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Rehbein S, Hamel D, Visser M, Rauh R. Psoroptes ovis mange in sheep: Organ and tissue weights as indicators of the impact on organismal metabolism, lymphatic system and body composition. Vet Parasitol 2025; 337:110492. [PMID: 40359810 DOI: 10.1016/j.vetpar.2025.110492] [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: 04/17/2025] [Revised: 05/04/2025] [Accepted: 05/04/2025] [Indexed: 05/15/2025]
Abstract
Although adverse effects on the welfare, skin pathology and host immune responses of ovine psoroptic mange are well described, there is only limited research on the impact on the performance of the animals and underlying pathogenicity. To provide objective data on effects of the disease at organismal level, weights of organs and tissues of sheep included in a parasiticide study with groups of mange-infested, mange-infested and treated and non-infested animals were evaluated. For the study, 48 young Merino sheep were formed randomly into three equal-sized groups on sex and body weight - to develop mange without intervention ('infested'), to develop mange and treated 10 weeks after initial infestation ('infested-treated') or to be prevented from mange infestation - and infested twice with Psoroptes ovis mites. Mange developed in all 'infested' and 'infested-treated' animals and was maintained by the 'infested' animals throughout the study while the 'infested-treated' animals became mite-negative four weeks after treatment. No mites established on the pre-infestation-treated sheep which served as 'non-infested' controls for the analyses. At slaughter 16 weeks after the initial mite infestation, the 'infested' animals had significantly (p < 0.05) lower relative (organ/tissue weight divided by live weight) omental fat, perirenal fat and thymus weights and higher relative liver, adrenal glands, prescapular and precrural lymph nodes, gastrointestinal tract, metacarpus bone and skin weights than the 'non-infested' animals. They also had significantly lower relative thymus and gastrointestinal tracts weights and higher relative adrenal glands, prescapular lymph nodes, precrural lymph nodes and skin weights than the 'infested-treated' animals. The organ/tissue weights of the 'infested-treated' animals indicated that many changes observed in the 'infested' animals improved substantially within six weeks of treatment. Analysis of the organ weights demonstrates the impact of ovine psoroptic mange on protein and energy metabolism (lower adipose tissues and higher liver and adrenal glands weights as measures of increased demand for maintenance or chronic stress of the mite infestation) and defense mechanisms (lower thymus weight reflecting suppression from increased adrenal activity and higher weight of the peripheral lymph nodes as local reaction to the continuous exposure of antigens originating from the mite-induced exudative dermatitis). In addition, higher gastrointestinal tract plus skin weights and higher metacarpus bone weight leading to lower dressing percentage and higher carcass bone ratio, respectively, reflect the change in body composition and tissue disposition resulting in overall reduction in market value.
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Affiliation(s)
- Steffen Rehbein
- Boehringer Ingelheim Vetmedica GmbH, Kathrinenhof Research Center, Rohrdorf, Germany.
| | - Dietmar Hamel
- Boehringer Ingelheim Vetmedica GmbH, Kathrinenhof Research Center, Rohrdorf, Germany
| | - Martin Visser
- Boehringer Ingelheim Vetmedica GmbH, Kathrinenhof Research Center, Rohrdorf, Germany
| | - Renate Rauh
- Boehringer Ingelheim Vetmedica GmbH, Kathrinenhof Research Center, Rohrdorf, Germany
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2
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Mayer A, Voller J, Varga I. Enigmatic thymus: Variations in anatomical localisation of thymic tissue as an easily misdiagnosed congenital anomaly in surgical practice. World J Clin Cases 2024; 12:5646-5652. [PMID: 39247750 PMCID: PMC11263050 DOI: 10.12998/wjcc.v12.i25.5646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 04/24/2024] [Accepted: 05/27/2024] [Indexed: 07/12/2024] Open
Abstract
We point out the issue of differential diagnosis regarding the finding of ectopically localised thymic tissue (a thymic cyst) in the neck. Thymic tissue can be found anywhere along its developmental tract of descent, from the angle of the mandible to the upper mediastinum. Disruption of the thymic descent can result in ectopically/abnormally localised islets of accessory thymic tissue, which may undergo cystic changes, as described in a case report by Sun et al. This anatomical variation of the thymus may be clinically misinterpreted as a neoplasm or other congenital anomalies as a branchial cyst, lymphatic malformation or cystic hygroma. The present editorial focuses on the challenge of establishing a diagnosis of ectopically localised tissue of thymus often presented as a lateral cervical mass, especially in the case of cystic variation/degeneration of this thymic tissue. We summarise hypotheses on the origin of such congenital cervical thymic cysts from the point of view of evolutionary history and embryology. We also discuss lesser-known facts about the anatomy, histopathology and developmental biology of the thymus as one of the most enigmatic organs in the human body.
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Affiliation(s)
- Alexander Mayer
- Fourth Department of Surgery, Faculty of Medicine, Comenius University and University Hospital Bratislava, Bratislava 81372, Slovakia
| | - Jaroslav Voller
- Faculty of Health Care Studies, University of Western Bohemia, Pilsen 30100, Czech Republic
| | - Ivan Varga
- Institute of Histology and Embryology, Faculty of Medicine, Comenius University in Bratislava, Bratislava 81372, Slovakia
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3
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Radi ZA, Khan N. Pathophysiology and human cancer risk assessment of pharmaceutical-induced thymoma in carcinogenicity studies. Toxicol Appl Pharmacol 2023; 466:116471. [PMID: 36934859 DOI: 10.1016/j.taap.2023.116471] [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: 01/23/2023] [Revised: 03/11/2023] [Accepted: 03/13/2023] [Indexed: 03/19/2023]
Abstract
Thymoma, a tumor of thymic lymphocytes or thymic epithelial cells (TECs), is a common spontaneous tumor in Wistar Han rats, especially in females with up to 18% incidence in controls. In addition to sex, there are rat strain differences in background incidence of thymomas such as Sprague Dawley versus Wistar Han rats. Human thymomas are very rare and without clear differences in incidence between males and females. Immunomodulatory and anti-inflammatory pharmaceutical drug classes, including Janus kinase inhibitors, increase the incidence of benign thymoma in two-year rat carcinogenicity studies. Potential non-genotoxic mechanisms that might contribute to the pathogenesis of thymoma development in one sex (female) Wistar Han rats include: (1) hormonal differences, (2) high proliferation rate of TECs, (3) delayed physiologic thymic involution, and/or (4) significant level of immunosuppression at high doses of a pharmaceutical drug. Factors to consider in the human cancer risk assessment of pharmaceutical-induced thymoma are: the genotoxicity of the test article, sex and strain of rats, exposure safety margins, and pathophysiologic differences and similarities of thymoma between rats and humans. Totality of weight of evidence approach and available data suggest thymomas observed in carcinogenicity studies of pharmaceutical drugs are not relevant for human risk at clinically relevant therapeutic doses.
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Affiliation(s)
- Zaher A Radi
- Pfizer Worldwide Research, Development and Medical, Drug Safety R&D, 1 Portland Street, Cambridge, MA 02140, USA.
| | - Nasir Khan
- Pfizer Worldwide Research, Development and Medical, Drug Safety R&D, Eastern Point Road, Groton, CT 06340, USA
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4
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Activation of macrophages mediates dietary restriction-induced splenic involution. Life Sci 2022; 310:121068. [DOI: 10.1016/j.lfs.2022.121068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 09/29/2022] [Accepted: 10/07/2022] [Indexed: 11/09/2022]
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Flomenbaum MA, Warner RC. Morphologic Markers of Acute and Chronic Stress in Child Abuse. Am J Clin Pathol 2022; 157:823-835. [PMID: 34919642 PMCID: PMC9171574 DOI: 10.1093/ajcp/aqab204] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 11/05/2021] [Indexed: 12/04/2022] Open
Abstract
OBJECTIVES To elucidate pathologic markers of acute and chronic stress found but rarely reported in chronic child abuse. METHODS Autopsies of 3 cases of fatal child abuse with well-documented chronic maltreatment are reported, with an emphasis on the nontraumatic findings of acute and chronic stress. RESULTS Besides the overwhelming physical injuries, all 3 children and 1 additional case obtained for consultation had telogen effluvium, a form of alopecia well known to be associated with stress in adults and some children but never reported in chronic abuse. All 3 had the microscopic findings of markedly involuted thymus, a well-known marker of physiologic stress in children but only occasionally referred to in child abuse. All 3 also had microscopic findings of myocardial necrosis associated with supraphysiologic levels of catecholamine, a well-documented finding associated with stress but rarely reported in fatalities associated with child abuse. Two of the 3 children also had Anitschkow-like nuclear changes in cardiac tissue, markers associated with prior, nonischemic myocardial pathologies that may be associated with prior episodes of acute stress. CONCLUSIONS Pathologists are urged to explore these markers as supportive evidence in their own investigations of possible child abuse fatalities, especially when associated with stress.
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Affiliation(s)
| | - Ryan C Warner
- Larner College of Medicine, University of Vermont, Burlington, VT, USA
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6
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Chiang KC, Kalantar-Zadeh K, Gupta A. Thymic Dysfunction and Atrophy in COVID-19 Disease Complicated by Inflammation, Malnutrition and Cachexia. Nutr Health 2022; 28:199-206. [PMID: 35234100 PMCID: PMC8891908 DOI: 10.1177/02601060221083160] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Background: The current COVID-19 pandemic has put millions of people, especially children at risk of protein-energy malnutrition (PEM) by pushing them into poverty and disrupting the global food supply chain. The thymus is severely affected by nutritional deficiencies and is known as a barometer of malnutrition. Aim: The present commentary provides a novel perspective on the role of malnutrition-induced thymic dysfunction, involution and atrophy on the risk and severity of disease in children during the COVID-19 pandemic. Methods: A review of pertinent indexed literature including studies examining the effects of malnutrition on the thymus and immune dysfunction in COVID-19. Results: Protein-energy malnutrition and micronutrient deficiencies of zinc, iron and vitamin A are known to promote thymic dysfunction and thymocyte loss in children. Malnutrition- and infection-induced thymic atrophy and immune dysfunction may increase the risk of first, progression of COVID-19 disease to more severe forms including development of multisystem inflammatory syndrome in children (MIS-C); second, slow the recovery from COVID-19 disease; and third, increase the risk of other infections. Furthermore, malnourished children may be at increased risk of contracting SARS-CoV-2 infection due to socioeconomic conditions that promote viral transmission amongst contacts and create barriers to vaccination. Conclusion: National governments and international organizations including WHO, World Food Program, and UNICEF should institute measures to ensure provision of food and micronutrients for children at risk in order to limit the health impact of the ongoing COVID-19 pandemic.
