The role of sex steroids and gonadectomy in the control of thymic involution

Hince, Melanie Natasha; Sakkal, Samy; Vlahos, Katerina; Dudakov, Jarrod A; Boyd, Richard; Chidgey, Ann Patricia

doi:10.1016/j.cellimm.2007.10.007

Cited by 114 publications

(101 citation statements)

References 189 publications

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“…related change results in a significant reduction in thymic size, overall thymocyte cell number, and the absolute number of single-positive CD4+ and CD8+ T cells that leave the thymus [61,62]. Castration has been demonstrated to restore thymic architecture, improve adaptive immunity in both sexes, alter lymphocyte cytokine profile, and in some cases, reverse the Th1/Th2 differences [49,60,[63][64][65][66]. We previously reported that castration did restore thymic architecture.…”

Section: Discussionmentioning

confidence: 99%

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Elevated Levels of Interferon-γ Production By Memory T Cells Do Not Promote Transplant Tolerance Resistance in Aged Recipients.

et al. 2014

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Immunosenescence predisposes the elderly to infectious and autoimmune diseases and impairs the response to vaccination. We recently demonstrated that ageing also impedes development of transplantation tolerance. Unlike their young counterparts (8-12 weeks of age) aged male recipients (greater than 12 months of age) transplanted with a full MHC-mismatched heart are resistant to tolerance mediated by anti-CD45RB antibody. Surprisingly, either chemical or surgical castration restored tolerance induction to levels observed using young recipients. Based on the strong impact of endocrine modulation on transplant tolerance, we explored the impact of ageing and castration on the immune system. Here we report a significant increase in the percentage of T cells that produce interferon-γ (IFN-γ) in aged male versus young male animals and that the overall increase in IFN-γ production was due to an expansion of IFN-γ-producing memory T cells in aged animals. In contrast to IFN-γ production, we did not observe differences in IL-10 expression in young versus old male mice. We hypothesized that endocrine modulation would diminish the elevated levels of IFN-γ production in aged recipients, however, we observed no significant reduction in the percentage of IFN-γ+ T cells upon castration. Furthermore, we neutralized interferon-γ by antibody and did not observe an effect on graft survival. We conclude that while elevated levels of interferon-γ serves as a marker of tolerance resistance in aged mice, other as yet to be identified factors are responsible for its cause. Defining these factors may be relevant to design of tolerogenic strategies for aged recipients.

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Section: Discussionmentioning

confidence: 99%

“…At the time of puberty and linked with an increase in sex steroid levels, the thymus atrophies [59,60]. This dramatic age- Figure 6.…”

Section: Discussionmentioning

confidence: 99%

Elevated Levels of Interferon-γ Production By Memory T Cells Do Not Promote Transplant Tolerance Resistance in Aged Recipients.

et al. 2014

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“…PTP-1B is localized on the surface of the endoplasmic reticulum, and is involved in negative regulation of LEPRb signalling through dephosphorylation of JAK2 after internalization of the LEPRb complex; the endoplasmic reticulum is also the site of action (via Ca++) of the IP3-PIP2-mediated pathway of the Kissprotein1, which in turn modulates GnRH secretion and ultimately LH and FSH secretion [neuroendocrine cells are hereby represented as if they were inside the membrane for practical purposes: in the real pathways the Kiss1 protein binds to the Kiss1 receptor (R), which is expressed on the membrane surface of both immune and neuroendocrine cells: the latter cells promote secretion of GnRH, which in turn stimulate secretion of LH and FSH]. JAK2 can also induce phosphorylation of the IRS1 and 2 proteins, which are responsible for PI3K/AKT and mTOR pathway activation would explain the reason for which disease activity usually decreases during late pregnancy, which is typically characterized by high levels of estriol and also the beneficial effects of estriol administration to nonpregnant MS females in improving the disease manifestations [46][47][48].…”

Section: The Role Of Gender Factors In Paediatric Msmentioning

confidence: 99%

The role of puberty and adolescence in the pathobiology of pediatric multiple sclerosis

