المؤلفون: Virginia L. Calder, Susan Lightman, G. Galatowicz, Renyang Gu, Xiaozhe Zhang, Aurelia Gondrand, Y.–H. Chen, Malihe Eskandarpour

المصدر: European Journal of Immunology. 50:1941-1951

مصطلحات موضوعية: education.field_of_study, Endothelium, T cell, Immunology, Population, chemical and pharmacologic phenomena, hemic and immune systems, C-C chemokine receptor type 6, Biology, CXCR3, Molecular biology, eye diseases, In vitro, Chemokine receptor, medicine.anatomical_structure, medicine, Immunology and Allergy, sense organs, education, Dexamethasone, medicine.drug

الوصف: Immunopathogenic roles for both Th1 (CD4+ IFN-γ+ ) and Th17 (CD4+ IL-17A+ ) cells have been demonstrated in experimental autoimmune uveitis (EAU). However, the role for Th17/Th1 (CD4+ T cells co-expressing IFN-γ and IL-17A) cells in EAU is not yet understood. Using interphotoreceptor retinoid-binding protein peptide-induced EAU in mice, we found increased levels of Th17/Th1 cells in EAU retinae (mean 9.6 ± 4.2%) and draining LNs (mean 8.4 ± 3.9%; p = 0.01) relative to controls. Topical dexamethasone treatment effectively reduced EAU severity and decreased retinal Th1 cells (p = 0.01), but had no impact on retinal Th17/Th1 or Th17 cells compared to saline controls. Using in vitro migration assays with mouse CNS endothelium, we demonstrated that Th17/Th1 cells were significantly increased within the migrated population relative to controls (mean 15.6 ± 9.5% vs. 1.9 ± 1.5%; p = 0.01). Chemokine receptor profiles of Th17/Th1 cells (CXCR3 and CCR6) did not change throughout the transendothelial migration process and were unaffected by dexamethasone treatment. These findings support a role for Th17/Th1 cells in EAU and their resistance to steroid inhibition suggests the importance of targeting both Th17 and Th17/Th1 cells for improving therapy.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::b7c51e3ddf1d1c43c6f66ee96c184daeTest
https://doi.org/10.1002/eji.202048616Test

المؤلفون: Susan Lightman, Virginia L. Calder, Yi-Hsing Chen

المصدر: International Journal of Molecular Sciences, Vol 22, Iss 9584, p 9584 (2021)

مصطلحات موضوعية: Adoptive cell transfer, experimental autoimmune uveitis, QH301-705.5, chemical and pharmacologic phenomena, Disease, Biology, Catalysis, Inorganic Chemistry, chemistry.chemical_compound, Th1 cells, medicine, IL-2 receptor, Physical and Theoretical Chemistry, Th17 cells, Biology (General), Molecular Biology, QD1-999, Spectroscopy, Th17/Th1 (CD4+IFNγ+IL-17+) cells, Effector, Th17/Treg (CD4+IL-17+FoxP3+) cells, Organic Chemistry, FOXP3, Retinal, hemic and immune systems, General Medicine, medicine.disease, Phenotype, Computer Science Applications, regulatory (Treg) T cells, Chemistry, chemistry, Immunology, Uveitis

الوصف: Non-infectious uveitis (NIU) is a potentially sight-threatening disease. Effector CD4+ T cells, especially interferon-γ-(IFNγ) producing Th1 cells and interleukin-17-(IL-17) producing Th17 cells, are the major immunopathogenic cells, as demonstrated by adoptive transfer of disease in a model of experimental autoimmune uveitis (EAU). CD4+FoxP3+CD25+ regulatory T cells (Tregs) were known to suppress function of effector CD4+ T cells and contribute to resolution of disease. It has been recently reported that some CD4+ T-cell subsets demonstrate shared phenotypes with another CD4+ T-cell subset, offering the potential for dual function. For example, Th17/Th1 (co-expressing IFNγ and IL-17) cells and Th17/Treg (co-expressing IL-17 and FoxP3) cells have been identified in NIU and EAU. In this review, we have investigated the evidence as to whether these ‘plastic CD4+ T cells’ are functionally active in uveitis. We conclude that Th17/Th1 cells are generated locally, are resistant to the immunosuppressive effects of steroids, and contribute to early development of EAU. Th17/Treg cells produce IL-17, not IL-10, and act similar to Th17 cells. These cells were considered pathogenic in uveitis. Future studies are needed to better clarify their function, and in the future, these cell subsets may in need to be taken into consideration for designing treatment strategies for disease.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5b5343fa20751245e863e2a1894a82c8Test
https://www.mdpi.com/1422-0067/22/17/9584Test

