|
1
|
Beer SA, Went M, Mills C, Wood C, Sud A, Allan JM, Houlston R, Kaiser MF. Mendelian randomization of immune cell phenotypes to discover potential drug targets for B-cell malignancy. Blood Cancer J 2025; 15:62. [PMID: 40199857 PMCID: PMC11979003 DOI: 10.1038/s41408-025-01277-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Revised: 03/28/2025] [Accepted: 04/01/2025] [Indexed: 04/10/2025] Open
Abstract
Although treatment options for B-cell malignancies have expanded, many patients continue to face limited response rates, highlighting an urgent need for new therapeutic targets. To prioritize candidate drug targets for B-cell malignancies, we employed Mendelian Randomization to estimate potentially causal relationships between 445 immune cell traits and six B-cell cancers: follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma (HL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM), totaling 22,922 cases and 394,204 controls. 163 traits showed a suggestive association with at least one B-cell malignancy (P < 0.05), with 34 traits being significant after correction for multiple testing (P < 2 × 10-4). By integrating findings with observational data and clinical trial evidence to support drug target candidacy, 24 cell surface markers were identified as druggable targets. In addition to established therapeutic targets such as CD3, CD20 and CD38, our analysis highlights BAFF-R and CD39 in HL, CD25 in MM, CD27 in CLL, CD80/86 in DLBCL, and CCR2 in FL and MZL as promising candidates for therapeutic inhibition. Our findings provide further support for the potential of human genetics to guide the identification of drug targets and address a productivity-limiting step.
Collapse
Affiliation(s)
- Sina A Beer
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
| | - Molly Went
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| | - Charlie Mills
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| | - Codie Wood
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| | - Amit Sud
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Harvard Medical School, Boston, MA, USA
- Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - James M Allan
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Richard Houlston
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| | - Martin F Kaiser
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| |
Collapse
|
|
2
|
Golušin Z, Maletin N, Denda N, Nišavić M, Radovanović B, Nikolić O. Autoimmune Thyroid Diseases in Chronic Spontaneous Urticaria: The Role of Hormones, Anti-Thyroid Antibodies, and Ultrasound. Diagnostics (Basel) 2025; 15:608. [PMID: 40075855 PMCID: PMC11899388 DOI: 10.3390/diagnostics15050608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2025] [Revised: 02/26/2025] [Accepted: 02/27/2025] [Indexed: 03/14/2025] Open
Abstract
Background/Objectives: Chronic spontaneous urticaria (CSU) is an immune-mediated skin disorder, with increasing evidence suggesting its association with autoimmune thyroid diseases. The presence of antithyroid antibodies (anti-TPO and anti-TG) and autoimmune thyroid disease indicates shared immunological mechanisms in the pathogenesis of both conditions. This study examines the prevalence of autoimmune thyroid changes in patients with CSU. Methods: The study was conducted as a combined retrospective-prospective observational analysis. It included 43 patients with CSU and 50 healthy participants in the control group. Thyroid hormone levels (TSH, T3, T4), anti-TPO and anti-TG antibodies, as well as ultrasound characteristics of the thyroid gland, were analyzed. Results: In patients with CSU, a higher prevalence of hypothyroidism (27.9% vs. 4% in the control group), hypertension, asthma, and diabetes were observed. Elevated levels of anti-TPO antibodies were found in 51.2% of CSU patients, compared to only 6% in the control group (p < 0.001). Similarly, anti-TG antibodies were increased in 41.9% of CSU patients, compared to 4% in the control group. Additionally, ultrasound analysis revealed significant differences in thyroid morphology, with a heterogeneous structure observed in 72.1% of CSU patients, compared to only 14% in the control group (p < 0.001). Nodular changes were present in 34.88% of CSU patients, whereas the prevalence in the control group was only 6% (p < 0.001). Conclusions: Our results confirm a significant association between CSU and autoimmune thyroid diseases, including a high prevalence of anti-TPO and anti-TG antibodies, hypothyroidism, diffuse heterogeneity, and nodular changes. Additionally, elevated T3 hormone levels were common among CSU patients, while T4 levels did not differ significantly from those in the control group.
Collapse
Affiliation(s)
- Zoran Golušin
- Faculty of Medicine, University of Novi Sad, 21102 Novi Sad, Serbia; (Z.G.); (N.D.); (M.N.); (B.R.); (O.N.)
- Clinic for Dermatovenerology, University Clinical Center of Vojvodina, 21102 Novi Sad, Serbia
| | - Nemanja Maletin
- Faculty of Medicine, University of Novi Sad, 21102 Novi Sad, Serbia; (Z.G.); (N.D.); (M.N.); (B.R.); (O.N.)
| | - Nikola Denda
- Faculty of Medicine, University of Novi Sad, 21102 Novi Sad, Serbia; (Z.G.); (N.D.); (M.N.); (B.R.); (O.N.)
| | - Miloš Nišavić
- Faculty of Medicine, University of Novi Sad, 21102 Novi Sad, Serbia; (Z.G.); (N.D.); (M.N.); (B.R.); (O.N.)
- Clinic for Dermatovenerology, University Clinical Center of Vojvodina, 21102 Novi Sad, Serbia
| | - Bojan Radovanović
- Faculty of Medicine, University of Novi Sad, 21102 Novi Sad, Serbia; (Z.G.); (N.D.); (M.N.); (B.R.); (O.N.)
- Department for Pathoanatomical Diagnostics, Department for Molecular Pathology, Oncology Institute of Vojvodina, 21208 Sremska Kamenica, Serbia
| | - Olivera Nikolić
- Faculty of Medicine, University of Novi Sad, 21102 Novi Sad, Serbia; (Z.G.); (N.D.); (M.N.); (B.R.); (O.N.)
- Center for Radiology, University Clinical Center of Vojvodina, 21102 Novi Sad, Serbia
| |
Collapse
|
|
3
|
Liu C, Niu Y, Jin J, Ulita SA, Lin Y, Cong J, Lei S, Chen J, Yang J. Elucidating the immunomodulatory effects of phytoestrogens and their groundbreaking applications in transplantation medicine. Int Immunopharmacol 2024; 143:113220. [PMID: 39405935 DOI: 10.1016/j.intimp.2024.113220] [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: 04/14/2024] [Revised: 09/13/2024] [Accepted: 09/18/2024] [Indexed: 10/30/2024]
Abstract
Phytoestrogens are natural compounds found in plants and plant-based foods. When ingested, they can affect the human body in the same way as estrogen produced by the body. Phytoestrogens affect the regulation, differentiation, and production of immune cells. People who consume polyphenol and flavonoid-rich foods have lower incidences of inflammation, autoimmune diseases, and cancer. In organ transplantation, immune rejection is a lifelong problem for patients. In clinical practice, acute rejection is treated with hormonal shock or immunosuppressive drugs. However, effective reversal measures for chronic rejection, specifically for prevention, are still lacking. Recipients are also prone to post-transplant complications such as new tumors, diabetes, hyperlipidemia, hyperuricemia, and cardiovascular and cerebrovascular diseases, owing to the long-term use of immunosuppressive drugs. Phytoestrogens play a promising role in immune regulation and exert curative effects on cardiovascular diseases and cancer. In this study, we reviewed the use of phytoestrogens in the fields of immune regulation and organ transplantation.
Collapse
Affiliation(s)
- Chen Liu
- Department of Immunology, Guilin Medical University, Guilin 541199, China; Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541199, China
| | - Yewei Niu
- Department of Immunology, Guilin Medical University, Guilin 541199, China; Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541199, China
| | - Jiamin Jin
- Department of Immunology, Guilin Medical University, Guilin 541199, China; Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541199, China
| | - Salsa Ayudia Ulita
- Department of Immunology, Guilin Medical University, Guilin 541199, China
| | - Yi Lin
- Department of Ultrasound, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, China
| | - Jiacheng Cong
- Department of Immunology, Guilin Medical University, Guilin 541199, China; Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541199, China
| | - Shangbo Lei
- Department of Immunology, Guilin Medical University, Guilin 541199, China; Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541199, China
| | - Jian Chen
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541199, China.
| | - Jinfeng Yang
- Department of Immunology, Guilin Medical University, Guilin 541199, China; Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541199, China.
| |
Collapse
|
|
4
|
Mousavian P, Mashayekhi Goyonlo V, Javanbakht M, Reza Jafari M, Moosavian H, Afzal Aghaei M, Malekzadeh M. Diphencyprone reduces the CD8+ lymphocytes and IL-4 and enhences IgG2a/IgG1 ratio in pathogenicity of acute leishmania major infection in BALB/c mice. Cytokine 2024; 184:156792. [PMID: 39488893 DOI: 10.1016/j.cyto.2024.156792] [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: 07/26/2024] [Revised: 10/06/2024] [Accepted: 10/19/2024] [Indexed: 11/05/2024]
Abstract
BACKGROUND The exact role of different immune cells and cytokines in control or promotion of intracellular growth of leishmania has still remained a controversial topic. The aim of the present study was to study effects of cellular changes and relevant cytokines in cell mediated immunity by diphencyprone (DCP) in pathogenicity of acute L.major infection in BALB/c mice. METHODS 45 healthy female BALB/c mice were injected with L. major promastigotes under the base of tail. The mice were randomly divided to three groups of 15 mice: (1) control group without any treatment. (2) acetone group: Acetone was applied topically on the cutaneous lesions weekly and (3) DCP group: DCP was applied topically on the cutaneous lesions with increasing concentrations to induce local allergy. The mice were followed by the end of eighth week, and then macroscopic changes, histopathology, immunology studies, and organ parasite burden were determined. RESULTS In DCP group, in comparison to other groups the ulcer size and parasite burden in ulcer site and spleen increased, significantly. There was a deep lymphohistiocytic infiltration in the ulcer site. Total IgG, IgG1, and IgG2a levels as well as IgG2a/IgG1 ratio and intracellular IFN-gamma in CD8+ lymphocytes were significantly higher. IL4 and T CD8+ lymphocytes were significantly lower in DCP group. The IgG2a/IgG1 ratio was more than 1 in all groups. CONCLUSION Our findings demonstrated that DCP reduced the CD8+ lymphocytes and IL-4 production. In spite of increased IgG2a/IgG1 ratio, the parasite burden and inflammation severity increased in infected mice. The results can show the pivotal role of CD8+ lymphocytes in conjunction with Th1 lymphocytes in the control of acute leishmania infection in mice.
Collapse
Affiliation(s)
| | - Vahid Mashayekhi Goyonlo
- Cutaneous Leishmaniasis Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Mohammad Javanbakht
- Nephrology and Urology Research Center, Clinical Science Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Mahmoud Reza Jafari
- Biotechnology Research Center and Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamidreza Moosavian
- Department of Clinical Pathology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Monovar Afzal Aghaei
- Department of Biostatistics, Faculty of Health, Mashhad University of Medical Sciences, Mashhad, Iran
| | | |
Collapse
|
|
5
|
Nguyen BA, Alexander MR, Harrison DG. Immune mechanisms in the pathophysiology of hypertension. Nat Rev Nephrol 2024; 20:530-540. [PMID: 38658669 PMCID: PMC12060254 DOI: 10.1038/s41581-024-00838-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/03/2024] [Indexed: 04/26/2024]
Abstract
Hypertension is a leading risk factor for morbidity and mortality worldwide. Despite current anti-hypertensive therapies, most individuals with hypertension fail to achieve adequate blood pressure control. Moreover, even with adequate control, a residual risk of cardiovascular events and associated organ damage remains. These findings suggest that current treatment modalities are not addressing a key element of the underlying pathology. Emerging evidence implicates immune cells as key mediators in the development and progression of hypertension. In this Review, we discuss our current understanding of the diverse roles of innate and adaptive immune cells in hypertension, highlighting key findings from human and rodent studies. We explore mechanisms by which these immune cells promote hypertensive pathophysiology, shedding light on their multifaceted involvement. In addition, we highlight advances in our understanding of autoimmunity, HIV and immune checkpoints that provide valuable insight into mechanisms of chronic and dysregulated inflammation in hypertension.
Collapse
Affiliation(s)
- Bianca A Nguyen
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Matthew R Alexander
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Institute for Infection, Immunology and Inflammation, Nashville, TN, USA
| | - David G Harrison
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
- Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
- Vanderbilt Institute for Infection, Immunology and Inflammation, Nashville, TN, USA.
- Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.
| |
Collapse
|
|
6
|
Khalilollah S, Kalantari Soltanieh S, Obaid Saleh R, Ali Alzahrani A, Ghaleb Maabreh H, Mazin Al-Hamdani M, Dehghani-Ghorbi M, Shafiei Khonachaei M, Akhavan-Sigari R. LncRNAs involvement in pathogenesis of immune-related disease via regulation of T regulatory cells, an updated review. Cytokine 2024; 179:156585. [PMID: 38579428 DOI: 10.1016/j.cyto.2024.156585] [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: 05/24/2023] [Revised: 03/03/2024] [Accepted: 03/20/2024] [Indexed: 04/07/2024]
Abstract
The pathophysiology of several illnesses, including cancer and autoimmune diseasesdepends on human regulatory T cells (Tregs), and abnormalities in these cells may function as triggers for these conditions. Cancer and autoimmune, and gynecological diseases are associated with the differentiation of the proinflammatory T cell subset TH17 and its balance with the production of Treg. Recently, long non-coding RNAs (lncRNAs) have become important regulatory molecules in a wide range of illnesses. During epigenetic regulation, they can control the expression of important genes at several levels by affecting transcription, post-transcriptional actions, translation, and protein modification. They might connect with different molecules, such as proteins, DNA and RNA, and their structural composition is intricate. Because lncRNAs regulatebiological processes, including cell division, death, and growth, they are linked to severaldiseases. A notable instance of this is the lncRNA NEAT1, which has been the subject of several investigations to ascertain its function in immune cell development. In the context of immune cell development, several additional lncRNAs have been connected to Treg cell differentiation. In this work, we summarize current findings about the diverse functions of lncRNAs in Treg cell differentiation and control of the Th17/Treg homeostasis in autoimmune disorders, cancers, as well as several gynecological diseases where Tregs are key players.
Collapse
Affiliation(s)
- Shayan Khalilollah
- Department of Neurosurgery, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | | | - Raed Obaid Saleh
- Department of Pathological Analysis, College of Applied Science, University of Fallujah, Al-Anbar, Iraq.
| | | | - Hatem Ghaleb Maabreh
- Department of Dermatovenerology, Foreign Languages, RUDN University (Peoples' Friendship University of Russia named after Patrice Lumumba), Moscow, Russia.
| | | | - Mahmoud Dehghani-Ghorbi
- Hematology-Oncology Department, Imam Hossein Educational Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | | | - Reza Akhavan-Sigari
- Department of Neurosurgery, University Medical Center, Tuebingen, Germany; Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw Management University Warsaw, Poland.
| |
Collapse
|
|
7
|
Forsyth KS, Jiwrajka N, Lovell CD, Toothacre NE, Anguera MC. The conneXion between sex and immune responses. Nat Rev Immunol 2024; 24:487-502. [PMID: 38383754 PMCID: PMC11216897 DOI: 10.1038/s41577-024-00996-9] [Citation(s) in RCA: 44] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/18/2024] [Indexed: 02/23/2024]
Abstract
There are notable sex-based differences in immune responses to pathogens and self-antigens, with female individuals exhibiting increased susceptibility to various autoimmune diseases, and male individuals displaying preferential susceptibility to some viral, bacterial, parasitic and fungal infections. Although sex hormones clearly contribute to sex differences in immune cell composition and function, the presence of two X chromosomes in female individuals suggests that differential gene expression of numerous X chromosome-linked immune-related genes may also influence sex-biased innate and adaptive immune cell function in health and disease. Here, we review the sex differences in immune system composition and function, examining how hormones and genetics influence the immune system. We focus on the genetic and epigenetic contributions responsible for altered X chromosome-linked gene expression, and how this impacts sex-biased immune responses in the context of pathogen infection and systemic autoimmunity.
Collapse
Affiliation(s)
- Katherine S Forsyth
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Nikhil Jiwrajka
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Division of Rheumatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Claudia D Lovell
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Natalie E Toothacre
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Montserrat C Anguera
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
| |
Collapse
|
|
8
|
Gill JS, Bansal B, Guo K, Huang F, Singh H, Hur J, Khan N, Mathur R. Mitochondrial Oxidative Stress Regulates FOXP3+ T-Cell Activity and CD4-Mediated Inflammation in Older Adults with Frailty. Int J Mol Sci 2024; 25:6235. [PMID: 38892421 PMCID: PMC11173216 DOI: 10.3390/ijms25116235] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 05/30/2024] [Accepted: 06/03/2024] [Indexed: 06/21/2024] Open
Abstract
In healthy older adults, the immune system generally preserves its response and contributes to a long, healthy lifespan. However, rapid deterioration in immune regulation can lead to chronic inflammation, termed inflammaging, which accelerates pathological aging and diminishes the quality of life in older adults with frailty. A significant limitation in current aging research is the predominant focus on comparisons between young and older populations, often overlooking the differences between healthy older adults and those experiencing pathological aging. Our study elucidates the intricate immunological dynamics of the CD4/Treg axis in frail older adults compared to comparable age-matched healthy older adults. By utilizing publicly available RNA sequencing and single-cell RNA sequencing (scRNAseq) data from peripheral blood mononuclear cells (PBMCs), we identified a specific Treg cell subset and transcriptional landscape contributing to the dysregulation of CD4+ T-cell responses. We explored the molecular mechanisms underpinning Treg dysfunction, revealing that Tregs from frail older adults exhibit reduced mitochondrial protein levels, impairing mitochondrial oxidative phosphorylation. This impairment is driven by the TNF/NF-kappa B pathway, leading to cumulative inflammation. Further, we gained a deeper understanding of the CD4/Treg axis by predicting the effects of gene perturbations on cellular signaling networks. Collectively, these findings highlight the age-related relationship between mitochondrial dysfunction in the CD4/Treg axis and its role in accelerating aging and frailty in older adults. Targeting Treg dysfunction offers a critical basis for developing tailored therapeutic strategies aimed at improving the quality of life in older adults.
Collapse
Affiliation(s)
- Jappreet Singh Gill
- Department of Geriatrics, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA; (J.S.G.); (B.B.); (H.S.)
- Department of Biomedical Engineering, School of Electrical Engineering and Computer Sciences, University of North Dakota, Grand Forks, ND 58292, USA
| | - Benu Bansal
- Department of Geriatrics, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA; (J.S.G.); (B.B.); (H.S.)
- Department of Biomedical Engineering, School of Electrical Engineering and Computer Sciences, University of North Dakota, Grand Forks, ND 58292, USA
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA; (K.G.); (F.H.); (J.H.)
| | - Kai Guo
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA; (K.G.); (F.H.); (J.H.)
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Fang Huang
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA; (K.G.); (F.H.); (J.H.)
| | - Harpreet Singh
- Department of Geriatrics, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA; (J.S.G.); (B.B.); (H.S.)
| | - Junguk Hur
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA; (K.G.); (F.H.); (J.H.)
| | - Nadeem Khan
- Department of Oral Biology, University of Florida, Gainsville, FL 32603, USA;
| | - Ramkumar Mathur
- Department of Geriatrics, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA; (J.S.G.); (B.B.); (H.S.)
| |
Collapse
|
|
9
|
Wang Q, Fang X, Sun B, Zhu K, Yao M, Wei S, Zhang A. Rosa roxburghii Tratt juice inhibits NF-κB and increases IL-2 to alleviates the Foxp3-mediated Tregs imbalance in the peripheral blood of arseniasis patients. Food Sci Biotechnol 2024; 33:935-944. [PMID: 38371687 PMCID: PMC10866849 DOI: 10.1007/s10068-023-01384-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 06/19/2023] [Accepted: 07/06/2023] [Indexed: 02/20/2024] Open
Abstract
Arsenic can cause immune inflammation, which is the basis of arsenic-induced damage to multiple organs and systems. Forkhead box P3 (Foxp3)-labelled CD4+CD25+ regulatory T cells (Tregs) play an essential role in maintaining immune homeostasis. Nuclear factor-κb (NF-κB) and Interleukin-2 (IL-2) are critical regulators of Foxp3. Rosa roxburghii Tratt (RRT) is an edible medicinal plant with anti-inflammation effects. In this study, a control group (n = 41) and an arseniasis group (n = 209) were recruited, and screened subjects from the arseniasis patients for RRTJ (n = 46) or placebo (n = 43) to explore the possible mechanism by which RRT alleviates immune inflammation. The results indicated that RRTJ can inhibits NF-κB and increases IL-2, and alleviates the Foxp3-mediated Tregs imbalance in the peripheral blood of arseniasis patients. In summary, these findings suggest a novel intervention or therapeutic target for immune inflammation in arseniasis patients and provide new evidence that RRTJ inhibits immune inflammation. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s10068-023-01384-0.
Collapse
Affiliation(s)
- Qi Wang
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Department of Toxicology, School of Public Health, Guizhou Medical University, Guiyang, 550025 Guizhou People’s Republic of China
| | - Xiaolin Fang
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Department of Toxicology, School of Public Health, Guizhou Medical University, Guiyang, 550025 Guizhou People’s Republic of China
| | - Baofei Sun
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Department of Toxicology, School of Public Health, Guizhou Medical University, Guiyang, 550025 Guizhou People’s Republic of China
| | - Kai Zhu
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Department of Toxicology, School of Public Health, Guizhou Medical University, Guiyang, 550025 Guizhou People’s Republic of China
| | - Maolin Yao
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Department of Toxicology, School of Public Health, Guizhou Medical University, Guiyang, 550025 Guizhou People’s Republic of China
| | - Shaofeng Wei
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Department of Toxicology, School of Public Health, Guizhou Medical University, Guiyang, 550025 Guizhou People’s Republic of China
| | - Aihua Zhang
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Department of Toxicology, School of Public Health, Guizhou Medical University, Guiyang, 550025 Guizhou People’s Republic of China
| |
Collapse
|
|
10
|
Lee EJ, Choi JG, Han JH, Kim YW, Lim J, Chung HS. Single-Cell RNA Sequencing Reveals Immuno-Oncology Characteristics of Tumor-Infiltrating T Lymphocytes in Photodynamic Therapy-Treated Colorectal Cancer Mouse Model. Int J Mol Sci 2023; 24:13913. [PMID: 37762216 PMCID: PMC10531263 DOI: 10.3390/ijms241813913] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 09/04/2023] [Accepted: 09/08/2023] [Indexed: 09/29/2023] Open
Abstract
Photodynamic therapy (PDT) has shown promise in reducing metastatic colorectal cancer (CRC); however, the underlying mechanisms remain unclear. Modulating tumor-infiltrating immune cells by PDT may be achieved, which requires the characterization of immune cell populations in the tumor microenvironment by single-cell RNA sequencing (scRNA-seq). Here, we determined the effect of Chlorin e6 (Ce6)-mediated PDT on tumor-infiltrating T cells using scRNA-seq analysis. We used a humanized programmed death-1/programmed death ligand 1 (PD-1/PD-L1) MC38 cell allograft mouse model, considering its potential as an immunogenic cancer model and in combination with PD-1/PD-L1 immune checkpoint blockade. PDT treatment significantly reduced tumor growth in mice containing hPD-1/PD-L1 MC38 tumors. scRNA-seq analysis revealed that the PDT group had increased levels of CD8+ activated T cells and CD8+ cytotoxic T cells, but decreased levels of exhausted CD8+ T cells. PDT treatment also enhanced the infiltration of CD8+ T cells into tumors and increased the production of key effector molecules, including granzyme B and perforin 1. These findings provide insight into immune-therapeutic modulation for CRC patients and highlight the potential of PDT in overcoming immune evasion and enhancing antitumor immunity.
Collapse
Affiliation(s)
- Eun-Ji Lee
- Korean Medicine Application Center, Korea Institute of Oriental Medicine (KIOM), Daegu 41062, Republic of Korea; (E.-J.L.); (J.-G.C.); (J.H.H.)
| | - Jang-Gi Choi
- Korean Medicine Application Center, Korea Institute of Oriental Medicine (KIOM), Daegu 41062, Republic of Korea; (E.-J.L.); (J.-G.C.); (J.H.H.)
| | - Jung Ho Han
- Korean Medicine Application Center, Korea Institute of Oriental Medicine (KIOM), Daegu 41062, Republic of Korea; (E.-J.L.); (J.-G.C.); (J.H.H.)
| | - Yong-Wan Kim
- Dongsung Cancer Center, Dongsung Biopharmaceutical, Daegu 41061, Republic of Korea; (Y.-W.K.); (J.L.)
| | - Junmo Lim
- Dongsung Cancer Center, Dongsung Biopharmaceutical, Daegu 41061, Republic of Korea; (Y.-W.K.); (J.L.)
| | - Hwan-Suck Chung
- Korean Medicine Application Center, Korea Institute of Oriental Medicine (KIOM), Daegu 41062, Republic of Korea; (E.-J.L.); (J.-G.C.); (J.H.H.)
