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Ghajar-Rahimi G, Yusuf N, Xu H. Ultraviolet Radiation-Induced Tolerogenic Dendritic Cells in Skin: Insights and Mechanisms. Cells 2025; 14:308. [PMID: 39996779 PMCID: PMC11854269 DOI: 10.3390/cells14040308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 02/12/2025] [Accepted: 02/14/2025] [Indexed: 02/26/2025] Open
Abstract
Ultraviolet (UV) radiation has profound effects on the immune system, including the induction of tolerogenic dendritic cells (DCs), which contribute to immune suppression and tolerance. This review explores the roles of conventional CD11c⁺ DCs, as well as cutaneous Langerhans cells and CD11b⁺ myeloid cells, in UV-induced immune modulation. Two key mechanisms underlying the immunosuppressive relationship between UV and DCs are discussed: the inactivation of DCs and the induction of tolerogenic DCs. DCs serve as a critical link between the innate and adaptive immune systems, serving as professional antigen-presenting cells. In this context, we explore how UV-induced DCs influence the activity of specific T cell subsets, including regulatory T lymphocytes and T helper cells, and shape immune outcomes. Finally, we highlight the implications of UV-induced tolerogenic DCs in select dermatologic pathologies, including cutaneous lupus, polymorphic light eruption, and skin cancer. Understanding the mechanisms by which UV radiation alters DC function offers insights into the complex interplay between environmental factors and immune regulation, providing potential avenues for preventive and therapeutic intervention in UV-induced skin diseases.
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Affiliation(s)
| | - Nabiha Yusuf
- Department of Dermatology, Heersink School of Medicine, University of Alabama, Birmingham, AL 35294, USA
| | - Hui Xu
- Department of Dermatology, Heersink School of Medicine, University of Alabama, Birmingham, AL 35294, USA
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2
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Karabatić Knezović S, Knezović D, Ban J, Matana A, Puizina Ivić N, Glavina Durdov M, Merćep M, Drmić Hofman I. Immunological Landscape of Non-Melanoma Skin Neoplasms: Role of CTLA4+IFN-γ+ Lymphocytes in Tumor Microenvironment Suppression. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:330. [PMID: 40005446 PMCID: PMC11857809 DOI: 10.3390/medicina61020330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 02/07/2025] [Accepted: 02/10/2025] [Indexed: 02/27/2025]
Abstract
Background and Objectives: This study explores the immunological landscapes of non-melanoma skin neoplasms (NMSNs), specifically keratoacanthoma (KA), squamous cell carcinoma (SCC), and common warts (VV). Although benign, KA shares histological similarities with low-grade SCC. The tumor microenvironment (TME) plays a key role in tumor progression, affecting angiogenesis, inflammation, and immune evasion. Viral infections, particularly human papillomavirus (HPV), are linked to NMSN development, with various HPV types identified in KA. VV, caused by HPV, serves as a comparative model due to its similar etiopathogenesis. Materials and Methods: This research examines the expression of CTLA4, a critical regulator of T-cell homeostasis, and IFN-γ, a cytokine with immunomodulatory and antiviral effects, in the TME of 41 KA, 37 SCC, and 55 VV samples using multichannel immunofluorescence. Results: The analysis revealed distinct patterns of CTLA4 and IFN-γ expression. SCC exhibited a higher prevalence of CTLA4+IFN-γ+ double-positive lymphocytes, suggesting a more immunosuppressive TME. In contrast, VV showed the highest expression of CTLA4+ cells, while both KA and VV had lower expressions of IFN-γ+ lymphocytes compared to SCC. The increased presence of CTLA4+IFN-γ+ double-positive lymphocytes in SCC suggests that the co-expression of these markers may exert a stronger effect on TME modulation than CTLA4 alone. Conclusions: These findings underscore the potential of immune profiling as a diagnostic tool to differentiate between benign and malignant lesions, such as KA and SCC. Furthermore, the presence of CTLA4+IFN-γ+ lymphocytes, particularly in SCC, may serve as a biomarker for tumor progression and a potential target for future immunotherapy strategies aimed at modulating the immune response in NMSN.
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Affiliation(s)
| | - Dora Knezović
- Laboratory for Cancer Research, School of Medicine, University of Split, 21000 Split, Croatia
| | - Jelena Ban
- Faculty of Biotechnology and Drug Development, University of Rijeka, 51000 Rijeka, Croatia; (J.B.); (M.M.)
| | - Antonela Matana
- University Department of Health Studies, University of Split, 21000 Split, Croatia;
| | - Neira Puizina Ivić
- Department of Dermatology, University Hospital of Split, 21000 Split, Croatia;
| | - Merica Glavina Durdov
- Department of Pathology, Forensic Medicine and Cytology, University Hospital of Split, 21000 Split, Croatia;
- Department of Pathology, School of Medicine, University of Split, 21000 Split, Croatia
| | - Mladen Merćep
- Faculty of Biotechnology and Drug Development, University of Rijeka, 51000 Rijeka, Croatia; (J.B.); (M.M.)
| | - Irena Drmić Hofman
- University Department of Health Studies, University of Split, 21000 Split, Croatia;
- Department of Medical Chemistry and Biochemistry, School of Medicine, University of Split, 21000 Split, Croatia
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3
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Schwarz A, Philippsen R, Schwarz T. Mouse Models of Allergic Contact Dermatitis: Practical Aspects. J Invest Dermatol 2023; 143:888-892. [PMID: 37211376 DOI: 10.1016/j.jid.2023.03.1668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 03/09/2023] [Indexed: 05/23/2023]
Abstract
Allergic contact dermatitis is a frequently observed dermatosis, especially in industrialized countries. Regarded as a classical type IV immune reaction (delayed type), the process can be separated into two pathogenetic parts: the induction phase where sensitization takes place and the elicitation phase in which inflammation is induced upon re-exposure to the same antigen. A murine model was established decades ago, which reliably reproduces both phases. Epicutaneously applied low-molecular-weight sensitizers bind to proteins (haptens) and become full antigens, which results in sensitization. Subsequent administration of the same hapten onto ear skin causes a swelling response. This reaction is antigen specific because it cannot be induced in nonsensitized mice or in sensitized mice with a different hapten. This model was used to study the mechanisms involved in allergic contact dermatitis and also was intensively utilized to study immunologic mechanisms, including antigen presentation and development of T effector or regulatory T cells. The model's major merit is its antigen specificity. It is highly reproducible, reliable, and simple to perform. In this paper, the methods of this technique are described to help researchers successfully establish this widely used model in laboratories. Describing the complex pathomechanisms underlying the model is beyond the scope of this article.
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Affiliation(s)
- Agatha Schwarz
- Department of Dermatology, Venereology and Allergology, University of Kiel, Kiel, Germany
| | - Rebecca Philippsen
- Department of Dermatology, Venereology and Allergology, University of Kiel, Kiel, Germany
| | - Thomas Schwarz
- Department of Dermatology, Venereology and Allergology, University of Kiel, Kiel, Germany.
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Maz MP, Martens JWS, Hannoudi A, Reddy AL, Hile GA, Kahlenberg JM. Recent advances in cutaneous lupus. J Autoimmun 2022; 132:102865. [PMID: 35858957 PMCID: PMC10082587 DOI: 10.1016/j.jaut.2022.102865] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/03/2022] [Accepted: 07/04/2022] [Indexed: 11/25/2022]
Abstract
Cutaneous lupus erythematosus (CLE) is an inflammatory and autoimmune skin condition that affects patients with systemic lupus erythematosus (SLE) and exists as an isolated entity without associated SLE. Flares of CLE, often triggered by exposure to ultraviolet (UV) light result in lost productivity and poor quality of life for patients and can be associated with trigger of systemic inflammation. In the past 10 years, the knowledge of CLE etiopathogenesis has grown, leading to promising targets for better therapies. Development of lesions likely begins in a pro-inflammatory epidermis, conditioned by excess type I interferon (IFN) production to undergo increased cell death and inflammatory cytokine production after UV light exposure. The reasons for this inflammatory predisposition are not well-understood, but may be an early event, as ANA + patients without criteria for autoimmune disease exhibit similar (although less robust) findings. Non-lesional skin of SLE patients also exhibits increased innate immune cell infiltration, conditioned by excess IFNs to release pro-inflammatory cytokines, and potentially increase activation of the adaptive immune system. Plasmacytoid dendritic cells are also found in non-lesional skin and may contribute to type I IFN production, although this finding is now being questioned by new data. Once the inflammatory cycle begins, lesional infiltration by numerous other cell populations ensues, including IFN-educated T cells. The heterogeneity amongst lesional CLE subtypes isn't fully understood, but B cells appear to discriminate discoid lupus erythematosus from other subtypes. Continued discovery will provide novel targets for additional therapeutic pursuits. This review will comprehensively discuss the contributions of tissue-specific and immune cell populations to the initiation and propagation of disease.
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Affiliation(s)
- Mitra P Maz
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA; Program in Immunology, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Jacob W S Martens
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA; Program in Immunology, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Andrew Hannoudi
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Alayka L Reddy
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Grace A Hile
- Department of Dermatology, University of Michigan, Ann Arbor, MI, 48109, USA
| | - J Michelle Kahlenberg
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Dermatology, University of Michigan, Ann Arbor, MI, 48109, USA.
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5
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Schwarz T, Schwarz A. Controllers of cutaneous regulatory T cells: ultraviolet radiation and the skin microbiome. Biol Chem 2021; 402:1575-1581. [PMID: 34506693 DOI: 10.1515/hsz-2021-0252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 08/19/2021] [Indexed: 11/15/2022]
Abstract
For the maintenance of homeostasis termination of immune reactions is as equally important as their induction. In this scenario regulatory T cells (Treg) play an important role. Accordingly a variety of inflammatory diseases are caused by an impairment of Treg. Hence, it is important to identify triggers by which Treg can be induced and activated, respectively. For quite a long time it is known that ultraviolet radiation can induce Treg which inhibit cutaneous immune reactions including contact hypersensitivity. Since these Treg inhibit in an antigen-specific fashion they may harbor therapeutic potential. However similar Treg can be induced also by other triggers which include vitamin D and antimicrobial peptides. Recently it was discovered that the gut microbiome controls the development of Treg in the intestine. The same may apply for the skin. Short chain fatty acids, microbiota-derived bacterial fermentation products, appear to induce and to activate Treg in the skin. Topical application of short chain fatty acids was shown to inhibit contact hypersensitivity and to reduce inflammation in the murine imiquimod-induced psoriasis-like skin inflammation model. Together, these data indicate that induction and activation of Treg may be a potential therapeutic strategy to treat inflammatory diseases in the future.
