lesional psoriatic skin of 32 patients compared with 10 healthy skin samples were evaluated by immunohistochemistry. RESULTS The presence of TRM markers in both the epidermis and skin with psoriatic eruptions was demonstrated in much higher amounts compared with the skin of healthy volunteers. A significant positive relationship was demonstrated between the expression of TRM markers in patients with plaque psoriasis and the duration of skin lesions. There was no relationship between the amount of TRM and the severity of plaque psoriasis. CONCLUSIONS A thorough understanding of the mechanisms responsible for the development and relapse of plaque psoriasis may contribute to the implementation of more effective therapies.
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Shah F, Patel S, Begum R, Dwivedi M. Emerging role of Tissue Resident Memory T cells in vitiligo: From pathogenesis to therapeutics. Autoimmun Rev 2021; 20:102868. [PMID: 34118458 DOI: 10.1016/j.autrev.2021.102868] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 03/20/2021] [Indexed: 02/07/2023]
Abstract
Vitiligo is an acquired depigmenting disorder which affects both skin and mucous membranes and autoimmunity has been strongly suggested to play a role in loss of melanocytes. The recurrence of skin macules at the same sites where they were observed prior to the treatment, suggests the existence of Tissue Resident Memory T cells (TRMs) that persist within the skin or peripheral tissues with a longer survivability. Emerging studies have shown that reactivation of these skin TRMs results into autoreactive TRM cells in various autoimmune diseases including vitiligo. This review focuses on different subsets (CD8+ TRMs and CD4+ TRMs) of TRM cells, their retention and survivability in the skin along with their pathomechanisms leading to melanocyte death and progression of vitiligo. In addition, the review describes the TRM cells as potential targets for developing effective therapeutics of vitiligo.
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Affiliation(s)
- Firdosh Shah
- C. G. Bhakta Institute of Biotechnology, Uka Tarsadia University, Tarsadi, Surat 394350, Gujarat, India
| | - Shivani Patel
- C. G. Bhakta Institute of Biotechnology, Uka Tarsadia University, Tarsadi, Surat 394350, Gujarat, India
| | - Rasheedunnisa Begum
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara 390 002, Gujarat, India
| | - Mitesh Dwivedi
- C. G. Bhakta Institute of Biotechnology, Uka Tarsadia University, Tarsadi, Surat 394350, Gujarat, India.
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17
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Lin F, Sun X, Lei J, Xu AE. Altered circulating memory T cells in vitiligo cases followed NB-UVB therapy. PHOTODERMATOLOGY PHOTOIMMUNOLOGY & PHOTOMEDICINE 2021; 38:76-82. [PMID: 34265118 PMCID: PMC9292791 DOI: 10.1111/phpp.12719] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 06/11/2021] [Accepted: 07/10/2021] [Indexed: 11/28/2022]
Abstract
Background Vitiligo represents a commonly diagnosed autoimmune disease caused by the depletion of epidermal melanocytes. Many subsets of T cells contribute to vitiligo pathogenesis, including resident and circulating memory T cells. Objectives To analyze the amounts of CD4+ and CD8+memory T‐cell subsets in peripheral blood specimens from vitiligo patients and alterations caused by narrowband ultraviolet B (NB‐UVB) phototherapy. Methods Circulating CD4+ and CD8+ central memory T (TCM) and effector memory T (TEM) cell frequencies in 33 patients with non‐segmental vitiligo and 16 healthy donors were evaluated by flow cytometry. Related chemokine levels were also detected. Results Peripheral blood CD4+ TCM and CD8+ TCM counts were markedly reduced in vitiligo cases while they were higher in active vitiligo compared with stable vitiligo cases. Circulating CD8+ TCM frequency in vitiligo was closely related to disease duration. Interestingly, CD4+ TCM and CD8+ TCM frequencies, alongside CXCL9 and CXCL10 amounts in peripheral blood of patients with vitiligo, were significantly decreased after NB‐UVB phototherapy. Conclusions Decreased frequencies of circulating CD4+ TCM and CD8+ TCM by NB‐UVB suggest a possible immunosuppressive effect of phototherapy. The chemokines CXCL9 and CXCL10 are the bridge between circulating and skin resident memory T cells. NB‐UVB blocks the homing of circulating memory T cells into vitiligo lesions by down‐regulating CXCL9 and CXCL10. Targeting the above proteins could provide novel, durable treatment options to cure and prevent flares of this disease.