- Korean Convergence Medical Science Major, University of Science and Technology (UST), KIOM Campus, Daegu 41062, Republic of Korea
| |
Collapse
|
|
11
|
CuMV VLPs Containing the RBM from SARS-CoV-2 Spike Protein Drive Dendritic Cell Activation and Th1 Polarization. Pharmaceutics 2023; 15:pharmaceutics15030825. [PMID: 36986686 PMCID: PMC10055701 DOI: 10.3390/pharmaceutics15030825] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 02/17/2023] [Accepted: 02/20/2023] [Indexed: 03/06/2023] Open
Abstract
Dendritic cells (DCs) are the most specialized and proficient antigen-presenting cells. They bridge innate and adaptive immunity and display a powerful capacity to prime antigen-specific T cells. The interaction of DCs with the receptor-binding domain of the spike (S) protein from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a pivotal step to induce effective immunity against the S protein-based vaccination protocols, as well as the SARS-CoV-2 virus. Herein, we describe the cellular and molecular events triggered by virus-like particles (VLPs) containing the receptor-binding motif from the SARS-CoV-2 spike protein in human monocyte-derived dendritic cells, or, as controls, in the presence of the Toll-like receptors (TLR)3 and TLR7/8 agonists, comprehending the events of dendritic cell maturation and their crosstalk with T cells. The results demonstrated that VLPs boosted the expression of major histocompatibility complex molecules and co-stimulatory receptors of DCs, indicating their maturation. Furthermore, DCs’ interaction with VLPs promoted the activation of the NF-kB pathway, a very important intracellular signalling pathway responsible for triggering the expression and secretion of proinflammatory cytokines. Additionally, co-culture of DCs with T cells triggered CD4+ (mainly CD4+Tbet+) and CD8+ T cell proliferation. Our results suggested that VLPs increase cellular immunity, involving DC maturation and T cell polarization towards a type 1 T cells profile. By providing deeper insight into the mechanisms of activation and regulation of the immune system by DCs, these findings will enable the design of effective vaccines against SARS-CoV-2.
Collapse
|
|
12
|
Murdaca G, Paladin F, Borro M, Ricciardi L, Gangemi S. Prevalence of Autoimmune and Autoinflammatory Diseases in Chronic Urticaria: Pathogenetic, Diagnostic and Therapeutic Implications. Biomedicines 2023; 11:410. [PMID: 36830946 PMCID: PMC9953398 DOI: 10.3390/biomedicines11020410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/24/2023] [Accepted: 01/28/2023] [Indexed: 01/31/2023] Open
Abstract
Chronic spontaneous urticaria (CSU) is defined as the almost daily occurrence of widespread wheals, angioedema, or both, for more than 6 weeks. It affects 1-2% of the general population, with a higher prevalence in female patients, and is more frequent patients over 20 years of age. More than half of all cases of chronic idiopathic urticaria are thought to occur due to an autoimmune mechanism, specifically the production of autoantibodies against the high-affinity immunoglobulin E (IgE) receptor (FcεRI). The quality of life in these patients is often greatly compromised, also due to the onset of comorbidities represented by other autoimmune diseases, such as thyroid disease, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, celiac disease, and type 1 diabetes, among others. This review aimed to analyze the close correlation between CSU and some autoimmune and autoinflammatory diseases, in order to encourage a multidisciplinary and multimorbid approach to the patient affected by CSU, which allows not only control of the natural course of the disease, but also any associated comorbidities.
Collapse
Affiliation(s)
- Giuseppe Murdaca
- Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy
- Ospedale Policlinico San Martino IRCCS, 16132 Genoa, Italy
| | - Francesca Paladin
- Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy
- Ospedale Policlinico San Martino IRCCS, 16132 Genoa, Italy
| | - Matteo Borro
- Internal Medicine Department, San Paolo Hospital, 17100 Savona, Italy
| | - Luisa Ricciardi
- Department of Clinical and Experimental Medicine, School and Operative Unit of Allergy and Clinical Immunology, University of Messina, 98125 Messina, Italy
| | - Sebastiano Gangemi
- Department of Clinical and Experimental Medicine, School and Operative Unit of Allergy and Clinical Immunology, University of Messina, 98125 Messina, Italy
| |
Collapse
|
|
13
|
Ghisleni C, Parma B, Cianci P, De Paoli A, Pangallo E, Agovino T, Cereda A, Bedeschi MF, Villa R, Fossati C, Modena P, Giudici C, Morando C, Memo L, Onesimo R, Zampino G, Salvatore S, Agosti M, Selicorni A. Celiac disease prevalence and predisposing-HLA in a cohort of 93 Williams-Beuren syndrome patients. Am J Med Genet A 2023; 191:84-89. [PMID: 36254687 DOI: 10.1002/ajmg.a.62990] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 09/20/2022] [Accepted: 09/24/2022] [Indexed: 12/14/2022]
Abstract
Williams-Beuren syndrome is considered to be at increased risk for celiac disease, as for recent literature data and celiac disease guidelines, despite pathogenic mechanisms are still unclear. Our study analyzed the prevalence of autoimmune disorders, HLA DQ2 and/or DQ8 haplotypes, of transglutaminase antibodies and of diagnosis of celiac disease in a cohort of 93 Williams-Beuren syndrome's patients (mean age 21.26 years). Our study showed an increased prevalence of celiac disease equal to 10.8% (10/93 patients). We did not find a significant different frequency of predisposing HLA in subjects with Williams-Beuren syndrome compared to literature data in the general population (49.5% vs. 42.9%, with p > .1), nor a susceptibility to autoimmunity. This suggests that the increased prevalence of celiac disease in Williams-Beuren syndrome cannot be ascribed to HLA haplotype and may be related to other factors that still need to be identified in these patients.
Collapse
Affiliation(s)
- Cecilia Ghisleni
- Department of Pediatric, "F. Del Ponte" Hospital, University of Insubria, Varese, Italy
| | - Barbara Parma
- Department of Pediatric, Mariani Foundation Center for Fragile Children, ASST-Lariana, Sant'Anna Hospital, San Fermo Della Battaglia (Como), Italy
| | - Paola Cianci
- Department of Pediatric, Mariani Foundation Center for Fragile Children, ASST-Lariana, Sant'Anna Hospital, San Fermo Della Battaglia (Como), Italy
| | - Anita De Paoli
- Department of Pediatric, Mariani Foundation Center for Fragile Children, ASST-Lariana, Sant'Anna Hospital, San Fermo Della Battaglia (Como), Italy
| | - Elisabetta Pangallo
- Department of Pediatric, Fondazione MBMM San Gerardo Hospital, Monza, Italy.,Department of Pediatric, "Papa Giovanni XXIII" Hospital, Bergamo, Italy
| | - Teresa Agovino
- Department of Pediatric, "Papa Giovanni XXIII" Hospital, Bergamo, Italy
| | - Anna Cereda
- Department of Pediatric, "Papa Giovanni XXIII" Hospital, Bergamo, Italy
| | | | - Roberta Villa
- Medical Genetics Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Chiara Fossati
- Department of Pediatric, Fondazione MBMM San Gerardo Hospital, Monza, Italy
| | | | | | - Carla Morando
- Department of Pediatrics, Neonatal Intensive Care Unit, San Bortolo Hospital of Vicenza, Vicenza, Italy
| | - Luigi Memo
- Department of Pediatrics, Neonatal Intensive Care Unit, San Bortolo Hospital of Vicenza, Vicenza, Italy
| | - Roberta Onesimo
- Department of Pediatric, Fondazione Policlinico Gemelli, Rome, Italy
| | - Giuseppe Zampino
- Department of Pediatric, Fondazione Policlinico Gemelli, Rome, Italy
| | - Silvia Salvatore
- Department of Pediatric, "F. Del Ponte" Hospital, University of Insubria, Varese, Italy
| | - Massimo Agosti
- Department of Pediatric, "F. Del Ponte" Hospital, University of Insubria, Varese, Italy
| | - Angelo Selicorni
- Department of Pediatric, Mariani Foundation Center for Fragile Children, ASST-Lariana, Sant'Anna Hospital, San Fermo Della Battaglia (Como), Italy
| |
Collapse
|
|
14
|
Tienforti D, Di Giulio F, Spagnolo L, Castellini C, Totaro M, Muselli M, Francavilla S, Baroni MG, Barbonetti A. Chronic urticaria and thyroid autoimmunity: a meta-analysis of case-control studies. J Endocrinol Invest 2022; 45:1317-1326. [PMID: 35181847 PMCID: PMC9184403 DOI: 10.1007/s40618-022-01761-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 02/07/2022] [Indexed: 11/24/2022]
Abstract
PURPOSE Autoimmunity has been implicated in some patients with idiopathic chronic urticaria (CU). Because of the frequency of autoimmune thyroid diseases, their association with CU deserves special attention. We tested both the existence and the extent of an association between thyroid autoimmunity and CU. METHODS A thorough search of PubMed, Scopus, Web of Science, and Cochrane databases was performed. Studies reporting the positivity rate for anti-thyroperoxidase antibodies (TPOAbs) in people with (cases) and without CU (controls) were included. Quality of the studies was assessed by the Newcastle-Ottawa Scale. Between-study heterogeneity was assessed by Cochrane Q and I2 tests, and the odds ratio (OR) for TPOAbs positivity was combined using random-effects models. RESULTS Nineteen studies provided information about TPOAbs positivity on 14,351 patients with CU and 12,404 controls. The pooled estimate indicated a more than fivefold increased risk of exhibiting TPOAbs positivity in the group with CU (pooled OR 5.18, 95% CI 3.27, 8.22; P < 0.00001). Correction for publication bias had a negligible effect on the overall estimate (pooled adjusted OR: 4.42, 95% CI 2.84, 6.87, P < 0.0001). Between‑study heterogeneity was established (I2 = 62%, Pfor heterogeneity = 0.0002) and when, according to meta‑regression models, a sensitivity analysis was restricted to the 16 studies with the highest quality scores, the OR for TPOAbs positivity rose to 6.72 (95% CI 4.56, 9.89; P < 0.00001) with no significant heterogeneity (I2 = 31%, Pfor heterogeneity = 0.11). CONCLUSIONS Patients with CU have a five-to-nearly sevenfold higher risk of displaying TPOAbs positivity. All patients with CU may well be offered a screening for thyroid autoimmunity.
Collapse
Affiliation(s)
- D Tienforti
- Andrology Unit, Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - F Di Giulio
- Andrology Unit, Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - L Spagnolo
- Andrology Unit, Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - C Castellini
- Andrology Unit, Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - M Totaro
- Andrology Unit, Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - M Muselli
- Epidemiology Division, Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - S Francavilla
- Andrology Unit, Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - M G Baroni
- Andrology Unit, Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
- Neuroendocrinology and Metabolic Diseases, IRCCS Neuromed, Pozzilli, Isernia, Italy
| | - A Barbonetti
- Andrology Unit, Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.
| |
Collapse
|
|
15
|
The ubiquitin ligase Cul5 regulates CD4 + T cell fate choice and allergic inflammation. Nat Commun 2022; 13:2786. [PMID: 35589717 PMCID: PMC9120070 DOI: 10.1038/s41467-022-30437-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 04/21/2022] [Indexed: 12/24/2022] Open
Abstract
Antigen encounter directs CD4+ T cells to differentiate into T helper or regulatory cells. This process focuses the immune response on the invading pathogen and limits tissue damage. Mechanisms that govern T helper cell versus T regulatory cell fate remain poorly understood. Here, we show that the E3 ubiquitin ligase Cul5 determines fate selection in CD4+ T cells by regulating IL-4 receptor signaling. Mice lacking Cul5 in T cells develop Th2 and Th9 inflammation and show pathophysiological features of atopic asthma. Following T cell activation, Cul5 forms a complex with CIS and pJak1. Cul5 deletion reduces ubiquitination and subsequent degradation of pJak1, leading to an increase in pJak1 and pSTAT6 levels and reducing the threshold of IL-4 receptor signaling. As a consequence, Cul5 deficient CD4+ T cells deviate from Treg to Th9 differentiation in low IL-4 conditions. These data support the notion that Cul5 promotes a tolerogenic T cell fate choice and reduces susceptibility to allergic asthma. Cytokine signaling influences the differentiation of CD4+ T cells into varying functional subsets. Here the authors show that an E3 ubiquitin ligase Cul5 alters TH2 and TH9 development and absence of Cul5 in T cells results in higher levels of allergy-associated IL-4 and IL-9 secreting T cells.
Collapse
|
|
16
|
Mirzaei R, Zamani F, Hajibaba M, Rasouli-Saravani A, Noroozbeygi M, Gorgani M, Hosseini-Fard SR, Jalalifar S, Ajdarkosh H, Abedi SH, Keyvani H, Karampoor S. The pathogenic, therapeutic and diagnostic role of exosomal microRNA in the autoimmune diseases. J Neuroimmunol 2021; 358:577640. [PMID: 34224949 DOI: 10.1016/j.jneuroim.2021.577640] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 06/19/2021] [Accepted: 06/22/2021] [Indexed: 02/08/2023]
Abstract
Exosomes are a nano-vesicle surrounded by a bilipid layer that can release from almost all cells and could be detected in tissues and biological liquids. These vesicles contain lipids, proteins, and nucleic acids (including DNA, mRNA, and miRNA) inside and on the exosomes' surface constitute their content. Exosomes can transfer their cargo into the recipient cell, which can modify recipient cells' biological activities. Recently it has been deciphering that the miRNA pattern of exosomes reveals the cellular pathophysiological situation and modifies various biological processes. Increasing data regarding exosomes highlights that the exosomes and their cargo, especially miRNAs, are implicated in the pathophysiology of various disorders, such as autoimmune disease. The current evidence on the deciphering of mechanisms in which exosomal miRNAs contributed to autoimmunity was indicated that exosomal miRNA might hold information that can reprogram the function of many of the immune cells involved in autoimmune diseases' pathogenesis. In the present study, we summarized the pathogenic role of exosomal miRNAs in several autoimmune diseases, including myasthenia gravis (MG), psoriasis, inflammatory bowel disease (IBD), type 1 diabetes (T1D), multiple sclerosis (MS), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjogren's Syndrome (SS), systemic sclerosis (SSc), vitiligo, and autoimmune thyroid diseases (AITD). Moreover, in this work, we present evidence of the potential role of exosomal miRNAs as therapeutic and diagnostic agents in autoimmune diseases.