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Affiliation(s)
- Thomas Schwarz
- Department of Dermatology, University Clinics Schleswig-Holstein, Campus Kiel, Arnold-Heller-Strasse 3, D-24105 Kiel, Germany
| | - Agatha Schwarz
- Department of Dermatology, University Clinics Schleswig-Holstein, Campus Kiel, Arnold-Heller-Strasse 3, D-24105 Kiel, Germany
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6
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Gum Arabic-induced oral photoprotection: Shifting the balance against circulating immune suppressive cytokines. SCIENTIFIC AFRICAN 2021. [DOI: 10.1016/j.sciaf.2021.e00973] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
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7
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Goes HFDO, Virgens AR, de Carvalho GC, Pietrobon AJ, Branco ACCC, Oliveira LMDS, Fernandes IG, Pereira NV, Sotto MN, Dos Reis VMS, Sato MN. Proinflammatory and regulatory mechanisms in allergic contact dermatitis caused by methylchloroisothiazolinone and methylisothiazolinone. Exp Dermatol 2020; 29:490-498. [PMID: 32049375 DOI: 10.1111/exd.14086] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 01/17/2020] [Accepted: 02/05/2020] [Indexed: 12/23/2022]
Abstract
BACKGROUND Methylchloroisothiazolinone (MCI) and methylisothiazolinone (MI) are the cause of an increasing number of contact allergies. Understanding the mechanisms by which MCI/MI induces proinflammatory and regulatory factors production is necessary to understand the outcome of allergic contact dermatitis (ACD). OBJECTIVES To evaluate the dysfunction of proinflammatory cytokines and regulatory factors in the positive MCI/MI patch test at the transcriptional and protein expression levels. Moreover, to analyse the cytokines production induced by MI in peripheral blood mononuclear cells (PBMCs). MATERIALS AND METHODS The selected patients had positive MCI/MI patch test results. The expression of proinflammatory factors was evaluated by q-PCR and immunochemistry at 48 hours of positive MCI/MI patch test. The MCI/MI- or MI- induced secretion of IL-1β, TNF and IL-6 by PBMC was analysed by flow cytometry. RESULTS The results showed a decreased TLR4 expression with upregulated IL6, FOXP3, IL10 and TGFβ mRNA expression as assessed by q-PCR at the site of the MCI/MI skin reaction. We detected increased protein levels of TLR4, FOXP3 and IL-10 in the dermis layer in the ACD reaction by immunocitochemistry. Moreover, MCI/MI induced proinflammatory cytokine production by PBMC through the NF-κB signalling pathway. CONCLUSION Considering the altered innate immune response triggered by MCI/MI sensitization, these findings indicate that the regulatory process at the induction phase of ACD is a crucial mechanism. Given the increase in occupational and domestic exposure to MCI/MI, the underlying immunological mechanisms should be understood.
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Affiliation(s)
- Heliana Freitas de Oliveira Goes
- Laboratory of Dermatology and Immunodeficiencies, LIM-56, Department of Dermatology, University of São Paulo Medical School, São Paulo, Brazil.,Department of Dermatology, University of São Paulo Medical School, São Paulo, Brazil
| | - Anangelica Rodrigues Virgens
- Laboratory of Dermatology and Immunodeficiencies, LIM-56, Department of Dermatology, University of São Paulo Medical School, São Paulo, Brazil.,Department of Dermatology, University of São Paulo Medical School, São Paulo, Brazil
| | - Gabriel Costa de Carvalho
- Laboratory of Dermatology and Immunodeficiencies, LIM-56, Department of Dermatology, University of São Paulo Medical School, São Paulo, Brazil
| | - Anna Julia Pietrobon
- Laboratory of Dermatology and Immunodeficiencies, LIM-56, Department of Dermatology, University of São Paulo Medical School, São Paulo, Brazil.,Department of Immunology, Institute of Biomedical Sciencies, University of São Paulo, São Paulo, Brazil
| | - Anna Cláudia Calvielli Castelo Branco
- Laboratory of Dermatology and Immunodeficiencies, LIM-56, Department of Dermatology, University of São Paulo Medical School, São Paulo, Brazil.,Department of Immunology, Institute of Biomedical Sciencies, University of São Paulo, São Paulo, Brazil
| | - Luanda Mara da Silva Oliveira
- Laboratory of Dermatology and Immunodeficiencies, LIM-56, Department of Dermatology, University of São Paulo Medical School, São Paulo, Brazil
| | - Iara G Fernandes
- Laboratory of Dermatology and Immunodeficiencies, LIM-56, Department of Dermatology, University of São Paulo Medical School, São Paulo, Brazil.,Department of Dermatology, University of São Paulo Medical School, São Paulo, Brazil
| | | | | | | | - Maria Notomi Sato
- Laboratory of Dermatology and Immunodeficiencies, LIM-56, Department of Dermatology, University of São Paulo Medical School, São Paulo, Brazil.,Department of Dermatology, University of São Paulo Medical School, São Paulo, Brazil
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8
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Kerkhof P, Gruijl F. Phototherapy in the perspective of the chronicity of psoriasis. J Eur Acad Dermatol Venereol 2020; 34:926-931. [DOI: 10.1111/jdv.16245] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Accepted: 01/21/2020] [Indexed: 12/14/2022]
Affiliation(s)
- P.C.M. Kerkhof
- Department of Dermatology Radboud University Nijmegen Medical Centre Nijmegen The Netherlands
| | - F.R. Gruijl
- Department of Dermatology Leids Universitair Medisch Centrum Nijmegen The Netherlands
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9
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FOXP3 and CTLA-4 genetic variants' influence on the susceptibility and clinical course of basal cell carcinoma. Postepy Dermatol Alergol 2020; 38:455-460. [PMID: 34377128 PMCID: PMC8330848 DOI: 10.5114/ada.2020.93368] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 01/27/2020] [Indexed: 12/13/2022] Open
Abstract
Introduction The pathogenesis of basal cell carcinoma (BCC) is multifactorial and not fully elucidated. Previous studies showed that behaviour of the tumour may be influenced by the immune system and identified CD4+CD25+FoxP3+ regulatory T cells (Tregs) as dominant immune cells in BCC microenvironment. The function and development of Tregs is regulated by FOXP3, encoding transcription factor Forkhead box P3. FOXP3 regulates transcription of many genes, including up-regulation of cytotoxic lymphocyte-associated antigen-4 gene (CTLA-4). Expressed on Tregs, CTLA-4 interacts with antigen-presenting cells to inhibit T-cell activation. Aim To investigate the role of two polymorphisms (rs3761548 and rs2232365) of FOXP3 and CTLA-4 polymorphism (rs5742909) in BCC patients from northern Poland. Material and methods We analysed 280 unrelated patients with BCC of mean age 70.93 ±11.53 (70.54 ±12.55 women, 71.38 ±10.26 men) and 200 healthy, unrelated age- and sex-matched volunteers. Results The differences in the occurrence of BCC between genotypes and alleles of the analysed polymorphisms were not statistically significant. In the studied group, the presence of the CC genotype in CTLA-4 rs5742909 polymorphism was statistically more frequent in patients with multiple BCCs. Conclusions It seems that the analysed FOXP3 and CTLA-4 polymorphisms do not influence the BCC susceptibility. CTLA-4 rs5742909 polymorphism may influence the susceptibility to multiple BCCs.
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Sisakht M, Darabian M, Mahmoodzadeh A, Bazi A, Shafiee SM, Mokarram P, Khoshdel Z. The role of radiation induced oxidative stress as a regulator of radio-adaptive responses. Int J Radiat Biol 2020; 96:561-576. [PMID: 31976798 DOI: 10.1080/09553002.2020.1721597] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Purpose: Various sources of radiation including radiofrequency, electromagnetic radiation (EMR), low- dose X-radiation, low-level microwave radiation and ionizing radiation (IR) are indispensable parts of modern life. In the current review, we discussed the adaptive responses of biological systems to radiation with a focus on the impacts of radiation-induced oxidative stress (RIOS) and its molecular downstream signaling pathways.Materials and methods: A comprehensive search was conducted in Web of Sciences, PubMed, Scopus, Google Scholar, Embase, and Cochrane Library. Keywords included Mesh terms of "radiation," "electromagnetic radiation," "adaptive immunity," "oxidative stress," and "immune checkpoints." Manuscripts published up until December 2019 were included.Results: RIOS induces various molecular adaptors connected with adaptive responses in radiation exposed cells. One of these adaptors includes p53 which promotes various cellular signaling pathways. RIOS also activates the intrinsic apoptotic pathway by depolarization of the mitochondrial membrane potential and activating the caspase apoptotic cascade. RIOS is also involved in radiation-induced proliferative responses through interaction with mitogen-activated protein kinases (MAPks) including p38 MAPK, ERK, and c-Jun N-terminal kinase (JNK). Protein kinase B (Akt)/phosphoinositide 3-kinase (PI3K) signaling pathway has also been reported to be involved in RIOS-induced proliferative responses. Furthermore, RIOS promotes genetic instability by introducing DNA structural and epigenetic alterations, as well as attenuating DNA repair mechanisms. Inflammatory transcription factors including macrophage migration inhibitory factor (MIF), nuclear factor κB (NF-κB), and signal transducer and activator of transcription-3 (STAT-3) paly major role in RIOS-induced inflammation.Conclusion: In conclusion, RIOS considerably contributes to radiation induced adaptive responses. Other possible molecular adaptors modulating RIOS-induced responses are yet to be divulged in future studies.
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Affiliation(s)
- Mohsen Sisakht
- Department of Medical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Maryam Darabian
- Department of Radiology, Faculty of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amir Mahmoodzadeh
- Department of Medical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.,Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ali Bazi
- Faculty of Allied Medical Sciences, Zabol University of Medical Sciences, Zabol, Iran
| | - Sayed Mohammad Shafiee
- Department of Medical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Pooneh Mokarram
- Department of Medical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Khoshdel
- Department of Medical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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11
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Liyanage UE, Law MH, Han X, An J, Ong JS, Gharahkhani P, Gordon S, Neale RE, Olsen CM, 23andMe Research Team, MacGregor S, Whiteman DC. Combined analysis of keratinocyte cancers identifies novel genome-wide loci. Hum Mol Genet 2019; 28:3148-3160. [PMID: 31174203 PMCID: PMC6737293 DOI: 10.1093/hmg/ddz121] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 05/30/2019] [Accepted: 06/03/2019] [Indexed: 12/12/2022] Open
Abstract
The keratinocyte cancers (KC), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common cancers in fair-skinned people. KC treatment represents the second highest cancer healthcare expenditure in Australia. Increasing our understanding of the genetic architecture of KC may provide new avenues for prevention and treatment. We first conducted a series of genome-wide association studies (GWAS) of KC across three European ancestry datasets from Australia, Europe and USA, and used linkage disequilibrium (LD) Score regression (LDSC) to estimate their pairwise genetic correlations. We employed a multiple-trait approach to map genes across the combined set of KC GWAS (total N = 47 742 cases, 634 413 controls). We also performed meta-analyses of BCC and SCC separately to identify trait specific loci. We found substantial genetic correlations (generally 0.5-1) between BCC and SCC suggesting overlapping genetic risk variants. The multiple trait combined KC GWAS identified 63 independent genome-wide significant loci, 29 of which were novel. Individual separate meta-analyses of BCC and SCC identified an additional 13 novel loci not found in the combined KC analysis. Three new loci were implicated using gene-based tests. New loci included common variants in BRCA2 (distinct to known rare high penetrance cancer risk variants), and in CTLA4, a target of immunotherapy in melanoma. We found shared and trait specific genetic contributions to BCC and SCC. Considering both, we identified a total of 79 independent risk loci, 45 of which are novel.