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Affiliation(s)
- Fuquan Lin
- Department of Dermatology, Hangzhou Third People's Hospital, Affiliated Hangzhou Dermatology Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiukun Sun
- Department of Dermatology, Hangzhou Third People's Hospital, Affiliated Hangzhou Dermatology Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiehao Lei
- Department of Dermatology, Hangzhou Third People's Hospital, Affiliated Hangzhou Dermatology Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ai-E Xu
- Department of Dermatology, Hangzhou Third People's Hospital, Affiliated Hangzhou Dermatology Hospital, Zhejiang University School of Medicine, Hangzhou, China
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18
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Toh JWT, Ferguson AL, Spring KJ, Mahajan H, Palendira U. Cytotoxic CD8+ T cells and tissue resident memory cells in colorectal cancer based on microsatellite instability and BRAF status. World J Clin Oncol 2021; 12:238-248. [PMID: 33959477 PMCID: PMC8085513 DOI: 10.5306/wjco.v12.i4.238] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 03/14/2021] [Accepted: 04/05/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Recent studies in non-colorectal malignancy have associated T resident memory (TRM) cells with improved patient survival. It is unknown if TRM plays a role in colorectal cancer (CRC).
AIM To examine the potential role of TRM cells in providing immunogenicity in CRC stratified by microsatellite instability (MSI) and BRAF status.
METHODS Patients with known MSI and BRAF mutation status were eligible for inclusion in this study. CRC tumour sections stained with haematoxylin and eosin were microscopically reviewed and the images scanned prior to assessment for location of invading edge and core of tumour. Sequential sections were prepared for quantitative multiplex immunohistochemistry (IHC) staining. Opal Multiplex IHC staining was performed with appropriate positive and negative controls and imaged using a standard fluorescent microscope fitted with a spectral scanning camera (Mantra) in conjunction with Mantra snap software. Images were unmixed and annotated in inForm 2.2.0. Statistical analysis was performed using Graphpad Prism Version 7 and Stata Version 15.
RESULTS Seventy-two patients with known MSI and BRAF status were included in the study. All patients were assessed for MSI by IHC and high resolution capillary electrophoresis testing and 44 of these patients successfully underwent quantitative multiplex IHC staining. Overall, there was a statistically significant increase in CD8+ TRM cells in the MSI (BRAF mutant and wild type) group over the microsatellite stable (MSS) group. There was a statistically significant difference in CD8+ TRM between high level MSI (MSI-H):BRAF mutant [22.57, 95% confidence interval (CI): 14.31-30.84] vs MSS [8.031 (95%CI: 4.698-11.36)], P = 0.0076 andMSI-H:BRAF wild type [16.18 (95%CI: 10.44-21.93)] vs MSS [8.031 (95%CI: 4.698-11.36)], P = 0.0279. There was no statistically significant difference in CD8 T cells (both CD8+CD103- and CD8+CD103+TRM) between MSI-H: BRAF mutant and wild type CRC.
CONCLUSION This study has shown that CD8+ TRM are found in greater abundance in MSI-H CRC, both BRAF mutant and MSI-H:BRAF wild type, when compared with their MSS counterpart. CD8+ TRM may play a role in the immunogenicity in MSI-H CRC (BRAF mutant and BRAF wild type). Further studies should focus on the potential immunogenic qualities of TRM cells and investigate potential immunotherapeutic approaches to improve treatment and survival associated with CRC.