Collapse
Affiliation(s)
- Rasoul Mirzaei
- Department of Microbiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Farhad Zamani
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Marzieh Hajibaba
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ashkan Rasouli-Saravani
- Department of Immunology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mina Noroozbeygi
- Department of Immunology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Melika Gorgani
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Seyed Reza Hosseini-Fard
- Department of Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Saba Jalalifar
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Ajdarkosh
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Seyed Hassnan Abedi
- Department of Internal Medicine, Rohani Hospital, Babol University of Medical Science, Babol, Iran
| | - Hossein Keyvani
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran; Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Sajad Karampoor
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran; Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
17
|
Das UN. Molecular biochemical aspects of salt (sodium chloride) in inflammation and immune response with reference to hypertension and type 2 diabetes mellitus. Lipids Health Dis 2021; 20:83. [PMID: 34334139 PMCID: PMC8327432 DOI: 10.1186/s12944-021-01507-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 07/14/2021] [Indexed: 12/18/2022] Open
Abstract
Obesity, insulin resistance, type 2 diabetes mellitus (T2DM) and hypertension (HTN) are common that are associated with low-grade systemic inflammation. Diet, genetic factors, inflammation, and immunocytes and their cytokines play a role in their pathobiology. But the exact role of sodium, potassium, magnesium and other minerals, trace elements and vitamins in the pathogenesis of HTN and T2DM is not known. Recent studies showed that sodium and potassium can modulate oxidative stress, inflammation, alter the autonomic nervous system and induce dysfunction of the innate and adaptive immune responses in addition to their action on renin-angiotensin-aldosterone system. These actions of sodium, potassium and magnesium and other minerals, trace elements and vitamins are likely to be secondary to their action on pro-inflammatory cytokines IL-6, TNF-α and IL-17 and metabolism of essential fatty acids that may account for their involvement in the pathobiology of insulin resistance, T2DM, HTN and autoimmune diseases.
Collapse
Affiliation(s)
- Undurti N Das
- UND Life Sciences, 2221 NW 5th St, Battle Ground, WA, 98604, USA.
| |
Collapse
|
|
18
|
Taurine promotes the production of CD4 +CD25 +FOXP3 + Treg cells through regulating IL-35/STAT1 pathway in a mouse allergic rhinitis model. Allergy Asthma Clin Immunol 2021; 17:59. [PMID: 34147127 PMCID: PMC8214264 DOI: 10.1186/s13223-021-00562-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 06/03/2021] [Indexed: 12/24/2022] Open
Abstract
Background Allergic rhinitis (AR) is one of the most widespread immune conditions worldwide. However, common treatments often present with significant side effects or are cost-prohibitive for much of the population. A plethora of treatments have been used for the treatment of AR including antihistamines, steroids, and immune modulators. Among the treatments which have shown potential for efficacy in treating AR with a minimum of side effects but remains understudied is the conditionally essential amino acid taurine. Taurine has been previously shown to reduce AR symptoms. Here, we examine the role of taurine in modulating T regulatory cells, modulating the cytokine response in AR, and restoring healthy nasal mucosa. Methods Blood samples from 20 healthy donors and 20 AR patients were compared for CD4+CD25+FoxP3+ T regulatory (Treg) cell population percentage, cytokine release, and STAT1 signaling with and without taurine treatment or IL-35 neutralization. An OVA-induced AR mouse model was administered vehicle, taurine, or taurine plus an IL-35 neutralizing antibody and assayed for sneezing frequency, inflammatory cytokine response, nasal mucosa goblet cell density, and T regulatory cell percentage. CD4+ cells were further examined for cytokine release, STAT1 phosphorylation, and response to an anti-IL-35 antibody with and without a STAT1 inhibitor. Results Comparison of blood from normal donors and AR patients showed a reduction in CD4+CD25+FoxP3+ Treg cells in AR patients and a strong correlation between Treg percentage and IL-35 release. A similar pattern of Treg suppression was found in untreated AR mice when compared to normal control mice wherein there was a reduction in Treg percentage and a corresponding decrease in IL-35 release. AR mice also demonstrated increased sneezing frequency, an infiltration of goblet cell in nasal mucosa, and a reduction in IL-35 release from CD4+ cells. Conversely, IL-4, IL-5, and IL-13 secretion from CD4+ cells were increased in AR model mice, as was STAT1 phosphorylation. When AR mice were treated with taurine, sneezing frequency and nasal mucosa goblet cell content were reduced while Treg abundance was increased to that of normal mice. Accordingly, IL-35 release was restored, while IL-4, IL-5, and IL-13 secretion from CD4+ cells were suppressed. Likewise, STAT1 phosphorylation was inhibited with taurine treatment. Taurine-treated mice also given an IL-35 neutralizing antibody exhibited AR pathology including frequent sneezing and high nasal goblet cell content while retaining a restoration of Tregs. Furthermore, murine AR model CD4+ cells exposed to recombinant IL-35 responded with a reduction in inflammatory cytokine release and a decrease in STAT1 phosphorylation, mimicking the effect of taurine treatment. Conclusions Taurine induces release of IL-35 in AR; IL-35 promotes the production of CD4+CD25+FoxP3+ Treg cells via a STAT1-dependent pathway. The restoration of Treg populations by taurine normalizes the inflammatory response, reduces AR symptomology, and reduces histopathologic signs of AR. Supplementary Information The online version contains supplementary material available at 10.1186/s13223-021-00562-1.
Collapse
|
|
19
|
Al-Bluwi GSM, AlNababteh AH, Östlundh L, Al-Shamsi S, Al-Rifai RH. Prevalence of Celiac Disease in Patients With Turner Syndrome: Systematic Review and Meta-Analysis. Front Med (Lausanne) 2021; 8:674896. [PMID: 34222285 PMCID: PMC8247446 DOI: 10.3389/fmed.2021.674896] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 05/26/2021] [Indexed: 01/15/2023] Open
Abstract
Introduction: Celiac disease (CD) is a multifactorial autoimmune disorder, and studies have reported that patients with Turner syndrome (TS) are at risk for CD. This systematic review and meta-analysis aimed to quantify the weighted prevalence of CD among patients with TS and determine the weighted strength of association between TS and CD. Methods: Studies published between January 1991 and December 2019 were retrieved from four electronic databases: PubMed, Scopus, Web of Science, and Embase. Eligible studies were identified and relevant data were extracted by two independent reviewers following specific eligibility criteria and a data extraction plan. Using the random-effects model, the pooled, overall and subgroup CD prevalence rates were determined, and sources of heterogeneity were investigated using meta-regression. Results: Among a total of 1,116 screened citations, 36 eligible studies were included in the quantitative synthesis. Nearly two-thirds of the studies (61.1%) were from European countries. Of the 6,291 patients with TS who were tested for CD, 241 were diagnosed with CD, with a crude CD prevalence of 3.8%. The highest and lowest CD prevalence rates of 20.0 and 0.0% were reported in Sweden and Germany, respectively. The estimated overall weighted CD prevalence was 4.5% (95% confidence interval [CI], 3.3–5.9, I2, 67.4%). The weighted serology-based CD prevalence in patients with TS (3.4%, 95% CI, 1.0–6.6) was similar to the weighted biopsy-based CD prevalence (4.8%; 95% CI, 3.4–6.5). The strength of association between TS and CD was estimated in only four studies (odds ratio 18.1, 95% CI, 1.82–180; odds ratio 4.34, 95% CI, 1.48–12.75; rate ratio 14, 95% CI, 1.48–12.75; rate ratio 42.5, 95% CI, 12.4–144.8). Given the lack of uniformity in the type of reported measures of association and study design, producing a weighted effect measure to evaluate the strength of association between TS and CD was unfeasible. Conclusion: Nearly 1 in every 22 patients with TS had CD. Regular screening for CD in patients with TS might facilitate early diagnosis and therapeutic management to prevent adverse effects of CD such as being underweight and osteoporosis.
Collapse
Affiliation(s)
- Ghada S M Al-Bluwi
- Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Asma H AlNababteh
- Institute of Public Health, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Linda Östlundh
- National Medical Library, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Saif Al-Shamsi
- Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Rami H Al-Rifai
- Institute of Public Health, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
| |
Collapse
|
|
20
|
Faraji F, Shojapour M, Farahani I, Ganji A, Mosayebi G. Reduced regulatory T lymphocytes in migraine patients. Neurol Res 2021; 43:677-682. [PMID: 33853506 DOI: 10.1080/01616412.2021.1915077] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Objectives: Migraine is a primary headache disorder with unknown pathophysiology. Recently, many studies have suggested the role of immune dysfunction in the pathophysiology of this disorder. In this study, we investigated the percentage of regulatory T cells (Treg cells) in different migraine categories.Methods: Peripheral blood samples of 40 newly diagnosed cases of migraine and 33 healthy individuals were collected for Treg cell analysis by flow cytometry.Results: The percentage of Treg cells in migraine patients with all subgroups including patients with or without auras and patients with chronic or episodic migraine was significantly lower than that of the control group. Also, a significant increase in the CD25 means fluorescence intensity (MFI) was observed in migraine without aura and chronic migraine groups, compared to the normal group.Conclusions: In this study, the number of Treg cells significantly decreased in new cases of migraine, which suggests that migraine is a result of an impairment in the immunological system or an autoimmune disease. Also, the insignificant difference in the number of Treg cells between the two categories of migraine suggests that there is no link between the reduced number of Treg cells and the emergence of aura symptoms or duration of the disease.
Collapse
Affiliation(s)
- Fardin Faraji
- Department of Neurology, School of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Mana Shojapour
- Molecular and Medicine Research Center, Arak University of Medical Sciences, Arak, Iran
| | - Iman Farahani
- Molecular and Medicine Research Center, Department of Microbiology and Immunology, School of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Ali Ganji
- Molecular and Medicine Research Center, Department of Microbiology and Immunology, School of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Ghasem Mosayebi
- Molecular and Medicine Research Center, Department of Microbiology and Immunology, School of Medicine, Arak University of Medical Sciences, Arak, Iran
| |
Collapse
|
|
21
|
Zhang J, Yuan J, Li Z, Fu C, Xu M, Yang J, Jiang X, Zhou B, Ye X, Xu C. Exploring and exploiting plant cyclic peptides for drug discovery and development. Med Res Rev 2021; 41:3096-3117. [PMID: 33599316 DOI: 10.1002/med.21792] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 01/10/2021] [Accepted: 01/31/2021] [Indexed: 01/07/2023]
Abstract
Ever since the discovery of insulin, natural peptides have become an important resource for therapeutic development. Decades of research has led to the discovery of a long list of peptide drugs with broad applications in clinics, from antibiotics to hypertension treatment to pain management. Many of these US FDA-approved peptide drugs are derived from microorganisms and animals. By contrast, the great potential of plant cyclic peptides as therapeutics remains largely unexplored. These macrocyclic peptides typically have rigid structures, good bioavailability and membrane permeability, making them appealing candidates for drug development and engineering. In this review, we introduce the three major classes of plant cyclic peptides and summarize their potential medical applications. We discuss how we can leverage the genome information of many different plants to quickly search for new cyclic peptides and how we can take advantage of the insights gained from their biosynthetic pathways to transform the process of production and drug development. These recent developments have provided a new angle for exploring and exploiting plant cyclic peptides, and we believe that many more peptide drugs derived from plants are about to come.