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Affiliation(s)
- Upekha E Liyanage
- Statistical Genetics Lab, QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD 4006, Australia
| | - Matthew H Law
- Statistical Genetics Lab, QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD 4006, Australia
| | - Xikun Han
- Statistical Genetics Lab, QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD 4006, Australia
| | - Jiyuan An
- Statistical Genetics Lab, QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD 4006, Australia
| | - Jue-Sheng Ong
- Statistical Genetics Lab, QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD 4006, Australia
| | - Puya Gharahkhani
- Statistical Genetics Lab, QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD 4006, Australia
| | - Scott Gordon
- Genetic Epidemiology, QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD 4006, Australia
| | - Rachel E Neale
- Cancer Aetiology and Prevention, QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD 4006, Australia
| | - Catherine M Olsen
- Cancer Control Group, QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD 4006, Australia
- Faculty of Medicine, The University of Queensland, Brisbane, QLD 4006, Australia
| | | | - Stuart MacGregor
- Statistical Genetics Lab, QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD 4006, Australia
| | - David C Whiteman
- Cancer Control Group, QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD 4006, Australia
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Hesterberg RS, Amorrortu RP, Zhao Y, Hampras S, Akuffo AA, Fenske N, Cherpelis B, Balliu J, Vijayan L, Epling-Burnette PK, Rollison DE. T Regulatory Cell Subpopulations Associated with Recent Ultraviolet Radiation Exposure in a Skin Cancer Screening Cohort. THE JOURNAL OF IMMUNOLOGY 2018; 201:3269-3281. [PMID: 30389774 DOI: 10.4049/jimmunol.1800940] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Accepted: 09/25/2018] [Indexed: 12/31/2022]
Abstract
UV radiation (UVR) causing DNA damage is a well-documented risk factor for nonmelanoma skin cancer. Although poorly understood, UVR may also indirectly contribute to carcinogenesis by promoting immune evasion. To our knowledge, we report the first epidemiological study designed to investigate the association between quantitative measures of UVR, obtained using a spectrophotometer, and circulating T regulatory (Treg) cells. In addition to total Treg cells, the proportion of functionally distinct Treg cell subsets defined by CD45RA and CD27 phenotypic markers, graded expression of FOXP3 and CD25, and those expressing cutaneous lymphocyte-associated Ag and the chemokine receptor CCR4 were enumerated in 350 individuals undergoing routine skin cancer screening exams and determined not to have prevalent skin cancer. No associations were identified for UVR exposure or the overall proportion of circulating Treg cells; however, Treg cell subpopulations with an activation-associated phenotype, CD45RA-/CD27-, and those expressing cutaneous homing receptors were significantly positively associated with UVR. These subpopulations of Treg cells also differed by age, sex, and race. After stratification by natural skin tone, and adjusting for age and sex, we found that spectrophotometer-based measures of UVR exposure, but not self-reported measures of past sun exposure, were positively correlated with the highest levels of these Treg cell subpopulations, particularly among lighter-skinned individuals. Findings from this large epidemiologic study highlight the diversity of human Treg cell subpopulations associated with UVR, thus raising questions about the specific coordinated expression of CD45RA, CD27, CCR4, and cutaneous lymphocyte-associated Ag on Treg cells and the possibility that UVR contributes to nonmelanoma skin cancer carcinogenesis through Treg cell-mediated immune evasion.
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Affiliation(s)
- Rebecca S Hesterberg
- Department of Immunology, Moffitt Cancer Center, Tampa, FL 33612.,Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL 33612
| | | | - Yayi Zhao
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL 33612; and
| | - Shalaka Hampras
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL 33612; and
| | - Afua A Akuffo
- Department of Immunology, Moffitt Cancer Center, Tampa, FL 33612.,Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL 33612
| | - Neil Fenske
- Department of Dermatology and Cutaneous Surgery, University of South Florida College of Medicine, Tampa, FL 33612
| | - Basil Cherpelis
- Department of Dermatology and Cutaneous Surgery, University of South Florida College of Medicine, Tampa, FL 33612
| | - Juliana Balliu
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL 33612; and
| | - Laxmi Vijayan
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL 33612; and
| | | | - Dana E Rollison
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL 33612; and
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Dietary grape seed proanthocyanidins inactivate regulatory T cells by promoting NER-dependent DNA repair in dendritic cells in UVB-exposed skin. Oncotarget 2018; 8:49625-49636. [PMID: 28548949 PMCID: PMC5564793 DOI: 10.18632/oncotarget.17867] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Accepted: 04/29/2017] [Indexed: 11/25/2022] Open
Abstract
Ultraviolet B (UVB) radiation induces regulatory T cells (Treg cells) and depletion of these Treg cells alleviates immunosuppression and inhibits photocarcinogenesis in mice. Here, we determined the effects of dietary grape seed proanthocyanidins (GSPs) on the development and activity of UVB-induced Treg cells. C3H/HeN mice fed a GSPs (0.5%, w/w)-supplemented or control diet were exposed to UVB (150 mJ/cm2) radiation, sensitized to 2,4-dinitrofluorobenzene (DNFB) and sacrificed 5 days later. FACS analysis indicated that dietary GSPs decrease the numbers of UVB-induced Treg cells. ELISA analysis of cultured sorted Treg cells indicated that secretion of immunosuppressive cytokines (interleukin-10, TGF-β) was significantly lower in Treg cells from GSPs-fed mice. Dietary GSPs also enhanced the ability of Treg cells from wild-type mice to stimulate production of IFNγ by T cells. These effects of dietary GSPs on Treg cell function were not found in XPA-deficient mice, which are incapable of repairing UVB-induced DNA damage. Adoptive transfer experiments revealed that naïve recipients that received Treg cells from GSPs-fed UVB-irradiated wild-type donors that had been sensitized to DNFB exhibited a significantly higher contact hypersensitivity (CHS) response to DNFB than mice that received Treg cells from UVB-exposed mice fed the control diet. There was no significant difference in the CHS response between mice that received Treg cells from UVB-irradiated XPA-deficient donors fed GSPs or the control diet. Furthermore, dietary GSPs significantly inhibited UVB-induced skin tumor development in wild-type mice but not in XPA-deficient mice. These results suggest that GSPs inactivate Treg cells by promoting DNA repair in dendritic cells in UVB-exposed skin.
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Ultraviolet Radiation-Induced Immunosuppression: Induction of Regulatory T Cells. Methods Mol Biol 2017; 1559:63-73. [DOI: 10.1007/978-1-4939-6786-5_5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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15
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Schalka S, Steiner D, Ravelli FN, Steiner T, Terena AC, Marçon CR, Ayres EL, Addor FAS, Miot HA, Ponzio H, Duarte I, Neffá J, Cunha JAJD, Boza JC, Samorano LDP, Corrêa MDP, Maia M, Nasser N, Leite OMRR, Lopes OS, Oliveira PD, Meyer RLB, Cestari T, Reis VMSD, Rego VRPDA. Brazilian consensus on photoprotection. An Bras Dermatol 2015; 89:1-74. [PMID: 25761256 PMCID: PMC4365470 DOI: 10.1590/abd1806-4841.20143971] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Accepted: 10/28/2014] [Indexed: 12/14/2022] Open
Abstract
Brazil is a country of continental dimensions with a large heterogeneity of climates
and massive mixing of the population. Almost the entire national territory is located
between the Equator and the Tropic of Capricorn, and the Earth axial tilt to the
south certainly makes Brazil one of the countries of the world with greater extent of
land in proximity to the sun. The Brazilian coastline, where most of its population
lives, is more than 8,500 km long. Due to geographic characteristics and cultural
trends, Brazilians are among the peoples with the highest annual exposure to the sun.
Epidemiological data show a continuing increase in the incidence of non-melanoma and
melanoma skin cancers. Photoprotection can be understood as a set of measures aimed
at reducing sun exposure and at preventing the development of acute and chronic
actinic damage. Due to the peculiarities of Brazilian territory and culture, it would
not be advisable to replicate the concepts of photoprotection from other developed
countries, places with completely different climates and populations. Thus the
Brazilian Society of Dermatology has developed the Brazilian Consensus on
Photoprotection, the first official document on photoprotection developed in Brazil
for Brazilians, with recommendations on matters involving photoprotection.