Salpietro

Polizzi

Recca

et al. 2018

Mult Scler Demyelinating Disord

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Multiple sclerosis (MS) is increasingly recognized in the paediatric age. In a smaller, but well-established, proportion of paediatric MS patients [20% of total paediatric MS cases: 0.2% to 0.7% of the total MS patients] the onset of disease is before 10 years of age [pre-pubescent (childhood) MS]; in the majority [80%] of paediatric MS patients, however [1.7% to 5.6% of the total MS population], the onset of disease is between 10 and 18 years [post-pubertal (juvenile) MS]. Notably, while pre-pubertal MS occurs almost equally in both genders (female/male ratio = 0.9:1; reverting to 0.4-0.6/1 in pre-school MS children) the female/male ratio rises to 2.2/3:1 in the post-pubertal age. Interestingly, precocious puberty has been associated to: (a) a higher risk of developing MS; and (b) a more severe disease course. In addition to that, males are more susceptible to MS (and manifest more neurodegeneration) than females the latter being however more inflammatory than males; pregnancy however reduces MS relapses. All the above findings led to the suggestion of an underlying female sex hormonal involvement in the pathophysiology of MS vs. a protective role of male sex hormones. Epigenetic perspectives indicate that the interplay between genetic background, environmental triggers and neuroendocrine changes, typically occurring around the time of adolescence, could all play a combined role in initiating and/or promoting MS with onset in the paediatric age including many of the most frequent disease-associated risk factors (e.g., overweight/obesity, low vitamin D levels, reduced sunlight exposure, Epstein-Barr virus infection). According to this proposed complex multifactorial model, susceptibility to MS may be thus acquired during pre-pubertal age and children have probably to wait until the adolescence to manifest their first clinical signs/symptoms.

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“…Clinically, a reversible reduction in sex steroids is achieved by the agonist variants of luteinising hormone releasing hormone (reviewed in Ref. 20). In mouse models sex-steroid ablation (SSA) can be achieved through surgical or chemical castration (reviewed in Refs.…”

Section: Introductionmentioning

confidence: 99%

Regeneration of dendritic cells in aged mice

et al. 2010

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Age-related thymic involution causes a decreased output of thymocytes from the thymus, thereby resulting in impairment of T cell-mediated immunity. While alterations in the T cell and non-haematopoietic stromal compartments have been described, the effects of thymic involution on thymic dendritic cells (DC) are not clearly known. Thymic DC play an essential role in shaping T cell-mediated immune responses by deleting self-reactive thymocytes to establish central tolerance and by inducing regulatory T-cell (Treg) development. It is therefore important to assess the prevalence of and alterations to thymic DC with age, as this may impact on their function. We assessed the numbers and proportions of the three distinct subsets of thymic DC in ageing mice, and showed that these subsets are differentially regulated. This is expected as thymic DC subsets have different origins of development. We further assessed the responses of thymic DC in a regenerative environment, such as that induced by sex-steroid ablation (SSA), and clearly showed that, consistent with global thymus regrowth, all three DC populations increased in numbers and regained their relative proportions to thymocytes after an initial lag period. These findings are important for the clinical translation of thymic regenerative approaches, and indicate that SSA facilitates the maintenance of critical processes such as negative selection and Treg induction through promoting thymic DC regeneration. INTRODUCTIONThe thymus has a central role in the deterioration of the immune system with age due to its natural involution.1 Some thymic decline is initially apparent from as early as the first year in humans, but then thymus undergoes more pronounced degeneration from puberty such that by ,25 years of age, the thymus has decreased to approximately 50% of its size at birth progressing through to ,10% capacity by the fifth and sixth decades.2 While the mechanisms of thymic involution have not been precisely defined, there is a clear correlation with the influence of sex steroids, the removal of which reverses thymic atrophy in animal models. 1,[3][4][5][6][7][8] The progressive decrease in thymus size with age is associated with a loss in thymic epithelial cells and a concomitant decrease in thymopoiesis 9 leading to a reduced thymic output of naive T cells.

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The role of sex steroids and gonadectomy in the control of thymic involution

Cited by 114 publications

References 189 publications

Elevated Levels of Interferon-γ Production By Memory T Cells Do Not Promote Transplant Tolerance Resistance in Aged Recipients.

Elevated Levels of Interferon-γ Production By Memory T Cells Do Not Promote Transplant Tolerance Resistance in Aged Recipients.

The role of puberty and adolescence in the pathobiology of pediatric multiple sclerosis

Regeneration of dendritic cells in aged mice

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