المؤلفون: Renyang Gu, Virginia L. Calder, Grazyna Galatowicz, Yi-Hsing Chen, Xiaozhe Zhang, Aurelia Gondrand, Susan Lightman, Malihe Eskandarpour

مصطلحات موضوعية: medicine.anatomical_structure, T cell, medicine.medical_treatment, Immunology, medicine, Autoimmune uveitis, Biology, Steroid

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::1bb4d6cdd4a191f42b5458128409ec8fTest
https://doi.org/10.1002/eji.202048616/v2/response1Test

المؤلفون: Malihe Eskandarpour, Robert A. Alexander, Virginia L. Calder, Peter Adamson

المصدر: The Journal of Immunology. 198:1093-1103

مصطلحات موضوعية: Receptors, CCR6, 0301 basic medicine, Adoptive cell transfer, Chromosomal Proteins, Non-Histone, Immunology, Down-Regulation, chemical and pharmacologic phenomena, Inflammation, Biology, Retina, Autoimmune Diseases, Uveitis, Mice, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, In vivo, medicine, Animals, Immunology and Allergy, Secretion, Orphan receptor, Tumor Necrosis Factor-alpha, Nuclear Proteins, Forkhead Transcription Factors, hemic and immune systems, Nuclear Receptor Subfamily 1, Group F, Member 3, Th1 Cells, In vitro, Bromodomain, 030104 developmental biology, Cancer research, Cytokines, Th17 Cells, Female, medicine.symptom, Transcription Factors, 030215 immunology

الوصف: Experimental autoimmune uveitis (EAU), in which CD4+ Th1 and/or Th17 cells are immunopathogenic, mimics various clinical features of noninfectious uveitis in humans. The impact of bromodomain extraterminal (BET) inhibitors on Th17 cell function was studied in a mouse model of EAU in vivo and in mouse and human Th17 cells in vitro. Two BET inhibitors (GSK151 and JQ1) were able to ameliorate the progression of inflammation in EAU and in mouse CD4+ T cells in vitro, downregulating levels of Th17 cells. Additionally, the uveitogenic capacity of Th17 cells to transfer EAU was abrogated by BET inhibitors in an adoptive transfer model. In human CD4+ T cells, a 5-d exposure to BET inhibitors was accompanied by a significant downregulation of Th17-associated genes IL-17A, IL-22, and retinoic acid–related orphan receptor γt. However, in vitro, the inhibitors had no effect on already polarized Th17 cells. The key finding is that, in response to BET inhibitors, Th17-enriched cultures developed a regulatory phenotype, upregulated FOXP3 expression and IL-10 secretion, and lost pathogenicity in vivo. We conclude that BET targeting of Th17 cells is a potential therapeutic opportunity for a wide range of inflammatory and autoimmune diseases, including uveitis.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::563d25efcfa6940610ea43d4af1f068fTest
https://doi.org/10.4049/jimmunol.1600735Test

المؤلفون: Samia Yazid, Andrew D. Dick, Peter Adamson, Colin J Chu, Peter Gardner, David A. Copland, Virginia L. Calder

المصدر: The American Journal of Pathology. 185:1324-1333

مصطلحات موضوعية: CD4-Positive T-Lymphocytes, Blotting, Western, Population, Inflammation, Autoimmune Diseases, Pathology and Forensic Medicine, Uveitis, Mice, Immune system, Sirtuin 1, medicine, Animals, education, Autoimmune disease, education.field_of_study, biology, Tumor Necrosis Factor-alpha, business.industry, Flow Cytometry, medicine.disease, Disease Models, Animal, Immunology, Adjunctive treatment, biology.protein, Female, Tumor necrosis factor alpha, medicine.symptom, business, hormones, hormone substitutes, and hormone antagonists