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Affiliation(s)
| | - Kamyar Kalantar-Zadeh
- Division of Nephrology, Hypertension
and Kidney Transplantation and Department of Medicine,
University of
California Irvine (UCI) School of Medicine,
USA
| | - Ajay Gupta
- Charak
Foundation, Orange, CA, USA
- Division of Nephrology, Hypertension
and Kidney Transplantation and Department of Medicine,
University of
California Irvine (UCI) School of Medicine,
USA
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Cantürk Tan F, Yalçin B, Yay AH, Tan B, Yeğin K, Daşdağ S. Effects of pre and postnatal 2450 MHz continuous wave (CW) radiofrequency radiation on thymus: Four generation exposure. Electromagn Biol Med 2022; 41:315-324. [PMID: 35635232 DOI: 10.1080/15368378.2022.2079673] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
This study aims to investigate the effects of pre- and postnatal 2450 MHz continuous wave (CW) radiofrequency radiation (RFR) on the thymus of rats spanning four generations. Four groups; sham, irradiated female, irradiated male, irradiated male and female, each consisting of four rats (one male and three females), were created. During the experiment, rats in the exposure groups were whole-body exposed to 2450 MHz CW-RFR for 12 h/day. Irradiation started one month before the fertilization in the experimental group. When the offspring were two months old, four rats, one male and three female, were allocated for the second-generation study. The remaining offspring were sacrificed under general anesthesia, and their thymuses were removed. The same procedure was applied to the next generation. Two months after the second generation gave birth, third-generation rats were decapitated, and their thymuses were removed. In all groups, cortex, medulla and resident cells could be clearly distinguished in the second and third generations. No differences were observed between the control and two experimental groups, defined as irradiated female and irradiated male. In contrast, vascularization was observed in the thymus of the fourth-generation offspring of the group where both males and females were irradiated. The number of offspring and mass of all rats decreased in the third-generation group. Pre-and postnatal 2450 MHz continuous wave radiofrequency radiation exposure may potentially affect the thymus of future generations.
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Affiliation(s)
| | - Betül Yalçin
- Department of Histology and Embryology, Erciyes University, Kayseri, Turkey
| | - Arzu Hanım Yay
- Department of Histology and Embryology, Erciyes University, Kayseri, Turkey
| | - Burak Tan
- Department of Physiology, Erciyes University, Kayseri, Turkey
| | - Korkut Yeğin
- Department of Electrical and Electronics Engineering, Ege University, İzmir, Turkey
| | - Süleyman Daşdağ
- Department of Biophysics, İstanbul Medeniyet University, İstanbul, Turkey
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8
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Gulla S, Reddy MC, Reddy VC, Chitta S, Bhanoori M, Lomada D. Role of thymus in health and disease. Int Rev Immunol 2022; 42:347-363. [PMID: 35593192 DOI: 10.1080/08830185.2022.2064461] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/26/2022] [Accepted: 04/04/2022] [Indexed: 01/04/2023]
Abstract
The thymus is a primary lymphoid organ, essential for the development of T-cells that will protect from invading pathogens, immune disorders, and cancer. The thymus decreases in size and cellularity with age referred to as thymus involution or atrophy. This involution causes decreased T-cell development and decreased naive T-cell emigration to the periphery, increased proportion of memory T cells, and a restricted, altered T-cell receptor (TCR) repertoire. The changes in composition and function of the circulating T cell pool as a result of thymic involution led to increased susceptibility to infectious diseases including the recent COVID and a higher risk for autoimmune disorders and cancers. Thymic involution consisting of both structural and functional loss of the thymus has a deleterious effect on T cell development, T cell selection, and tolerance. The mechanisms which act on the structural (cortex and medulla) matrix of the thymus, the gradual accumulation of genetic mutations, and altered gene expressions may lead to immunosenescence as a result of thymus involution. Understanding the molecular mechanisms behind thymic involution is critical for identifying diagnostic biomarkers and targets for treatment help to develop strategies to mitigate thymic involution-associated complications. This review is focused on the consequences of thymic involution in infections, immune disorders, and diseases, identifying potential checkpoints and potential approaches to sustain or restore the function of the thymus particularly in elderly and immune-compromised individuals.
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Affiliation(s)
- Surendra Gulla
- Department of Biotechnology and Bioinformatics, Yogi Vemana University, Kadapa, Andhra Pradesh, India
| | - Madhava C Reddy
- Department of Biotechnology and Bioinformatics, Yogi Vemana University, Kadapa, Andhra Pradesh, India
| | - Vajra C Reddy
- Katuri Medical College and Hospital, Chinnakondrupadu, Guntur, India
| | | | - Manjula Bhanoori
- Department of Biochemistry, Osmania University, Hyderabad, Telangana State, India
| | - Dakshayani Lomada
- Department of Genetics and Genomics, Yogi Vemana University, Kadapa, Andhra Pradesh, India
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9
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Caspani G, Green M, Swann JR, Foster JA. Microbe-Immune Crosstalk: Evidence That T Cells Influence the Development of the Brain Metabolome. Int J Mol Sci 2022; 23:3259. [PMID: 35328680 PMCID: PMC8952415 DOI: 10.3390/ijms23063259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 02/06/2022] [Accepted: 03/10/2022] [Indexed: 11/21/2022] Open
Abstract
Cross-talk between the immune system and the brain is essential to neuronal development, neuronal excitability, neuroplasticity, and neurotransmission. Gut microbiota are essential to immune system development and immune function; hence, it is essential to consider more broadly the microbiota-immune-brain axis in neurodevelopment. The gut, brain, and microbial metabolomes obtained from C57Bl/6 and T-cell-deficient mice across four developmental timepoints (postnatal day 17, 24, 28, and 84) were studied by 1H NMR spectroscopy. 16S rRNA gene sequencing was performed on cecal and fecal samples. In the absence of T-cells, the developmental trajectory of the gut microbiota and of the host's metabolic profile was altered. The novel insights from this work include (1) the requirement of functional T-cells for the normal trajectory of microbiotal development and the metabolic maturation of the supra-organism, (2) the potential role for Muribaculaceae taxa in modulating the cecal availability of metabolites previously implicated with a role in the gut-brain axis in T-cell deficient mice, and (3) the impact of T-cell-deficiency on central levels of neuroactive metabolites.
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Affiliation(s)
- Giorgia Caspani
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London SW7 2AZ, UK; (G.C.); (J.R.S.)
| | - Miranda Green
- Department of Psychiatry & Behavioral Neurosciences, McMaster University, Hamilton, ON L8S 4L8, Canada;
| | - Jonathan R. Swann
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London SW7 2AZ, UK; (G.C.); (J.R.S.)
- School of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
| | - Jane A. Foster
- Department of Psychiatry & Behavioral Neurosciences, McMaster University, Hamilton, ON L8S 4L8, Canada;
- St. Joseph’s Healthcare, Hamilton, ON L8N 4A6, Canada
- Centre for Depression and Suicide Studies, St. Michael’s Hospital, Toronto, ON M5B 1A6, Canada
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10
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Hester AK, Semwal MK, Cepeda S, Xiao Y, Rueda M, Wimberly K, Venables T, Dileepan T, Kraig E, Griffith AV. Redox regulation of age-associated defects in generation and maintenance of T cell self-tolerance and immunity to foreign antigens. Cell Rep 2022; 38:110363. [PMID: 35172147 PMCID: PMC8898380 DOI: 10.1016/j.celrep.2022.110363] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 11/22/2021] [Accepted: 01/19/2022] [Indexed: 12/20/2022] Open
Abstract
Thymic atrophy reduces naive T cell production and contributes to increased susceptibility to viral infection with age. Expression of tissue-restricted antigen (TRA) genes also declines with age and has been thought to increase autoimmune disease susceptibility. We find that diminished expression of a model TRA gene in aged thymic stromal cells correlates with impaired clonal deletion of cognate T cells recognizing an autoantigen involved in atherosclerosis. Clonal deletion in the polyclonal thymocyte population is also perturbed. Distinct age-associated defects in the generation of antigen-specific T cells include a conspicuous decline in generation of T cells recognizing an immunodominant influenza epitope. Increased catalase activity delays thymic atrophy, and here, we show that it mitigates declining production of influenza-specific T cells and their frequency in lung after infection, but does not reverse declines in TRA expression or efficient negative selection. These results reveal important considerations for strategies to restore thymic function.
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Affiliation(s)
- Allison K Hester
- Department of Microbiology, Immunology and Molecular Genetics, University of Texas Long School of Medicine, UT Health San Antonio, San Antonio, TX 78229, USA
| | - Manpreet K Semwal
- Department of Microbiology, Immunology and Molecular Genetics, University of Texas Long School of Medicine, UT Health San Antonio, San Antonio, TX 78229, USA
| | - Sergio Cepeda
- Department of Microbiology, Immunology and Molecular Genetics, University of Texas Long School of Medicine, UT Health San Antonio, San Antonio, TX 78229, USA
| | - Yangming Xiao
- Department of Microbiology, Immunology and Molecular Genetics, University of Texas Long School of Medicine, UT Health San Antonio, San Antonio, TX 78229, USA
| | - Meghan Rueda
- Department of Microbiology, Immunology and Molecular Genetics, University of Texas Long School of Medicine, UT Health San Antonio, San Antonio, TX 78229, USA
| | - Kymberly Wimberly
- Department of Microbiology, Immunology and Molecular Genetics, University of Texas Long School of Medicine, UT Health San Antonio, San Antonio, TX 78229, USA
| | | | - Thamotharampillai Dileepan
- Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455, USA; Department of Microbiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Ellen Kraig
- Department of Cell Systems and Anatomy, University of Texas Long School of Medicine, UT Health San Antonio, San Antonio, TX 78229, USA
| | - Ann V Griffith
- Department of Microbiology, Immunology and Molecular Genetics, University of Texas Long School of Medicine, UT Health San Antonio, San Antonio, TX 78229, USA.
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11
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Knežević M, Ivanišević M, Kojović N, Starčević A. The effect of traumatic exposure on thymus weight level after dexamethasone application in rats. MEDICINSKI PODMLADAK 2022. [DOI: 10.5937/mp73-33448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
Abstract
Introduction: Thymus is the central lymphoid organ responsible for proper immune cell maturation, hence ensuring functional T cell repertoire. Stress induces elevated levels of hormones that profoundly alter immune response. Susceptibility to physiologically synthesised and exogenously applied glucocorticoids make thymus an ideal substrate for anatomical and morphological analysis. Aim: Our research aimed to investigate the impact of endogenous and exogenous glucocorticoids on thymus weight level. Material and methods: Experimental procedure was conducted on male Wistar rats, 12 in total, divided into 2 groups - control and experimental. Latter was exposed to two kinds of stressors. Acute stress included immobilization with exposure to the predator's odor. Chronic social stress included rotation of the animals held in pairs. On the 11th day of the experimental procedure, half of the experimental group received dexamethasone treatment (impact of endogenous + exogenous glucocorticoids) while the other half did not (impact of endogenous glucocorticoids). After the experiment, animals were sacrificed and their thymuses were obtained and measured. For statistical analysis, ANOVA was used to test differences between groups and LSD test for each group testing. Results: Results showed statistically significant differences between the thymus mass of different groups (F=4.336, p=0.048). The part of the experimental group that received dexamethasone had a smaller thymus weight level compared to the part of the experimental group that received no treatment (p=0.024). No statistically relevant results were obtained after comparing thymus masses from impact of endogenous glucocorticoids and control group (p>0.05). Conclusion: Exogenous glucocorticoids induce morphological changes in thymus which are observed in decreased weight level. Stress induced thymus apoptosis, but it was not sufficient to lead to decrease in thymic mass. Our further experiments will put emphasis on understanding of morphological and anatomical changes caused by stress.