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Affiliation(s)
- Sérgio Schalka
- Photobiology Department, Sociedade Brasileira de Dermatologia, São Paulo, SP, Brazil
| | | | | | | | | | | | - Eloisa Leis Ayres
- Center of Dermatology Prof. Rene Garrido Neves, City Health Foundation, Rio de Janeiro, RJ, Brazil
| | | | | | - Humberto Ponzio
- Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Ida Duarte
- Charity Hospital, Santa Casa de Misericórdia, São Paulo, SP, Brazil
| | - Jane Neffá
- Fluminense Federal University, Niterói, RJ, Brazil
| | | | | | | | | | - Marcus Maia
- Charity Hospital, Santa Casa de Misericórdia, São Paulo, SP, Brazil
| | - Nilton Nasser
- Federal University of Santa Catarina, Blumenau, SC, Brazil
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Hori T, Kuribayashi K, Saito K, Wang L, Torii M, Uemoto S, Kato T. Alloantigen-specific CD4(+) regulatory T cells induced in vivo by ultraviolet irradiation after alloantigen immunization require interleukin-10 for their induction and activation, and flexibly mediate bystander immunosuppression of allograft rejection. Transpl Immunol 2015; 32:156-163. [PMID: 25861842 DOI: 10.1016/j.trim.2015.03.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2015] [Revised: 03/31/2015] [Accepted: 03/31/2015] [Indexed: 01/04/2023]
Abstract
Ultraviolet (UV) irradiation prior to antigen immunization is employed to induce antigen-specific regulatory T cells (Tregs). UV-induced Tregs demonstrate unique bystander suppression, although antigen-specific activation is required initially. We previously reported the phenotype of alloantigen-specific transferable Tregs induced by UV-B irradiation after immunization was the same as T regulatory type 1-like CD4(+) T cells, with antigen-specific interleukin (IL)-10 production. Here, by using semi-allogeneic transplantation models in vivo, we investigated the role of IL-10 in the induction and activation of these Tregs, and the possibility of bystander suppression of third-party allograft rejection. Naïve mice (H-2(b)) were immunized with alloantigen (H-2(b/d)), and received UV-B irradiation (40 kJ/m(2)) 1 week later. Four weeks afterwards, splenic CD4(+) T cells were purified from the UV-irradiated immunized mice, and were transferred into naïve mice (H-2(b)). Allografts expressing the same alloantigen as T-cell donors were immunized against (H-2(b/d)) or an irrelevant alloantigen (H-2(b/k)) were transplanted to CD4(+) T-cell-transferred mice, and an alloantigen-specific prolongation of allograft survival observed. Experiments where IL-10 was neutralized by monoclonal antibody in the induction or effector phase revealed that IL-10 is critical, not only for induction but also for immunosuppressive function of CD4(+) Tregs induced by UV irradiation after alloantigen immunization. Third-party allografts (H-2(d/k)) were transplanted to CD4(+) T-cell-transferred mice, and graft survival was also prolonged. Even a graft only partially compatible with immunized alloantigen worked well in vivo to activate CD4(+) Tregs induced by UV irradiation after alloantigen immunization, which resulted in the bystander suppression of third-party allograft rejection.
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Affiliation(s)
- Tomohide Hori
- Department of Cellular and Molecular Immunology, Mie University Graduate School of Medicine, Tsu, Japan; Department of Hepato-pancreato-biliary and Transplant Surgery, Kyoto University Hospital, Kyoto, Japan.
| | - Kagemasa Kuribayashi
- Department of Cellular and Molecular Immunology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Kanako Saito
- Department of Cellular and Molecular Immunology, Mie University Graduate School of Medicine, Tsu, Japan; Department of Hematology and Medical Oncology, Mie University Hospital, Tsu, Japan
| | - Linan Wang
- Department of Cellular and Molecular Immunology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Mie Torii
- Department of Cellular and Molecular Immunology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Shinji Uemoto
- Department of Hepato-pancreato-biliary and Transplant Surgery, Kyoto University Hospital, Kyoto, Japan
| | - Takuma Kato
- Department of Cellular and Molecular Immunology, Mie University Graduate School of Medicine, Tsu, Japan.
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Kammeyer A, Luiten R. Oxidation events and skin aging. Ageing Res Rev 2015; 21:16-29. [PMID: 25653189 DOI: 10.1016/j.arr.2015.01.001] [Citation(s) in RCA: 554] [Impact Index Per Article: 55.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 12/15/2014] [Accepted: 01/05/2015] [Indexed: 10/24/2022]
Abstract
The rate of skin aging, or that of tissue in general, is determined by a variable predominance of tissue degeneration over tissue regeneration. This review discusses the role of oxidative events of tissue degeneration and aging in general, and for the skin in particular. The mechanisms involved in intrinsic and extrinsic (photo-) aging are described. Since photoaging is recognized as an important extrinsic aging factor, we put special emphasize on the effects of UV exposure on aging, and its variable influence according to global location and skin type. We here summarise direct photochemical effects of UV on DNA, RNA, proteins and vitamin D, the factors contributing to UV-induced immunosuppression, which may delay aging, the nature and origin of reactive oxygen species (ROS) and reactive nitrogen species (RNS) as indirect contributors for aging, and the consequences of oxidative events for extracellular matrix (ECM) degradation, such as that of collagen. We conclude that conflicting data on studies investigating the validity of the free radical damage theory of aging may reflect variations in the level of ROS induction which is difficult to quantify in vivo, and the lack of targeting of experimental ROS to the relevant cellular compartment. Also mitohormesis, an adaptive response, may arise in vivo to moderate ROS levels, further complicating interpretation of in vivo results. We here describes how skin aging is mediated both directly and indirectly by oxidative degeneration.This review indicates that skin aging events are initiated and often propagated by oxidation events, despite recently recognized adaptive responses to oxidative stress.
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Hori T, Kuribayashi K, Saito K, Wang L, Torii M, Uemoto S, Iida T, Yagi S, Kato T. Ultraviolet-induced alloantigen-specific immunosuppression in transplant immunity. World J Transplant 2015; 5:11-18. [PMID: 25815267 PMCID: PMC4371157 DOI: 10.5500/wjt.v5.i1.11] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Revised: 12/02/2014] [Accepted: 01/19/2015] [Indexed: 02/05/2023] Open
Abstract
After the first observation of the immunosuppressive effects of ultraviolet (UV) irradiation was reported in 1974, therapeutic modification of immune responses by UV irradiation began to be investigated in the context immunization. UV-induced immunosuppression is via the action of regulatory T cells (Tregs). Antigen-specific Tregs were induced by high-dose UV-B irradiation before antigen immunization in many studies, as it was considered that functional alteration and/or modulation of antigen-presenting cells by UV irradiation was required for the induction of antigen-specific immunosuppression. However, it is also reported that UV irradiation after immunization induces antigen-specific Tregs. UV-induced Tregs are also dominantly transferable, with interleukin-10 being important for UV-induced immunosuppression. Currently, various possible mechanisms involving Treg phenotype and cytokine profile have been suggested. UV irradiation accompanied by alloantigen immunization induces alloantigen-specific transferable Tregs, which have potential therapeutic applications in the transplantation field. Here we review the current status of UV-induced antigen-specific immunosuppression on the 40th anniversary of its discovery.
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Immune-priming of the tumor microenvironment by radiotherapy: rationale for combination with immunotherapy to improve anticancer efficacy. Am J Clin Oncol 2015; 38:90-7. [PMID: 25616204 DOI: 10.1097/coc.0b013e3182868ec8] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
A clear contribution of the immune system to eradication of tumors has been supported by recent developments in the field of immunotherapy. Durable clinical responses obtained after treatment with immunomodulatory agents such as ipilimumab (Yervoy) and anti-PD-1 antibody (BMS-936558), have established that harnessing the immune response against chemoresistant tumors can result in their complete eradication. However, only a subset of patients benefit from these therapeutic approaches. Accumulating evidence suggests that tumors with a preexisting active immune microenvironment might have a better response to immunotherapy. In a number of preclinical and clinical studies, many cytotoxic agents elicit changes within tumors and their microenvironment that may make these malignant cells more sensitive to an efficient immune cell attack. Therefore, it is plausible that combining immunotherapy with standard anticancer therapies such as chemotherapy or radiotherapy will provide synergistic antitumor effects. Despite a large collection of preclinical data, the immune mechanisms that might contribute to the efficacy of conventional cytotoxic therapies and their combinations with immunotherapeutic approaches have not yet been extensively studied in the clinical setting and warrant further investigation. This review will focus on current knowledge of the immunomodulatory effects of one such cytotoxic treatment, radiotherapy, and explore different pathways by which its combination with immunomodulatory antibodies might contribute toward more efficacious antitumor immunity.
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Abstract
The ultraviolet (UV) radiation contained in sunlight is a powerful immune suppressant. While exposure to UV is best known for its ability to cause skin cancer, it is also associated with protection against a range of autoimmune diseases, particularly multiple sclerosis (MS). Although the precise mechanism by which sunlight affords protection from MS remains to be determined, some have hypothesised that UV immunosuppression explains the "latitude-gradient effect" associated with MS. By stimulating the release of soluble factors in exposed skin, UV activates immune suppressive pathways that culminate in the induction of regulatory cells in distant tissues. Each and every one of the immune suppressive cells and molecules activated by UV exposure are potential targets for treating and preventing MS. A thorough understanding of the mechanisms involved is therefore required if we are to realise the therapeutic potential of photoimmunology.
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Affiliation(s)
- Felix Marsh-Wakefield
- Cellular Photoimmunology Group, Discipline of Infectious Diseases and Immunology, Sydney Medical School, University of Sydney, Camperdown, Australia.,Department of Dermatology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.,Discipline of Dermatology, Bosch Institute, Sydney Medical School, University of Sydney, Camperdown, Australia
| | - Scott N Byrne
- Cellular Photoimmunology Group, Discipline of Infectious Diseases and Immunology, Sydney Medical School, University of Sydney, Camperdown, Australia. .,Department of Dermatology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia. .,Discipline of Dermatology, Bosch Institute, Sydney Medical School, University of Sydney, Camperdown, Australia. .,Infectious Diseases and Immunology, Level 5 (East), The Charles Perkins Centre Hub (D17), University of Sydney, Camperdown, NSW, 2006, Australia.
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Breuer J, Schwab N, Schneider-Hohendorf T, Marziniak M, Mohan H, Bhatia U, Gross CC, Clausen BE, Weishaupt C, Luger TA, Meuth SG, Loser K, Wiendl H. Ultraviolet B light attenuates the systemic immune response in central nervous system autoimmunity. Ann Neurol 2014; 75:739-58. [DOI: 10.1002/ana.24165] [Citation(s) in RCA: 92] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2014] [Revised: 04/17/2014] [Accepted: 04/21/2014] [Indexed: 12/22/2022]
Affiliation(s)
| | | | | | | | - Hema Mohan
- Department of Neurology; University of Münster; Münster
| | | | | | - Björn E. Clausen
- Institute for Molecular Medicine, Johannes Gutenberg-University Mainz; Mainz
| | | | - Thomas A. Luger
- Department of Dermatology; University of Münster; Münster
- Interdisciplinary Center of Clinical Research; Münster
- Cluster of Excellence EXC 1003, Cells in Motion; Münster Germany
| | - Sven G. Meuth
- Department of Neurology; University of Münster; Münster
- Interdisciplinary Center of Clinical Research; Münster
- Cluster of Excellence EXC 1003, Cells in Motion; Münster Germany
| | - Karin Loser
- Department of Dermatology; University of Münster; Münster
- Interdisciplinary Center of Clinical Research; Münster
- Cluster of Excellence EXC 1003, Cells in Motion; Münster Germany
| | - Heinz Wiendl
- Department of Neurology; University of Münster; Münster
- Interdisciplinary Center of Clinical Research; Münster
- Cluster of Excellence EXC 1003, Cells in Motion; Münster Germany
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Peiser M, Hitzler M, Luch A. On the role of co-inhibitory molecules in dendritic cell: T helper cell coculture assays aimed to detect chemical-induced contact allergy. EXPERIENTIA SUPPLEMENTUM (2012) 2014; 104:115-35. [PMID: 24214622 DOI: 10.1007/978-3-0348-0726-5_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
T cells play a pivotal role in sensitization and elicitation of type IV allergic reactions. While T helper cells sustain and maintain the differentiation of further effector cells, regulatory T cells are involved in control of cytokine release and proliferation, and T killer cells execute cellular lysis, thereby leading to certain levels of tissue damage. According to their central role, the widely applied and OECD-supported test method for the assessment of the sensitization potential of a chemical, i.e., the local lymph node assay (LLNA), relies on the detection of the immune-responsive proliferation of lymphocytes. However, most sensitization assays recently developed take advantage of the initiators of sensitization, dendritic cells (DCs) or DC-like cell lines. Here, we focus on inhibitory molecules expressed on the surface of DCs and their corresponding receptors on T cells. We summarize insight into the function of CTLA-4, the ligands of inducible co-stimulators (ICOSs), and on the inhibitory receptor programmed death (PD). The targeting of immune cell surface receptors by inhibitory molecules holds some promise with regard to the development of T cell-based sensitization assays. Firstly, a broader and more sensitive dynamic range of detection could be achieved by blocking inhibitors or by removing inhibiting regulatory T cells from the assays. Secondly, the actual expression levels of inhibitory molecules could be also a valuable indicator for the process of sensitization. Finally, inhibitory molecules in coculture test systems are supposed to have a major influence on DCs by reverse signaling, thereby affecting their differentiation and maturation status in a feedback loop. In conclusion, inhibitory ligands of DC surface receptors and/or their cognate receptors on T cells could serve as useful tools in cell-based assays, directly influencing toxicological endpoints such as sensitization.