الوصف: Elevated tumor necrosis factor (TNF) α levels are associated with chronic autoimmune diseases in which effects of TNFα on immune cells are multiple and complex. Analysis of uveitis in mice exhibiting severe autoimmune inflammation, resulting in a destructive subtotal loss of photoreceptors, revealed the presence of high plasma levels of TNFα and a significant population of CD4 + TNFα + cells in the periphery and the eye at peak disease (TNFα hi ). We have shown previously by pharmacological activation that the deacetylase Sirtuin 1 (SIRT1) has an anti-inflammatory role in a less severe, TNFα lo model of uveitis. We now show that SIRT1 activation fails to clinically suppress severe TNFα hi disease, whereas glucocorticoid treatment is successful. TNFα has been reported to mediate cleavage and inactivation of SIRT1 during inflammation, and at peak disease we observed both full-length and cleaved SIRT1 in draining lymph node cells. In vivo systemic TNFα blockade suppressed severe ocular disease and restricted SIRT1 cleavage in the periphery, maintaining full-length active SIRT1 protein. When combining a suboptimal TNFα blockade with SIRT1 activation, a synergistic suppression of severe disease compared with TNFα blockade alone occurred. Our data suggest a new role for TNFα in exacerbating the severity of autoimmune disease by regulating SIRT1 cleavage in draining lymph node effector cells. SIRT1 activation may be effective as an adjunctive treatment for inflammatory conditions not fully controlled by TNFα inhibitors.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1ff099c2ad32ee6a142af8049ddeaeeaTest
https://doi.org/10.1016/j.ajpath.2015.01.017Test

المؤلفون: Grazyna Galatowicz, Nicole Carnt, Virginia L. Calder, Vicente M. Montanez, Neyme Veli

المصدر: ResearcherID

مصطلحات موضوعية: Adult, Male, medicine.medical_specialty, Contact Lenses, Enzyme-Linked Immunosorbent Assay, Proinflammatory cytokine, Keratitis, 03 medical and health sciences, 0302 clinical medicine, Ophthalmology, medicine, Humans, Interferon gamma, Eye Infections, Parasitic, Prospective Studies, Eye Proteins, biology, business.industry, Eye infection, Middle Aged, medicine.disease, biology.organism_classification, Acanthamoeba, Contact lens, Acanthamoeba keratitis, Acanthamoeba Keratitis, Case-Control Studies, Tears, 030221 ophthalmology & optometry, Cytokines, Female, business, 030215 immunology, medicine.drug

الوصف: PURPOSE: To determine differences in key tear film cytokines between mild and severe cases of acanthamoeba keratitis (AK) and control contact lens (CL) wearers. METHODS: This was a prospective study of CL wearers with AK attending Moorfields Eye Hospital and control CL wearers from the Institute of Optometry, London. Basal tear specimens were collected by 10-μL capillary tubes (BLAUBRAND intraMark, Wertheim, Germany), and tear protein levels were measured with a multiplex magnetic bead array (Luminex 100; Luminex Corporation, Austin, TX) for cytokines interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-17A, IL-17E, IL-17F, IL-22, and interferon gamma and with enzyme-linked immunosorbent assay (Abcam, Cambridge, United Kingdom) for CXCL2. Severe cases of AK were defined as having active infection for over 12 months and at least 1 severe inflammatory event. RESULTS: One hundred and thirty-two tear samples were collected from a total of 61 cases (15 severe and 46 mild–moderate) and 22 controls. IL-8, part of the Toll-like receptor 4 cytokine cascade, was found to be expressed at a detectable level more often in cases of AK than in control CL wearers (P = 0.003) and in higher concentrations in severe cases than in milder forms of the disease (z = −2.35). IL-22, part of the IL-10 family, and a proinflammatory Th17 cytokine, was detected more often in severe cases than in milder forms of AK (P < 0.02). CONCLUSIONS: Profiling patients with AK during disease shows differences in cytokine levels between severe and milder disease that may inform clinical management. The Toll-like receptor 4 and IL-10/Th17 inflammatory pathways should be included in further investigations of this disease.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0f72ffd04455c6c82a779a5374ac78adTest
https://pubmed.ncbi.nlm.nih.gov/28489721Test

المؤلفون: David Abraham, John Dart, Markella Ponticos, Daniel R. Saban, Julie T. Daniels, Virginia L. Calder, Suryanarayana Rayapureddi, Valerie P J Saw, Sarah D. Ahadome, Jill T. Norman