Collapse
Affiliation(s)
- Jingjing Zhang
- Department of Geriatric Medicine, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China.,Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, Guangdong, China
| | - Jimin Yuan
- Department of Geriatric Medicine, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China
| | - Zhijie Li
- Department of Geriatric Medicine, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China
| | - Chunjin Fu
- Department of Geriatric Medicine, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China
| | - Menglong Xu
- Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA
| | - Jing Yang
- Department of Geriatric Medicine, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China
| | - Xin Jiang
- Department of Geriatric Medicine, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China
| | - Boping Zhou
- Department of Infectious Diseases, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China
| | - Xiufeng Ye
- Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China
| | - Chengchao Xu
- Department of Geriatric Medicine, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China.,Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA
| |
Collapse
|
|
22
|
Helmin KA, Morales-Nebreda L, Torres Acosta MA, Anekalla KR, Chen SY, Abdala-Valencia H, Politanska Y, Cheresh P, Akbarpour M, Steinert EM, Weinberg SE, Singer BD. Maintenance DNA methylation is essential for regulatory T cell development and stability of suppressive function. J Clin Invest 2021; 130:6571-6587. [PMID: 32897881 DOI: 10.1172/jci137712] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 09/02/2020] [Indexed: 12/22/2022] Open
Abstract
Tregs require Foxp3 expression and induction of a specific DNA hypomethylation signature during development, after which Tregs persist as a self-renewing population that regulates immune system activation. Whether maintenance DNA methylation is required for Treg lineage development and stability and how methylation patterns are maintained during lineage self-renewal remain unclear. Here, we demonstrate that the epigenetic regulator ubiquitin-like with plant homeodomain and RING finger domains 1 (Uhrf1) is essential for maintenance of methyl-DNA marks that stabilize Treg cellular identity by repressing effector T cell transcriptional programs. Constitutive and induced deficiency of Uhrf1 within Foxp3+ cells resulted in global yet nonuniform loss of DNA methylation, derepression of inflammatory transcriptional programs, destabilization of the Treg lineage, and spontaneous inflammation. These findings support a paradigm in which maintenance DNA methylation is required in distinct regions of the Treg genome for both lineage establishment and stability of identity and suppressive function.
Collapse
Affiliation(s)
- Kathryn A Helmin
- Division of Pulmonary and Critical Care Medicine, Department of Medicine
| | | | | | - Kishore R Anekalla
- Division of Pulmonary and Critical Care Medicine, Department of Medicine
| | - Shang-Yang Chen
- Division of Pulmonary and Critical Care Medicine, Department of Medicine
| | | | - Yuliya Politanska
- Division of Pulmonary and Critical Care Medicine, Department of Medicine
| | - Paul Cheresh
- Division of Pulmonary and Critical Care Medicine, Department of Medicine
| | | | | | - Samuel E Weinberg
- Division of Pulmonary and Critical Care Medicine, Department of Medicine.,Department of Pathology
| | - Benjamin D Singer
- Division of Pulmonary and Critical Care Medicine, Department of Medicine.,Department of Biochemistry and Molecular Genetics.,Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| |
Collapse
|
|
23
|
Effects of CpG oligodeoxynucleotides on the differentiation of Treg/Th17 cells. Mol Immunol 2021; 132:199-208. [PMID: 33454107 DOI: 10.1016/j.molimm.2021.01.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 11/21/2020] [Accepted: 01/03/2021] [Indexed: 01/01/2023]
Abstract
AIM The balance between Th17 cells and T regulatory (Treg) cells has emerged as a prominent factor in regulating cancer development. However, the effect of CpG oligodeoxynucleotides (ODNs) on the differentiation of Treg/Th17 cells has not been well studied. We sought here to explore the function of CpG ODNs in the differentiation of Tregs and Th17 cells in vitro and in vivo. METHODS Mouse spleen cells were cultured with anti-CD3 monoclonal antibodies in vitro. Tregs and Th17 cell differentiation was induced by transforming growth factor (TGF)-β and interleukin (IL)-2, or TGF-β, IL-6, and IL-23, respectively. Then cells were treated with two CpG ODNs, CpG 1982, or CpG 1826. FBL-3-inoculated C57Bl/6 mice were treated with CpG 1826, tumor vaccine, or combination of CpG 1826 and tumor vaccine. After treatment, spleen cells and serum were isolated, and Tregs/Th17 cells were detected by flow cytometry. The expression of forkhead box P3 (Foxp3), retinoid-related orphan receptor gamma-t (RORγt), IL-10, and IL-17 mRNA was measured by real-time PCR, and protein levels were measured by Western blot and enzyme-linked immunosorbent assay. RESULTS The frequency of Treg cells increased significantly (p < 0.05) in the FBL-3-inoculated leukemia mouse model compared with control mice, whereas the frequency of Th17 cells did not change. Median survival of mice after treatment with CpG 1826 and tumor vaccine was significantly prolonged compared with that of control mice (p < 0.05). The frequency of induced Treg cells decreased after treatment with CpG 1826, whereas the frequency of Th17 cells induced by cytokines in vitro and in the murine leukemia model increased following treatment with CpG 1826. Furthermore, after treatment with CpG 1826, the mRNA and protein levels of Foxp3 and IL-10 decreased significantly both in vitro and in vivo (p < 0.05), whereas those of RORγt and IL-17 increased significantly (p < 0.05). CONCLUSION CpG 1826 may inhibit the differentiation of Treg cells induced by cytokines, promote the differentiation of Th17 cells in vitro and in murine leukemia models, and prolong the median survival of mice with leukemia.
Collapse
|
|
24
|
ATEŞ E, AMASYALI A, ORYAŞIN E, YAVAŞ İ, YILMAZ M, BOZDOĞAN B, EROL H. Benign Prostatik Patolojilerde Regülatuvar T Hücrelerinin (Treg) Değerlendirilmesi: Pilot Çalışma. KAHRAMANMARAŞ SÜTÇÜ İMAM ÜNIVERSITESI TIP FAKÜLTESI DERGISI 2020. [DOI: 10.17517/ksutfd.820604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
|
|
25
|
Matas J, Llorenç V, Fonollosa A, Díaz-Valle D, Esquinas C, de la Maza MTS, Figueras-Roca M, Artaraz J, Berasategui B, Mesquida M, Adán A, Molins B. Systemic Regulatory T Cells and IL-6 as Prognostic Factors for Anatomical Improvement of Uveitic Macular Edema. Front Immunol 2020; 11:579005. [PMID: 33101305 PMCID: PMC7545109 DOI: 10.3389/fimmu.2020.579005] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 09/14/2020] [Indexed: 12/15/2022] Open
Abstract
Purpose To investigate whether systemic immune mediators and circulating regulatory T cells (Tregs) could be prognostic factors for anatomic outcomes in macular edema secondary to non-infectious uveitis (UME). Methods Multicenter, prospective, observational, 12-month follow-up study of 60 patients with UME. Macular edema was defined as central subfield thickness (CST) > 300 μm measured with spectral domain optical coherence tomography (SD-OCT). Serum samples and peripheral blood mononuclear cells (PBMC) were obtained from venous blood extraction at baseline. Serum levels of IL-1β, IL-6, IL-8, IL-17, MCP-1, TNF-α, IL-10, and VEGF were determined by Luminex. Tregs population, defined as CD3+CD4+FoxP3+ in PBMC, was determined by flow cytometry. Main outcome measure was the predictive association between searched mediators and CST sustained improvement, defined as CST < 300 microns or a 20% CST decrease, at 6 months maintained until 12-months compared to baseline levels. Results Multivariate logistic regression analysis showed an association between CST sustained improvement at 12 months follow-up and IL-6 and Tregs baseline levels. Higher IL-6 levels were associated with less events of UME improvement (OR: 0.67, 95% CI (0.45-1.00), P = 0.042), whereas higher levels of Tregs favored such improvement (OR: 1.25, 95% CI: 1.12-2.56, P = 0.049). Conclusions Increased levels of Tregs and reduced levels of IL-6 in serum may be prognostic factors of sustained anatomical improvement in UME. These findings could enforce the opportunity to develop more efficient and personalized therapeutic approaches to improve long-term visual prognosis in patients with UME.
Collapse
Affiliation(s)
- Jessica Matas
- Group of Ocular Inflammation, Institut d’Investigacions Biomèdiques Agustí Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain
| | - Victor Llorenç
- Group of Ocular Inflammation, Institut d’Investigacions Biomèdiques Agustí Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain
| | - Alex Fonollosa
- Department of Ophthalmology, BioCruces Health Research Institute, Hospital Cruces, University of the Basque Country, Baracaldo, Spain
| | - David Díaz-Valle
- Ophthalmology Department and Health Research Institute (IdISSC), Hospital Clinic of San Carlos, Madrid, Spain
| | - Cristina Esquinas
- Valle Hebron Research Institute, Autonomous University of Barcelona, Barcelona, Spain
| | - Maria Teresa Sainz de la Maza
- Group of Ocular Inflammation, Institut d’Investigacions Biomèdiques Agustí Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain
| | - Marc Figueras-Roca
- Group of Ocular Inflammation, Institut d’Investigacions Biomèdiques Agustí Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain
| | - Joseba Artaraz
- Department of Ophthalmology, BioCruces Health Research Institute, Hospital Cruces, University of the Basque Country, Baracaldo, Spain
| | - Barbara Berasategui
- Department of Ophthalmology, BioCruces Health Research Institute, Hospital Cruces, University of the Basque Country, Baracaldo, Spain
| | - Marina Mesquida
- Group of Ocular Inflammation, Institut d’Investigacions Biomèdiques Agustí Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain
| | - Alfredo Adán
- Group of Ocular Inflammation, Institut d’Investigacions Biomèdiques Agustí Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain
| | - Blanca Molins
- Group of Ocular Inflammation, Institut d’Investigacions Biomèdiques Agustí Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain
| |
Collapse
|
|
26
|
Liczbiński P, Michałowicz J, Bukowska B. Molecular mechanism of curcumin action in signaling pathways: Review of the latest research. Phytother Res 2020; 34:1992-2005. [PMID: 32141677 DOI: 10.1002/ptr.6663] [Citation(s) in RCA: 104] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 01/16/2020] [Accepted: 02/15/2020] [Indexed: 02/06/2023]
Abstract
Recently, many studies have been conducted trying to explain the molecular mechanism of curcumin action in various pathological states of the cell and the organism. Curcumin is considered to play a role in the regulation of T-lymphocytes function in the lymphoid tissue of the large intestine, apoptosis of the human papilloma and the activity of the 26S proteasome, and p53 level. Research works have shown that curcumin in tumor can regulate reactive oxygen species (ROS) and cytosolic calcium ion level as well as affect other signaling molecules [nuclear factor kappa B (NF-KB), cytokines] triggering endoplasmic reticulum and mitochondrial stress, and thus contributing to death of cancer cells. Curcumin can also arrest of the cell cycle in the G2/M phase leading to apoptosis and/or reduction in cancer cells proliferation. Moreover, curcumin is capable of crossing the blood-brain barrier, and thus it may protect the neurons from oxidative stress and inflammation. Finally, curcumin may play a role in cardiological protection and it is possible to use it in the protection of liver and spleen against oxidative and inflammatory injury. Among signaling pathways regulated by curcumin, the most important seem to be those related with regulation of oxidative stress and inhibition of NF-кB activity.
Collapse
Affiliation(s)
- Przemysław Liczbiński
- Department of Environmental Biotechnology, Lodz University of Technology, Łódź, Poland
| | - Jaromir Michałowicz
- Faculty of Biology and Environmental Protection, Department of Biophysics of Environmental Pollution, University of Lodz, Łódź, Poland
| | - Bożena Bukowska
- Faculty of Biology and Environmental Protection, Department of Biophysics of Environmental Pollution, University of Lodz, Łódź, Poland
| |
Collapse
|
|
27
|
Dekkema GJ, Abdulahad WH, Bijma T, Moran SM, Ryan L, Little MA, Stegeman CA, Heeringa P, Sanders JSF. Urinary and serum soluble CD25 complements urinary soluble CD163 to detect active renal anti-neutrophil cytoplasmic autoantibody-associated vasculitis: a cohort study. Nephrol Dial Transplant 2020; 34:234-242. [PMID: 29506265 DOI: 10.1093/ndt/gfy018] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 01/15/2018] [Indexed: 12/28/2022] Open
Abstract
Background Early detection of renal involvement in anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is of major clinical importance to allow prompt initiation of treatment and limit renal damage. Urinary soluble cluster of differentiation 163 (usCD163) has recently been identified as a potential biomarker for active renal vasculitis. However, a significant number of patients with active renal vasculitis test negative using usCD163. We therefore studied whether soluble CD25 (sCD25), a T cell activation marker, could improve the detection of renal flares in AAV. Methods sCD25 and sCD163 levels in serum and urine were measured by enzyme-linked immunosorbent assay in 72 patients with active renal AAV, 20 with active extrarenal disease, 62 patients in remission and 18 healthy controls. Urinary and blood CD4+ T and CD4+ T effector memory (TEM) cell counts were measured in 22 patients with active renal vasculitis. Receiver operating characteristics (ROC) curves were generated and recursive partitioning was used to calculate whether usCD25 and serum soluble CD25 (ssCD25) add utility to usCD163. Results usCD25, ssCD25 and usCD163 levels were significantly higher during active renal disease and significantly decreased after induction of remission. A combination of usCD25, usCD163 and ssCD25 outperformed all individual markers (sensitivity 84.7%, specificity 95.1%). Patients positive for sCD25 but negative for usCD163 (n = 10) had significantly higher C-reactive protein levels and significantly lower serum creatinine and proteinuria levels compared with the usCD163-positive patients. usCD25 correlated positively with urinary CD4+ T and CD4+ TEM cell numbers, whereas ssCD25 correlated negatively with circulating CD4+ T and CD4+ TEM cells. Conclusion Measurement of usCD25 and ssCD25 complements usCD163 in the detection of active renal vasculitis.