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Affiliation(s)
- Matthias Peiser
- Department of Product Safety, German Federal Institute for Risk Assessment (BfR), Max-Dohrn-Strasse 8-10, 10589, Berlin, Germany,
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Yang MF, Baron ED. Update on the immunology of UV and visible radiation therapy: phototherapy, photochemotherapy and photodynamic therapy. ACTA ACUST UNITED AC 2014. [DOI: 10.1586/17469872.3.1.85] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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Role of Th17 cells in skin inflammation of allergic contact dermatitis. Clin Dev Immunol 2013; 2013:261037. [PMID: 24023564 PMCID: PMC3759281 DOI: 10.1155/2013/261037] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2013] [Accepted: 07/08/2013] [Indexed: 02/06/2023]
Abstract
Extending the classical concept considering an imbalance exclusively of T helper(h) 1 and Th2 cells on the bottom of many inflammatory diseases, Th17 cells were recently described. Today, there is sufficient experimental evidence to classify psoriasis and allergic contact dermatitis (ACD) amongst other inflammatory skin disorders as IL-17 associated diseases. In several human studies, T-cell-clones could be isolated from eczema biopsies, and high IL-17 levels were observed after challenge with allergen. In the last years, the phenotype of these IL-17 releasing T cells was in the focus of discussion. It has been suggested that Th17 could be identified by expression of retinoic acid receptor-related orphan receptor (ROR)C (humans) or RORγt (mice) and IL-17, accompanied by the absence of IFN-γ and IL-22. In cells from skin biopsies, contact allergens elevate IL-17A, IL-23, and RORC within the subset of Th cells. The indications for a participation of Th17 in the development of ACD are supported by data from IL-17 deficient mice with reduced contact hypersensitivity (CHS) reactions that could be restored after transplantation of wild type CD4+ T cells. In addition to Th17 cells, subpopulations of CD8+ T cells and regulatory T cells are further sources of IL-17 that play important roles in ACD as well. Finally, the results from Th17 cell research allow today identification of different skin diseases by a specific profile of signature cytokines from Th cells that can be used as a future diagnostic tool.
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Sleijffers A, Garssen J, Vos JG, Loveren H. Ultraviolet light and resistance to infectious diseases. J Immunotoxicol 2012; 1:3-14. [PMID: 18958636 DOI: 10.1080/15476910490438333] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022] Open
Abstract
Exposure to ultraviolet (UV) radiation, as in sunlight, can modulate immune responses in animals and humans. This immunomodulation can lead to positive health effects especially with respect to certain autoimmune diseases and allergies. However, UV-induced immunomodulation has also been shown to be deleterious. Experimental animal studies have revealed that UV exposure can impair the resistance to many infectious agents, such as bacteria, parasites, viruses, and fungi. Importantly, these effects are not restricted to skin-associated infections, but also concern systemic infections. UV radiation induces a multistep process, locally in the skin as well as systemically, that ultimately leads to immunosuppression. The first event is the absorption of "UV" photons by chromophores, or so-called photoreceptors, such as DNA and urocanic acid (UCA) in the upper cell layers of the skin. Upon absorption of UV radiation, trans-UCA isomerizes to the cis-isomer. Cis-UCA is likely the most important mediator of UV-induced immunosuppression, as this compound has been shown to modulate the induction of contact type hypersensitivity and delayed type hypersensitivity, allograft rejection, and the functions of monocytes and T-lymphocytes as well as natural killer cells. The real consequences of UV-induced immunomodulation on resistance to infectious diseases for humans are not fully known. Risk estimations have been performed through extrapolation of animal data, obtained from infection models, to the human situation. This estimation indicated that UV doses relevant to outdoor exposure can impair the human immune system sufficiently to have effects on resistance to infections, but also indicated that human data are necessary to further quantify and validate this risk estimation. Further information has been obtained from vaccination studies in human volunteers as ethical reasons prohibit studies with infectious agents. Studies in mice and human volunteers on the effects of prior UVB exposure on hepatitis B vaccination responses revealed suppressed cellular and humoral immune responses in mice but not in human volunteers. However, subgroups within the performed human volunteer study made by determination of cytokine polymorphisms or UVB-induced mediators, revealed that some individuals have suppressed hepatitis B vaccination responses after UVB exposure. Thus, it might be concluded that the human immune system can be affected by UVB exposure, and decreased resistance to infectious diseases can be expected after sun exposure.
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Affiliation(s)
- Annemarie Sleijffers
- Laboratory for Toxicology, Pathology and Genetics, National Institute of Public Health and the Environment, Bilthoven, The Netherlands
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Abstract
Allergic contact dermatitis is the quintessential example of a delayed-in-time and T-cell-mediated immune response. In the last decade, many of the molecular events required to initiate (or block) such a response have been uncovered. Textbook and journal reviews have emphasized the costimulatory requirements, with less focus on the coinhibitory signals that are of equal importance in understanding this central event of adaptive immunity. To fill this gap, we offer a compendium of discoveries characterizing the ligand-receptor pairs inhibiting T-cell activation and of selected illnesses and therapeutic applications that illuminate their role in health and disease.
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Affiliation(s)
- Shinjita Das
- Department of Dermatology, The University of Texas Southwestern Medical Center and Dallas Veterans Affairs Medical Center, Dallas, TX, USA.
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Reversal of iC3b-inhibited dendritic cell differentiation via inhibition of the extracellular signal-regulated mitogen-activated protein kinase promotes CD4(+) T cell proliferation. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2012; 111:50-8. [PMID: 22513093 DOI: 10.1016/j.jphotobiol.2012.03.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/08/2011] [Revised: 03/21/2012] [Accepted: 03/22/2012] [Indexed: 01/25/2023]
Abstract
OBJECTIVES To investigate the roles of ERK1/2 and p38 MAPK cascades in the differentiation of iC3b-combined CD14(+) monocyte into CD1a(+) MDDC, and to study how these cells influence CD4(+) T cell proliferation. METHODS CD14(+) monocyte was co-cultured with iC3b with or without inhibitors specific for ERK1/2 or p38 MAPK pathways for 2days, then the expressions of CD14, CD1a, phophso-ERK1/2, phophso-p38, IL-10 and IL-12 p70 were detected, and CD4(+) T cell proliferation was measured via (3)H-TdR as well. RESULTS Maturation of CD1a(+) DC was inhibited by iC3b along with downregulated expressions of CD1a, phophso-p38 and IL-12p70 and upregulated expressions of phophso-ERK1/2 and IL-10, and the CD4(+) T cell proliferation was restrained accordingly. When pretreated with inhibitor specific for ERK1/2 pathway, the inhibited maturation of imDC was reversed prominently with a higher level expression of CD1a and IL-12p70, whereas expressions of phophso-ERK1/2 and IL-10 were lowered, and accordingly the CD4(+) T cell proliferation restored significantly. CONCLUSIONS iC3b inhibited the differentiation of CD14(+) monocytes into CD1a(+) MDDCs via ERK1/2 pathway, and restoration of CD1a(+) MDDCs maturation occurred with the treatment of inhibitors specific for ERK1/2 pathway. Meanwhile, treatment of the inhibitor for the ERK1/2 cascade reversed the inhibited CD4(+) T cell proliferation, implying a potential possibility for clinical intervention.
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Abstract
Cutaneous malignant melanoma is rapidly increasing in the developed world and continues to be a challenge in the clinic. Although extensive epidemiologic evidence points to solar UV as the major risk factor for melanoma, there is a significant gap in our knowledge about how this most ubiquitous environmental carcinogen interacts with the largest organ of the mammalian body (skin) at the microenvironmental and molecular level. We review some recent advances that have started to close this gap.
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Affiliation(s)
- M Raza Zaidi
- Laboratory of Cancer Biology & Genetics, National Cancer Institute, NIH, Bethesda, Maryland 20892-4264, USA.
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Stein P, Weber M, Prüfer S, Schmid B, Schmitt E, Probst HC, Waisman A, Langguth P, Schild H, Radsak MP. Regulatory T cells and IL-10 independently counterregulate cytotoxic T lymphocyte responses induced by transcutaneous immunization. PLoS One 2011; 6:e27911. [PMID: 22114725 PMCID: PMC3218067 DOI: 10.1371/journal.pone.0027911] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2011] [Accepted: 10/27/2011] [Indexed: 01/15/2023] Open
Abstract
Background The imidazoquinoline derivate imiquimod induces inflammatory responses and protection against transplanted tumors when applied to the skin in combination with a cognate peptide epitope (transcutaneous immunization, TCI). Here we investigated the role of regulatory T cells (Treg) and the suppressive cytokine IL-10 in restricting TCI-induced cytotoxic T lymphocyte (CTL) responses. Methodology/Principal Findings TCI was performed with an ointment containing the TLR7 agonist imiquimod and a CTL epitope was applied to the depilated back skin of C57BL/6 mice. Using specific antibodies and FoxP3-diphteria toxin receptor transgenic (DEREG) mice, we interrogated inhibiting factors after TCI: by depleting FoxP3+ regulatory T cells we found that specific CTL-responses were greatly enhanced. Beyond this, in IL-10 deficient (IL-10-/-) mice or after blocking of IL-10 signalling with an IL-10 receptor specific antibody, the TCI induced CTL response is greatly enhanced indicating an important role for this cytokine in TCI. However, by transfer of Treg in IL-10-/- mice and the use of B cell deficient JHT-/- mice, we can exclude Treg and B cells as source of IL-10 in the setting of TCI. Conclusion/Significance We identify Treg and IL-10 as two important and independently acting suppressors of CTL-responses induced by transcutaneous immunization. Advanced vaccination strategies inhibiting Treg function and IL-10 release may lead the development of effective vaccination protocols aiming at the induction of T cell responses suitable for the prophylaxis or treatment of persistent infections or tumors.
