Leukemia Inhibitory Factor, Oncostatin M, IL-6, and Stem Cell Factor mRNA Expression in Human Thymus Increases with Age and Is Associated with Thymic Atrophy

Sempowski, Gregory D.; Hale, Laura P.; Sundy, John S.; Massey, Janice M.; Koup, Richard A.; Douek, Daniel C.; Patel, Dhavalkumar D.; Haynes, Barton F.

doi:10.4049/jimmunol.164.4.2180

Cited by 258 publications

(235 citation statements)

References 46 publications

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“…Taken together, these data show that the perturbation is likely to occur through signal strength, or downstream. Mediators of increased LT biological activity such as IL-6, also associated with reduced thymic epithelium in aged and autoimmune settings (71)(72)(73) and found here to be increased in the NZB thymus, may play a role, and a lack of negative feedback for chemokine expression is also possible. Regardless of their driving force, increased expression of CCL19 and CCL21 is a plausible mechanism for intrathymic retention of mature T and B cells (43,50).…”

Section: Discussionmentioning

confidence: 59%

Reduced Thymic Aire Expression and Abnormal NF-κB2 Signaling in a Model of Systemic Autoimmunity

Fletcher

Seach²,

Reiseger³

et al. 2009

The Journal of Immunology

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The thymic stromal niche normally directs the production and export of a self-tolerant T cell repertoire. Many models of spontaneous autoimmunity, however, develop thymic architectural abnormalities before disease onset. Although this is suspected to affect central tolerance induction, creating an autoimmune predisposition, in-depth analysis of the microenvironment within these thymi is lacking, such that the mechanisms and likely direct effects on the T cell repertoire are unknown or speculative. Here we show that NZB mice, the first described model for systemic autoimmunity, demonstrate a complex thymic phenotype, including a lack of the autoimmune regulator (Aire), early defects in thymic epithelial cell (TEC) expansion, and evidence for altered NF-κB2 signaling. Analysis of medullary TEC revealed a numerical loss of the Aire-expressing MHC class IIhigh (mTEC-high) subset as well reduced Aire protein and mRNA per cell. RelB expression was also reduced, while chemokines CCL19 and CCL21 were increased. Unexpectedly, the proportion of cortex and medulla in the NZB mice was normal from 36 wk, despite worsening architectural abnormalities. These data show that the NZB defect is more complex than previously appreciated, segregating into early numerical TEC deficiencies that correct with age, late degeneration of the niche architecture that does not affect TEC number, and a persistent reduction in Aire and RelB expression per cell acquired upon mTEC-high differentiation.

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Section: Discussionmentioning

confidence: 59%

Reduced Thymic Aire Expression and Abnormal NF-κB2 Signaling in a Model of Systemic Autoimmunity

Fletcher

Seach²,

Reiseger³

et al. 2009

The Journal of Immunology

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“…It is intriguing that the effect is most profound on thymocytes. Perhaps GH induces some cytokine production, such as IL-7, that has been proposed to be a mediator of thymic development (23,24). Using BrdU to label dividing cells in the spleen, we observed a higher number of dividing cells in treated mice, suggesting that GHS is inducing these lymphoid cells to enter the cell cycle.…”

Section: Discussionmentioning

confidence: 61%

Immune Enhancing Effect of a Growth Hormone Secretagogue

Koo¹,

Huang²,

Camacho³

et al. 2001

The Journal of Immunology

104

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Growth hormone (GH) has been known to enhance immune responses, whether directly or through the insulin like growth factor-1, induced by GH. Recently a nonpeptidyl small m.w. compound, a GH secretagogue (GHS), was found to induce the production of GH by the pituitary gland. In this study, we examined the effect of GHS in immunological functions of 5- to 6-wk-old and 16- to 24-month-old mice. In young mice, we observed a significant increase in PBLs, but T and B cell-proliferative responses were not consistently enhanced. The old mice, treated with GHS for 3 wk, did not show increases in peripheral lymphocytes, but they exhibited a statistically significant increase in thymic cellularity and differentiation. When inoculated with a transplantable lymphoma cell line, EL4, the treated old mice showed statistically significant resistance to the initiation of tumors and the subsequent metastases. Generation of CTL to EL4 cells was also enhanced in the treated mice, suggesting that GHS has a considerable immune enhancing effect, particularly in the old mice. We have also found that GHS promoted better thymic engraftment in bone marrow transplant of SCID mice. We found more cycling cells in the spleens of treated mice, suggesting that GHS may exert its immune enhancing effect by promoting cell division in lymphoid cells. These observations ascribe to GHS a novel therapy possible for aging, AIDS, and transplant individuals, whose immune functions are compromised.

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“…Jamieson et al (1999) reported that thymopoietic potential per cell, as measured by the quantification of T-cell receptor excision circles (TRECs), remains constant up to 56 years and those thymocytes recognize a broad range of antigens. The maintenance of the thymopoietic potential per cell was subsequently confirmed in both mice (Sempowski et al 2002) and humans (Sempowski et al 2000;Gruver et al 2007). Nevertheless, none of these works assessed a direct association between thymic function-related markers and peripheral naive subsets.…”

Section: Introductionmentioning

confidence: 89%

Thymopoiesis in elderly human is associated with systemic inflammatory status

Ferrando‐Martínez

Franco

Hernández

et al. 2009

AGE

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Immunosenescence studies of age-related immune system damage focused on clinical lymphopenic situations or androgenic blockade have revealed new insights about adult human immune reconstitution. However, as far as we know, the extent of lymphopoiesis in the thymus of elderly humans remains unclear. To this effect, we have analyzed 65 adult human thymuses (from 36 to 81 years; median age 68.6 years) obtained from patients who underwent cardiac surgery. Our results show a correlation between CD4 + CD8 + double-positive (DP) cells and both the age (inverse) and percentage (direct) of peripheral naive T cells, indicating that the thymus is still able to affect the peripheral lymphocyte pool even in the elderly. We also found significant correlation between the degree of thymopoiesis and the inflammation markers, as shown by the inverse correlations between DP and the percentage of neutrophils and IL-6 levels and the percentage of peripheral lymphocytes. Furthermore, in a multivariate linear regression the percentage of DP and IL-7 levels, but not age, were independently associated with the percentage of neutrophils. In conclusion, the thymus maintains, even in the elderly, an active thymopoiesis that rejuvenates the peripheral naive T-cell pool. Moreover, age-related thymopoietic decay is associated with the peripheral inflammation markers.

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Leukemia Inhibitory Factor, Oncostatin M, IL-6, and Stem Cell Factor mRNA Expression in Human Thymus Increases with Age and Is Associated with Thymic Atrophy

Cited by 258 publications

References 46 publications

Reduced Thymic Aire Expression and Abnormal NF-κB2 Signaling in a Model of Systemic Autoimmunity

Reduced Thymic Aire Expression and Abnormal NF-κB2 Signaling in a Model of Systemic Autoimmunity

Immune Enhancing Effect of a Growth Hormone Secretagogue

Thymopoiesis in elderly human is associated with systemic inflammatory status

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