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Affiliation(s)
- James Wei Tatt Toh
- Division of Surgery and Anaesthesia, Department of Colorectal Surgery, Westmead Hospital, Westmead Clinical School, The University of Sydney, Ingham Institute for Applied Medical Research, Westmead 2145, NSW, Australia
| | - Angela L Ferguson
- Department of Infectious Diseases and Immunology, School of Medical Sciences, Faculty of Medicine and Health, Human Viral & Cancer Immunology, Centenary Institute, Charles Perkin Centre, The University of Sydney, Sydney 2000, NSW, Australia
| | - Kevin J Spring
- Medical Oncology Group, Ingham Institute for Applied Medical Research, Liverpool Hospital, Liverpool Clinical School, University of Western Sydney, South Western Clinical School UNSW, Liverpool 2170, NSW, Australia
| | - Hema Mahajan
- Department of Anatomical Pathology, ICPMR, Westmead Hospital, Westmead 2145, NSW, Australia
| | - Umaimainthan Palendira
- Department of Immunology and Infectious Diseases, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney 2000, NSW, Australia
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19
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Boniface K, Passeron T, Seneschal J, Tulic MK. Targeting Innate Immunity to Combat Cutaneous Stress: The Vitiligo Perspective. Front Immunol 2021; 12:613056. [PMID: 33936032 PMCID: PMC8079779 DOI: 10.3389/fimmu.2021.613056] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 03/22/2021] [Indexed: 02/06/2023] Open
Abstract
Multiple factors are involved in the process leading to melanocyte loss in vitiligo including environmental triggers, genetic polymorphisms, metabolic alterations, and autoimmunity. This review aims to highlight current knowledge on how danger signals released by stressed epidermal cells in a predisposed patient can trigger the innate immune system and initiate a cascade of events leading to an autoreactive immune response, ultimately contributing to melanocyte disappearance in vitiligo. We will explore the genetic data available, the specific role of damage-associated-molecular patterns, and pattern-recognition receptors, as well as the cellular players involved in the innate immune response. Finally, the relevance of therapeutic strategies targeting this pathway to improve this inflammatory and autoimmune condition is also discussed.
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Affiliation(s)
- Katia Boniface
- Univ. Bordeaux, INSERM, BMGIC, U1035, Immuno-dermatology Team, Bordeaux, France
| | - Thierry Passeron
- INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Côte d'Azur University, Nice, France.,Côte d'Azur University, Department of Dermatology, CHU Nice, Nice, France
| | - Julien Seneschal
- Univ. Bordeaux, INSERM, BMGIC, U1035, Immuno-dermatology Team, Bordeaux, France.,Department of Dermatology and Pediatric Dermatology, National Reference Center for Rare Skin Disorders, Hôpital Saint-André, Bordeaux, France
| | - Meri K Tulic
- INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Côte d'Azur University, Nice, France
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20
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Chen J, Li S, Li C. Mechanisms of melanocyte death in vitiligo. Med Res Rev 2021; 41:1138-1166. [PMID: 33200838 PMCID: PMC7983894 DOI: 10.1002/med.21754] [Citation(s) in RCA: 135] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 10/16/2020] [Accepted: 11/01/2020] [Indexed: 12/12/2022]
Abstract
Vitiligo is an autoimmune depigment disease results from extensive melanocytes destruction. The destruction of melanocyte is thought to be of multifactorial causation. Genome-wide associated studies have identified single-nucleotide polymorphisms in a panel of susceptible loci as risk factors in melanocyte death. But vitiligo onset can't be solely attributed to a susceptive genetic background. Oxidative stress triggered by elevated levels of reactive oxygen species accounts for melanocytic molecular and organelle dysfunction, a minority of melanocyte demise, and melanocyte-specific antigens exposure. Of note, the self-responsive immune function directly contributes to the bulk of melanocyte deaths in vitiligo. The aberrantly heightened innate immunity, type-1-skewed T helper, and incompetent regulatory T cells tip the balance toward autoreaction and CD8+ cytotoxic T lymphocytes finally execute the killing of melanocytes, possibly alarmed by resident memory T cells. In addition to the well-established apoptosis and necrosis, we discuss several death modalities like oxeiptosis, ferroptosis, and necroptosis that are probably employed in melanocyte destruction. This review focuses on the various mechanisms of melanocytic death in vitiligo pathogenesis to demonstrate a panorama of that. We hope to provide new insights into vitiligo pathogenesis and treatment strategies by the review.