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12
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Paiola M, Moreira C, Hétru J, Duflot A, Pinto PIS, Scapigliati G, Knigge T, Monsinjon T. Prepubertal gonad investment modulates thymus function: evidence in a teleost fish. J Exp Biol 2021; 224:238091. [PMID: 33789987 DOI: 10.1242/jeb.238576] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 01/20/2021] [Indexed: 12/12/2022]
Abstract
Thymus plasticity following gonadectomy or sex hormone replacement has long since exemplified sex hormone effects on the immune system in mammals and, to a lesser extent, in 'lower vertebrates', including amphibians and fish. Nevertheless, the underlying physiological significances as well as the ontogenetic establishment of this crosstalk remain largely unknown. Here, we used a teleost fish, the European sea bass, Dicentrarchus labrax, to investigate: (1) whether the regulation of thymus plasticity relies on resource trade-off with somatic growth and reproductive investment and (2) if the gonad-thymus interaction takes place during gonadal differentiation and development. Because gonadal development and, supposedly, thymus function in sea bass depend on environmental changes associated with the winter season, we evaluated thymus changes (foxn1 expression, and thymocyte and T cell content) in juvenile D. labrax raised for 1 year under either constant or fluctuating photoperiod and temperature. Importantly, in both conditions, intensive gonadal development following sex differentiation coincided with a halt of thymus growth, while somatic growth continued. To the best of our knowledge, this is the first study showing that gonadal development during prepuberty regulates thymus plasticity. This finding may provide an explanation for the initiation of the thymus involution related to ageing in mammals. Comparing fixed and variable environmental conditions, our work also demonstrates that the extent of the effects on the thymus, which are related to reproduction, depend on ecophysiological conditions, rather than being directly related to sexual maturity and sex hormone levels.
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Affiliation(s)
- Matthieu Paiola
- Normandy University, FR CNRS 3730 SCALE, UMR-I 02 INERIS-URCA-ULH Environmental Stress and Aquatic Biomonitoring (SEBIO), University of Le Havre Normandy, 76600 Le Havre, France
| | - Catarina Moreira
- Normandy University, FR CNRS 3730 SCALE, UMR-I 02 INERIS-URCA-ULH Environmental Stress and Aquatic Biomonitoring (SEBIO), University of Le Havre Normandy, 76600 Le Havre, France
| | - Julie Hétru
- Normandy University, FR CNRS 3730 SCALE, UMR-I 02 INERIS-URCA-ULH Environmental Stress and Aquatic Biomonitoring (SEBIO), University of Le Havre Normandy, 76600 Le Havre, France
| | - Aurélie Duflot
- Normandy University, FR CNRS 3730 SCALE, UMR-I 02 INERIS-URCA-ULH Environmental Stress and Aquatic Biomonitoring (SEBIO), University of Le Havre Normandy, 76600 Le Havre, France
| | - Patricia I S Pinto
- Laboratory of Comparative Endocrinology and Integrative Biology, CCMAR - Centre of Marine Sciences, University of Algarve, 8005-139 Faro, Portugal
| | - Giuseppe Scapigliati
- Department for Innovation in Biological, Agro-food and Forest Systems, Tuscia University, 01100 Viterbo, Italy
| | - Thomas Knigge
- Normandy University, FR CNRS 3730 SCALE, UMR-I 02 INERIS-URCA-ULH Environmental Stress and Aquatic Biomonitoring (SEBIO), University of Le Havre Normandy, 76600 Le Havre, France
| | - Tiphaine Monsinjon
- Normandy University, FR CNRS 3730 SCALE, UMR-I 02 INERIS-URCA-ULH Environmental Stress and Aquatic Biomonitoring (SEBIO), University of Le Havre Normandy, 76600 Le Havre, France
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13
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Larnkjær A, Michaelsen KF, Rytter MJH, Mølgaard C, Laursen RP. Effect of probiotics on thymus size and markers of infection in late infancy: a randomized controlled trial. Pediatr Res 2021; 89:563-568. [PMID: 32305995 DOI: 10.1038/s41390-020-0895-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 03/24/2020] [Accepted: 03/30/2020] [Indexed: 11/09/2022]
Abstract
BACKGROUND Probiotics are known to stimulate the immune system but the effect on thymus size in late infancy is unknown. We examined the effect of probiotics on thymus size and C-reactive protein (CRP) in healthy Danish infants starting daycare. We further examined associations between thymus size, CRP and recent infections. METHODS The study included 186 children randomized to a combination of Lactobacillus rhamnosus, LGG® and Bifidobacterium animalis spp. lactis, BB-12® or placebo for 6 months. Thymus size, assessed as thymus index (TI) and thymus weight index (TWI), was measured by ultrasound at baseline and at endpoint. Blood samples were drawn to measure CRP. Infections were parent-reported. RESULTS There was no significant difference in thymus size between the probiotic group and placebo (p ≥ 0.248) but TWI tended to be higher in the probiotic group corresponding to 5% higher than placebo (p = 0.068) in an adjusted model. There was no effect of probiotics on CRP (p = 0.331). At the endpoint, thymus size was inversely associated with CRP (p ≤ 0.040), diarrhea (p ≤ 0.050), and TI was also associated with the absence from daycare due to respiratory or gastrointestinal infections (p = 0.010). CONCLUSION The probiotic intervention had no effect on thymus size or CRP in Danish children at the age of starting daycare. IMPACT Overall there was no effect on thymus size of a combination of Lactobacillus rhamnosus, LGG® and Bifidobacterium animalis spp. lactis, BB-12® administered to Danish children starting daycare. This study examines the effect of probiotics on thymus size in healthy children when they start daycare thus exposed for infections while their immune system is still developing. This has to our knowledge not been described before. We found no significant difference in thymus size between the probiotic and placebo groups, but for thymus weight index, there was a trend. This should be investigated further in studies designed for this as primary outcome.
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Affiliation(s)
- Anni Larnkjær
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
| | - Kim F Michaelsen
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Maren J H Rytter
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.,Department of Pediatrics, Slagelse Hospital, Slagelse, Denmark
| | - Christian Mølgaard
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Rikke P Laursen
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
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14
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Razali N, Hohjoh H, Inazumi T, Maharjan BD, Nakagawa K, Konishi M, Sugimoto Y, Hasegawa H. Induced Prostanoid Synthesis Regulates the Balance between Th1- and Th2-Producing Inflammatory Cytokines in the Thymus of Diet-Restricted Mice. Biol Pharm Bull 2020; 43:649-662. [PMID: 32238706 DOI: 10.1248/bpb.b19-00838] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Multiple external and internal factors have been reported to induce thymic involution. Involution involves dramatic reduction in size and function of the thymus, leading to various immunodeficiency-related disorders. Therefore, clarifying and manipulating molecular mechanisms governing thymic involution are clinically important, although only a few studies have dealt with this issue. In the present study, we investigated the molecular mechanisms underlying thymic involution using a murine acute diet-restriction model. Gene expression analyses indicated that the expression of T helper 1 (Th1)-producing cytokines, namely interferon-γ and interleukin (IL)-2, was down-regulated, while that of Th2-producing IL-5, IL-6, IL-10 and IL-13 was up-regulated, suggesting that acute diet-restriction regulates the polarization of naïve T cells to a Th2-like phenotype during thymic involution. mRNAs for prostanoid biosynthetic enzymes were up-regulated by acute diet-restriction. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses detected the increased production of prostanoids, particularly prostaglandin D2 and thromboxane B2, a metabolite of thromboxane A2, in the diet-restricted thymus. Administration of non-steroidal anti-inflammatory drugs, namely aspirin and etodolac, to inhibit prostanoid synthesis suppressed the biased expression of Th1- and Th2-cytokines as well as molecular markers of Th1 and Th2 cells in the diet-restricted thymus, without affecting the reduction of thymus size. In vitro stimulation of thymocytes with phorbol myristate acetate (PMA)/ionomycin confirmed the polarization of thymocytes from diet-restricted mice toward Th2 cells. These results indicated that the induced production of prostanoids during diet-restriction-induced thymic involution is involved in the polarization of naïve T cells in the thymus.
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Affiliation(s)
| | - Hirofumi Hohjoh
- Laboratory of Hygienic Sciences, Kobe Pharmaceutical University
| | - Tomoaki Inazumi
- Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University
| | | | - Kimie Nakagawa
- Laboratory of Hygienic Sciences, Kobe Pharmaceutical University
| | | | - Yukihiko Sugimoto
- Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University
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15
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Tong QY, Zhang JC, Guo JL, Li Y, Yao LY, Wang X, Yang YG, Sun LG. Human Thymic Involution and Aging in Humanized Mice. Front Immunol 2020; 11:1399. [PMID: 32733465 PMCID: PMC7358581 DOI: 10.3389/fimmu.2020.01399] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 06/01/2020] [Indexed: 12/14/2022] Open
Abstract
Thymic involution is an important factor leading to the aging of the immune system. Most of what we know regarding thymic aging comes from mouse models, and the nature of the thymic aging process in humans remains largely unexplored due to the lack of a model system that permits longitudinal studies of human thymic involution. In this study, we sought to explore the potential to examine human thymic involution in humanized mice, constructed by transplantation of fetal human thymus and CD34+ hematopoietic stem/progenitor cells into immunodeficient mice. In these humanized mice, the human thymic graft first underwent acute recoverable involution caused presumably by transplantation stress, followed by an age-related chronic form of involution. Although both the early recoverable and later age-related thymic involution were associated with a decrease in thymic epithelial cells and recent thymic emigrants, only the latter was associated with an increase in adipose tissue mass in the thymus. Furthermore, human thymic grafts showed a dramatic reduction in FOXN1 and AIRE expression by 10 weeks post-transplantation. This study indicates that human thymus retains its intrinsic mechanisms of aging and susceptibility to stress-induced involution when transplanted into immunodeficient mice, offering a potentially useful in vivo model to study human thymic involution and to test therapeutic interventions.
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Affiliation(s)
- Qing-Yue Tong
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China.,National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, China
| | - Jue-Chao Zhang
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China.,National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, China
| | - Jing-Long Guo
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China.,National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, China
| | - Yang Li
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China.,National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, China
| | - Li-Yu Yao
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China
| | - Xue Wang
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China.,National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, China
| | - Yong-Guang Yang
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China.,National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, China.,International Center of Future Science, Jilin University, Changchun, China
| | - Li-Guang Sun
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China.,National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, China
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16
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Gong B, Wang X, Li B, Li Y, Lu R, Zhang K, Li B, Ma Y, Li Y. miR-205-5p inhibits thymic epithelial cell proliferation via FA2H-TFAP2A feedback regulation in age-associated thymus involution. Mol Immunol 2020; 122:173-185. [PMID: 32371259 DOI: 10.1016/j.molimm.2020.04.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 03/02/2020] [Accepted: 04/13/2020] [Indexed: 12/28/2022]
Abstract
Thymic epithelial cells (TECs) are essential regulators of T cell development and selection. microRNAs (miRNAs) play critical roles in regulating TECs proliferation during thymus involution. miR-205-5p is highly expressed in TECs and increases with age. However, the function and potential mechanism of miR-205-5p in TECs are not clear. miRNA expression was profiled using TECs from male and female mice at 1 and 3 months old. A total of 325 differentially expressed miRNAs (DEMs) were detected at different ages in two sexes. 24 of the DEMs had the same trend between males and females. Among them, miR-205-5p had the highest fold change. Our results showed that the expression of miR-205-5p was dramatically increased in TECs from 1 to 9 months old mice. miR-205-5p mimic inhibited TECs proliferation. Moreover, we confirmed that Fa2h was the direct target gene of miR-205-5p and FA2H was significantly decreased in TECs with increased expression of miR-205-5p. Silencing of Fa2h inhibited TECs proliferation. Furthermore, we found that the expression of Tfap2a could be promoted by FA2H and that TFAP2A could interact with miR-205-5p in TECs. Overall, miR-205-5p is an important regulator of TECs proliferation and regulates age-associated thymus involution via the miR-205-5p-FA2H-TFAP2A feedback regulatory circuit. miR-205-5p might act as a potential biomarker in TECs for age-related thymus involution.
