ABSTRACT
Immunosenescence, characterized by complex modifications of immunity with age, could be related to frailty syndrome in elderly individuals, leading to an inadequate response to minimal aggression. Functional decline (i.e., the loss of ability to perform activities of daily living) is related to frailty and decreased physiological reserves and is a frequent outcome of hospitalization in older patients. Links between immunosenescence and frailty have been explored and 20 immunological parameters, including insulin-like growth factor-1 (IGF-1), thymopoeisis, and telomere length, were shown to be affected in elderly patients with functional decline. A strong relationship between IGF-1 and thymic ouput was evidenced. IGF-1, a mediator of growth hormone (GH), was subsequently shown to induce interleukin-7 secretion in cultured primary human thymic epithelial cells. We are exploring the stress hypothesis in which an acute stressor is used as the discriminator of frailty susceptibility. GH can counteract the deleterious immunosuppressive effects of stress-induced steroids. Under nonstress conditions, the immunosenescent system preserves physiological responses, while under stress conditions, the combination of immunosenescence and a defect in the somatotrope axis might lead to functional decline.
Subject(s)
Frail Elderly , Growth Hormone-Releasing Hormone/metabolism , Growth Hormone/metabolism , Immunosenescence/physiology , Insulin-Like Growth Factor I/metabolism , Activities of Daily Living , Aged, 80 and over , Biomarkers , Cells, Cultured , Growth Hormone/genetics , Hematopoiesis/immunology , Hematopoiesis/physiology , Humans , Immunosenescence/immunology , Interleukin-7/metabolism , Stress, Physiological/physiology , Telomere Homeostasis/physiologyABSTRACT
AIMS: We address the question of the expression and the role of the growth hormone/insulin-like growth factor (GH/IGF) axis in the thymus. METHODS: Using RT-qPCR, the expression profile of various components of the somatotrope GH/IGF axis was measured in different thymic cell types and during thymus embryogenesis in Balb/c mice. The effect of GH on T cell differentiation was explored via thymic organotypic culture. RESULTS: Transcription of Gh, Igf1, Igf2 and their related receptors predominantly occurred in thymic epithelial cells (TEC), while a low level of Gh and Igf1r transcription was also evidenced in thymic T cells (thymocytes). Gh, Ghr, Ins2, Igf1, Igf2, and Igfr1 displayed distinct expression profiles depending on the developmental stage. The protein concentrations of IGF-1 and IGF-2 were in accordance with the profile of their gene expression. In fetal thymus organ cultures (FTOC) derived from Balb/c mice, treatment with exogenous GH resulted in a significant increase of double negative CD4-CD8- T cells and CD4+ T cells, together with a decrease in double positive CD4+CD8+ T cells. These changes were inhibited by concomitant treatment with GH and the GH receptor (GHR) antagonist pegvisomant. However, GH treatment also induced a significant decrease in FTOC Gh, Ghr and Igf1 expression. CONCLUSION: These data show that the thymotropic properties of the somatotrope GH/IGF-1 axis involve an interaction between exogenous GH and GHR expressed by TEC. Since thymic IGF-1 is not increased by GH treatment, the effects of GH upon T cell differentiation could implicate a different local growth factor or cytokine.
Subject(s)
Cell Differentiation/immunology , Growth Hormone/metabolism , Insulin-Like Growth Factor II/metabolism , Insulin-Like Growth Factor I/metabolism , Receptor, IGF Type 1/metabolism , Thymus Gland/immunology , Animals , Cell Differentiation/genetics , Cells, Cultured , Epithelial Cells/metabolism , Gene Expression/physiology , Growth Hormone/genetics , Growth Hormone/immunology , Insulin/genetics , Insulin/immunology , Insulin/metabolism , Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor I/immunology , Insulin-Like Growth Factor II/genetics , Insulin-Like Growth Factor II/immunology , Mice , Mice, Inbred BALB C , Organ Culture Techniques , Real-Time Polymerase Chain Reaction , Receptor, IGF Type 1/genetics , Receptor, IGF Type 1/immunology , Receptors, Somatotropin/genetics , Receptors, Somatotropin/immunology , Receptors, Somatotropin/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/metabolism , Thymocytes/metabolism , Thymus Gland/embryology , Thymus Gland/metabolismABSTRACT
Before being able to react against infectious non-self-antigens, the immune system has to be educated in recognition and tolerance of neuroendocrine self-proteins. This sophisticated educational process takes place only in the thymus. The development of an autoimmune response directed to neuroendocrine glands has been shown to result from a thymus dysfunction in programming immunological self-tolerance to neuroendocrine-related antigens. This thymus dysfunction leads to a breakdown of immune homeostasis with an enrichment of 'forbidden' self-reactive T cells and a deficiency in self-antigen-specific natural regulatory T cells in the peripheral T lymphocyte repertoire. A large number of neuroendocrine self-antigens are expressed by the thymic epithelium, under the control of the autoimmune regulator (AIRE) gene/protein in the medulla. Based on the close homology and cross-tolerance between thymic type 1 diabetes-related self-antigens and peripheral antigens targeted in ß-cells by autoimmunity, a novel type of vaccination is currently developed for the prevention and cure of type 1 diabetes. If this approach were found to be effective in reprogramming immunological tolerance that is absent or broken in this disease, it could pave the way for the design of negative/tolerogenic self-vaccines against other endocrine and organ-specific autoimmune disorders.