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Affiliation(s)
- Pamela Stein
- Institute for Immunology, Johannes Gutenberg University Medical Center, Mainz, Germany
| | - Michael Weber
- Institute for Immunology, Johannes Gutenberg University Medical Center, Mainz, Germany
| | - Steve Prüfer
- Institute for Immunology, Johannes Gutenberg University Medical Center, Mainz, Germany
| | - Beate Schmid
- Institute for Immunology, Johannes Gutenberg University Medical Center, Mainz, Germany
| | - Edgar Schmitt
- Institute for Immunology, Johannes Gutenberg University Medical Center, Mainz, Germany
| | - Hans-Christian Probst
- Institute for Immunology, Johannes Gutenberg University Medical Center, Mainz, Germany
| | - Ari Waisman
- Institute for Molecular Medicine, Johannes Gutenberg-University Medical Center, Mainz, Germany
| | - Peter Langguth
- Department of Biopharmaceutics and Pharmaceutical Technology, Johannes Gutenberg University, Mainz, Germany
| | - Hansjörg Schild
- Institute for Immunology, Johannes Gutenberg University Medical Center, Mainz, Germany
| | - Markus P. Radsak
- Third Department of Medicine, Johannes Gutenberg University Medical Center, Mainz, Germany
- * E-mail:
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In vivo reprogramming of UV radiation-induced regulatory T-cell migration to inhibit the elicitation of contact hypersensitivity. J Allergy Clin Immunol 2011; 128:826-33. [PMID: 21762977 DOI: 10.1016/j.jaci.2011.06.005] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2011] [Revised: 05/03/2011] [Accepted: 06/01/2011] [Indexed: 12/15/2022]
Abstract
BACKGROUND Regulatory T (Treg) cells induced by UV radiation (UVR) inhibit only the induction and not the elicitation of contact hypersensitivity (CHS) because they migrate into the lymph nodes but not the skin. The tissue-homing receptor expression and migratory behavior of Treg cells can be altered by means of in vitro coincubation with skin-derived antigen-presenting cells. On this in vitro treatment, Treg cells migrate into the skin and thus inhibit the elicitation of CHS. OBJECTIVE We attempted to determine whether Treg cells can be induced by UVR in sensitized mice and manipulated entirely in vivo in such a way that they suppress the elicitation of immune responses. METHODS Treg cells were induced by applying contact allergens onto UV-exposed skin in wild-type, langerin diphtheria toxin receptor knock-in, or depletion of Treg cell transgenic mice. RESULTS UVR-induced Treg cells inhibit the elicitation of CHS in sensitized mice when stimulated by means of an antigen-specific boost through the skin. This requires cutaneous antigen-presenting cells that alter the migratory behavior of Treg cells and drive them out of the lymph nodes into the skin. CONCLUSIONS The indication is that antigen-specific Treg cells can be induced in sensitized hosts and manipulated in such a way that they suppress the elicitation of specific immune reactions. Because this is achieved entirely in vivo without invasive interventions, our findings might have important implications for strategies aiming to induce and use Treg cells in a therapeutic setting.
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Destro F, Sforza F, Sicurella M, Marescotti D, Gallerani E, Baldisserotto A, Marastoni M, Gavioli R. Proteasome inhibitors induce the presentation of an Epstein-Barr virus nuclear antigen 1-derived cytotoxic T lymphocyte epitope in Burkitt's lymphoma cells. Immunology 2011; 133:105-14. [PMID: 21342184 DOI: 10.1111/j.1365-2567.2011.03416.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
The Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) is generally expressed in all EBV-associated tumours and is therefore an interesting target for immunotherapy. However, evidence for the recognition and elimination of EBV-transformed and Burkitt's lymphoma (BL) cells by cytotoxic T lymphocytes (CTLs) specific for endogenously presented EBNA1-derived epitopes remains elusive. We confirm here that CTLs specific for the HLA-B35/B53-presented EBNA1-derived HPVGEADYFEY (HPV) epitope are detectable in the majority of HLA-B35 individuals, and recognize EBV-transformed B lymphocytes, thereby demonstrating that the GAr domain does not fully inhibit the class I presentation of the HPV epitope. In contrast, BL cells are not recognized by HPV-specific CTLs, suggesting that other mechanisms contribute to providing a full protection from EBNA1-specific CTL-mediated lysis. One of the major differences between BL cells and lymphoplastoid cell lines (LCLs) is the proteasome; indeed, proteasomes from BL cells demonstrate far lower chymotryptic and tryptic-like activities compared with proteasomes from LCLs. Hence, inefficient proteasomal processing is likely to be the main reason for the poor presentation of this epitope in BL cells. Interestingly, we show that treatments with proteasome inhibitors partially restore the capacity of BL cells to present the HPV epitope. This indicates that proteasomes from BL cells, although less efficient in degrading reference substrates than proteasomes from LCLs, are able to destroy the HPV epitope, which can, however, be generated and presented after partial inhibition of the proteasome. These findings suggest the use of proteasome inhibitors, alone or in combination with other drugs, as a strategy for the treatment of EBNA1-carrying tumours.
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Affiliation(s)
- Federica Destro
- Department of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, Italy
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33
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Dupont E, Craciun L. UV-induced immunosuppressive and anti-inflammatory actions: mechanisms and clinical applications. Immunotherapy 2010; 1:205-10. [PMID: 20635942 DOI: 10.2217/1750743x.1.2.205] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
The introduction in 1974 of psoralens UVA (PUVA) therapy followed in 1987 by extracorporeal photopheresis (ECP) has launched UV light in medicine field. A significant number of potential mechanisms could be linked to the basic cellular UV action (i.e., DNA damage and subsequent cells apoptosis). Phagocytosis by macrophages and dendritic cells (DCs) leads, through a receptor-mediated process, to their modulation. A state of antigen-specific tolerance is induced by induction of Treg cells, inhibition of DCs, which remain at a an immature state, inhibition of production of the proinflammatory cytokines IL-2, IFN-gamma, TNF-alpha and IL-12, and induction of production of cytokines IL-10, TGF-beta and IL-1Ra. Beside cutaneous T-cell lymphoma, use of ECP remains experimental except for graft-versus-host disease, especially the chronic-resistant form. The sparing action of corticosteroids as described in studies on transplantation deserves further attention.
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Affiliation(s)
- Etienne Dupont
- Department of Immunology, Hematology & Transfusion, Erasme Hospital, Brussels, Belgium
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34
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Hammes S, Hermann J, Roos S, Ockenfels H. UVB 308-nm excimer light and bath PUVA: combination therapy is very effective in the treatment of prurigo nodularis. J Eur Acad Dermatol Venereol 2010; 25:799-803. [DOI: 10.1111/j.1468-3083.2010.03865.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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35
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KARAKAWA M, KOMINE M, TAKEKOSHI T, SAKURAI N, MINATANI Y, TADA Y, SAEKI H, TAMAKI K. Duration of remission period of narrowband ultraviolet B therapy on psoriasis vulgaris. J Dermatol 2010; 38:655-60. [DOI: 10.1111/j.1346-8138.2010.01053.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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UVR-Induced Regulatory T Cells Switch Antigen-Presenting Cells from a Stimulatory to a Regulatory Phenotype. J Invest Dermatol 2010; 130:1914-21. [DOI: 10.1038/jid.2010.59] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
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38
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Yoshiki R, Kabashima K, Sakabe JI, Sugita K, Bito T, Nakamura M, Malissen B, Tokura Y. The mandatory role of IL-10-producing and OX40 ligand-expressing mature Langerhans cells in local UVB-induced immunosuppression. THE JOURNAL OF IMMUNOLOGY 2010; 184:5670-7. [PMID: 20400709 DOI: 10.4049/jimmunol.0903254] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The mechanism underlying the local UVB-induced immunosuppression is a central issue to be clarified in photoimmunology. There have been reported a considerable number of cells and factors that participate in the sensitization phase-dependent suppression, including Langerhans cells (LCs), regulatory T cells, IL-10, and TNF-alpha. The recent important finding that LC-depleted mice rather exhibit enhanced contact hypersensitivity responses urged us to re-evaluate the role of LCs along with dermal dendritic cells (dDCs) in the mechanism of UVB-induced immunosuppression. We studied the surface expression of OX40 ligand (OX40L) and the intracellular expression of IL-10 in LCs and dDCs from UVB-irradiated (300 mJ/cm(2)) skin of BALB/c mice and those migrating to the regional lymph nodes from UVB-irradiated, hapten-painted mice. In epidermal and dermal cell suspensions prepared from the UVB-irradiated skin, LCs expressed OX40L as well as CD86 and produced IL-10 at a higher level than Langerin(-) dDCs. The UVB-induced immunosuppression was attenuated by the administration of IL-10-neutralizing or OX40L-blocking Abs. In mice whose UVB-irradiated, hapten-painted skin was dissected 1 d after hapten application, the contact hypersensitivity response was restored, because this treatment allowed dDCs but not LCs to migrate to the draining lymph nodes. Moreover, LC-depleted mice by using Langerin-diphtheria toxin receptor-knocked-in mice showed impaired UVB-induced immunosuppression. These results suggest that IL-10-producing and OX40L-expressing LCs in the UVB-exposed skin are mandatory for the induction of Ag-specific regulatory T cells.
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Affiliation(s)
- Ryutaro Yoshiki
- Department of Dermatology, University of Occupational and Environmental Health, Fukuoka, Japan.