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Affiliation(s)
- Bishuang Gong
- College of Veterinary Medicine, South China Agricultural University, China
| | - Xintong Wang
- College of Veterinary Medicine, South China Agricultural University, China
| | - Boning Li
- the Department of Cardiology, Shenzhen Children's Hospital, Shenzhen, China
| | - Ying Li
- College of Veterinary Medicine, South China Agricultural University, China
| | - Rui Lu
- College of Veterinary Medicine, South China Agricultural University, China
| | - Kaizhao Zhang
- College of Veterinary Medicine, South China Agricultural University, China
| | - Bingxin Li
- College of Veterinary Medicine, South China Agricultural University, China
| | - Yongjiang Ma
- College of Veterinary Medicine, South China Agricultural University, China.
| | - Yugu Li
- College of Veterinary Medicine, South China Agricultural University, China.
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17
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Nacka-Aleksić M, Pilipović I, Kotur-Stevuljević J, Petrović R, Sopta J, Leposavić G. Sexual dimorphism in rat thymic involution: a correlation with thymic oxidative status and inflammation. Biogerontology 2019; 20:545-569. [DOI: 10.1007/s10522-019-09816-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Accepted: 05/12/2019] [Indexed: 01/05/2023]
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18
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Gavia-García G, Rosas-Trejo MDLÁ, García-Mendoza E, Toledo-Pérez R, Königsberg M, Nájera-Medina O, Luna-López A, González-Torres MC. t-BHQ Protects Against Oxidative Damage and Maintains the Antioxidant Response in Malnourished Rats. Dose Response 2018; 16:1559325818796304. [PMID: 30263018 PMCID: PMC6156215 DOI: 10.1177/1559325818796304] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 07/19/2018] [Accepted: 07/24/2018] [Indexed: 12/31/2022] Open
Abstract
Objective: Tert-butylhydroquinone (t-BHQ) protective effect against oxidative damage in thymus from malnourished pops-rats was evaluated. Methods: Malnutrition in pops-rats was induced during the lactation period and first-, second-, and third-degree malnourished rats were studied (MN1, MN2, and MN3). To determine t-BHQ protective effect, lipid peroxidation (LPx) was assessed, as well as the carbonyl content. The reduced glutathione and glutathione disulfide content were determined and antioxidant enzyme activities were measured. Results: Oxidative protein damage, LPx, and Nuclear Factor-κB (NF-κB) content, increased in the MN2 and MN3 compared to well-nourished rats, associated with lower protein content and antioxidant activity of superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase. Tert-butylhydroquinone treatment induced a protective effect against lipids and proteins oxidative damage, as well as decrease in NF-κB in MN rats and restored the antioxidant mechanisms, mostly GPx and SOD. No differences were found between male and female animals. Conclusions: Results show that higher body weight deficit leads to increased oxidative damage and probably inflammation, attributable to alterations in antioxidant mechanisms. These effects were reversed by the t-BHQ-treatment, which restores the antioxidant response. Our findings suggest that t-BHQ could be an interesting pharmacological intervention, but it needs to be studied further.
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Affiliation(s)
- Graciela Gavia-García
- Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, CDMX, Mexico.,Posgrado en Biología Experimental, Universidad Autónoma Metropolitana-Iztapalapa, CDMX, Mexico
| | - María de Los Ángeles Rosas-Trejo
- Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, CDMX, Mexico.,Posgrado en Biología Experimental, Universidad Autónoma Metropolitana-Iztapalapa, CDMX, Mexico
| | - Eduardo García-Mendoza
- Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, CDMX, Mexico
| | - Rafael Toledo-Pérez
- Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, CDMX, Mexico.,Posgrado en Biología Experimental, Universidad Autónoma Metropolitana-Iztapalapa, CDMX, Mexico
| | - Mina Königsberg
- Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, CDMX, Mexico
| | - Oralia Nájera-Medina
- Departamento de Atención a la Salud, Universidad Autónoma Metropolitana-Xochimilco, CDMX, Mexico
| | - Armando Luna-López
- Departamento de Investigación Básica, Instituto Nacional de Geriatría, CDMX, Mexico
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19
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Clark SM, Vaughn CN, Soroka JA, Li X, Tonelli LH. Neonatal adoptive transfer of lymphocytes rescues social behaviour during adolescence in immune-deficient mice. Eur J Neurosci 2018; 47:968-978. [PMID: 29430738 DOI: 10.1111/ejn.13860] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Revised: 02/02/2018] [Accepted: 02/05/2018] [Indexed: 12/23/2022]
Abstract
Accumulating evidence has shown that lymphocytes modulate behaviour and cognition by direct interactions with the central nervous system. Studies have shown that reconstitution by adoptive transfer of lymphocytes from wild type into immune-deficient mice restores a number of neurobehavioural deficits observed in these models. Moreover, it has been shown that these effects are mostly mediated by T lymphocytes. Studies of adoptive transfer thus far have employed adult mice, but whether lymphocytes may also modulate behaviour during development remains unknown. In this study, neonate lymphocyte-deficient Rag2-/- mice were reconstituted within 48 hours after birth with lymphoid cells from transgenic donors expressing green fluorescent protein, allowing for their identification in various tissues in recipient mice while retaining all functional aspects. Adolescent Rag2-/- and reconstituted Rag2-/- along with C57BL/6J wild-type mice underwent a series of behavioural tests, including open field, social interaction and sucrose preference tests. At 12 weeks, they were evaluated in the Morris water maze (MWM). Reconstituted mice showed changes in almost all aspects of behaviour that were assessed, with a remarkable complete rescue of impaired social behaviour displayed by adolescent Rag2-/- mice. Consistent with previous reports in adult mice, neonatal reconstitution in Rag2-/- mice restored spatial memory in the MWM. The presence of donor lymphocytes in the brain of neonatally reconstituted Rag2-/- mice was confirmed at various developmental points. These findings provide evidence that lymphocytes colonize the brain during post-natal development and modulate behaviour across the lifespan supporting a role for adaptive immunity during brain maturation.
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Affiliation(s)
- Sarah M Clark
- Laboratory of Behavioral Neuroimmunology, Department of Psychiatry, University of Maryland School of Medicine, 685 W. Baltimore Street, MSTF Building Room 934E, Baltimore, MD, 21201, USA.,Research and Development Service, Department of Veterans Affairs, VA Maryland Health Care System, Baltimore, MD, USA
| | - Chloe N Vaughn
- Laboratory of Behavioral Neuroimmunology, Department of Psychiatry, University of Maryland School of Medicine, 685 W. Baltimore Street, MSTF Building Room 934E, Baltimore, MD, 21201, USA
| | - Jennifer A Soroka
- Laboratory of Behavioral Neuroimmunology, Department of Psychiatry, University of Maryland School of Medicine, 685 W. Baltimore Street, MSTF Building Room 934E, Baltimore, MD, 21201, USA
| | - Xin Li
- Laboratory of Behavioral Neuroimmunology, Department of Psychiatry, University of Maryland School of Medicine, 685 W. Baltimore Street, MSTF Building Room 934E, Baltimore, MD, 21201, USA
| | - Leonardo H Tonelli
- Laboratory of Behavioral Neuroimmunology, Department of Psychiatry, University of Maryland School of Medicine, 685 W. Baltimore Street, MSTF Building Room 934E, Baltimore, MD, 21201, USA.,Research and Development Service, Department of Veterans Affairs, VA Maryland Health Care System, Baltimore, MD, USA
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20
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Human Milk and Allergic Diseases: An Unsolved Puzzle. Nutrients 2017; 9:nu9080894. [PMID: 28817095 PMCID: PMC5579687 DOI: 10.3390/nu9080894] [Citation(s) in RCA: 89] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Revised: 08/01/2017] [Accepted: 08/01/2017] [Indexed: 02/07/2023] Open
Abstract
There is conflicting evidence on the protective role of breastfeeding in relation to the development of allergic sensitisation and allergic disease. Studies vary in methodology and definition of outcomes, which lead to considerable heterogeneity. Human milk composition varies both within and between individuals, which may partially explain conflicting data. It is known that human milk composition is very complex and contains variable levels of immune active molecules, oligosaccharides, metabolites, vitamins and other nutrients and microbial content. Existing evidence suggests that modulation of human breast milk composition has potential for preventing allergic diseases in early life. In this review, we discuss associations between breastfeeding/human milk composition and allergy development.
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21
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Birk NM, Nissen TN, Zingmark V, Kjærgaard J, Thøstesen LM, Kofoed PE, Stensballe LG, Andersen A, Nielsen SD, Benn CS, Pryds O, Jeppesen DL. Bacillus Calmette-Guérin vaccination, thymic size, and thymic output in healthy newborns. Pediatr Res 2017; 81:873-880. [PMID: 28157835 PMCID: PMC5605675 DOI: 10.1038/pr.2017.27] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Accepted: 11/30/2016] [Indexed: 12/03/2022]
Abstract
BACKGROUND The Bacillus Calmette-Guérin vaccine (BCG) has been associated with beneficial nonspecific effects on infant health. We aimed to examine the effect of BCG at birth on thymic size and the associations between thymic output, circulating lymphocytes, risk of infection, and thymic size. METHODS In infants randomized to BCG or no BCG, thymic index (TI), and thymic/weight index (TWI) were measured by ultrasound at birth and at the age of 3 mo. T cell subpopulations including CD4+ T cells, CD8+ T cells, and recent thymic emigrants (RTEs) were assessed by flow cytometry. Infections up to age 3 mo were parent-reported. RESULTS BCG vaccination did not affect thymic size at age 3 mo, measured as TI. At birth, the number of lymphocytes, CD4+ T cells, CD8+ T cells, and RTEs were positively associated with TI and TWI. Furthermore, a reduced risk of infections up to age 3 mo was associated with a large thymic size at birth. CONCLUSION We found no effect of BCG vaccination on thymic size. The positive association between thymic output, lymphocytes, reduced risk of infections, and TI/TWI suggests that assessment of TI/TWI by ultrasound may be a predictor of the immunological capacity in the newborn.
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Affiliation(s)
- Nina Marie Birk
- Department of Pediatrics, Copenhagen University Hospital, Hvidovre, Denmark,()
| | | | - Vera Zingmark
- Department of Pediatrics, Copenhagen University Hospital, Hvidovre, Denmark
| | - Jesper Kjærgaard
- The Department of Pediatrics and Adolescent Medicine, Juliane Marie Centret, Rigshospitalet, Copenhagen University Hospital, Denmark
| | | | | | - Lone Graff Stensballe
- The Department of Pediatrics and Adolescent Medicine, Juliane Marie Centret, Rigshospitalet, Copenhagen University Hospital, Denmark
| | - Andreas Andersen
- Research Center for Vitamins and Vaccines (CVIVA), Statens Serum Institut, Copenhagen, Denmark
| | - Susanne Dam Nielsen
- Department of infectious diseases, Rigshospitalet, Copenhagen University Hospital, Denmark
| | - Christine Stabell Benn
- Research Center for Vitamins and Vaccines (CVIVA), Statens Serum Institut, Copenhagen, Denmark
| | - Ole Pryds
- Department of Pediatrics, Copenhagen University Hospital, Hvidovre, Denmark
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Abstract
This review aims to address the mechanisms of compromised immune tolerance contributing to the development and maintenance of Alopecia Areata (AA). Our goal is to also highlight future treatment opportunities and therapeutics that will safely and efficiently restore hair growth and maintain patients in remission. AA is a presumptive autoimmune disorder that coincides and genetically clusters to several other autoimmune diseases. In this review, we pay attention to the learnings from the mechanistic research and drug development in these other autoimmune conditions. Interestingly, most of these diseases have been linked to compromised central and peripheral tolerance, and increased intestinal inflammation with enhanced gut permeability. Break of tolerance and priming of the autoreactive T-cells to attack antigenic epitopes in the hair follicle most likely requires several steps which include escape from negative selection and compromised peripheral tolerance. Local skin-related changes are also of importance due to the patchy manifestation of the skin areas with loss of hair, particularly in the early disease. Here, we discuss the defective mechanisms of tolerance, both central and peripheral, and hypothesize that the disease is driven by areas of tolerance break, and that these could be targeted for successful therapeutic interventions.
