Analysis of the human thymic perivascular space during aging

Flores, Kristina G.; Li, Jie; Sempowski, Gregory D.; Haynes, Barton F.; Hale, Laura P.

doi:10.1172/jci7558

Cited by 207 publications

(167 citation statements)

References 32 publications

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“…Interestingly, the enlargement of thymic PVS was reported in a few other autoimmune disorders such as myasthenia gravis in humans (24) and in BWF 1 mice, a murine model for systemic lupus erythematosus (25). In these mice, B1 cells migrate aberrantly in the thymus during the development of lupus nephritis and their intra-PVS accumulation was correlated with the altered expression of the chemokine CXCL13 and adhesion molecules.…”

Section: Discussionmentioning

confidence: 90%

Multivectorial Abnormal Cell Migration in the NOD Mouse Thymus

Mendes-da-Cruz

Smaniotto

Keller

et al. 2008

The Journal of Immunology

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We previously described a fibronectin/VLA-5-dependent impairment of NOD thymocyte migration, correlated with partial thymocyte arrest within thymic perivascular spaces. Yet, NOD thymocytes still emigrate, suggesting the involvement of other cell migration-related alterations. In this context, the aim of this work was to study the role of extracellular matrix ligands, alone or in combination with the chemokine CXCL12, in NOD thymocyte migration. Intrathymic contents of CXCL12, fibronectin, and laminin were evaluated by immunohistochemistry while the expression of corresponding receptors was ascertained by flow cytometry. Thymocyte migration was measured using Transwell chambers and transendothelial migration was evaluated in the same system, but using an endothelial cell monolayer within the chambers. NOD thymocytes express much lower VLA-5 than C57BL/6 thymocytes. This defect was particularly severe in CD4+ thymocytes expressing Foxp3, thus in keeping with the arrest of Foxp3+ cells within the NOD giant perivascular spaces. We observed an enhancement in CXCL12, laminin, and fibronectin deposition and colocalization in the NOD thymus. Furthermore, we detected altered expression of the CXCL12 receptor CXCR4 and the laminin receptor VLA-6, as well as enhanced migratory capacity of NOD thymocytes toward these molecules, combined or alone. Moreover, transendothelial migration of NOD thymocytes was diminished in the presence of exogenous fibronectin. Our data unravel the existence of multiple cell migration-related abnormalities in NOD thymocytes, comprising both down- and up-regulation of specific responses. Although remaining to be experimentally demonstrated, these events may have consequences on the appearance of autoimmunity in NOD mice.

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Section: Discussionmentioning

confidence: 90%

Multivectorial Abnormal Cell Migration in the NOD Mouse Thymus

Mendes-da-Cruz

Smaniotto

Keller

et al. 2008

The Journal of Immunology

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“…There is an accompanying loss of functional capacity, cellular integrity, and diversity of both CD4 + and CD8 + T cell repertoires (Dewan et al, 2012;Haynes and Maue, 2009;Larbi et al, 2008;Weiskopf et al, 2009). T cells develop in the thymus, which atrophies with age (Flores et al, 1999;Ginaldi et al, 2001), changing the proportions of naïve and memory T cells in the periphery. Although memory CD4 + and CD8 + T cells are increased with ageing they are functionally compromised exhibiting reductions in proliferation, cytokine production, and reduced cognate helper function, compared with young naïve cells.…”

