Author Correction: Balance between Estrogens and Proinflammatory Cytokines Regulates Chemokine Production Involved in Thymic Germinal Center Formation.

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H3K27me3 dynamics dictate evolving uterine states in pregnancy and parturition.

Uncovering the causes of pregnancy complications such as preterm labor requires greater insight into how the uterus remains in a noncontractile state until term and then surmounts this state to enter labor. Here, we show that dynamic generation and erasure of the repressive histone modification tri-methyl histone H3 lysine 27 (H3K27me3) in decidual stromal cells dictate both elements of pregnancy success in mice. In early gestation, H3K27me3-induced transcriptional silencing of select gene targets ensured uterine quiescence by preventing the decidua from expressing parturition-inducing hormone receptors, manifesting type 1 immunity, and most unexpectedly, generating myofibroblasts and associated wound-healing responses. In late gestation, genome-wide H3K27 demethylation allowed for target gene upregulation, decidual activation, and labor entry. Pharmacological inhibition of H3K27 demethylation in late gestation not only prevented term parturition, but also inhibited delivery while maintaining pup viability in a noninflammatory model of preterm parturition. Immunofluorescence analysis of human specimens suggested that similar regulatory events might occur in the human decidua. Together, these results reveal the centrality of regulated gene silencing in the uterine adaptation to pregnancy and suggest new areas in the study and treatment of pregnancy disorders.

Balance between Estrogens and Proinflammatory Cytokines Regulates Chemokine Production Involved in Thymic Germinal Center Formation.

The early-onset form of Myasthenia Gravis (MG) is prevalent in women and associates with ectopic germinal centers (GCs) development and inflammation in the thymus. we aimed to investigate the contribution of estrogens in the molecular processes involved in thymic GCs formation. We examined expression of genes involved in anti-acetylcholine receptor (AChR) response in MG, MHC class II and α-AChR subunit as well as chemokines involved in GC development (CXCL13, CCL21and CXCL12). In resting conditions, estrogens have strong regulatory effects on thymic epithelial cells (TECs), inducing a decreased protein expression of the above molecules. In knockout mouse models for estrogen receptor or aromatase, we observed that perturbation in estrogen transduction pathway altered MHC Class II, α-AChR, and CXCL13 expression. However, in inflammatory conditions, estrogen effects were partially overwhelmed by pro-inflammatory cytokines. Interestingly, estrogens were able to control production of type I interferon and therefore play dual roles during inflammatory events. In conclusion, we showed that estrogens inhibited expression of α-AChR and HLA-DR in TECs, suggesting that estrogens may alter the tolerization process and favor environment for an autoimmune response. By contrast, under inflammatory conditions, estrogen effects depend upon strength of the partner molecules with which it is confronted to.

T cell behavior at the maternal-fetal interface.

Understanding the function of T cells at the maternal-fetal interface remains one of the most difficult problems in reproductive immunology. A great deal of work over the last two decades has led to the view that the T cells that populate the decidua have important roles in both normal and pathological pregnancies, but the exact nature of these roles has remained unclear. Indeed, the old assumption that decidual T cells are uniformly threatening to fetal survival because the placenta is fundamentally an 'allograft' has given way to the idea that different T cell subsets contribute in different ways to pregnancy success or failure. Accordingly, some T cells are thought to protect the placenta from immune rejection and facilitate embryo implantation, while others are thought to contribute to pregnancy pathologies such as preeclampsia and spontaneous abortion. Here, we review the current state of information on the behavior of decidual T cells with a focus on both mouse and human studies, and with an emphasis on the many unresolved areas within this overall emerging framework.

Chemokine gene silencing in decidual stromal cells limits T cell access to the maternal-fetal interface.

The chemokine-mediated recruitment of effector T cells to sites of inflammation is a central feature of the immune response. The extent to which chemokine expression levels are limited by the intrinsic developmental characteristics of a tissue has remained unexplored. We show in mice that effector T cells cannot accumulate within the decidua, the specialized stromal tissue encapsulating the fetus and placenta. Impaired accumulation was in part attributable to the epigenetic silencing of key T cell-attracting inflammatory chemokine genes in decidual stromal cells, as evidenced by promoter accrual of repressive histone marks. These findings give insight into mechanisms of fetomaternal immune tolerance, as well as reveal the epigenetic modification of tissue stromal cells as a modality for limiting effector T cell trafficking.