المصدر: JCI insight. 1(12)

مصطلحات موضوعية: 0301 basic medicine, Adult, Male, Pathology, medicine.medical_specialty, Conjunctiva, Pemphigoid, Benign Mucous Membrane, Retinoic acid, Aldehyde dehydrogenase, Tretinoin, 03 medical and health sciences, chemistry.chemical_compound, Cicatrix, Mice, 0302 clinical medicine, Fibrosis, In vivo, Disulfiram, medicine, Animals, Humans, Cells, Cultured, Aged, Aged, 80 and over, Mucous Membrane, biology, Mucous membrane, General Medicine, Aldehyde Dehydrogenase, Fibroblasts, Middle Aged, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, chemistry, 030221 ophthalmology & optometry, Cancer research, biology.protein, Female, medicine.drug, Research Article

الوصف: Mucous membrane pemphigoid (MMP) is a systemic mucosal scarring disease, commonly causing blindness, for which there is no antifibrotic therapy. Aldehyde dehydrogenase family 1 (ALDH1) is upregulated in both ocular MMP (OMMP) conjunctiva and cultured fibroblasts. Application of the ALDH metabolite, retinoic acid (RA), to normal human conjunctival fibroblasts in vitro induced a diseased phenotype. Conversely, application of ALDH inhibitors, including disulfiram, to OMMP fibroblasts in vitro restored their functionality to that of normal controls. ALDH1 is also upregulated in the mucosa of the mouse model of scarring allergic eye disease (AED), used here as a surrogate for OMMP, in which topical application of disulfiram decreased fibrosis in vivo. These data suggest that progressive scarring in OMMP results from ALDH/RA fibroblast autoregulation, that the ALDH1 subfamily has a central role in immune-mediated ocular mucosal scarring, and that ALDH inhibition with disulfiram is a potential and readily translatable antifibrotic therapy.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c8f46e77582c1681e471fbd0d3d5c28aTest
https://pubmed.ncbi.nlm.nih.gov/27699226Test

المؤلفون: Priyatham S Mettu, Virginia L. Calder, Nancy J. Reyes, Scott W. Cousins, Daniel R. Saban, Sarah D. Ahadome, Rose Mathew

المصدر: JCI insight. 1(12)

مصطلحات موضوعية: 0301 basic medicine, T cell, Retinoic acid, Aldehyde dehydrogenase, Retinoid X receptor, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, In vivo, Fibrosis, medicine, Fibroblast, biology, business.industry, General Medicine, medicine.disease, eye diseases, 030104 developmental biology, medicine.anatomical_structure, chemistry, Integrin alpha M, 030220 oncology & carcinogenesis, Immunology, biology.protein, business, Research Article

الوصف: Fibrosis is a shared end-stage pathway to lung, liver, and heart failure. In the ocular mucosa (conjunctiva), fibrosis leads to blindness in trachoma, pemphigoid, and allergy. The indirect fibrogenic role of DCs via T cell activation and inflammatory cell recruitment is well documented. However, here we demonstrate that DCs can directly induce fibrosis. In the mouse model of allergic eye disease (AED), classical CD11b+ DCs in the ocular mucosa showed increased activity of aldehyde dehydrogenase (ALDH), the enzyme required for retinoic acid synthesis. In vitro, CD11b+ DC-derived ALDH was associated with 9-cis-retinoic acid ligation to retinoid x receptor (RXR), which induced conjunctival fibroblast activation. In vivo, stimulating RXR led to rapid onset of ocular mucosal fibrosis, whereas inhibiting ALDH activity in DCs or selectively depleting DCs markedly reduced fibrosis. Collectively, these data reveal a profibrotic ALDH-dependent pathway by DCs and uncover a role for DC retinoid metabolism.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1cd1cab8743b1ea7cc5346cf3296f318Test
https://pubmed.ncbi.nlm.nih.gov/27595139Test

المؤلفون: Virginia L. Calder, Julie T. Daniels, Maria Notara, G. Galatowicz, Alex J. Shortt