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23
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Shilovsky GA, Feniouk BA, Skulachev VP. Thymic Involution in Ontogenesis: Role in Aging Program. BIOCHEMISTRY (MOSCOW) 2016; 80:1629-31. [PMID: 26638690 DOI: 10.1134/s0006297915120135] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
In most mammals, involution of the thymus occurs with aging. In this issue of Biochemistry (Moscow) devoted to phenoptosis, A. V. Khalyavkin considered involution of a thymus as an example of the program of development and further--of proliferation control and prevention of tumor growth. However, in animals devoid of a thymus (e.g. naked mice), stimulation of carcinogenesis, but not its prevention was observed. In this report, we focus on the involution of the thymus as a manifestation of the aging program (slow phenoptosis). We also consider methods of reversal/arrest of this program at different levels of organization of life (cell, tissue, and organism) including surgical manipulations, hormonal effects, genetic techniques, as well as the use of conventional and mitochondria-targeted antioxidants. We conclude that programmed aging (at least on the model of age-dependent thymic atrophy) can be inhibited.
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Affiliation(s)
- G A Shilovsky
- Lomonosov Moscow State University, Belozersky Institute of Physico-Chemical Biology, Moscow, 119991, Russia.
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24
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Rehbein S, Visser M, Meyer M, Lindner T. Ivermectin treatment of bovine psoroptic mange: effects on serum chemistry, hematology, organ weights, and leather quality. Parasitol Res 2015; 115:1519-28. [DOI: 10.1007/s00436-015-4885-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2015] [Accepted: 12/11/2015] [Indexed: 11/30/2022]
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25
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Mehta S. Assessment of thymus size in healthy term neonates using sonography - A study from tertiary care hospital of Central India. J Neonatal Perinatal Med 2015; 8:143-7. [PMID: 26410439 DOI: 10.3233/npm-15814067] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
OBJECTIVE A cross-sectional study was done to assess the size of thymus in term healthy infants using sonography and to assess its variation in size, shape, location, echogenicity and echotexture for both male and female reference population. MATERIAL AND METHODS A total of 250 term healthy neonates of either sex were subjected to thymic sonography. The shape, size in maximal anteroposterior, longitudinal, and transverse dimensions of both right and left lobes of thymus was evaluated. Their echotexture and echogenicity were determined and standards for reference population were calculated. The results were statistically evaluated. RESULTS According to the shape; the thymus was quadrilateral in 156 neonates (62%), round in 37 (15%), bilobate in 32 (13%), and crescent shaped in 25 (10%) in transverse scan. According to the echo texture, the thymus echogenicity was homogeneous and almost similar or slightly less to that of the liver and spleen in most cases 200 [80%] and was coarse in 50 (20%). In all subjects, the echogenicity of the thymus was less than that of the thyroid gland. Variations in location of the thymus were found in 70 (28%) neonates. The range of mean AP diameter was 0.39-2.36 cm (mean 1.43 ± 0.3), that of transverse 1.4 - 4.3 cm (mean 2.16 ± 0.54) and that of thymic index 1.2-5.1 cm2 (mean 2.98 ± 0.64). CONCLUSIONS A normative range was calculated for standard population, which can be used as a reference for comparing thymus size for both normal and diseased neonates for various immunological diseases.
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Metabolic Damage and Premature Thymus Aging Caused by Stromal Catalase Deficiency. Cell Rep 2015; 12:1071-9. [PMID: 26257169 PMCID: PMC4797338 DOI: 10.1016/j.celrep.2015.07.008] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Revised: 06/25/2015] [Accepted: 07/01/2015] [Indexed: 11/30/2022] Open
Abstract
T lymphocytes are essential mediators of immunity that are produced by the thymus in proportion to its size. The thymus atrophies rapidly with age, resulting in progressive diminution of new T cell production. This decreased output is compensated by duplication of existing T cells, but it results in gradual dominance by memory T cells and decreased ability to respond to new pathogens or vaccines. Here, we show that accelerated and irreversible thymic atrophy results from stromal deficiency in the reducing enzyme catalase, leading to increased damage by hydrogen peroxide generated by aerobic metabolism. Genetic complementation of catalase in stromal cells diminished atrophy, as did chemical antioxidants, thus providing a mechanistic link between antioxidants, metabolism, and normal immune function. We propose that irreversible thymic atrophy represents a conventional aging process that is accelerated by stromal catalase deficiency in the context of an intensely anabolic (lymphoid) environment.
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Rilett KC, Friedel M, Ellegood J, MacKenzie RN, Lerch JP, Foster JA. Loss of T cells influences sex differences in behavior and brain structure. Brain Behav Immun 2015; 46:249-60. [PMID: 25725160 DOI: 10.1016/j.bbi.2015.02.016] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Revised: 02/10/2015] [Accepted: 02/18/2015] [Indexed: 12/13/2022] Open
Abstract
Clinical and animal studies demonstrate that immune-brain communication influences behavior and brain function. Mice lacking T cell receptor β and δ chains were tested in the elevated plus maze, open field, and light-dark test and showed reduced anxiety-like behavior compared to wild type. Interestingly sex differences were observed in the behavioural phenotype of TCRβ-/-δ- mice. Specifically, female TCRβ-/-δ- mice spent more time in the light chamber compared to wild type females, whereas male TCRβ-/-δ- spent more time in the center of the open field compared to wild type males. In addition, TCRβ-/-δ- mice did not show sex differences in activity-related behaviors observed in WT mice. Ex vivo brain imaging (7 Tesla MRI) revealed volume changes in hippocampus, hypothalamus, amygdala, periaqueductal gray, and dorsal raphe and other brain regions between wild type and T cell receptor knockout mice. There was also a loss of sexual dimorphism in brain volume in the bed nucleus of the stria terminalis, normally the most sexually dimorphic region in the brain, in immune compromised mice. These data demonstrate the presence of T cells is important in the development of sex differences in CNS circuitry and behavior.
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Affiliation(s)
- Kelly C Rilett
- Neurosci. Grad Program, McMaster Univ., Hamilton, ON, Canada
| | - Miriam Friedel
- Mouse Imaging Ctr., Hosp. for Sick Children, Toronto, ON, Canada
| | - Jacob Ellegood
- Mouse Imaging Ctr., Hosp. for Sick Children, Toronto, ON, Canada
| | - Robyn N MacKenzie
- Psychiatry & Behavioural Neurosciences, McMaster Univ., Hamilton, ON, Canada
| | - Jason P Lerch
- Mouse Imaging Ctr., Hosp. for Sick Children, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Jane A Foster
- Psychiatry & Behavioural Neurosciences, McMaster Univ., Hamilton, ON, Canada; Brain-Body Institute, St. Joseph's Healthcare, Hamilton, ON, Canada.
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Misa-Agustiño M, Leiro-Vidal J, Gomez-Amoza J, Jorge-Mora M, Jorge-Barreiro F, Salas-Sánchez A, Ares-Pena F, López-Martín E. EMF radiation at 2450MHz triggers changes in the morphology and expression of heat shock proteins and glucocorticoid receptors in rat thymus. Life Sci 2015; 127:1-11. [DOI: 10.1016/j.lfs.2015.01.027] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Revised: 12/29/2014] [Accepted: 01/23/2015] [Indexed: 01/12/2023]
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Moeller M, Hirose M, Mueller S, Roolf C, Baltrusch S, Ibrahim S, Junghanss C, Wolkenhauer O, Jaster R, Köhling R, Kunz M, Tiedge M, Schofield PN, Fuellen G. Inbred mouse strains reveal biomarkers that are pro-longevity, antilongevity or role switching. Aging Cell 2014; 13:729-38. [PMID: 24862908 PMCID: PMC4326954 DOI: 10.1111/acel.12226] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/25/2014] [Indexed: 01/23/2023] Open
Abstract
Traditionally, biomarkers of aging are classified as either pro-longevity or antilongevity. Using longitudinal data sets from the large-scale inbred mouse strain study at the Jackson Laboratory Nathan Shock Center, we describe a protocol to identify two kinds of biomarkers: those with prognostic implication for lifespan and those with longitudinal evidence. Our protocol also identifies biomarkers for which, at first sight, there is conflicting evidence. Conflict resolution is possible by postulating a role switch. In these cases, high biomarker values are, for example, antilongevity in early life and pro-longevity in later life. Role-switching biomarkers correspond to features that must, for example, be minimized early, but maximized later, for optimal longevity. The clear-cut pro-longevity biomarkers we found reflect anti-inflammatory, anti-immunosenescent or anti-anaemic mechanisms, whereas clear-cut antilongevity biomarkers reflect inflammatory mechanisms. Many highly significant blood biomarkers relate to immune system features, indicating a shift from adaptive to innate processes, whereas most role-switching biomarkers relate to blood serum features and whole-body phenotypes. Our biomarker classification approach is applicable to any combination of longitudinal studies with life expectancy data, and it provides insights beyond a simplified scheme of biomarkers for long or short lifespan.
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Affiliation(s)
- Mark Moeller
- Institute for Biostatistics and Informatics in Medicine und Ageing Research Rostock University Medical Center Rostock Germany
| | - Misa Hirose
- Department of Dermatology University of Lübeck Lübeck Germany
| | - Sarah Mueller
- Division of Gastroenterology Department of Medicine II Rostock University Medical Center Rostock Germany
| | - Catrin Roolf
- Department of Hematology/Oncology/Palliative Medicine Rostock University Medical Center Rostock Germany
| | - Simone Baltrusch
- Institute of Medical Biochemistry and Molecular Biology Rostock University Medical Center Rostock Germany
| | - Saleh Ibrahim
- Department of Dermatology University of Lübeck Lübeck Germany
| | - Christian Junghanss
- Department of Hematology/Oncology/Palliative Medicine Rostock University Medical Center Rostock Germany
| | - Olaf Wolkenhauer
- Department of Systems Biology and Bioinformatics University of Rostock Rostock Germany
| | - Robert Jaster
- Division of Gastroenterology Department of Medicine II Rostock University Medical Center Rostock Germany
| | - Rüdiger Köhling
- Institute of Physiology Rostock University Medical Center Rostock Germany
| | - Manfred Kunz
- Department of Dermatology, Venereology and Allergology University of Leipzig Leipzig Germany
| | - Markus Tiedge
- Institute of Medical Biochemistry and Molecular Biology Rostock University Medical Center Rostock Germany
| | - Paul N. Schofield
- Department of Physiology, Development and Neuroscience University of Cambridge Cambridge UK
| | - Georg Fuellen
- Institute for Biostatistics and Informatics in Medicine und Ageing Research Rostock University Medical Center Rostock Germany
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Abstract
PURPOSE OF REVIEW Aging of the hematopoietic system is associated with myeloid malignancies, anemia and immune dysfunction. As hematopoietic stem cells (HSCs) generate all cells of the hematopoietic system, age-associated changes in HSCs may underlie many features of the aged hematopoietic system. Recent findings on age-associated changes in HSCs are reviewed here. RECENT FINDINGS Aged HSCs are myeloid biased, have acquired DNA damage and are functionally compromised. However, overall function of the HSC compartment is well maintained through age-associated expansion of HSCs. Many age-related changes in the hematopoietic system, in particular the clonal myeloid bias of HSCs and the decrease in B and T-cell development, in fact begin during development. Furthermore, HSCs possess specific protective mechanisms aimed at maintaining their number, even at the expense of accumulating damaged cells. SUMMARY We argue that age-related changes in HSCs and in the hematopoietic system may not entirely be due to a degenerative aging process, but are the result of developmental and stem cell-protective mechanisms aimed at maximizing fitness during reproductive life. These mechanisms may be disadvantageous later in life as damaged HSCs accumulate and establishment of responses to neoantigens becomes compromised because of the reduced generation of naive T and B cells.