Collapse
Affiliation(s)
- Gerjan J Dekkema
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Wayel H Abdulahad
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.,Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Theo Bijma
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.,Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, Groningen, The Netherlands
| | - Sarah M Moran
- Trinity Health Kidney Centre, Trinity College Dublin, Dublin, Ireland
| | - Louise Ryan
- Trinity Health Kidney Centre, Trinity College Dublin, Dublin, Ireland
| | - Mark A Little
- Trinity Health Kidney Centre, Trinity College Dublin, Dublin, Ireland
| | - Coen A Stegeman
- Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, Groningen, The Netherlands
| | - Peter Heeringa
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Jan-Stephan F Sanders
- Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, Groningen, The Netherlands
| |
Collapse
|
|
28
|
Abstract
Myasthenia gravis (MG) is an autoimmune disease caused by antibodies against the acetylcholine receptor (AChR), muscle-specific kinase (MuSK) or other AChR-related proteins in the postsynaptic muscle membrane. Localized or general muscle weakness is the predominant symptom and is induced by the antibodies. Patients are grouped according to the presence of antibodies, symptoms, age at onset and thymus pathology. Diagnosis is straightforward in most patients with typical symptoms and a positive antibody test, although a detailed clinical and neurophysiological examination is important in antibody-negative patients. MG therapy should be ambitious and aim for clinical remission or only mild symptoms with near-normal function and quality of life. Treatment should be based on MG subgroup and includes symptomatic treatment using acetylcholinesterase inhibitors, thymectomy and immunotherapy. Intravenous immunoglobulin and plasma exchange are fast-acting treatments used for disease exacerbations, and intensive care is necessary during exacerbations with respiratory failure. Comorbidity is frequent, particularly in elderly patients. Active physical training should be encouraged.
Collapse
|
|
29
|
Morales-Nebreda L, McLafferty FS, Singer BD. DNA methylation as a transcriptional regulator of the immune system. Transl Res 2019; 204:1-18. [PMID: 30170004 PMCID: PMC6331288 DOI: 10.1016/j.trsl.2018.08.001] [Citation(s) in RCA: 93] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 07/31/2018] [Accepted: 08/02/2018] [Indexed: 12/13/2022]
Abstract
DNA methylation is a dynamic epigenetic modification with a prominent role in determining mammalian cell development, lineage identity, and transcriptional regulation. Primarily linked to gene silencing, novel technologies have expanded the ability to measure DNA methylation on a genome-wide scale and uncover context-dependent regulatory roles. The immune system is a prototypic model for studying how DNA methylation patterning modulates cell type- and stimulus-specific transcriptional programs. Preservation of host defense and organ homeostasis depends on fine-tuned epigenetic mechanisms controlling myeloid and lymphoid cell differentiation and function, which shape innate and adaptive immune responses. Dysregulation of these processes can lead to human immune system pathology as seen in blood malignancies, infections, and autoimmune diseases. Identification of distinct epigenotypes linked to pathogenesis carries the potential to validate therapeutic targets in disease prevention and management.
Collapse
Affiliation(s)
- Luisa Morales-Nebreda
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
| | - Fred S McLafferty
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
| | - Benjamin D Singer
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois; Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois; Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
| |
Collapse
|
|
30
|
Choi BY, Choi Y, Park JS, Kang LJ, Baek SH, Park JS, Bahn G, Cho Y, Kim HK, Han J, Sul JH, Baik SH, Hyun DH, Arumugam TV, Yang S, Han JW, Kang YM, Cho YW, Park JH, Jo DG. Inhibition of Notch1 induces population and suppressive activity of regulatory T cell in inflammatory arthritis. Am J Cancer Res 2018; 8:4795-4804. [PMID: 30279738 PMCID: PMC6160763 DOI: 10.7150/thno.26093] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Accepted: 07/27/2018] [Indexed: 12/14/2022] Open
Abstract
Inhibition of Notch signalling has shown anti-inflammatory properties in vivo and in vitro models of rheumatoid arthritis (RA). The objective of this study was to determine whether Notch1 might play a role in regulating T-regulatory cells (Tregs) in animal models of RA. Methods: Collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) were induced in C57BL/6, Notch1 antisense transgenic (NAS) or DBA1/J mice. We examined whether pharmacological inhibitors of γ-secretase (an enzyme required for Notch1 activation) and antisense-mediated knockdown of Notch1 could attenuate the severity of inflammatory arthritis in CIA and CAIA mice. Proportions of CD4+CD25+Foxp3+ Treg cells were measured by flow cytometry. To assess the suppressive capacity of Treg toward responder cells, CFSE-based suppression assay of Treg was performed. Results: γ-secretase inhibitors and antisense-mediated knockdown of Notch1 reduced the severity of inflammatory arthritis in both CIA and CAIA mice. Pharmacological and genetic inhibition of Notch1 signalling induced significant elevation of Treg cell population in CIA and CAIA mice. We also demonstrated that inhibition of Notch signalling suppressed the progression of inflammatory arthritis through modulating the expansion and suppressive function of regulatory T (Treg) cells. Conclusion: Pharmacological and genetic inhibition of Notch1 signalling suppresses the progression of inflammatory arthritis through modulating the population and suppressive function of Treg cells in animal models of RA.
Collapse
|
|
31
|
In vivo effects of aspirin and cyclosporine on regulatory T cells and T-cell cytokine production in healthy dogs. Vet Immunol Immunopathol 2018; 197:63-68. [DOI: 10.1016/j.vetimm.2018.01.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 01/06/2018] [Accepted: 01/09/2018] [Indexed: 11/20/2022]
|
|
32
|
Rossi MT, Arisi M, Lonardi S, Lorenzi L, Ungari M, Serana F, Fusano M, Moggio E, Calzavara-Pinton PG, Venturini M. Cutaneous infiltration of plasmacytoid dendritic cells and T regulatory cells in skin lesions of polymorphic light eruption. J Eur Acad Dermatol Venereol 2018; 32:985-991. [PMID: 29430717 DOI: 10.1111/jdv.14866] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 01/25/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND Polymorphic light eruption (PLE) is the most common autoimmune photodermatosis. Plasmacytoid dendritic cells (PDCs) are important mediators of innate antimicrobial immunity involved in the pathogenesis of many inflammatory skin diseases. In addition to PDCs, regulatory T cells (Tregs) are involved in controlling inflammation and adaptive immunity in skin by their immunosuppressive capacity. OBJECTIVE The aim of this study was to investigate the presence of PDCs and Tregs in photoexposed skin from PLE compared to healthy skin. METHODS Patients with PLE diagnosis and healthy controls were recruited and underwent a photoprovocative test. A 4-mm punch biopsy was taken from the site of positive photoprovocation test reaction, and immunohistochemistry for BDCA2 as marker for PDCs, CD4 and FOXP3 as markers for Tregs was performed. Double immunostain for FOXP3 and CD4 was performed as well. Absolute counts for CD4, BDCA2 and FOXP3 were performed in at least 5 High Power Fields (HPF). Percentage of CD4-, BDCA2- and CD4FOXP3-positive cells over the total inflammatory infiltrate was assessed for each case. RESULTS We enrolled 23 patients and controls. BDCA2+ cells were present in 91.3% of PLE skin samples and 100% of healthy volunteer. Both in PLE patients and healthy controls, PDCs distribution was mainly dermic (P < 0.05). Compared to healthy controls, both epidermic and dermic BDCA2+ cells count were significantly higher in PLE patients (P < 0.05). Both in PLE patients and healthy controls, Tregs distribution was mainly dermic (P < 0.05). The presence of both CD4+ cells and FOXP3+ cells was significantly higher in the dermis of PLE patients compared to controls (P < 0.05). Relative percentages of cellular infiltrations confirmed these results. CONCLUSIONS D-PDCS and Tregs may play a significant role in the development of PLE, and dermal distribution of PDCs in PLE skin biopsies seems to confirm a possible overlap with cutaneous lupus erythematosus (CLE).
Collapse
Affiliation(s)
- M T Rossi
- Dermatology Department, ASST Spedali Civili di Brescia, University of Brescia, Brescia, Italy
| | - M Arisi
- Dermatology Department, ASST Spedali Civili di Brescia, University of Brescia, Brescia, Italy
| | - S Lonardi
- Department of Pathology, ASST Spedali Civili di Brescia, University of Brescia, Brescia, Italy
| | - L Lorenzi
- Department of Pathology, ASST Spedali Civili di Brescia, University of Brescia, Brescia, Italy
| | - M Ungari
- Department of Pathology, Ospedale Maggiore di Cremona, Cremona, Italy
| | - F Serana
- CREA, Diagnostics Department, ASST Spedali Civili di Brescia, University of Brescia, Brescia, Italy
| | - M Fusano
- Dermatology Department, ASST Spedali Civili di Brescia, University of Brescia, Brescia, Italy
| | - E Moggio
- Dermatology Department, ASST Spedali Civili di Brescia, University of Brescia, Brescia, Italy
| | - P G Calzavara-Pinton
- Dermatology Department, ASST Spedali Civili di Brescia, University of Brescia, Brescia, Italy
| | - M Venturini
- Dermatology Department, ASST Spedali Civili di Brescia, University of Brescia, Brescia, Italy
| |
Collapse
|
|
33
|
Combined Treatment with Methylprednisolone and Human Bone Marrow-Derived Mesenchymal Stem Cells Ameliorate Experimental Autoimmune Encephalomyelitis. Tissue Eng Regen Med 2018; 15:183-194. [PMID: 30603546 DOI: 10.1007/s13770-017-0101-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 10/16/2017] [Accepted: 11/19/2017] [Indexed: 10/18/2022] Open
Abstract
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Although advances have been made in the treatment of MS, such as the use of IFN-β, glucocorticoids and stem cells, the therapeutic effects of these treatments are not sufficient. In the present study, we evaluated whether the combination of methylprednisolone (MP) and human bone marrow-derived mesenchymal stem cells (BM-MSCs) could enhance the therapeutic effectiveness in experimental autoimmune encephalomyelitis (EAE), a model for MS. EAE was induced by immunizing C57BL/6 mice with myelin oligodendrocyte glycoprotein 35-55 (MOG 35-55). The immunized mice received an intraperitoneal injection of MP (20 mg/kg), an intravenous injection of BM-MSCs (1 × 106 cells) or both on day 14 after immunization. Combination treatment significantly ameliorated the clinical symptoms, along with attenuating inflammatory infiltration and demyelination, compared to either treatment alone. Secretion of pro-inflammatory cytokines (IFN-γ, TNF-α, IL-17) was significantly reduced, and anti-inflammatory cytokines (IL-4, IL-10) was significantly increased by the combination treatment as compared to either treatment alone. Flow cytometry analysis of MOG-reactivated T cells in spleen showed that combination treatment reduced the number of CD4+CD45+ and CD8+ T cells, and increased the number of CD4+CD25+Foxp3+ regulatory T cells. Furthermore, combination treatment enhanced apoptosis in MOG-reactivated CD4+ T cells, a key cellular subset in MS pathogenesis. Combination treatment with MP and BM-MSCs provides a novel treatment protocol for enhancing therapeutic effects in MS.
Collapse
|
|
34
|
OKAZAKI K, UCHIDA K. Current perspectives on autoimmune pancreatitis and IgG4-related disease. PROCEEDINGS OF THE JAPAN ACADEMY. SERIES B, PHYSICAL AND BIOLOGICAL SCIENCES 2018; 94:412-427. [PMID: 30541967 PMCID: PMC6374139 DOI: 10.2183/pjab.94.027] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/12/2023]
Abstract
IgG4-related disease (IgG4-RD) is a fibroinflammatory disorder recognized as a novel clinical entity with either synchronous or metachronous multi-organ involvement. Patients with IgG4-RD show diffuse or focal organ enlargement and mass-forming or nodular/thickened lesions with abundant infiltration of IgG4-positive plasmacytes and fibrosis, and such patients respond well to steroid treatment. It should be differentiated from mimics by a combination of serum IgG4 level, imaging features, and histopathological findings. The current first-line drug is corticosteroids, or rituximab in high-risk patients for steroid intolerance. Although relapse rates are high, standardized protocols for relapsed cases have not been approved yet. Based on genetic factors, disease-specific or -related antigens, abnormal innate and adaptive immunity may be involved, although the precise pathogenic mechanism and long-term outcome still remain unclear.
