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The role of estrogen within the Neuroendocrine system and immune system. Monica Delgado Bio 520 Winter 2009. Neuroendocrine System and Immune System: Hypothalamic-Pituitary-Adrenal Axis. www.nature.com/.../n6/fig_tab/nm0606-612_F1.html. Estrogen. Estrogens are a group of steroid compounds - PowerPoint PPT Presentation
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Monica DelgadoBio 520
Winter 2009
www.nature.com/.../n6/fig_tab/nm0606-612_F1.html
Estrogens are a group of steroid compounds
Like all steroid hormones, estrogens readily diffuse across the cell membrane; inside the cell, where they interact with estrogen receptors (ERs)
Produced mainly by developing follicles in the ovaries
Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) stimulate the production of estrogen in the ovaries
Present in both men and women
Usually present higher in women
Estrogen receptor (ER) are activated by 17-β-estradiol (estrogen)
Two types of ERs exist: ER (intracellular receptor) and the estrogen G protein coupled receptor (GPR30)
Barnard, A., et al Neuroimmunomodulation (2008)
Estrogens have a degenerative effect on the primary lymphoid organs, affecting the development, maturation and function of the immune system
Nearly 79% of autoimmune disease patients in the USA are women ERs are present on bone marrow (BM) stromal cells and resident
multipotential stem cells Today’s focus looks at the one of the primary target s of estrogen; the thymus
(which undergoes phenotypic alterations when exposed to estrogen) However, normal thymic development has also been shown to be dependent
on the estradiol/ERα signaling pathway Estrogen treatment has been shown to activate phagocytic activity and
enhance Fc-γR expression on splenic-macrophages Estradiol drastically reduces the lineage-negative Flt3+ Sca-1+ cKit+
population in the BM (a population that contains thymic homing progenators) Lin- Sca-1+ cKit+ (LSK) cells are the principal circulating progenitors with T
lineage potential
Barnard, A., et al Neuroimmunomodulation (2008)Kletcha, A,, et al Journal of Endocrinology (2006)
Barnard, A., et al Neuroimmunomodulation (2008)
In adults, T-cell precursors enter the thymus at the cortico-medullary junction
Uncommited progenators include CD4- CD8- double negative 1 (DN1) cells, in region 2 cells differentiate into the DN2 stage and undergo a proliferative clonal expansion (loss of NK cell potential)
T-cell lineage commitment and the onset of T-cell receptor β-chain rearrangement occurs in DN3 stage (region 3)
Transition from DN to CD4+ CD8+ DP occurs in region 4
DP cells then migrate back through the cortex and into the medulla
Nature Reviews Immunology 4, 278-289 (April 2004)
High levels of estrogens contribute to the development of autoimmunity as a result of degenerative effects on the primary lymphoid organs
Significant thymic atrophy began 48h after infection of estradiol
(A) Thymus cellularity declines over the period of 6 days where it reached a minimun of 19% (compared to control)
(B) Preferential reduction of DP thymocytes due to estrodiol
Age-matched pairs of 6-12wk old male C57BL/6 mice (strain used to show Th1 responses) were injected daily with vehicle only or 17-β-estradiol for 1-6 days
(A) While total BM cellularity was not affected, after 24h there was a greater than 60% reduction in the percentage of Flt3+ LSK cells in estradiol treated mice
(B) Further reduction seen at 48h with decrease in lineage-negative c-Kit+ cells, LSK cells, and Flt3+ LSK cells
Loss of cells in the BM is not likely to contribute significantly to the depletion of DP thymocytes
CD117 also calledC-kit is a cytokine receptor found on Hematopoietic stem cells
% of total bone marrow
% of Lin-, c-Kit cells
% of bone marrow LSK cells
Pregnancy constitutes a major challenge to the immune system
Although localized mechanisms contribute to fetal evasion from immune attack, maternal alloreactive lymphocytes persist