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Gui J, Morales AJ, Maxey SE, Bessette KA, Ratcliffe NR, Kelly JA, Craig RW. MCL1 increases primitive thymocyte viability in female mice and promotes thymic expansion into adulthood. Int Immunol 2011; 23:647-59. [PMID: 21937457 DOI: 10.1093/intimm/dxr073] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Increasing the pool of cells at early T-cell developmental stages enhances thymopoiesis and is especially beneficial when T-cell production is compromised by radiation or aging. Within the immature double-negative (DN; CD4(-)CD8(-)) thymocyte subpopulation, the DN1 subset contains the most primitive cells including the rare early T-cell progenitors (ETPs). In the present study, a human MCL1 transgene, under the control of its endogenous promoter, resulted in enlargement of an undistorted thymus in C57/BL6 mice. Enlargement occurred in females but not males, being seen at 1 month of age and maintained during progression into adulthood as the thymus underwent involution. The small DN1 subset was expanded disproportionally (ETPs increasing from ∼0.016 to 0.03% of thymocytes), while more mature thymocytes were increased proportionally (1.5-fold) along with the stroma. DN1 cells from transgenic females exhibited increased viability with maintained proliferation, and their survival in primary culture was extended. Exposure of transgenic females to γ-irradiation also revealed an expanded pool of radioresistant DN1 cells exhibiting increased viability. While the viability of DN1 cells from transgenic males was equivalent to that of their non-transgenic counterparts directly after harvest, it was enhanced in culture-suggesting that the effect of the transgene was suppressed in the in vivo environment of the male. Viability was increased in ETPs from transgenic females, but unchanged in more mature thymocytes, indicating that primitive cells were affected selectively. The MCL1 transgene thus increases the viability and pool size of primitive ETP/DN1 cells, promoting thymopoiesis and radioresistance in peripubescent females and into adulthood.
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Affiliation(s)
- Jingang Gui
- Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH 03755, USA
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Dorko F, Kluchová D, Boleková A, Spakovská T, Borošová T, Lovasová K. Influence of surgical and chemical orchidectomy on weight and distribution of AChE-nerve fibres in thymuses of adult rats. Eur J Histochem 2011; 55:e22. [PMID: 22073369 PMCID: PMC3203471 DOI: 10.4081/ejh.2011.e22] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2010] [Accepted: 05/15/2011] [Indexed: 11/23/2022] Open
Abstract
The thymus is a crossroad between the immune and neuroendocrine systems. As such, it is innervated by acetylcholinesterase (AChE)-positive fibres of the vagus, the recurrent laryngeal and the phrenic nerves. It is well know, that the innervations density of the thymus increases with age. In our study, adult rats were orchidectomized (surgically and chemically by the application of a luteinizing hormone-releasing hormone). The density of AChE-positive nerve fibres in thymuses, as well as the weight of thymuses was examined. The authors found that both surgical and chemical orchidectomy result in macroscopic and microscopic regeneration of the atrophied thymuses. In regenerated rat’s thymuses after orchidectomy the density of AChE-positive nerve fibres was markedly higher in comparison with the control animals. The distribution, as well as the density of AChE-positive nerve fibres in regenerated thymuses after orchidectomy evokes the images of its innervations like in young animals before age-related involution. The authors also found a markedly higher weight of thymuses of orchidectomized rats in comparison with the control groups. In recent study the authors proved that after 8 weeks surgical orchidectomy leads to the regeneration of thymic AChE-positive innervation and chemical orchidectomy by administration of luteinizing hormone-releasing hormone after 4 weeks of adult rats.
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Affiliation(s)
- F Dorko
- Department of Anatomy, Faculty of Medicine, P.J. Šafárik University in Košice, Slovakia.
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It's not all equal: a multiphasic theory of thymic involution. Biogerontology 2011; 13:77-81. [PMID: 21773717 DOI: 10.1007/s10522-011-9349-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2011] [Accepted: 07/06/2011] [Indexed: 12/15/2022]
Abstract
Regression of the thymus is a key feature of immunosenescence, which coincides with a decrease in T cell output and contributes to the restriction of the T cell repertoire in the elderly, leading to increased susceptibility to illness and disease. However, the mechanisms involved in thymic involution are still not fully known. Although, it is often believed that thymic involution occurs during the onset of puberty, increasing data suggests alterations to the thymus happen much earlier in life. Therefore, the changes in the thymus and subsequent thymic function may not just be an ageing phenomenon. In this article, we propose that there are several, non-linear, phases to thymic atrophy, which are regulated by different mechanisms, including the familiar age-dependent thymic involution and a much earlier growth-dependent thymic involution.
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Bukovsky A. Immune maintenance of self in morphostasis of distinct tissues, tumour growth and regenerative medicine. Scand J Immunol 2011; 73:159-89. [PMID: 21204896 DOI: 10.1111/j.1365-3083.2010.02497.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Morphostasis (tissue homeostasis) is a complex process consisting of three circumstances: (1) tissue renewal from stem cells, (2) preservation of tissue cells in a proper differentiated state and (3) maintenance of tissue quantity. This can be executed by a tissue control system (TCS) consisting of vascular pericytes, immune system-related components--monocyte-derived cells (MDC), T cells and immunoglobulins and autonomic innervation. Morphostasis is established epigenetically, during the critical developmental period corresponding to the morphogenetic immune adaptation. Subsequently, the tissues are maintained in a state of differentiation reached during the adaptation by a 'stop effect' of MDC influencing markers of differentiating tissue cells and presenting self-antigens to T cells. Retardation or acceleration of certain tissue differentiation during adaptation results in its persistent functional immaturity or premature ageing. The tissues being absent during adaptation, like ovarian corpus luteum, are handled as a 'graft.' Morphostasis is altered with age advancement, because of the degenerative changes of the immune system. That is why the ageing of individuals and increased incidence of neoplasia and degenerative diseases occur. Hybridization of tumour stem cells with normal tissue cells causes an augmentation of neoplasia by host pericytes and MDC stimulating a 'regeneration' of depleted functional cells. Degenerative diseases are associated with apoptosis. If we are able to change morphostasis in particular tissue, we may disrupt apoptotic process of the cell. An ability to manage the 'stop effect' of MDC may provide treatment for early post-natal tissue disorders, improve regenerative medicine and delay physical, mental and hormonal ageing.
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Affiliation(s)
- A Bukovsky
- Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
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Silva AB, Palmer DB. Evidence of conserved neuroendocrine interactions in the thymus: intrathymic expression of neuropeptides in mammalian and non-mammalian vertebrates. Neuroimmunomodulation 2011; 18:264-70. [PMID: 21952678 DOI: 10.1159/000329493] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The function of lymphoid organs and immune cells is often modulated by hormones, steroids and neuropeptides produced by the neuroendocrine and immune systems. The thymus intrinsically produces these factors and a comparative analysis of the expression of neuropeptides in the thymus of different species would highlight the evolutionary importance of neuroendocrine interaction in T cell development. In this review, we highlight the evidence which describes the intrathymic expression and function of various neuropeptides and their receptors, in particular somatostatin, substance P, vasointestinal polypeptide, calcitonin gene-related peptide and neuropeptide Y, in mammals (human, rodent) and non-mammals (avian, amphibian and teleost), and conclude that neuropeptides play a conserved role in vertebrate thymocyte development.
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Affiliation(s)
- Alberto B Silva
- Infection and Immunity Group, Department of Veterinary Basic Sciences, Royal Veterinary College, London, UK
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Ito T, Takii T, Maruyama M, Hayashi D, Wako T, Asai A, Horita Y, Taniguchi K, Yano I, Yamamoto S, Onozaki K. Effectiveness of BCG vaccination to aged mice. IMMUNITY & AGEING 2010; 7:12. [PMID: 20809944 PMCID: PMC2936867 DOI: 10.1186/1742-4933-7-12] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/13/2010] [Accepted: 09/01/2010] [Indexed: 12/21/2022]
Abstract
Background The tuberculosis (TB) still increases in the number of new cases, which is estimated to approach 10 million in 2010. The number of aged people has been growing all over the world. Ageing is one of risk factors in tuberculosis because of decreased immune responses in aged people. Mycobacterium bovis Bacillus Calmette Guérin (BCG) is a sole vaccine currently used for TB, however, the efficacy of BCG in adults is still a matter of debate. Emerging the multidrug resistant Mycobacterium tuberculosis (MDR-TB) make us to see the importance of vaccination against TB in new light. In this study, we evaluated the efficacy of BCG vaccination in aged mice. Results The Th1 responses, interferon-γ production and interleukin 2, in BCG inoculated aged mice (24-month-old) were comparable to those of young mice (4- to 6-week-old). The protection activity of BCG in aged mice against Mycobacterium tuberculosis H37Rv was also the same as young mice. Conclusion These findings suggest that vaccination in aged generation is still effective for protection against tuberculosis.
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Affiliation(s)
- Tsukasa Ito
- Department of Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe, Mizuho, Nagoya 467-8603, Japan.
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Zlamy M, Prelog M. Thymectomy in early childhood: a model for premature T cell immunosenescence? Rejuvenation Res 2010; 12:249-58. [PMID: 19673593 DOI: 10.1089/rej.2009.0864] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
The thymus is the main source of recent thymic emigrants (RTE) and naïve T cells. The aging of the immune system (immunosenescence) is characterized by loss of thymic function, decreased numbers of RTE, peripheral proliferation of mature T cells, and oligoclonal expansions of specific T cell subpopulations. As shown in several studies, thymectomized patients demonstrate signs of premature immunosenescence reminiscent of aged people, such as decreased proportions of naïve T cells and RTE, a compensatory increase of mature T cell subpopulations with increased proliferation rates, restriction of the T cell receptor repertoire, and a delayed response to new antigens and vaccinations. This review demonstrates that, despite some limitations, childhood thymectomy may serve as an useful model for premature immunosenescence, mimicking changes expected after physiological thymus involution in the elderly. Thus, it may prove an insightful tool for obtaining better understanding of human naïve T cell development, thymic function, and maintenance of the naïve T cell pool.