المصدر: Stem Cell Research. 5:188-200

مصطلحات موضوعية: STAT3 Transcription Factor, Abcg2, Apoptosis, Limbus Corneae, Stem cell marker, Stroma, medicine, ATP Binding Cassette Transporter, Subfamily G, Member 2, Humans, Limbal stem cell, Receptor, STAT3, Cell Proliferation, Corneal epithelium, Medicine(all), biology, Interleukin-6, Stem Cells, Tumor Suppressor Proteins, Epithelium, Corneal, Cell Biology, General Medicine, Coculture Techniques, Neoplasm Proteins, Cell biology, medicine.anatomical_structure, Immunology, Trans-Activators, biology.protein, ATP-Binding Cassette Transporters, sense organs, Stromal Cells, Stem cell, Transcription Factors, Developmental Biology

الوصف: The corneal epithelium is maintained by the limbal epithelial stem cells (LESCs). In this study, an in vitro model is proposed for the investigation of cell-cell interactions involving LESC maintenance. Imaging of the limbal niche demonstrated close spatial arrangement between basal limbal epithelial cells within putative LESC niche structures and fibroblasts in the stroma. Interactions of the human limbal epithelial (HLE) cells and mitotically active human limbal fibroblasts (HLF) were studied for the first time in a serum-free in vitro model that simulated aspects of the limbal niche microenvironment. HLE cocultured in a ratio 3:1 with HLF exhibited enhanced expression of the putative stem cell markers ABCG2 and p63α and holoclones were preserved as shown by colony-forming efficiency assays, clonal analysis, and colony characterisation. Interleukin 6 (IL6) was found to be up-regulated in the 3.1SF system when compared to the HLE culture with growth-arrested fibroblasts and serum (gold standard system, GS). IL6 caused a time-dependent phosphorylation of STAT3 in HLE cells. STAT3 and IL6 inhibition in 3.1SF cultures significantly reduced HLE colony-forming efficiency, suggesting a previously undetected STAT3-mediated involvement of IL6 in the maintenance of HLE cells in a progenitor-like state.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e7a49b9dcdb3c057f6ea865789569282Test
https://doi.org/10.1016/j.scr.2010.07.002Test

المؤلفون: Yolanda Diebold, Itziar Fernández, Carmen García-Vázquez, Margarita Calonge, G. Galatowicz, Virginia L. Calder, Amalia Enríquez-de-Salamanca, Jianping Gao, Michael E. Stern

المصدر: Cytokine. 44:160-167

مصطلحات موضوعية: Chemokine, medicine.medical_treatment, Immunology, Apoptosis, Inflammation, Models, Biological, Biochemistry, Cell Line, Proinflammatory cytokine, Interferon-gamma, medicine, Humans, Immunology and Allergy, Secretion, Molecular Biology, Conjunctivitis, Allergic, Endophthalmitis, Interleukin-13, biology, Tumor Necrosis Factor-alpha, business.industry, Epithelial Cells, Hematology, Cytokine, biology.protein, Cytokines, Tumor necrosis factor alpha, Cytokine secretion, Interleukin-4, medicine.symptom, business, Conjunctiva

الوصف: Objectives: We examined the differential secretion of cytokines by a conjunctival epithelial cell line in response to proinflammatory cytokines to identify the potential contributions during ocular surface inflammation. Methods: A conjunctival epithelial cell line was exposed to IFN-γ, TNF-α, IL-4, or IL-13, and cytokine production was determined in supernatants at different times after exposure. Cell apoptosis was measured by flow cytometry. Results: TNF-α induced the greatest effect on cytokine secretion, which was time-dependent. TNF-α-stimulated secretion of IL-12p40 was significantly increased by 30 min; GM-CSF, MCP-1, IL-6, IL-7, IL-8, and RANTES were significantly increased by 2 h, and IFN-γ and IL-1α by 24 h. After 48 h, TNF-α also induced a significant increase in IL-1β, IL-3, and IP-10 secretion. IFN-γ significantly enhanced IP-10 and RANTES secretion after 48 h of exposure. Following IL-4 treatment there was a significant increase in eotaxin-1 after 24 h, and IL-12p40 and IL-3 after 48 h. IL-13 significantly increased the secretion of eotaxin-1 after 24 h, and IL-8 after 48 h. Conclusion: Our results suggest that conjunctival epithelial cells are an important source of cytokines and chemokines that are regulated by proinflammatory cytokines and may play an important role in ocular surface inflammation.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d65380b92c2b31d37823a6b0608bbdedTest
https://doi.org/10.1016/j.cyto.2008.07.007Test