Collapse
Affiliation(s)
- Kazuichi OKAZAKI
- Department of Gastroenterology and Hepatology, Kansai Medical University, Osaka, Japan
- Correspondence should be addressed: K. Okazaki, Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan (e-mail: )
| | - Kazushige UCHIDA
- Department of Gastroenterology and Hepatology, Kansai Medical University, Osaka, Japan
| |
Collapse
|
|
35
|
Won HY, Shin JH, Oh S, Jeong H, Hwang ES. Enhanced CD25 +Foxp3 + regulatory T cell development by amodiaquine through activation of nuclear receptor 4A. Sci Rep 2017; 7:16946. [PMID: 29208963 PMCID: PMC5717225 DOI: 10.1038/s41598-017-17073-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Accepted: 11/21/2017] [Indexed: 01/10/2023] Open
Abstract
CD4+ T cells play key roles in the regulation of immune responses against pathogenic infectious antigens via development into effector T helper and induced regulatory T (iTreg) cells. Particularly, CD4+CD25+Foxp3+ iTreg cells are crucial for maintaining immune homeostasis and controlling inflammatory diseases. Anti-inflammatory drugs that enhance iTreg cell generation would be effective at preventing and treating inflammatory and autoimmune diseases. In this study, we examined whether anti-malarial and anti-arthritic amodiaquine (AQ) could affect iTreg cell development. Despite the anti-proliferative activity of AQ, AQ only moderately decreased iTreg cell proliferation but substantially increased IL-2 production by iTreg cells. Furthermore, AQ dose-dependently increased iTreg cell development and significantly upregulated iTreg cell markers including CD25. Interestingly, CD25 expression was decreased at later stages of iTreg cell development but was sustained in the presence of AQ, which was independent of IL-2 signaling pathway. AQ directly increased CD25 gene transcription by enhancing the DNA-binding and transcriptional activity of nuclear receptor 4 A. Most importantly, in vivo administration of AQ attenuated inflammatory colitis, resulted in the increased iTreg cells and decreased inflammatory cytokines. The ability of anti-malarial AQ to potentiate iTreg cell development makes it a promising drug for preventing and treating inflammatory and autoimmune diseases.
Collapse
MESH Headings
- Amodiaquine/pharmacology
- Animals
- Cell Proliferation/drug effects
- Colitis/drug therapy
- Colitis/etiology
- DNA-Binding Proteins/genetics
- DNA-Binding Proteins/metabolism
- Forkhead Transcription Factors/metabolism
- Interleukin-2/metabolism
- Interleukin-2 Receptor alpha Subunit/genetics
- Interleukin-2 Receptor alpha Subunit/metabolism
- Male
- Mice, Inbred C57BL
- Mice, Knockout
- Nerve Tissue Proteins/genetics
- Nerve Tissue Proteins/metabolism
- Nuclear Receptor Subfamily 4, Group A, Member 1/genetics
- Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism
- Nuclear Receptor Subfamily 4, Group A, Member 2/genetics
- Nuclear Receptor Subfamily 4, Group A, Member 2/metabolism
- Receptors, Interleukin-2/metabolism
- Receptors, Steroid/genetics
- Receptors, Steroid/metabolism
- Receptors, Thyroid Hormone/genetics
- Receptors, Thyroid Hormone/metabolism
- T-Lymphocytes, Regulatory/drug effects
- T-Lymphocytes, Regulatory/physiology
- Transforming Growth Factor beta/pharmacology
Collapse
Affiliation(s)
- Hee Yeon Won
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Korea
| | - Ji Hyun Shin
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Korea
| | - Sera Oh
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Korea
| | - Hana Jeong
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Korea
| | - Eun Sook Hwang
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Korea.
| |
Collapse
|
|
36
|
Abstract
PURPOSE OF REVIEW Tubulointerstitial nephritis and uveitis (TINU) is an important yet underrecognized ocular inflammatory syndrome. This review summarizes key historical publications that identified and defined the syndrome, and more recent literature that reveal the importance of urinary β2-microglobulin testing and kidney biopsy in the diagnostic evaluation of patients with TINU. Additionally, research studies providing new insights into disease pathogenesis are highlighted. RECENT FINDINGS In contrast with initial reports of TINU manifesting exclusively as an anterior uveitis in pediatric patients, more recent reports have identified TINU in patients of all ages with a wide range of ocular manifestations. Urinary β2-microglobulin has emerged as a sensitive and specific laboratory screening test, and the role of kidney biopsy in differentiating TINU from sarcoidosis continues to evolve. Genetic studies have identified HLA-DQA101, HLA-DQB105, and HLA-DRB101 as high-risk alleles and the identification of antimonomeric C-reactive protein antibodies suggests a role for humoral immunity in disease pathogenesis. Management strategies have evolved to include systemic anti-inflammatory treatment as a result of important outcome studies in patients with significant renal and ocular disease. SUMMARY With greater recognition, understanding, and treatment of this syndrome, both ocular inflammation and renal disease can be better addressed.
Collapse
Affiliation(s)
- Kaivon Pakzad-Vaezi
- Department of Ophthalmology, University of Washington, Seattle, Washington, USA
| | | |
Collapse
|
|
37
|
Park JS, Oh Y, Park O, Foss CA, Lim SM, Jo DG, Na DH, Pomper MG, Lee KC, Lee S. PEGylated TRAIL ameliorates experimental inflammatory arthritis by regulation of Th17 cells and regulatory T cells. J Control Release 2017; 267:163-171. [PMID: 29017854 DOI: 10.1016/j.jconrel.2017.10.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 09/02/2017] [Accepted: 10/06/2017] [Indexed: 12/24/2022]
Abstract
TNF-related apoptosis-inducing ligand (TRAIL) is a death ligand that can induce apoptosis in cells expressing its cognate death receptors (DRs). Previously, we demonstrated the therapeutic potential of recombinant human TRAIL in experimental rheumatoid arthritis (RA) models. However, the mechanisms of how DR-mediated apoptosis elicits these actions is not known. Here, we show that systemically administering a potent, long-acting PEGylated TRAIL (TRAILPEG) is profoundly anti-rheumatic against two complementary experimental RA mouse models, collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA), via targeting IL-17 secreting Th17 cells and regulatory T cells (Treg). Systemic administration of TRAILPEG after disease onset ameliorated the severity of inflammatory arthritis including arthritis indices, paw thickness, cartilage damage and neutrophil infiltration in both CIA and CAIA models. Additionally, the levels of inflammatory molecules (p-p65, ICAM-1, Cox-2, MMP3, and iNOS), pro-inflammatory cytokines (TNF-α, IL-1β, IFN-γ, IL-6, IL-17) and accumulation of activated macrophages were significantly reduced after the TRAILPEG treatment. Importantly, TRAILPEG decreased the number of pro-inflammatory Th17 cells in inflamed arthritic joints through TRAIL-induced apoptosis while increasing anti-inflammatory Treg population in vivo. These results suggest that TRAILPEG ameliorates autoimmunity by targeting the Th 17-Tregs axis, making it a promising candidate drug for the treatment of RA.
Collapse
Affiliation(s)
- Jong-Sung Park
- Russell H, Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA
| | - Yumin Oh
- Russell H, Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA
| | - Ogyi Park
- Russell H, Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA
| | - Catherine A Foss
- Russell H, Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA
| | - Sung Mook Lim
- School of Pharmacy, SungKyunKwan University, Suwon 16419, Republic of Korea
| | - Dong-Gyu Jo
- School of Pharmacy, SungKyunKwan University, Suwon 16419, Republic of Korea
| | - Dong Hee Na
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Martin G Pomper
- Russell H, Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Kang Choon Lee
- School of Pharmacy, SungKyunKwan University, Suwon 16419, Republic of Korea.
| | - Seulki Lee
- Russell H, Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21287, USA.
| |
Collapse
|
|
38
|
Regulatory immune cells and functions in autoimmunity and transplantation immunology. Autoimmun Rev 2017; 16:435-444. [DOI: 10.1016/j.autrev.2017.03.011] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Accepted: 01/26/2017] [Indexed: 12/15/2022]
|
|
39
|
Ferluga J, Kouser L, Murugaiah V, Sim RB, Kishore U. Potential influences of complement factor H in autoimmune inflammatory and thrombotic disorders. Mol Immunol 2017; 84:84-106. [PMID: 28216098 DOI: 10.1016/j.molimm.2017.01.015] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Revised: 01/11/2017] [Accepted: 01/13/2017] [Indexed: 01/01/2023]
Abstract
Complement system homeostasis is important for host self-protection and anti-microbial immune surveillance, and recent research indicates roles in tissue development and remodelling. Complement also appears to have several points of interaction with the blood coagulation system. Deficiency and altered function due to gene mutations and polymorphisms in complement effectors and regulators, including Factor H, have been associated with familial and sporadic autoimmune inflammatory - thrombotic disorders, in which autoantibodies play a part. These include systemic lupus erythematosus, rheumatoid arthritis, atypical haemolytic uremic syndrome, anti-phospholipid syndrome and age-related macular degeneration. Such diseases are generally complex - multigenic and heterogeneous in their symptoms and predisposition/susceptibility. They usually need to be triggered by vascular trauma, drugs or infection and non-complement genetic factors also play a part. Underlying events seem to include decline in peripheral regulatory T cells, dendritic cell, and B cell tolerance, associated with alterations in lymphoid organ microenvironment. Factor H is an abundant protein, synthesised in many cell types, and its reported binding to many different ligands, even if not of high affinity, may influence a large number of molecular interactions, together with the accepted role of Factor H within the complement system. Factor H is involved in mesenchymal stem cell mediated tolerance and also contributes to self-tolerance by augmenting iC3b production and opsonisation of apoptotic cells for their silent dendritic cell engulfment via complement receptor CR3, which mediates anti-inflammatory-tolerogenic effects in the apoptotic cell context. There may be co-operation with other phagocytic receptors, such as complement C1q receptors, and the Tim glycoprotein family, which specifically bind phosphatidylserine expressed on the apoptotic cell surface. Factor H is able to discriminate between self and nonself surfaces for self-protection and anti-microbe defence. Factor H, particularly as an abundant platelet protein, may also modulate blood coagulation, having an anti-thrombotic role. Here, we review a number of interaction pathways in coagulation and in immunity, together with associated diseases, and indicate where Factor H may be expected to exert an influence, based on reports of the diversity of ligands for Factor H.
Collapse
Affiliation(s)
- Janez Ferluga
- Biosciences, College of Health and Life Sciences, Brunel University London, Uxbridge, UB8 3PH, United Kingdom
| | - Lubna Kouser
- Biosciences, College of Health and Life Sciences, Brunel University London, Uxbridge, UB8 3PH, United Kingdom
| | - Valarmathy Murugaiah
- Biosciences, College of Health and Life Sciences, Brunel University London, Uxbridge, UB8 3PH, United Kingdom
| | - Robert B Sim
- Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom
| | - Uday Kishore
- Biosciences, College of Health and Life Sciences, Brunel University London, Uxbridge, UB8 3PH, United Kingdom.
| |
Collapse
|
|
40
|
Nakken B, Bodolay E, Szodoray P. Cytokine Milieu in Undifferentiated Connective Tissue Disease: a Comprehensive Review. Clin Rev Allergy Immunol 2016; 49:152-62. [PMID: 25274451 DOI: 10.1007/s12016-014-8452-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Undifferentiated connective tissue disease (UCTD) is a unique clinical entity, a potential forerunner of well-established systemic autoimmune/rheumatic diseases. UCTD is characterized by the presence of various clinical symptoms, as well as a diverse repertoire of autoantibodies, resembling systemic autoimmune diseases. Since approximately one third of these patients consequently transform into a full-blown systemic autoimmune/rheumatic disease, it is of major importance to assess pathogenic factors leading to this progression. In view of the fact that the serological and clinical picture of UCTD and systemic autoimmune diseases are very similar, it is assumed that analogous pathogenic factors perpetuate both disease entities. In systemic autoimmune conditions, a quantitative and qualitative impairment of regulatory T cells has been shown previously, and in parallel, a relative dominance of pro-inflammatory Th17 cells has been introduced. Moreover, the imbalance between regulatory and Th17 cells plays a pivotal role in the initiation and propagation of UCTD. Additionally, we depict a cytokine imbalance, which give raise to a biased T cell homeostasis from the UCTD phase throughout the fully developed systemic autoimmune disease stage. The levels of interleukin (IL)-6, IL-12, IL-17, IL-23, and interferon (IFN)-γ were pathologically increased with a parallel reduction of IL-10. We believe that the assessment of Th17/Treg cell ratio, as well as the simultaneous quantitation of cytokines may give a useful diagnostic tool at the early UCTD stage to identify patients with a higher chance of consecutive disease progression toward serious systemic autoimmune diseases. Moreover, the early targeted immunomodulating therapy in these patients may decelerate, or even stop this progression, before the development of serious autoimmune conditions with organ damage.