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Affiliation(s)
- Manuela Zlamy
- Department of Pediatrics, Pediatrics I, Medical University Innsbruck, Austria
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38
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Somatostatin-14 induces different changes in the thymus of peripubertal and young adult rats. ACTA VET-BEOGRAD 2010. [DOI: 10.2298/avb1004339r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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CD8 T Cells in old mice contribute to the innate immune response to Mycobacterium tuberculosis via interleukin-12p70-dependent and antigen-independent production of gamma interferon. Infect Immun 2009; 77:3355-63. [PMID: 19470747 DOI: 10.1128/iai.00295-09] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Elderly individuals have increased morbidity and mortality associated with infectious diseases due in part to the progressive age-associated decline in immune function. Despite this, the old mouse model of Mycobacterium tuberculosis infection has revealed a CD8- and gamma interferon (IFN-gamma)-dependent early resistance to infection. In this study, we investigated the mechanism by which CD8 T cells from old mice contributed to the early immune response to M. tuberculosis. Following a low-dose aerosol infection with M. tuberculosis, CD8 T cells were identified as being a dominant source of IFN-gamma expression in the lungs of old mice early after infection, before the typical onset of antigen-specific immunity. In addition, M. tuberculosis-induced IFN-gamma production by CD8 T cells isolated from naïve old mice was major histocompatibility complex class I independent but was dependent on interleukin-12p70, confirming an innate role of CD8 T cells during M. tuberculosis infection. Moreover, the ability of CD8 T cells from old mice to produce increased innate IFN-gamma levels in response to M. tuberculosis infection was defined as a unique function of CD8 T cells from old mice and not the aged lung environment. Finally, we have identified increased expression of SET as being one possible mechanism by which CD8 T cells from old mice produce enhanced levels of IFN-gamma. Additional characterizations of the signaling events that lead to enhanced innate IFN-gamma production by CD8 T cells in old mice may lead to novel strategies to further enhance or perpetuate beneficial immune responses in the elderly.
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Lustig A, Carter A, Bertak D, Enika D, Vandanmagsar B, Wood W, Becker KG, Weeraratna AT, Taub DD. Transcriptome analysis of murine thymocytes reveals age-associated changes in thymic gene expression. Int J Med Sci 2009; 6:51-64. [PMID: 19214242 PMCID: PMC2640475 DOI: 10.7150/ijms.6.51] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2009] [Accepted: 02/08/2009] [Indexed: 01/24/2023] Open
Abstract
The decline in adaptive immunity, naïve T-cell output and a contraction in the peripheral T cell receptor (TCR) repertoire with age are largely attributable to thymic involution and the loss of critical cytokines and hormones within the thymic microenvironment. To assess the molecular changes associated with this loss of thymic function, we used cDNA microarray analyses to examine the transcriptomes of thymocytes from mice of various ages ranging from very young (1 month) to very old (24 months). Genes associated with various biological and molecular processes including oxidative phosphorylation, T- and B- cell receptor signaling and antigen presentation were observed to significantly change with thymocyte age. These include several immunoglobulin chains, chemokine and ribosomal proteins, annexin A2, vav 1 and several S100 signaling proteins. The increased expression of immunoglobulin genes in aged thymocytes could be attributed to the thymic B cells which were found to be actively producing IgG and IgM antibodies. Upon further examination, we found that purified thymic T cells derived from aged but not young thymi also exhibited IgM on their cell surface suggesting the possible presence of auto-antibodies on the surface thymocytes with advancing age. These studies provide valuable insight into the cellular and molecular mechanisms associated with thymic aging.
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Affiliation(s)
- Ana Lustig
- Laboratory of Immunology, National Institute on Aging-Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA
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Heikenwalder M, Prinz M, Zeller N, Lang KS, Junt T, Rossi S, Tumanov A, Schmidt H, Priller J, Flatz L, Rülicke T, Macpherson AJ, Holländer GA, Nedospasov SA, Aguzzi A. Overexpression of lymphotoxin in T cells induces fulminant thymic involution. THE AMERICAN JOURNAL OF PATHOLOGY 2008; 172:1555-70. [PMID: 18483211 PMCID: PMC2408416 DOI: 10.2353/ajpath.2008.070572] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 02/14/2008] [Indexed: 01/12/2023]
Abstract
Activated lymphocytes and lymphoid-tissue inducer cells express lymphotoxins (LTs), which are essential for the organogenesis and maintenance of lymphoreticular microenvironments. Here we describe that T-cell-restricted overexpression of LT induces fulminant thymic involution. This phenotype was prevented by ablation of the LT receptors tumor necrosis factor receptor (TNFR) 1 or LT beta receptor (LTbetaR), representing two non-redundant pathways. Multiple lines of transgenic Ltalphabeta and Ltalpha mice show such a phenotype, which was not observed on overexpression of LTbeta alone. Reciprocal bone marrow transfers between LT-overexpressing and receptor-ablated mice show that involution was not due to a T cell-autonomous defect but was triggered by TNFR1 and LTbetaR signaling to radioresistant stromal cells. Thymic involution was partially prevented by the removal of one allele of LTbetaR but not of TNFR1, establishing a hierarchy in these signaling events. Infection with the lymphocytic choriomeningitis virus triggered a similar thymic pathology in wt, but not in Tnfr1(-/-) mice. These mice displayed elevated TNFalpha in both thymus and plasma, as well as increased LTs on both CD8(+) and CD4(-)CD8(-) thymocytes. These findings suggest that enhanced T cell-derived LT expression helps to control the physiological size of the thymic stroma and accelerates its involution via TNFR1/LTbetaR signaling in pathological conditions and possibly also in normal aging.
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Affiliation(s)
- Mathias Heikenwalder
- Institute of Neuropathology, University Hospital of Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland.
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Histochemical and molecular overview of the thymus as site for T-cells development. ACTA ACUST UNITED AC 2008; 43:73-120. [PMID: 18555891 DOI: 10.1016/j.proghi.2008.03.001] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2008] [Accepted: 03/11/2008] [Indexed: 12/19/2022]
Abstract
The thymus represents the primary site for T cell lymphopoiesis, providing a coordinated set for critical factors to induce and support lineage commitment, differentiation and survival of thymus-seeding cells. One irrefutable fact is that the presence of non-lymphoid cells through the thymic parenchyma serves to provide coordinated migration and differentiation of T lymphocytes. Moreover, the link between foetal development and normal anatomy has been stressed in this review. Regarding thymic embryology, its epithelium is derived from the embryonic endodermal layer, with possible contributions from the ectoderm. A series of differentiating steps is essential, each of which must be completed in order to provide the optimum environment for thymic development and function. The second part of this article is focused on thymic T-cell development and differentiation, which is a stepwise process, mediated by a variety of stromal cells in different regions of the organ. It depends strongly on the thymic microenvironment, a cellular network formed by epithelial cells, macrophages, dendritic cells and fibroblasts, that provide the combination of cellular interactions, cytokines and chemokines to induce thymocyte precursors for the generation of functional T cells. The mediators of this process are not well defined but it has been demonstrated that some interactions are under neuroendocrine control. Moreover, some studies pointed out that reciprocal signals from developing T cells also are essential for establishment and maintenance of the thymic microenvironment. Finally, we have also highlighted the heterogeneity of the lymphoid, non-lymphoid components and the multi-phasic steps of thymic differentiation. In conclusion, this review contributes to an understanding of the complex mechanisms in which the foetal and postnatal thymus is involved. This could be a prerequisite for developing new therapies specifically aimed to overcome immunological defects, linked or not-linked to aging.
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Park HY, Hertz-Picciotto I, Petrik J, Palkovicova L, Kocan A, Trnovec T. Prenatal PCB exposure and thymus size at birth in neonates in Eastern Slovakia. ENVIRONMENTAL HEALTH PERSPECTIVES 2008; 116:104-9. [PMID: 18197307 PMCID: PMC2199273 DOI: 10.1289/ehp.9769] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/28/2006] [Accepted: 08/14/2007] [Indexed: 05/02/2023]
Abstract
BACKGROUND Polychlorinated biphenyls (PCBs) are ubiquitous environmental toxicants, for which animal studies demonstrate immunotoxic effects, including thymic atrophy and suppressed immune responses; human investigations of similar end points are sparse. The thymus is essential for the differentiation and maturation of T-cell lymphocytes. OBJECTIVES The objective of this study was to examine the association between prenatal PCB exposures and estimated thymus volume in infants from eastern Slovakia, a region where PCBs were produced until 1984. METHODS Mothers were enrolled at delivery, and maternal blood samples were collected for analysis of 15 PCB congeners, p,p'-DDT [1,1,1-trichloro-2,2'-bis(p-chlorophenyl)ethane], and p,p'-DDE [1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene]. Each mother was interviewed to obtain information on sociodemographic characteristics, past pregnancies, occupational history, medication history, and living environment. Neonatal thymus volume was estimated using ultrasound measurements on the third or fourth day after birth. Thymic index was calculated on 982 newborns from mothers with PCB measurements. We developed a predictive model of the natural log of the thymic index using multiple linear regression with covariates selected from the bivariate analyses. RESULTS Prenatal PCB exposure was associated with a smaller thymic index at birth [beta= -36 (natural log-transformed; nanograms per gram lipids); p = 0.047]. District of residence and delivery also predicted thymic index. Male sex, later gestational age, larger birth weight z-score, and Roma ethnicity were associated with a larger thymic index, whereas respiratory illness was associated with a lower thymic index. CONCLUSIONS This study provides the first evidence to date that PCB exposure in neonates is associated with a smaller thymic volume, suggesting possible impaired immunologic development.
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Affiliation(s)
- Hye-Youn Park
- Division of Epidemiology, Department of Public Health Sciences, School of Medicine, University of California, Davis, California, USA
| | - Irva Hertz-Picciotto
- Division of Epidemiology, Department of Public Health Sciences, School of Medicine, University of California, Davis, California, USA
- Address correspondence to I. Hertz-Picciotto, University of California, TB168, One Shields Ave., UC Davis, CA 95616. Telephone: (530) 752-3025. Fax: (530) 752-3230. E-mail:
| | - Jan Petrik
- Department of Toxic Organic Pollutants and
| | - Lubica Palkovicova
- Department of Environmental Medicine, Slovak Medical University, Bratislava, Slovakia
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Petrović-Dergović DM, Rakin AK, Dimitrijević LA, Ristovski JS, Kustrimović NZ, Mićić MV. Changes in thymus size, cellularity and relation between thymocyte subpopulations in young adult rats induced by somatostatin-14. Neuropeptides 2007; 41:485-93. [PMID: 17761280 DOI: 10.1016/j.npep.2007.06.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2007] [Revised: 05/24/2007] [Accepted: 06/29/2007] [Indexed: 12/15/2022]
Abstract
The role of somatostatin on inhibition of both normal and tumor cell cycle, secretion of endocrine and exocrine cells, as well as induction apoptosis is well documented. However, its effect on T cell development and thymic structure is not fully clarified. In order to investigate the influence of somatostatin in vivo on the thymus structure and T cell development, the young adult Albino Oxford male rats were intracerebroventriculary treated with somatostatin-14. We examined the thymus compartments and its cellularity, through assessment of morphometric parameters by stereological method, and the relation between thymocytes subpopulations, over expression of CD4, CD8 and T-cell receptor (TCR) alpha beta by flow cytometry. Additionally, we also determined the body and thymus weight of the rats, during the first three months of life, to define the time of SRIH-14 application. A decrease of relative thymus weight from the fourth weeks of postnatal life, and an unchanged relative thymus weight obtained in treated group indicates that SRIH-14 in young adult rats inhibits growth of whole organism, not only thymus. The changes in the absolute number and numerical density of cortical thymocytes indicate that SRIH-14 alters the true lymphoid tissue. SRIH-14 changes relation between thymocyte subsets, increase number of CD4(-)CD8(-)TCR alpha beta(-) and CD4(-)CD8(+)TCR alpha beta(hi) thymocyte subsets as well as the CD4(-)CD8(-)TCR alpha beta(low/hi) thymocytes, while decrease number of CD4(+)CD8(+) TCR alpha beta(-/low/hi) thymocyte subsets. These results indicate that somatostatin-14 is not involved in the control of the physiologic involution of the thymus, although induces thymic weight loss through the reduction of true lymphoid tissue. In addition, changes in frequency of thymocyte subpopulations, especially immature cells, indicate that SRIH-14 modulates thymocytes development and maturation.