In addition to their function in suppressing autoimmune responses, maternal regulatory T cells suppress aggressive allogeneic response directed at the fetus
Positive effects of pregnancy (counter hypothesis)
(A) Regulatory T cells prevent rejection of the fetal allograft
In an allogeneic context, regulatory T cells are necessary for the prevention of a maternal immune response against the fetus
Allogeneic = sourced from a genetically non-identical member of the same speciesSyngeneic = Genetically identical or closely related, immunologically compatible
Filled circles = females fertilized by C57BL/6 males (Th1 response)Open circles= females fertilzed by BALB/c males (Th2 response)Filled boxes= non pregnant females
Exposure to pregnancy levels of E2 reduced thymic size and cellularity (A)
Thymic atrophy was attenuated in AERKO mice but not obliterated (B)
E2 induced thymic atrophy was fractionally seen in both ER-α and GPR30-but not in ERβ-deficient mice (B)
Suggest that ERα and GPR30, but not Erβ, played partial roles in E2-induced thymic atrophy
Note: Erα- and Erβ-knockout (AERKO and BERKO) mice
Critique: Column B thymic size irregularities were not addressed
Note: DERKO = mice with inactivated ERα and ERβ
The estrogenic response to thymic atrophy were absent or largely reduced in DERKO mice
WT – DERKO / WT X 100
100 – Dependent effect
E2 Treatment inhibits TNF-α producing inflammatory cells in CNS of mice with Experimental autoimmune encephalomyelitis (EAE)
Myelin oligodendrocyte glycoprotein (MOG)-35-55-stimulated CNS mononuclear cells from E2-treated C57BL/6J mice showed a large reduction in intracellular staining TNF-α
Critique: Increase in T cell was not really addressed
Estrogen treatment increases nitric oxide levels in the supernatants from Con-A-stimulated splenocytes when compared to that from placebo treated mice
Blocking with Con-A + CTLA-41g fusion protein leads to a decrease in nitric oxide levels
Previous studies by Karpuzoglu’s group suggest that estrogen-induced up-regulation of iNOS/nitric oxide in activated splenocytes is likely to be mediated through IFN-γ
Note:Con-A = T cell mitogenCTLA4 (Cytotoxic T-Lymphocyte Antigen 4)
Article Conclusions made Support Hypothesis?
Zoller and Kersh (2006) Estradiol drastically reduces the thymic homing progenators in the BM (thymic atrophy)
Y
Aluvihare, Kallikourdis, and Betz (2004)
Regulatory T Cells Mediate Maternal Tolerance to the Fetus
N (counter aspect)
Wang et al (2008) GPR30 Contributes to Estrogen-Induced Thymic Atrophy
Y
Lindberg, M. K., et al (2002) Estrogen effects such as thymic atrophy are mainly EFα mediated
Y
Offner, H., and Polanczyk, M. (2006)
E2 treatment inhibits TNF-α producing inflammatory cells in CNS of mice with EAT
N
Karpuzoglu, E., Ahmed, S. A. (2006)
Estrogens are not only involved in regulation of normal immune responses, but also are implicated in many autoimmune diseases
Y
Elevated estradiol induces loss of T lineage progenators in the BM (Zoller and Kersh 2006)
Regulatory T cells are required for the maternal immune system to tolerate the fetal allograft (Aluvihare, Kallikourdis, and Betz 2004)
Wang et al showed that E2-induced thymic atrophy involves both ERα and GPR30, but not ERβ
Karpuzoglu’s group showed that estrogen treatment in mice markedly upregulates the levels of iNOS mRNA through IFN-γ; Also estrogens are not only involved in regulation of normal immune responses, but also are implicated in many autoimmune diseases
The exact pathway of estrogen-induced thymic degeneration is yet to be elucidated/established
Further research should focus on the different and frequently opposite effects exerted by physiologic and pharmacologic doses of estrogens (dose-related effects)
Further studies must be directed to the inflammatory mediators (i.e., cytokines) that seem to alter the peripheral metabolism of sex hormones and complicate the effects of sex hormones on susceptibility to autoimmunity
There are no available data on cytokine measurements on non-immune hyperthyroidsm
Questions?