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Affiliation(s)
- Jianru Chen
- Department of DermatologyXijing hospital, Fourth Military Medical UniversityXi'anShannxiChina
| | - Shuli Li
- Department of DermatologyXijing hospital, Fourth Military Medical UniversityXi'anShannxiChina
| | - Chunying Li
- Department of DermatologyXijing hospital, Fourth Military Medical UniversityXi'anShannxiChina
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21
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Zhang J, Yu S, Hu W, Wang M, Abudoureyimu D, Luo D, Li T, Long L, Zeng H, Cheng C, Lei Z, Teng J, Kang X. Comprehensive Analysis of Cell Population Dynamics and Related Core Genes During Vitiligo Development. Front Genet 2021; 12:627092. [PMID: 33679890 PMCID: PMC7933673 DOI: 10.3389/fgene.2021.627092] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 01/26/2021] [Indexed: 11/25/2022] Open
Abstract
Vitiligo is a common immune-related depigmentation condition, and its pathogenesis remains unclear. This study used a combination of bioinformatics methods and expression analysis techniques to explore the relationship between immune cell infiltration and gene expression in vitiligo. Previously reported gene expression microarray data from the skin (GSE53146 and GSE75819) and peripheral blood (GSE80009 and GSE90880) of vitiligo patients and healthy controls was used in the analysis. R software was used to filter the differentially expressed genes (DEGs) in each dataset, and the KOBAS 2.0 server was used to perform functional enrichment analysis. Compared with healthy controls, the upregulated genes in skin lesions and peripheral blood leukocytes of vitiligo patents were highly enriched in immune response pathways and inflammatory response signaling pathways. Immunedeconv software and the EPIC method were used to analyze the expression levels of marker genes to obtain the immune cell population in the samples. In the lesional skin of vitiligo patients, the proportions of macrophages, B cells and NK cells were increased compared with healthy controls. In the peripheral blood of vitiligo patients, CD8+ T cells and macrophages were significantly increased. A coexpression analysis of the cell populations and DEGs showed that differentially expressed immune and inflammation response genes had a strong positive correlation with macrophages. The TLR4 receptor pathway, interferon gamma-mediated signaling pathway and lipopolysaccharide-related pathway were positively correlated with CD4+ T cells. Regarding immune response-related genes, the overexpression of IFITM2, TNFSF10, GZMA, ADAMDEC1, NCF2, ADAR, SIGLEC16, and WIPF2 were related to macrophage abundance, while the overexpression of ICOS, GPR183, RGS1, ILF2 and CD28 were related to CD4+ T cell abundance. GZMA and CXCL10 expression were associated with CD8+ T cell abundance. Regarding inflammatory response-related genes, the overexpression of CEBPB, ADAM8, CXCR3, and TNIP3 promoted macrophage infiltration. Only ADORA1 expression was associated with CD4+ T cell infiltration. ADAM8 and CXCL10 expression were associated with CD8+ T cell abundance. The overexpression of CCL18, CXCL10, FOS, NLRC4, LY96, HCK, MYD88, and KLRG1, which are related to inflammation and immune responses, were associated with macrophage abundance. We also found that immune cells infiltration in vitiligo was associated with antigen presentation-related genes expression. The genes and pathways identified in this study may point to new directions for vitiligo treatment.
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Affiliation(s)
- Jingzhan Zhang
- Department of Dermatology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
- Xinjiang Key Laboratory of Dermatology Research, Urumqi, China
| | - Shirong Yu
- Department of Dermatology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
- Xinjiang Key Laboratory of Dermatology Research, Urumqi, China
| | - Wen Hu
- Department of Dermatology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
- Xinjiang Key Laboratory of Dermatology Research, Urumqi, China
| | - Man Wang
- Department of Gastroenterology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Dilinuer Abudoureyimu
- Department of Dermatology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
- Xinjiang Key Laboratory of Dermatology Research, Urumqi, China
| | - Dong Luo
- Department of Dermatology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
- Xinjiang Key Laboratory of Dermatology Research, Urumqi, China
| | - Tingting Li
- Department of Dermatology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
- Xinjiang Key Laboratory of Dermatology Research, Urumqi, China
| | - Linglong Long
- Department of Dermatology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
- Xinjiang Key Laboratory of Dermatology Research, Urumqi, China
| | - Hui Zeng
- Center for Genome Analysis, ABLife Inc., Wuhan, China
| | - Chao Cheng
- Center for Genome Analysis, ABLife Inc., Wuhan, China
| | - Zixian Lei
- Department of Dermatology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
- Xinjiang Key Laboratory of Dermatology Research, Urumqi, China
| | - Jianan Teng
- Department of Dermatology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
- Medical School, Shihezi University, Shihezi, China
| | - Xiaojing Kang
- Department of Dermatology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
- Xinjiang Key Laboratory of Dermatology Research, Urumqi, China
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22
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Tokura Y, Phadungsaksawasdi P, Kurihara K, Fujiyama T, Honda T. Pathophysiology of Skin Resident Memory T Cells. Front Immunol 2021; 11:618897. [PMID: 33633737 PMCID: PMC7901930 DOI: 10.3389/fimmu.2020.618897] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 12/21/2020] [Indexed: 12/11/2022] Open
Abstract