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Affiliation(s)
- Danica M Petrović-Dergović
- Immunology Research Center Branislav Jankovic, Institute of Immunology and Virology Torlak, Belgrade, Serbia
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Characteristics of age-related changes in rat thymus: morphometric analysis and epithelial cell network in various thymic compartments. Biogerontology 2007; 9:93-108. [PMID: 18030593 DOI: 10.1007/s10522-007-9117-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2007] [Accepted: 11/04/2007] [Indexed: 01/21/2023]
Abstract
Structural alterations in thymuses of female rats during the first 2 years of life were evaluated by morphometric analysis and, then, correlated with organization of epithelial cells in various thymic compartments, examined for their cytokeratin immunoreactivity. With an advancing age, the thymuses demonstrated morphological modifications related to maturation and senescence, the dynamics of which varied between particular thymic compartments, and involved subpopulations of thymic epithelial cells. In the entire period of life the most dynamic changes were found in the cortex while the medulla was demonstrated to be a rather "stable" region. Morphometric studies revealed a negative correlation between the volume of thymic cortex and medulla and age of rats and a linear, positive relationship between the volume of connective tissue compartment and age. Changes in organization of epithelial network in the medulla preceded those observed in the cortex. Decreased proliferative activity of subset of medullary cells, which probably represented a self-renewable population, was accompanied by alterations in the immunocytochemically characterized (cytokeratines) differentiation process. At the same period of life, hypertrophy and hyperplasia of superficial epithelial cells seems to functionally replace medullary cells. This process begins around 3rd month of life and expands on all thymic compartments. The first changes in the cortex appeared around 8th month and were connected with reduced cytokeratin immunoreactivity. The involution observed in older animals was preceded by age-related alterations in epithelial network pattern which, in the course of stable morphometric parameters (between 5th and 12th month), showed character of a structural and functional adaptation.
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Kajantie E, Phillips DIW, Osmond C, Barker DJP, Forsén T, Eriksson JG. Spontaneous hypothyroidism in adult women is predicted by small body size at birth and during childhood. J Clin Endocrinol Metab 2006; 91:4953-6. [PMID: 16984989 DOI: 10.1210/jc.2006-1093] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND The relationships of early growth with coronary heart disease and type 2 diabetes have received considerable attention. It is not known whether fetal or childhood growth is linked with autoimmune disorders. OBJECTIVE Our objective was to assess whether the risk of adult-onset spontaneous hypothyroidism is predicted by body size at birth and during childhood. DESIGN AND SETTING We conducted a birth cohort study in Helsinki, Finland. PARTICIPANTS A total of 293 women who were born between 1934 and 1944 and had their heights and weights recorded at birth and during childhood participated in the study. MEASUREMENTS We measured spontaneous hypothyroidism, defined as: 1) a disease history confirmed from medical records, or 2) previously undiagnosed hypothyroidism (TSH > 10 mU/liter). RESULTS Twenty women (6.8%) had spontaneous hypothyroidism; 18 had been diagnosed previously, between 43 and 65 yr of age, and two had undiagnosed subclinical hypothyroidism. In addition, 59 women were thyroid peroxidase antibody positive. Compared with the 214 thyroid peroxidase antibody-negative women with no thyroid disorder, those with spontaneous hypothyroidism had on average 252 g [95% confidence interval (CI), 61 to 443 g; P = 0.01] lower birth weight and 1.2 cm (95% CI, 0.5 to 2.0 cm; P = 0.002) shorter length at birth. The odds of developing hypothyroidism increased 4.4-fold per kilogram decrease in birth weight (95% CI, 1.4 to 14.1). Hypothyroid subjects had been shorter in early childhood and had lower body mass index during later childhood. CONCLUSIONS Small body size at birth and during childhood increases the risk of spontaneous hypothyroidism in adult women.
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Affiliation(s)
- Eero Kajantie
- National Public Health Institute, Department of Epidemiology and Health Promotion, Mannerheimintie 166, 00300 Helsinki, Finland.
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Mandal D, Bhattacharyya A, Lahiry L, Choudhuri T, Sa G, Das T. Failure in peripheral immuno-surveillance due to thymic atrophy: Importance of thymocyte maturation and apoptosis in adult tumor-bearer. Life Sci 2005; 77:2703-16. [PMID: 16019036 DOI: 10.1016/j.lfs.2005.05.038] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2004] [Accepted: 05/03/2005] [Indexed: 11/24/2022]
Abstract
Tumor-induced immunosuppression often leads to failure in cancer therapy. Here, in an attempt to understand the course of tumor-dependent immunosuppression in young adult murine model, we found that in Ehrlich's ascites carcinoma (EAC) bearing mice, CD4(+) and CD8(+) populations of peripheral blood were depleted within first week of tumor inoculation. However, there was a rise in these populations at the end of second week only to fall back severely at the end of third week. These pulsating changes were also reflected in spleen. Interestingly, in thymus, production of CD4(+) and CD8(+) increased during first two weeks of tumor inoculation indicating the effort of thymus to replenish these populations in peripheral blood and spleen in response to their initial depletion, restricting tumor growth in between first and second weeks. However, at third week, due to (a) block in thymocyte maturation leading to increase in CD4(-)8(-) and decrease in CD4(+)8(+), (b) inhibition in formation of functional isotypes, and (c) thymocyte apoptosis, thymic reinforcement was stalled. Further investigation for the underlying mechanism of such thymic atrophy revealed down-regulation of anti-apoptotic protein Bcl-2 and up-regulation of pro-apoptotic protein Bax, resulting in decreased Bcl-2/Bax ratio thereby inducing apoptosis. Above findings accounted for the significant decrease in CD4(+) and CD8(+) of peripheral blood and spleen by the end of third week culminating in total collapse in the fight back mechanism of host and uncontrolled growth of tumor. All these results signify the importance of thymus in modulating the immune status of the host during tumor development.
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Harenberg A, Girkontaite I, Giehl K, Fischer KD. The Lsc RhoGEF mediates signaling from thromboxane A2 to actin polymerization and apoptosis in thymocytes. Eur J Immunol 2005; 35:1977-86. [PMID: 15884057 DOI: 10.1002/eji.200425769] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The Lsc RhoGEF (also known as p115-RhoGEF) is a GTP exchange factor (GEF), an activator of GTPases of the Rho family. Lsc has a RhoGEF domain specific for Rho GTPase and a regulator of G protein signaling (RGS) domain specific for Galpha(12/13) subunits. One G protein receptor that can couple to Galpha(12/13) subunits is the receptor for thromboxane A(2 )(TXA(2)), thromboxane-prostanoid (called TP), which is highly expressed in immature thymocytes. TXA(2) has been implicated in thymocyte apoptosis. We found that Lsc(-/-) mice on a BALB/c background show thymic hyperplasia due to increased numbers of thymocytes and that these numbers further increase with the age of the mice. To investigate a role for Lsc in TXA(2) signaling, we analyzed activation of primary thymocytes by TXA(2) in vitro. TXA(2)-induced apoptosis of double-positive thymocytes and Rho activation required Lsc, and TXA(2) stimulation of actin polymerization and cofilin phosphorylation required both Lsc and Rho kinase (ROCK). Additionally, in the absence of Lsc, phosphorylation of the survival kinase Akt in response to TXA(2) was greatly enhanced. Together, these data demonstrate that Lsc is essential for mediating TXA(2 )signaling involved in apoptosis and actin organization and suggest that TXA(2) regulates thymic cellularity via Lsc.
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Affiliation(s)
- Anke Harenberg
- Department of Physiological Chemistry, University of Ulm, Ulm, Germany
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Silva IA, Graber J, Nyland JF, Silbergeld EK. In vitro HgCl2 exposure of immune cells at different stages of maturation: effects on phenotype and function. ENVIRONMENTAL RESEARCH 2005; 98:341-8. [PMID: 15910788 DOI: 10.1016/j.envres.2005.01.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/11/2004] [Revised: 01/18/2005] [Accepted: 01/18/2005] [Indexed: 05/02/2023]
Abstract
This is the first study to investigate the hypothesis that the immunotoxic effects of inorganic mercury may be modulated by inherent differences in the responsiveness of immune cells related to the age of the donor. We exposed cells from lymph nodes, spleen, and thymus, collected from 7- and 10-day-old CD.1 pups, as well as from adult CD.1 mice, in terms of the effects of mercury in vitro on responses to Con-A stimulation with respect to proliferation, cytokine production, and cell phenotype. The effects of mercury on proliferation were age and organ dependent, while effects on cytokine production were only age dependent. Effects of mercury were observed only on splenocyte T-cell subpopulations and only in cells from 10-day-old pups and from adults. Mercury had no effect on IFN-gamma and IL-4 production by splenocytes from 7-day-old pups, but significantly decreased release of these cytokines by splenocytes from 10-day-old pups and adults. Hg did not affect IL-4 production by lymph node cells or thymocytes. In lymph node cells Hg affected IFN-gamma production only at 7 days. These data indicate that inherent properties of immune cells at different stages of development may influence the response to immunotoxicants.
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Affiliation(s)
- I A Silva
- Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, 615 N. Wolfe Street, Room E6644, Baltimore, MD 21205, USA
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Yekeler E, Tambag A, Tunaci A, Genchellac H, Dursun M, Gokcay G, Acunas G. Analysis of the thymus in 151 healthy infants from 0 to 2 years of age. JOURNAL OF ULTRASOUND IN MEDICINE : OFFICIAL JOURNAL OF THE AMERICAN INSTITUTE OF ULTRASOUND IN MEDICINE 2004; 23:1321-1326. [PMID: 15448322 DOI: 10.7863/jum.2004.23.10.1321] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
OBJECTIVE A prospective sonographic study of the normal thymus was performed to determine the size changes with age and to compare the results according to some clinical conditions, such as sex, breast versus formula feeding, and term or preterm status. METHODS One hundred fifty-one healthy infants underwent thymic sonography. Maximal transverse and longitudinal dimensions and anteroposterior dimensions of the right and left lobes were measured, and thymic indices were calculated. Mean values of thymic measurements for each group (sex, age, breast or formula feeding, and term or preterm status) were determined. The results were statistically evaluated. RESULTS Thymic dimensions showed the maximal values at about 4 to 6 months and gradually decreased after 6 to 8 months. No significant differences were found between mean values of thymic dimensions according to the sex and formula- versus breast-fed groups. As expected, the term group had greater thymic size values than the preterm group, probably because of positive correlations between thymus size, birth weight, and height. CONCLUSIONS The thymus is clearly and easily visualized on sonography in the 0- to 2-year age period. This may be useful for evaluating qualitative and quantitative properties of the thymus and determining size changes according to age in various clinical conditions.
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Affiliation(s)
- Ensar Yekeler
- Department of Radiology, Istanbul University, Istanbul Faculty of Medicine, 34390 Capa, Istanbul, Turkey.
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