Collapse
Affiliation(s)
- Britt Nakken
- Institute of Immunology, Rikshospitalet, Oslo University Hospital, Sognsvannsveien 20, Oslo, Norway, N-0027
| | - Edit Bodolay
- Department of Clinical Immunology, Institute of Medicine, University of Debrecen Medical and Health Science Centre, Debrecen, Hungary
| | - Peter Szodoray
- Institute of Immunology, Rikshospitalet, Oslo University Hospital, Sognsvannsveien 20, Oslo, Norway, N-0027.
| |
Collapse
|
|
41
|
Deficiency of T-regulatory cells exaggerates angiotensin II-induced microvascular injury by enhancing immune responses. J Hypertens 2016; 34:97-108. [PMID: 26630215 DOI: 10.1097/hjh.0000000000000761] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
AIMS T-regulatory lymphocyte (Treg) adoptive transfer prevented angiotensin (Ang) II-induced hypertension and microvascular injury. Scurfy mice are deficient in Treg because of a mutation in the transcription factor forkhead box P3 (Foxp3) gene. Enhanced Ang II effects in the absence of Treg would unambiguously demonstrate their vascular protective role. We hypothesized that adoptive transfer of Scurfy vs. wild-type T cells will exacerbate Ang II-induced microvascular damage in T and B-cell-deficient recombination-activating gene 1 (Rag1) knockout mice. METHODS AND RESULTS Rag1 knockout mice were injected with vehicle, 10(7) T cells from wild-type or Scurfy mice or 10 (6)wild-type Treg alone or in combination with Scurfy T cells, and then infused or not with Ang II (490 ng/kg per min, subcutaneous) for 14 days. Ang II increased SBP in all the groups, but DBP only in wild-type and Scurfy T-cell groups. Ang II-induced endothelial dysfunction and oxidative stress in perivascular adipose tissue (PVAT) of mesenteric arteries of the wild-type T-cell group, whereas these were exaggerated in the Scurfy T-cell group. Ang II enhanced microvascular remodeling and stiffness in vehicle and Scurfy T-cell groups. Ang II increased monocyte chemotactic protein-1 expression in the vascular wall and PVAT, monocyte/macrophage infiltration and proinflammatory polarization in PVAT and the renal cortex, and T-cell infiltration in the renal cortex only in the Scurfy T-cell group. Treg coinjection in the vehicle and Scurfy T-cell groups prevented or reduced the effects of Ang II. CONCLUSION FOXP3+ Treg deficiency exaggerates Ang II-induced microvascular injury by modulating innate and adaptive immune responses.
Collapse
|
|
42
|
Zhao HM, Xu R, Huang XY, Cheng SM, Huang MF, Yue HY, Wang X, Zou Y, Lu AP, Liu DY. Curcumin improves regulatory T cells in gut-associated lymphoid tissue of colitis mice. World J Gastroenterol 2016; 22:5374-5383. [PMID: 27340353 PMCID: PMC4910658 DOI: 10.3748/wjg.v22.i23.5374] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2016] [Revised: 03/29/2016] [Accepted: 04/15/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the probable pathway by which curcumin (Cur) regulates the function of Treg cells by observing the expression of costimulatory molecules of dendritic cells (DCs).
METHODS: Experimental colitis was induced by administering 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)/ethanol solution. Forty male C57BL/6 mice were randomly divided into four groups: normal, TNBS + Cur, TNBS + mesalazine (Mes) and TNBS groups. The mice in the TNBS + Cur and TNBS +Mes groups were treated with Cur and Mes, respectively, while those in the TNBS group were treated with physiological saline for 7 d. After treatment, the curative effect of Cur was evaluated by colonic weight, colonic length, weight index of the colon, and histological observation and score. The levels of CD4+CD25+Foxp3+ T cells (Treg cells) and costimulatory molecules of DCs were measured by flow cytometry. Also, related cytokines were analyzed by enzyme-linked immunosorbent assay.
RESULTS: Cur alleviated inflammatory injury of the colonic mucosa, decreased colonic weigh and histological score, and restored colonic length. The number of Treg cells was increased, while the secretion of TNF-α, IL-2, IL-6, IL-12 p40, IL-17 and IL-21 and the expression of costimulatory molecules (CD205, CD54 [ICAM-1], TLR4, CD252[OX40 L], CD256 [RANK] and CD254 [RANK L]) of DCs were notably inhibited in colitis mice treated with Cur.
CONCLUSION: Cur potentially modulates activation of DCs to enhance the suppressive functions of Treg cells and promote the recovery of damaged colonic mucosa in inflammatory bowel disease.
Collapse
|
|
43
|
A Gain-Of-Function Mutation in the Plcg2 Gene Protects Mice from Helicobacter felis-Induced Gastric MALT Lymphoma. PLoS One 2016; 11:e0150411. [PMID: 26966907 PMCID: PMC4788355 DOI: 10.1371/journal.pone.0150411] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2015] [Accepted: 02/13/2016] [Indexed: 01/04/2023] Open
Abstract
Gastric mucosa-associated lymphoid tissue (MALT) lymphomas develop from a chronic Helicobacter infection. Phospholipase C gamma 2 (PLCG2) is important for B-cell survival and proliferation. We used BALB/c mice with a gain-of-function mutation in the Plcg2 gene (Ali5) to analyze its role in the development of gastric MALT lymphoma. Heterozygous BALB/c Plcg2Ali5/+ and wildtype (WT) mice were infected with Helicobacter felis (H. felis) and observed up to 16 months for development of gastric MALT lymphomas. In contrast to our initial hypothesis, Plcg2Ali5/+ mice developed MALT lymphomas less frequently than their WT littermates after long-term infection of 16 months. Infected Plcg2Ali5/+ mice showed downregulation of proinflammatory cytokines and decreased H. felis-specific IgG1 and IgG2a antibody responses. These results suggested a blunted immune response of Plcg2Ali5/+ mice towards H. felis infection. Intriguingly, Plcg2Ali5/+ mice harboured higher numbers of CD73 expressing regulatory T cells (Tregs), possibly responsible for impaired immune response towards Helicobacter infection. We suggest that Plcg2Ali5/+ mice may be protected from developing gastric MALT lymphomas as a result of elevated Treg numbers, reduced response to H. felis and decrease of proinflammatory cytokines.
Collapse
|
|
44
|
|
|
45
|
Arumugam M, Parthasarathy V. Reduction of CD4+CD25+ regulatory T-cells in migraine: Is migraine an autoimmune disorder? J Neuroimmunol 2016; 290:54-9. [DOI: 10.1016/j.jneuroim.2015.11.015] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Revised: 11/17/2015] [Accepted: 11/18/2015] [Indexed: 01/08/2023]
|
|
46
|
Iwahashi C, Fujimoto M, Nomura S, Serada S, Nakai K, Ohguro N, Nishida K, Naka T. CTLA4-Ig suppresses development of experimental autoimmune uveitis in the induction and effector phases: Comparison with blockade of interleukin-6. Exp Eye Res 2015; 140:53-64. [DOI: 10.1016/j.exer.2015.08.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Revised: 07/04/2015] [Accepted: 08/17/2015] [Indexed: 12/14/2022]
|
|
47
|
Selected Aspects in the Pathogenesis of Autoimmune Diseases. Mediators Inflamm 2015; 2015:351732. [PMID: 26300591 PMCID: PMC4537751 DOI: 10.1155/2015/351732] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Accepted: 02/24/2015] [Indexed: 11/26/2022] Open
Abstract
Autoimmune processes can be found in physiological circumstances. However, they are quenched with properly functioning regulatory mechanisms and do not evolve into full-blown autoimmune diseases. Once developed, autoimmune diseases are characterized by signature clinical features, accompanied by sustained cellular and/or humoral immunological abnormalities. Genetic, environmental, and hormonal defects, as well as a quantitative and qualitative impairment of immunoregulatory functions, have been shown in parallel to the relative dominance of proinflammatory Th17 cells in many of these diseases. In this review we focus on the derailed balance between regulatory and Th17 cells in the pathogenesis of autoimmune diseases. Additionally, we depict a cytokine imbalance, which gives rise to a biased T-cell homeostasis. The assessment of Th17/Treg-cell ratio and the simultaneous quantitation of cytokines, may give a useful diagnostic tool in autoimmune diseases. We also depict the multifaceted role of dendritic cells, serving as antigen presenting cells, contributing to the development of the pathognomonic cytokine signature and promote cellular and humoral autoimmune responses. Finally we describe the function and role of extracellular vesicles in particular autoimmune diseases. Targeting these key players of disease progression in patients with autoimmune diseases by immunomodulating therapy may be beneficial in future therapeutic strategies.
Collapse
|
|
48
|
Vargas-Rojas MI, Solleiro-Villavicencio H, Soto-Vega E. Th1, Th2, Th17 and Treg levels in umbilical cord blood in preeclampsia. J Matern Fetal Neonatal Med 2015; 29:1642-5. [DOI: 10.3109/14767058.2015.1057811] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
|
|
49
|
Tedder TF. B10 cells: a functionally defined regulatory B cell subset. THE JOURNAL OF IMMUNOLOGY 2015; 194:1395-401. [PMID: 25663677 DOI: 10.4049/jimmunol.1401329] [Citation(s) in RCA: 237] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
B cells are commonly thought to enhance inflammatory immune responses. However, specific regulatory B cell subsets recently were identified that downregulate adaptive and innate immunity, inflammation, and autoimmunity through diverse molecular mechanisms. In both mice and humans, a rare, but specific, subset of regulatory B cells is functionally characterized by its capacity to produce IL-10, a potent inhibitory cytokine. For clarity, this regulatory B cell subset has been labeled as B10 cells, because their ability to downregulate immune responses and inflammatory disease is fully attributable to IL-10, and their absence or loss exacerbates disease symptoms in mouse models. This review preferentially focuses on what is known about mouse B10 cell development, phenotype, and effector function, as well as on mechanistic studies that demonstrated their functional importance during inflammation, autoimmune disease, and immune responses.
Collapse
Affiliation(s)
- Thomas F Tedder
- Department of Immunology, Duke University Medical Center, Durham, NC 27710
| |
Collapse
|
|
50
|
Molins B, Mesquida M, Lee RWJ, Llorenç V, Pelegrín L, Adán A. Regulatory T cell levels and cytokine production in active non-infectious uveitis: in-vitro effects of pharmacological treatment. Clin Exp Immunol 2015; 179:529-38. [PMID: 25354724 PMCID: PMC4337685 DOI: 10.1111/cei.12479] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2014] [Indexed: 12/20/2022] Open
Abstract
The aim of this study was to quantify the proportion of regulatory T cells (Treg ) and cytokine expression by peripheral blood mononuclear cells (PBMCs) in patients with active non-infectious uveitis, and to evaluate the effect of in-vitro treatment with infliximab, dexamethasone and cyclosporin A on Treg levels and cytokine production in PBMCs from uveitis patients and healthy subjects. We included a group of 21 patients with active non-infectious uveitis and 18 age-matched healthy subjects. The proportion of forkhead box protein 3 (FoxP3)(+) Treg cells and intracellular tumour necrosis factor (TNF)-α expression in CD4(+) T cells was determined by flow cytometry. PBMCs were also either rested or activated with anti-CD3/anti-CD28 and cultured in the presence or absence of dexamethasone, cyclosporin A and infliximab. Supernatants of cultured PBMCs were collected and TNF-α, interleukin (IL)-10, IL-17 and interferon (IFN)-γ levels were measured by enzyme-linked immunosorbent assay (ELISA). No significant differences were observed in nTreg levels between uveitis patients and healthy subjects. However, PBMCs from uveitis patients produced significantly higher amounts of TNF-α and lower amounts of IL-10. Dexamethasone treatment in vitro significantly reduced FoxP3(+) Treg levels in PBMCs from both healthy subjects and uveitis patients, and all tested drugs significantly reduced TNF-α production in PBMCs. Dexamethasone and cyclosporin A significantly reduced IL-17 and IFN-γ production in PBMCs and dexamethasone up-regulated IL-10 production in activated PBMCs from healthy subjects. Our results suggest that PBMCs from patients with uveitis express more TNF-α and less IL-10 than healthy subjects, and this is independent of FoxP3(+) Treg levels. Treatment with infliximab, dexamethasone and cyclosporin A in vitro modulates cytokine production, but does not increase the proportion of FoxP3(+) Treg cells.
Collapse
Affiliation(s)
- B Molins
- Institut Clinic d'Oftalmologia, Hospital Clinic de Barcelona, University of BarcelonaBarcelona, Spain
- Fundacio Clinic per la Recerca Biomedica, IDIBAPSBarcelona, Spain
| | - M Mesquida
- Institut Clinic d'Oftalmologia, Hospital Clinic de Barcelona, University of BarcelonaBarcelona, Spain
| | - R W J Lee
- Inflammation and Immunotherapy Theme, National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, University Hospitals Bristol NHS Foundation Trust and University of BristolBristol, UK
| | - V Llorenç
- Institut Clinic d'Oftalmologia, Hospital Clinic de Barcelona, University of BarcelonaBarcelona, Spain
| | - L Pelegrín
- Institut Clinic d'Oftalmologia, Hospital Clinic de Barcelona, University of BarcelonaBarcelona, Spain
| | - A Adán
- Institut Clinic d'Oftalmologia, Hospital Clinic de Barcelona, University of BarcelonaBarcelona, Spain
| |
Collapse
|