Tissue resident memory T (TRM) cells reside in peripheral, non-lymphoid tissues such as the skin, where they act as alarm-sensor cells or cytotoxic cells. Physiologically, skin TRM cells persist for a long term and can be reactivated upon reinfection with the same antigen, thus serving as peripheral sentinels in the immune surveillance network. CD8+CD69+CD103+ TRM cells are the well-characterized subtype that develops in the epidermis. The local mediators such as interleukin (IL)-15 and transforming growth factor (TGF)-β are required for the formation of long-lived TRM cell population in skin. Skin TRM cells engage virus-infected cells, proliferate in situ in response to local antigens and do not migrate out of the epidermis. Secondary TRM cell populations are derived from pre-existing TRM cells and newly recruited TRM precursors from the circulation. In addition to microbial pathogens, topical application of chemical allergen to skin causes delayed-type hypersensitivity and amplifies the number of antigen-specific CD8+ TRM cells at challenged site. Skin TRM cells are also involved in the pathological conditions, including vitiligo, psoriasis, fixed drug eruption and cutaneous T-cell lymphoma (CTCL). The functions of these TRM cells seem to be different, depending on each pathology. Psoriasis plaques are seen in a recurrent manner especially at the originally affected sites. Upon stimulation of the skin of psoriasis patients, the CD8+CD103+CD49a- TRM cells in the epidermis seem to be reactivated and initiate IL-17A production. Meanwhile, autoreactive CD8+CD103+CD49a+ TRM cells secreting interferon-γ are present in lesional vitiligo skin. Fixed drug eruption is another disease where skin TRM cells evoke its characteristic clinical appearance upon administration of a causative drug. Intraepidermal CD8+ TRM cells with an effector-memory phenotype resident in the skin lesions of fixed drug eruption play a major contributing role in the development of localized tissue damage. CTCL develops primarily in the skin by a clonal expansion of a transformed TRM cells. CD8+ CTCL with the pagetoid epidermotropic histology is considered to originate from epidermal CD8+ TRM cells. This review will discuss the current understanding of skin TRM biology and their contribution to skin homeostasis and diseases.
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Affiliation(s)
- Yoshiki Tokura
- Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.,Department of Cellular & Molecular Anatomy, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | | | - Kazuo Kurihara
- Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Toshiharu Fujiyama
- Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Tetsuya Honda
- Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan
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23
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Le Poole IC. Myron Gordon Award paper: Microbes, T-cell diversity and pigmentation. Pigment Cell Melanoma Res 2021; 34:244-255. [PMID: 33438345 DOI: 10.1111/pcmr.12957] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 12/12/2020] [Accepted: 12/25/2020] [Indexed: 12/15/2022]
Abstract
Melanocytes are static, minimally proliferative cells. This leaves them vulnerable in vitiligo. Yet upon malignant transformation, they form vicious tumors. This profound switch in physiology is accompanied by genetic change and is driven by environmental factors. If UV exposure in younger years supports malignant transformation and melanoma formation, it can likewise impart mutations on melanocytes that reduce their viability, to initiate vitiligo. A wide variety of microbes can influence these diametrically opposed outcomes before either disease takes hold. These microbes are vehicles of change that we are only beginning to study. Once a genetic modification occurs, there is a wide variety of immune cells ready to respond. Though it does not act alone, the T cell is among the most decisive responders in this process. The same biochemical process that offered the skin protection by producing melanin can become an Achilles heel for the cell when the T cells target melanosomal enzymes or, on occasion, neoantigens. T cells are precise, determined, and consequential when they strike. Here, we probe the relationship between the microbiome and its metabolites, epithelial integrity, and the activation of T cells that target benign and malignant melanocytes in vitiligo and melanoma.
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Affiliation(s)
- I Caroline Le Poole
- Department of Dermatology, Microbiology and Immunology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University at Chicago, Chicago, IL, USA
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24
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Aghamajidi A, Raoufi E, Parsamanesh G, Jalili A, Salehi-Shadkami M, Mehrali M, Mohsenzadegan M. The attentive focus on T cell-mediated autoimmune pathogenesis of psoriasis, lichen planus and vitiligo. Scand J Immunol 2020; 93:e13000. [PMID: 33190330 DOI: 10.1111/sji.13000] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 09/16/2020] [Accepted: 11/10/2020] [Indexed: 12/14/2022]
Abstract
T cell-mediated autoimmune skin diseases develop as a result of the aberrant immune response to the skin cells with T cells playing a central role. These chronic inflammatory skin diseases encompass various types including psoriasis, lichen planus and vitiligo. These diseases show similarities in their immune-pathophysiology. In the last decade, immunomodulating agents have been very successful in the management of these diseases thanks to a better understanding of the pathophysiology. In this review, we will discuss the immunopathogenic mechanisms and highlight the role of T lymphocytes in psoriasis, lichen planus and vitiligo. This study could provide new insights into a better understanding of targeted therapeutic pathways and biological therapies.