Coordinate regulation of tissue macrophage and dendritic cell population dynamics by CSF-1.

Tissue macrophages (Mφs) and dendritic cells (DCs) play essential roles in tissue homeostasis and immunity. How these cells are maintained at their characteristic densities in different tissues has remained unclear. Aided by a novel flow cytometric technique for assessing relative rates of blood-borne precursor recruitment, we examined Mφ and DC population dynamics in the pregnant mouse uterus, where rapid tissue growth facilitated a dissection of underlying regulatory mechanisms. We demonstrate how Mφ dynamics, and thus Mφ tissue densities, are locally controlled by CSF-1, a pleiotropic growth factor whose in situ level of activity varied widely between uterine tissue layers. CSF-1 acted in part by inducing Mφ proliferation and in part by stimulating the extravasation of Ly6C(hi) monocytes (Mos) that served as Mφ precursors. Mo recruitment was dependent on the production of CCR2 chemokine receptor ligands by uterine Mφs in response to CSF-1. Unexpectedly, a parallel CSF-1-regulated, but CCR2-independent pathway influenced uterine DC tissue densities by controlling local pre-DC extravasation rates. Together, these data provide cellular and molecular insight into the regulation of Mφ tissue densities under noninflammatory conditions and reveal a central role for CSF-1 in the coordination of Mφ and DC homeostasis.

Regulatory and pathogenic mechanisms in human autoimmune myasthenia gravis.

The thymus is frequently hyperplastic in young female myasthenia gravis (MG) patients presenting with anti-acetylcholine receptor (AChR) antibodies. This thymic pathology is characterized by the presence of ectopic germinal centers (GCs) containing B cells involved at least partially in the production of pathogenic anti-AChR antibodies. Our recent studies have furthered our understanding of the mechanisms leading to GC formation in the hyperplastic thymus. First, we showed that CXCL13 and CCL21, chemokines involved in GC formation, are overexpressed in MG thymus. Second, we demonstrated an increase in pro-inflammatory activity in the thymus from MG patients and its partial normalization by glucocorticoids, as evidenced by gene expression profile. Third, we found that pro-inflammatory cytokines are able to upregulate the expression of AChR subunits in thymic epithelial and myoid cells. Fourth, we showed that the function of T regulatory (Treg) cells, whose role is to downregulate the immune response, is severely impaired in the thymus of MG patients; such a defect could explain the chronic immune activation observed consistently in MG thymic hyperplasia. Altogether, these new data suggest that CXCL13 and CCL21, which are produced in excess in MG thymus, attract peripheral B cells and activated T cells, which are maintained chronically activated in the inflammatory thymic environment because of the defect in suppressive activity of Treg cells. Presence of AChR in the thymus and upregulation of its expression by the pro-inflammatory environment contribute to the triggering and maintenance of the anti-AChR autoimmune response.

Differential estrogen receptor expression in autoimmune myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disease associated with thymic hyperplasia and is much more prevalent in women than men. In this study we investigated potential changes in estrogen receptor (ER) expression in thymic hyperplasia. We first quantified by real-time PCR the relative expression of ER alpha and ER beta in normal thymus and found that the ER beta to ER alpha ratio was inverted in thymocytes (8.6 +/- 1.2), compared with thymic epithelial cells (0.18 +/- 0.05). The ER transcript number gradually decreased in thymic epithelial cells during culture, indicating that the thymic environment influences ER expression. CD4+ helper T cells expressed higher level of ERs, compared with CD8+ cells, as assessed by flow cytometry in thymocytes and peripheral blood mononuclear cells. In MG patients, we found an increased expression of ER alpha on thymocytes and both ERs on T cells from peripheral blood mononuclear cells, indicating that the signals provided by thymic and peripheral microenvironments are distinct. Finally, activation of normal thymocytes by proinflammatory cytokines induced increased expression of ERs especially in the CD4+ subset, suggesting that an excess of proinflammatory cytokines could explain the increase of ERs expression on MG lymphocytes. The dysregulation of ER expression in MG lymphocytes could affect the maintenance of the homeostatic conditions and might influence the progression of the autoimmune response.