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39
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Schwarz A, Noordegraaf M, Maeda A, Torii K, Clausen BE, Schwarz T. Langerhans cells are required for UVR-induced immunosuppression. J Invest Dermatol 2010; 130:1419-27. [PMID: 20090769 DOI: 10.1038/jid.2009.429] [Citation(s) in RCA: 111] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Painting of haptens onto UVR-exposed skin does not result in sensitization but induces regulatory T cells (Treg). This was explained by UVR-mediated depletion of Langerhans cells (LCs). Furthermore, migration of UVR-damaged but still viable LCs into lymph nodes appears to be essential to induce Treg. Accordingly, the steroid mometasone, which kills LCs, inhibited sensitization but did not induce Treg. In Langerin-diphtheria toxin receptor knock-in (DTR) mice, LCs can be depleted by injection of diphtheria toxin (DT). LC-depleted mice could be sensitized though less pronounced than wild-type mice, but sensitization was not suppressed by UVR. Similarly, Treg did not develop. Langerin is not only expressed in LCs but also in some dermal dendritic cells (dDCs). Langerin-positive dDCs repopulate within 10 days after depletion, whereas LCs are still absent. Langerin-DTR mice treated with DT 10 days before UVR and sensitization were still resistant to UVR-induced inhibition of contact hypersensitivity (CHS). Similarly, Treg did not arise. As in this setting only LCs but not Langerin-positive dDCs are absent, LCs appear to be essential for both the suppression of CHS and the induction of Treg by UVR. This supports the concept that LCs are more important for the downregulation than the induction of immune responses in the skin.
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Affiliation(s)
- Agatha Schwarz
- Department of Dermatology, University Kiel, Kiel, Germany
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40
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Ludwig RJ, Bergmann P, Garbaraviciene J, von Stebut E, Radeke HH, Gille J, Diehl S, Hardt K, Henschler R, Kaufmann R, Pfeilschifter JM, Boehncke WH. Platelet, not endothelial, P-selectin expression contributes to generation of immunity in cutaneous contact hypersensitivity. THE AMERICAN JOURNAL OF PATHOLOGY 2010; 176:1339-45. [PMID: 20056837 DOI: 10.2353/ajpath.2010.081100] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Leukocyte extravasation is a prerequisite for host defense and autoimmunity alike. Detailed understanding of the tightly controlled and overlapping sequences of leukocyte extravasation might aid development of novel therapeutic strategies. Leukocyte extravasation is initiated by interaction of selectins with appropriate carbohydrate ligands. Lack of P-selectin expression leads to decreased contact hypersensitivity responses. Yet, it remains unclear if this is due to inhibition of leukocyte extravasation to the skin or due to interference with initial immune activation in lymph nodes. In line with previous data, we here report a decreased contact hypersensitivity response, induced by 2,4,-dinitrofluorobenzene (DNFB), in P-selectin-deficient mice. Eliciting an immune reaction towards DNFB in wild-type mice, followed by adoptive transfer to P-selectin-deficient mice, had no impact on inflammatory response in recipients. This was significantly reduced in wild-type recipient mice adoptively transferred with DNFB immunity generated in P-selectin-deficient mice. To investigate if platelet or endothelial P-selectin was involved, mice solely lacking platelet P-selectin expression generated by bone marrow transplantation were used. Adoptive transfer of immunity from wild-type mice reconstituted with P-selectin-deficient bone marrow led to a decrease of inflammatory response. Comparing this decrease to the one observed using P-selectin-deficient mice, no differences were observed. Our observations indicate that platelet, not endothelial, P-selectin contributes to generation of immunity in DNFB-induced contact hypersensitivity.
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Affiliation(s)
- Ralf J Ludwig
- Department of Dermatology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
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41
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Ludwig RJ, Hardt K, Hatting M, Bistrian R, Diehl S, Radeke HH, Podda M, Schön MP, Kaufmann R, Henschler R, Pfeilschifter JM, Santoso S, Boehncke WH. Junctional adhesion molecule (JAM)-B supports lymphocyte rolling and adhesion through interaction with alpha4beta1 integrin. Immunology 2009; 128:196-205. [PMID: 19740376 DOI: 10.1111/j.1365-2567.2009.03100.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Junctional adhesion molecule-A (JAM-A), JAM-B and JAM-C have been implicated in leucocyte transmigration. As JAM-B binds to very late activation antigen (VLA)-4, a leucocyte integrin that contributes to rolling and firm adhesion of lymphocytes to endothelial cells through binding to vascular cell adhesion molecule (VCAM)-1, we hypothesized that JAM-B is also involved in leucocyte rolling and firm adhesion. To test this hypothesis, intravital microscopy of murine skin microvasculature was performed. Rolling interactions of murine leucocytes were significantly affected by blockade of JAM-B [which reduced rolling interactions from 9.1 +/- 2.6% to 3.2 +/- 1.2% (mean +/- standard deviation)]. To identify putative ligands, T lymphocytes were perfused over JAM-B-coated slides in a dynamic flow chamber system. JAM-B-dependent rolling and sticking interactions were observed at low shear stress [0.3 dyn/cm(2): 220 +/- 71 (mean +/- standard deviation) versus 165 +/- 88 rolling (P < 0.001; Mann-Whitney rank sum test) and 2.6 +/- 1.3 versus 1.0 +/- 0.7 sticking cells/mm(2)/min (P = 0.026; Mann-Whitney rank sum test) on JAM-B- compared with baseline], but not at higher shear forces (1.0 dyn/cm(2)). As demonstrated by antibody blocking experiments, JAM-B-mediated rolling and sticking of T lymphocytes was dependent on alpha4 and beta1 integrin, but not JAM-C expression. To investigate whether JAM-B-mediated leucocyte-endothelium interactions are involved in a disease-relevant in vivo model, adoptive transfer experiments in 2,4,-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity reactions were performed in mice in the absence or in the presence of a function-blocking JAM-B antibody. In this model, JAM-B blockade during the sensitization phase impaired the generation of the immune response to DNFB, which was assessed as the increase in ear swelling in untreated, DNFB-challenged mice, by close to 40% [P = 0.037; analysis of variance (anova)]. Overall, JAM-B appears to contribute to leucocyte extravasation by facilitating not only transmigration but also rolling and adhesion.
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Affiliation(s)
- Ralf J Ludwig
- Department of Dermatology, Clinic of the J.W. Goethe University, Frankfurt am Main, Germany.
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Haldar C, Ahmad R. Photoimmunomodulation and melatonin. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2009; 98:107-17. [PMID: 20080417 DOI: 10.1016/j.jphotobiol.2009.11.014] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/28/2008] [Revised: 11/27/2009] [Accepted: 11/30/2009] [Indexed: 12/15/2022]
Abstract
The seasons, and daily physical rhythms can have a profound effect on the physiology of the living organism, which includes immune status. The immune system can be influenced by a variety of signals and one of them is photic stimulus. Light may regulate the immunity through the neuroendocrine system leading to the most recent branch of research the "Photoimmunomodulation". Mammals perceive visible light (400-700 nm) through some specialized photoreceptors located in retina like retinal ganglion cells (RGC). This photic signal is then delivered to the visual cortex from there to the suprachiasmatic nucleus (SCN) of the hypothalamic region. Melatonin--one of the universally accepted chronobiotic molecule secreted by the pineal gland is now emerging as one of the most effective immunostimulatory compound in rodents and as oncostatic molecule at least in human. Its synthesis decreases with light activation along with norepinephrine and acetylcholine. The changes in level of melatonin may lead to alterations (stimulatory/inhibitory) in immune system. The evidences for the presence of melatonin receptor subtypes on lymphoid tissues heralded the research area about mechanism of action for melatonin. Further, melatonin receptor subtypes-MT1 and MT2 was noted on pars tuberalis, SCN and on lymphatic tissues suggesting a direct action of melatonin in modulation of immunity by photoperiod as well. The nuclear receptors (ROR, RZR etc.) of melatonin are known for its free radical scavenging actions and might be indirectly controlling the immune function.
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Affiliation(s)
- C Haldar
- Pineal Research Lab., Department of Zoology, Banaras Hindu University, Varanasi 221 005, India.
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43
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Welsh MM, Applebaum KM, Spencer SK, Perry AE, Karagas MR, Nelson HH. CTLA4 variants, UV-induced tolerance, and risk of non-melanoma skin cancer. Cancer Res 2009; 69:6158-63. [PMID: 19622768 PMCID: PMC2928067 DOI: 10.1158/0008-5472.can-09-0415] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Although skin tumors are highly immunogenic, exposure to UV radiation is known to suppress immune responses via regulatory T cells. Specifically, the activity of cytotoxic lymphocyte-associated antigen-4 (CTLA-4) is integral in regulating the development of UV-induced tolerance and, concomitantly, skin cancers. Due to the inverse relationship between tumor surveillance and autoimmunity, we hypothesize that the same genetic variant in the CTLA4 locus that increases risk for autoimmune diseases is associated with decreased risk of non-melanoma skin cancer (NMSC). We analyzed whether the polymorphism CT60 or haplotypes of CTLA4 influence odds of developing the major types of NMSC, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), in a population-based case-control study of Caucasians in New Hampshire (849 controls, 930 BCC, and 713 SCC). The CTLA4 CT60 GG genotype was associated with decreased odds for BCC and SCC, controlling for age, sex, lifetime number of severe sunburns, and skin type [BCC: odds ratio (OR), 0.7; 95% confidence interval (95% CI), 0.5-0.9; SCC: OR, 0.7; 95% CI, 0.5-1.0]. For BCC, this decrease was apparent largely among those with a higher lifetime number of severe sunburns (P(interaction) = 0.0074). There were significantly decreased odds of disease associated with two haplotypes, which possess the CT60 G allele. Additionally, lifetime number of severe sunburns modestly altered the effects of the CTLA4 haplotypes in BCC, and the association seemed driven by the CT60 single nucleotide polymorphism. In conclusion, genetic variation at the CTLA4 locus may be etiologically important in NMSC, the most prevalent malignancy in the United States.
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Affiliation(s)
- Marleen M. Welsh
- Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts
| | - Katie M. Applebaum
- Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts
- Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts
| | - Steven K. Spencer
- Section of Dermatology, Department of Medicine, Dartmouth Medical School, Lebanon, New Hampshire
| | - Ann E. Perry
- Department of Pathology, Dartmouth Hitchcock Medical Center, Dartmouth Medical School, Lebanon, New Hampshire
| | - Margaret R. Karagas
- Section of Biostatistics and Epidemiology, Department of Community and Family Medicine, and the Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, New Hampshire
| | - Heather H. Nelson
- Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
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Wolf P, Byrne SN, Gruber-Wackernagel A. New insights into the mechanisms of polymorphic light eruption: resistance to ultraviolet radiation-induced immune suppression as an aetiological factor. Exp Dermatol 2009; 18:350- 6. [PMID: 19348001 DOI: 10.1111/j.1600-0625.2009.00859.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
An abnormal immune response has long been thought responsible for the patho-aetiology of polymorphic light eruption, the most common photodermatosis. Recent evidence indicates that polymorphic light eruption patients are resistant to the immune suppressive effects of sunlight, a phenomenon that leads to the formation of skin lesions upon seasonal sun exposure. This immunological abnormality in polymorphic light eruption supports the concept of the biological significance and evolutionary logic of sunlight-induced immune suppression, i.e. the prevention of immune responses to photo-induced neo-antigens in the skin, thereby preventing autoimmunity and skin rashes. This article focuses on the immunological alterations in polymorphic light eruption and the pathogenic significance to the disease state and skin carcinogenesis.