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Affiliation(s)
- Azin Aghamajidi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ehsan Raoufi
- Department of Medical Biotechnology, School of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Gilda Parsamanesh
- Department of Immunology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Ahmad Jalili
- Dermatology & Skin Care, Buergenstock Medical Center, Obbuergen, Switzerland
| | - Mohammad Salehi-Shadkami
- Student Research Committee, School of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Marjan Mehrali
- Student Research Committee, School of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Monireh Mohsenzadegan
- Department of Medical Laboratory Science, Faculty of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran
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25
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Scott P. Long-Lived Skin-Resident Memory T Cells Contribute to Concomitant Immunity in Cutaneous Leishmaniasis. Cold Spring Harb Perspect Biol 2020; 12:cshperspect.a038059. [PMID: 32839202 DOI: 10.1101/cshperspect.a038059] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Memory T cells, which protect against reinfection in many diseases, have predominantly been characterized in models of acute viral or bacterial infection. In contrast, memory T cells are less well understood in diseases where pathogens persist following disease resolution, such as leishmaniasis, in spite of the fact that these infections often lead to immunity to reinfection, termed concomitant immunity. Defining the T cells that mediate concomitant immunity is an important step in developing vaccines for these diseases. One set of protective T cells are short-lived effector T cells requiring constant stimulation, which would be difficult to maintain by vaccination. However, parasite-independent memory T cells, including central memory T cells (Tcm) and skin-resident T cells (Trm) have recently been described in leishmaniasis. Given their location, Trm cells are particularly suited for protection, and were found to globally seed the skin following Leishmania infection or immunization. Upon challenge, Trm cells rapidly respond to reduce the parasite burden, suggesting that developing strategies to generate parasite-independent Trm cells will be an important step in the quest for a successful leishmaniasis vaccine.
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Affiliation(s)
- Phillip Scott
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-4539, USA
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MicroRNA-21-Enriched Exosomes as Epigenetic Regulators in Melanomagenesis and Melanoma Progression: The Impact of Western Lifestyle Factors. Cancers (Basel) 2020; 12:cancers12082111. [PMID: 32751207 PMCID: PMC7464294 DOI: 10.3390/cancers12082111] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 07/16/2020] [Accepted: 07/24/2020] [Indexed: 02/06/2023] Open
Abstract
DNA mutation-induced activation of RAS-BRAF-MEK-ERK signaling associated with intermittent or chronic ultraviolet (UV) irradiation cannot exclusively explain the excessive increase of malignant melanoma (MM) incidence since the 1950s. Malignant conversion of a melanocyte to an MM cell and metastatic MM is associated with a steady increase in microRNA-21 (miR-21). At the epigenetic level, miR-21 inhibits key tumor suppressors of the RAS-BRAF signaling pathway enhancing proliferation and MM progression. Increased MM cell levels of miR-21 either result from endogenous upregulation of melanocytic miR-21 expression or by uptake of miR-21-enriched exogenous exosomes. Based on epidemiological data and translational evidence, this review provides deeper insights into environmentally and metabolically induced exosomal miR-21 trafficking beyond UV-irradiation in melanomagenesis and MM progression. Sources of miR-21-enriched exosomes include UV-irradiated keratinocytes, adipocyte-derived exosomes in obesity, airway epithelium-derived exosomes generated by smoking and pollution, diet-related exosomes and inflammation-induced exosomes, which may synergistically increase the exosomal miR-21 burden of the melanocyte, the transformed MM cell and its tumor environment. Several therapeutic agents that suppress MM cell growth and proliferation attenuate miR-21 expression. These include miR-21 antagonists, metformin, kinase inhibitors, beta-blockers, vitamin D, and plant-derived bioactive compounds, which may represent new options for the prevention and treatment of MM.
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27
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Abstract
Linked Article:Martins et al. Br J Dermatol 2020; 183:899–908.