Section: Naïve and Memory T Cells In Agingmentioning

confidence: 99%

Nutrition, diet and immunosenescence

Maijó

Clements

Ivory

et al. 2014

Mechanisms of Ageing and Development

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Ageing is characterized by immunosenescence and the progressive decline in immunity in association with an increased frequency of infections and chronic disease. This complex process affects both the innate and adaptive immune systems with a progressive decline in most immune cell populations and defects in activation resulting in loss of function. Although host genetics and environmental factors, such as stress, exercise and diet can impact on the onset or course of immunosenescence, the mechanisms involved are largely unknown. This review focusses on identifying the most significant aspects of immunosenescence and on the evidence that nutritional intervention might delay this process, and consequently improve the quality of life of the elderly. We would like to thank the reviewers for their careful review of our manuscript, which has been revised accordingly. Below, we have provided a point-by-point reply to the issues raised: AbstractAgeing is characterized by immunosenescence and the progressive decline in immunity in association with an increased frequency of infections and chronic disease. This complex process affects both the innate and adaptive immune systems with a progressive decline in most immune cell populations and defects in activation resulting in loss of function. Although host genetics and environmental factors, such as stress, exercise and diet can impact on the onset or course of immunosenescence, the mechanisms involved are largely unknown. This review focusses on identifying the most significant aspects of immunosenescence and on the evidence that nutritional intervention might delay this process, and consequently improve the quality of life of the elderly.

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“…Isotype-matched control mAbs were obtained from Sigma (St. Louis, MO). Immunohistochemical staining was performed on 4-m formalin-fixed paraffin-embedded thymus sections as described (12).…”

Section: Immunohistological Studiesmentioning

confidence: 99%

“…We have previously shown that the human postnatal thymus is a chimeric organ comprised of central (thymocytes in the thymic epithelial space) and peripheral (T cells from the periphery in the thymic perivascular space) components (12,14). The percentage of the areas within adult thymuses with ongoing thymopoiesis, as measured by percent thymic epithelial space (1,12), decreases with age (1, 15, 16).…”

Section: Analysis Of Thymuses From Thymectomized Mg Patientsmentioning

confidence: 99%

“…The percentage of the areas within adult thymuses with ongoing thymopoiesis, as measured by percent thymic epithelial space (1,12), decreases with age (1, 15, 16). Moreover, patients with MG have accelerated thymic atrophy (1,12), and the "hyperplastic" MG thymus actually represents exuberant peripheral T and B cells in the thymic perivascular space. The true epithelial space of many MG thymuses is actually "hypoplastic" with few CD4/CD8 DP, CD1a ϩ developing cortical thymocytes (12,17).…”

Section: Analysis Of Thymuses From Thymectomized Mg Patientsmentioning

confidence: 99%

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Effect of Thymectomy on Human Peripheral Blood T Cell Pools in Myasthenia Gravis

Sempowski

Thomasch

Gooding

et al. 2001

The Journal of Immunology

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The human thymus is required for establishment of the T cell pool in fetal life, but postnatal thymectomy does not lead to immunodeficiency in humans. Because thymectomy in humans is performed for treatment of myasthenia gravis (MG), we have studied patients with MG for effects of thymectomy on peripheral blood (PB) naive (CD45RA+, CD62L+) and memory (CD45RO+) T cells. We have also determined the effect of thymectomy on levels of PB cells containing signal joint TCR δ excision circles (TRECs), a molecular marker of thymus emigrants that have divided few times after leaving the thymus. In 17 nonthymectomized and 26 thymectomized MG patients studied at varying times after thymectomy (1 day to 41 years), we found no significant mean difference in PB T cell TREC levels between ages 40 and 80 years. However, both thymectomized and nonthymectomized MG patients had lower PB T cell TREC levels than did age-matched normal subjects (p < 0.0001 for both). These data demonstrated that MG itself or treatment for MG decreased thymopoiesis independent of thymectomy. Next, to control for disease activity and treatment, we prospectively studied 10 MG patients before and from 27 to 517 days after thymectomy. We found that thymectomy decreased CD4 or CD8 T cell TREC concentrations most when thymopoiesis was active before thymectomy (six of six patients), but had little effect in patients when thymopoiesis was minimal (four of four patients). In contrast, there was no significant effect of thymectomy on absolute numbers of naive PB T cells. Thus, in MG, removal of a thymus with active thymopoiesis resulted in a significant fall in PB TREC+ T cells postthymectomy.

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Analysis of the human thymic perivascular space during aging

Cited by 207 publications

References 32 publications

Multivectorial Abnormal Cell Migration in the NOD Mouse Thymus

Multivectorial Abnormal Cell Migration in the NOD Mouse Thymus

Nutrition, diet and immunosenescence

Effect of Thymectomy on Human Peripheral Blood T Cell Pools in Myasthenia Gravis

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