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Affiliation(s)
- Peter Wolf
- Research Unit for Photodermatology, Department of Dermatology, Medical University of Graz, Graz, Austria.
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45
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Skin application of ketoprofen systemically suppresses contact hypersensitivity by inducing CD4+ CD25+ regulatory T cells. J Dermatol Sci 2009; 53:216-21. [DOI: 10.1016/j.jdermsci.2008.10.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2008] [Revised: 10/28/2008] [Accepted: 10/30/2008] [Indexed: 12/20/2022]
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46
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Maeda A, Schwarz A, Bullinger A, Morita A, Peritt D, Schwarz T. Experimental extracorporeal photopheresis inhibits the sensitization and effector phases of contact hypersensitivity via two mechanisms: generation of IL-10 and induction of regulatory T cells. THE JOURNAL OF IMMUNOLOGY 2009; 181:5956-62. [PMID: 18941184 DOI: 10.4049/jimmunol.181.9.5956] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Extracorporeal photopheresis (ECP) is used to treat immune-mediated diseases including transplant rejection and graft-vs-host-disease. An experimental murine model of ECP utilizing contact hypersensitivity (CHS) revealed that ECP inhibits the sensitization of CHS and induces regulatory T cells (Treg). In this study, we find that ECP inhibits not only the sensitization but also the effector phase of CHS, although Treg only inhibited sensitization. IL-10 was determined to be a critical component of the effector phase inhibition and also a driving force in developing Treg. Thus, we propose that the inhibition of the effector phase of CHS by ECP is a process that does not require Treg but may be mediated via enhanced IL-10 as suggested by the use of IL-10-deficient mice. This suggests that ECP has at least two mechanisms of action, one inhibiting the effector phase of CHS and one generating Treg, which in turn can inhibit CHS sensitization and is responsible for the transferable protection. Together, this may help explain the clinical benefits of ECP in prophylactic, acute, and therapeutic settings.
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Affiliation(s)
- Akira Maeda
- Department of Dermatology, University Kiel, Kiel, Germany
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Maeda A, Beissert S, Schwarz T, Schwarz A. Phenotypic and functional characterization of ultraviolet radiation-induced regulatory T cells. THE JOURNAL OF IMMUNOLOGY 2008; 180:3065-71. [PMID: 18292529 DOI: 10.4049/jimmunol.180.5.3065] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Sensitization through UV-exposed skin induces regulatory T cells (Treg). In contrast to the classical CD4+CD25+ Treg that act contact dependent, UV-induced Treg (UV-Treg) suppress via IL-10, indicating a distinct subtype that requires further characterization. Depletion studies revealed that UV-Treg express the glucocorticoid-induced TNF family-related receptor (GITR) and the surface molecule neuropilin-1. The injection of T cells from UV-tolerized mice after depletion of UV-Treg into naive recipients enabled a contact hypersensitivity response, indicating that tolerization also induces T effector cells. Adoptive transfer experiments using IL-10-deficient mice indicated that the IL-10 required for suppression is derived from UV-Treg and not from host-derived cells. Activation of UV-Treg is Ag specific, however, once activated suppression is nonspecific (bystander suppression). Hence, speculations exist about the therapeutic potential of Treg generated in response to Ag that are not necessarily the precise Ag driving the pathogenic process. Thus, we studied the consequences of multiple injections of 2,4-dintrofluorobenzene (DNFB)-specific Treg into ears of naive mice followed by multiple DNFB challenges. DNFB-specific Treg were injected once weekly into the left ears of naive mice and DNFB challenge was performed always 24 h later. After three injections, a challenging dose of DNFB was applied on the right ear. This resulted in pronounced ear swelling, indicating that the subsequent boosting of DNFB-specific Treg had caused sensitization of the naive mice against DNFB. These data demonstrate that UV-Treg express GITR and neuropilin-1 and act via bystander suppression. However, constant boosting of Treg with Ag doses in the challenging range results in final sensitization that might limit their therapeutic potential.
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Affiliation(s)
- Akira Maeda
- Department of Dermatology, University Kiel, Kiel, Germany
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Jonson CO, Pihl M, Nyholm C, Cilio CM, Ludvigsson J, Faresjö M. Regulatory T cell-associated activity in photopheresis-induced immune tolerance in recent onset type 1 diabetes children. Clin Exp Immunol 2008; 153:174-81. [PMID: 18549445 DOI: 10.1111/j.1365-2249.2008.03625.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Extracorporeal photochemotherapy (ECP) has demonstrated immunological effects. The proposed cytotoxic lymphocyte antigen 4 (CTLA-4) involvement, together with forkhead box P3 (FoxP3) and transforming growth factor (TGF)-beta are associated with regulatory T cell activity. The aim of the study was to evaluate the regulatory T cell-associated effect of ECP in recent onset type 1 diabetic (T1D) children. Children (n = 20) with T1D received photopheresis 8-methoxypsoralen + ECP or placebo + shampheresis. Peripheral blood mononuclear cells (PBMC) collected pretreatment (day 1) and post-treatment (day 90) were stimulated with phytohaemagglutinin (PHA) and T1D-associated glutamic acid decarboxylase 65 (GAD(65)) peptide a.a. 247-279. CTLA-4, sCTLA-4, FoxP3 and TGF-beta mRNA transcription was quantified. Photopheresis-treated individuals' relative mRNA expression was generally maintained during the course of the study. Placebo individuals increased in spontaneous CTLA-4 mRNA (P < 0.05) but decreased in expression after stimulation with GAD(65)-peptide (P < 0.05) and PHA (P < 0.05). Spontaneous TGF-beta (P < 0.05) increased whereas PHA- (P < 0.01) and GAD(65)-peptide (P < 0.01)-induced TGF-beta expression decreased in the placebo group, whereas it was maintained in the treated group. Without intervention, expression of CTLA-4 and TGF-beta, stimulated with PHA and GAD(65) peptide, decreased with time, with a parallel reduction of GAD(65)-peptide and PHA-stimulated TGF-beta expression. These parameters were counteracted by ECP. In conclusion, our results indicate that ECP maintains regulatory T cell-associated activity in recent-onset T1D.
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Affiliation(s)
- C-O Jonson
- Division of Pediatrics and Diabetes Research Centre, Department of Molecular and Clinical Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden
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Komura K. [Ultraviolet: a regulator of immunity]. NIHON RINSHO MEN'EKI GAKKAI KAISHI = JAPANESE JOURNAL OF CLINICAL IMMUNOLOGY 2008; 31:125-131. [PMID: 18587222 DOI: 10.2177/jsci.31.125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
Abstract
Humans establish acquired immune systems during the growth, which can sufficiently eliminate pathogen avoiding immune responses to self, such as allergy and autoimmunity. An imbalance of the acquired immune system leads up to immune-mediated disorders. Ultraviolet (UV) exposure helps to establish the normal peripheral tolerance to contact allergen avoiding excessive immune responses. By contrast, UV develops kinds of autoimmune diseases on rare occasions, suggesting that abnormality in the process of UV-induced peripheral tolerance may induce these diseases. To elucidate the mechanism of UV-induced tolerance is possible to provide a new approach for the management of immune diseases. In the current review, focus is on the suggested players of UV-induced tolerance, blocking mechanisms on the elicitation phase of contact hypersensitivity, and the association between UV and autoimmunity. The major impact in basic immunology in this area is the discovery of cell surface marker of regulatory T cells. Therefore, we first discuss about the association of regulatory/suppressor T cells with UV-induced tolerance. Since the elicitation phase depends on cellular influx into the inflammatory sites, which is tightly regulated by adhesion molecules, we also focused on the role of adhesion molecules. Finally, this paper also includes statistical findings concerning the association between UV-radiation and the prevalence of a myositis specific autoantibody. Thus, UV is one of the nice regulators of an immune network and the knowledge of UV-mediated immune regulation will be translated into new therapeutic strategies to human immune-mediated disorders.
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Affiliation(s)
- Kazuhiro Komura
- Department of Dermatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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Toichi E, Lu KQ, Swick AR, McCormick TS, Cooper KD. Skin-infiltrating monocytes/macrophages migrate to draining lymph nodes and produce IL-10 after contact sensitizer exposure to UV-irradiated skin. J Invest Dermatol 2008; 128:2705-2715. [PMID: 18509360 DOI: 10.1038/jid.2008.137] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Low-dose UVB exposure induces antigen-specific unresponsiveness to antigen(s) introduced through UV-irradiated skin (tolerance). Analysis of cytokine expression in murine draining lymph nodes (DLNs) revealed that IL-12p40 mRNA and protein expression as well as IL-12p70 protein were upregulated after application of the contact sensitizer 2,4 dinitro-1-fluorobenzene (DNFB) to normal skin. The cellular source of IL-12p40 mRNA was CD11c+ cells. By contrast, following DNFB application to UV-irradiated skin (UV+DNFB), IL-12p40 mRNA was not upregulated, and DLN IL-12p40 and p70 proteins were reduced. UVB irradiation alone did not upregulate IL-10 mRNA, but UV+DNFB upregulated IL-10 mRNA as early as 3-6 hours after DNFB application, immediately preceding a decrease of IL-12p40 mRNA from the level induced by UVB. The infiltration of F4/80+ cells into UV-irradiated skin was followed by a rapid and remarkable increase of F4/80+CD11c(-) cells in DLN 3 hours following DNFB application. FITC/DNFB skin painting and subsequent enzyme-linked immunospot assay demonstrated that flow-sorted FITC+F4/80+CD11c(-) cells from the DLN produce IL-10. Thus, monocytes/macrophages that infiltrated into the skin following UVB exposure migrate to the DLN triggered by contact sensitizers. Production of IL-10 by migrating macrophages, in conjunction with IL-12 inhibition in the DLN, likely reflects a role as mobile suppressive mediators for locally induced UV tolerance.
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Affiliation(s)
- Eiko Toichi
- Department of Dermatology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio, USA; Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Kurt Q Lu
- Department of Dermatology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio, USA
| | - Alan R Swick
- Department of Dermatology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio, USA
| | - Thomas S McCormick
- Department of Dermatology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio, USA
| | - Kevin D Cooper
- Department of Dermatology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio, USA; Department of Dermatology, Veterans Administration Medical Center, Cleveland, Ohio, USA.
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