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Affiliation(s)
- T R Matos
- Department of Dermatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
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28
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Hirai T, Whitley SK, Kaplan DH. Migration and Function of Memory CD8 + T Cells in Skin. J Invest Dermatol 2020; 140:748-755. [PMID: 31812277 PMCID: PMC7573784 DOI: 10.1016/j.jid.2019.09.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 09/17/2019] [Accepted: 09/26/2019] [Indexed: 12/21/2022]
Abstract
CD8+ memory T cells provide anamnestic host defense against intracellular pathogens and cancer immunosurveillance but are also pathogenic in some autoimmune diseases. In mouse skin, there are two unique subsets of CD8+ memory T cells, resident memory cells that reside long-term in steady state skin and recirculating memory cells that are transient. They have distinct mechanisms of recruitment, development, and maintenance in response to skin-derived signals. In this review, we will focus on these mechanisms and the functional relationship of these two types of CD8+ memory cells with host defense and disease.
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Affiliation(s)
- Toshiro Hirai
- Department of Dermatology, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Sarah K Whitley
- Department of Dermatology, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Daniel H Kaplan
- Department of Dermatology, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.
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29
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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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30
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Chen L, Shen Z. Tissue-resident memory T cells and their biological characteristics in the recurrence of inflammatory skin disorders. Cell Mol Immunol 2019; 17:64-75. [PMID: 31595056 DOI: 10.1038/s41423-019-0291-4] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Accepted: 08/25/2019] [Indexed: 11/09/2022] Open
Abstract
The skin is the largest organ of the body. The establishment of immunological memory in the skin is a crucial component of the adaptive immune response. Once naive T cells are activated by antigen-presenting cells, a small fraction of them differentiate into precursor memory T cells. These precursor cells ultimately develop into several subsets of memory T cells, including central memory T (TCM) cells, effector memory T (TEM) cells, and tissue resident memory T (TRM) cells. TRM cells have a unique transcriptional profile, and their most striking characteristics are their long-term survival (longevity) and low migration in peripheral tissues, including the skin. Under physiological conditions, TRM cells that reside in the skin can respond rapidly to pathogenic challenges. However, there is emerging evidence to support the vital role of TRM cells in the recurrence of chronic inflammatory skin disorders, including psoriasis, vitiligo, and fixed drug eruption, under pathological or uncontrolled conditions. Clarifying and characterizing the mechanisms that are involved in skin TRM cells will help provide promising strategies for reducing the frequency and magnitude of skin inflammation recurrence. Here, we discuss recent insights into the generation, homing, retention, and survival of TRM cells and share our perspectives on the biological characteristics of TRM cells in the recurrence of inflammatory skin disorders.
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Affiliation(s)
- Ling Chen
- Department of Dermatology, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Zhu Shen
- Department of Dermatology, Institute of Dermatology and Venereology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital; School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.
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31
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Willemsen M, Linkutė R, Luiten RM, Matos TR. Skin-resident memory T cells as a potential new therapeutic target in vitiligo and melanoma. Pigment Cell Melanoma Res 2019; 32:612-622. [PMID: 31230406 PMCID: PMC6851629 DOI: 10.1111/pcmr.12803] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 05/16/2019] [Accepted: 06/14/2019] [Indexed: 12/13/2022]
Abstract
Tissue-resident memory T (TRM ) cells are abundant in the memory T cell pool and remain resident in peripheral tissues, such as the skin, where they act as alarm sensors or cytotoxic killers. TRM cells persist long after the pathogen is eliminated and can respond rapidly upon reinfection with the same antigen. When aberrantly activated, skin-located TRM cells have a profound role in various skin disorders, including vitiligo and melanoma. Autoreactive TRM cells are present in human lesional vitiligo skin and mouse models of vitiligo, which suggests that targeting these cells could be effective as a durable treatment strategy for vitiligo. Furthermore, emerging evidence indicates that induction of melanoma-reactive TRM cells is needed to achieve effective protection against tumor growth. This review highlights seminal reports about skin-resident T cells, focusing mainly on their role in the context of vitiligo and melanoma, as well as their potential as therapeutic targets in both diseases.
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Affiliation(s)
- Marcella Willemsen
- Department of Dermatology and Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, University of Amsterdam, Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam, the Netherlands
| | - Rugile Linkutė
- Department of Dermatology and Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, 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, University of Amsterdam, Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam, the Netherlands
| | - Tiago R Matos
- Department of Dermatology and Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, University of Amsterdam, Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam, the Netherlands
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