Cells In Peripheral Tissues Research Articles

Mind the GAPS: Glia associated with psychological stress.

Glial cells are an integral component of the nervous system, performing crucial functions that extend beyond structural support, including modulation of the immune system, tissue repair, and maintaining tissue homeostasis. Recent studies have highlighted the importance of glial cells as key mediators of stress responses across different organs. This review focuses on the roles of glial cells in peripheral tissues in health and their involvement in diseases linked to psychological stress. Populations of glia associated with psychological stress ("GAPS") emerge as a promising target cell population in our basic understanding of stress-associated pathologies, highlighting their role as mediators of the deleterious effects of psychological stress on various health conditions. Ultimately, new insights into the impact of stress on glial cell populations in the periphery may support clinical efforts aimed at improving the psychological state of patients for improved health outcomes.

A RORE-dependent Intronic Enhancer in the IL-7 Receptor-α Locus Controls Glucose Metabolism via Vγ4+ γδT17 Cells.

The IL-7R regulates the homeostasis, activation, and distribution of T cells in peripheral tissues. Although several transcriptional enhancers that regulate IL-7Rα expression in αβ T cells have been identified, enhancers active in γδ T cells remain unknown. In this article, we discovered an evolutionarily conserved noncoding sequence (CNS) in intron 2 of the IL-7Rα-chain (IL-7Rα) locus and named this region CNS9. CNS9 contained a conserved retinoic acid receptor-related orphan receptor (ROR)-responsive element (RORE) and exerted RORγt-dependent enhancer activity invitro. Mice harboring point mutations in the RORE in CNS9 (CNS9-RORmut) showed reduced IL-7Rα expression in IL-17-producing Vγ4+ γδ T cells. In addition, the cell number and IL-17A production of Vγ4+ γδ T cells were reduced in the adipose tissue of CNS9-RORmut mice. Consistent with the reduction in IL-17A, CNS9-RORmut mice exhibited decreased IL-33 expression in the adipose tissue, resulting in fewer regulatory T cells and glucose intolerance. The CNS9-ROR motif was partially responsible for IL-7Rα expression in RORγt+ regulatory T cells, whereas IL-7Rα expression was unaffected in RORγt-expressing Vγ2+ γδ T cells, Th17 cells, type 3 innate lymphoid cells, and invariant NKT cells. Our results indicate that CNS9 is a RORΕ-dependent, Vγ4+ γδ T cell-specific IL-7Rα enhancer that plays a critical role in adipose tissue homeostasis via regulatory T cells, suggesting that the evolutionarily conserved RORΕ in IL-7Rα intron 2 may influence the incidence of type 2 diabetes.

Invariant γδTCR natural killer-like effector T cells in the naked mole-rat

The naked mole-rat (Heterocephalus glaber) is a long-lived rodent species showing resistance to the development of cancer. Although naked mole-rats have been reported to lack natural killer (NK) cells, γδ T cell-based immunity has been suggested in this species, which could represent an important arm of the immune system for antitumor responses. Here, we investigate the biology of these unconventional T cells in peripheral tissues (blood, spleen) and thymus of the naked mole-rat at different ages by TCR repertoire profiling and single-cell gene expression analysis. Using our own TCR annotation in the naked mole-rat genome, we report that the γδ TCR repertoire is dominated by a public invariant Vγ4-2/Vδ1-4 TCR, containing the complementary-determining-region-3 (CDR3)γ CTYWDSNYAKKLF / CDR3δ CALWELRTGGITAQLVF that are likely generated by short-homology-repeat-driven DNA rearrangements. This invariant TCR is specifically found in γδ T cells expressing genes associated with NK cytotoxicity and is generated in both the thoracic and cervical thymus of the naked mole-rat until adult life. Our results indicate that invariant Vγ4-2/Vδ1-4 NK-like effector T cells in the naked mole-rat can contribute to tumor immunosurveillance by γδ TCR-mediated recognition of a common molecular signal.

Research progress on the roles of dopamine and dopamine receptors in digestive system diseases.

Dopamine (DA) is a neurotransmitter synthesized in the human body that acts on multiple organs throughout the body, reaching them through the blood circulation. Neurotransmitters are special molecules that act as messengers by binding to receptors at chemical synapses between neurons. As ligands, they mainly bind to corresponding receptors on central or peripheral tissue cells. Signalling through chemical synapses is involved in regulating the activities of various body systems. Lack of DA or a decrease in DA levels in the brain can lead to serious diseases such as Parkinson's disease, schizophrenia, addiction and attention deficit disorder. It is widely recognized that DA is closely related to neurological diseases. As research on the roles of brain-gut peptides in human physiology and pathology has deepened in recent years, the regulatory role of neurotransmitters in digestive system diseases has gradually attracted researchers' attention, and research on DA has expanded to the field of digestive system diseases. This review mainly elaborates on the research progress on the roles of DA and DRs related to digestive system diseases. Starting from the biochemical and pharmacological properties of DA and DRs, it discusses the therapeutic value of DA- and DR-related drugs for digestive system diseases.

CD47 promotes peripheral T cell survival by preventing dendritic cell–mediated T cell necroptosis

Conventional dendritic cells (cDCs) are required for peripheral T cell homeostasis in lymphoid organs, but the molecular mechanism underlying this requirement has remained unclear. We here show that T cell-specific CD47-deficient (Cd47 ΔT) mice have a markedly reduced number of T cells in peripheral tissues. Direct interaction of CD47-deficient T cells with cDCs resulted in activation of the latter cells, which in turn induced necroptosis of the former cells. The deficiency and cell death of T cells in Cd47 ΔT mice required expression of its receptor signal regulatory protein α on cDCs. The development of CD4+ T helper cell-dependent contact hypersensitivity and inhibition of tumor growth by cytotoxic CD8+ T cells were both markedly impaired in Cd47 ΔT mice. CD47 on T cells thus likely prevents their necroptotic cell death initiated by cDCs and thereby promotes T cell survival and function.

Melatonin, circadian rhythms and breast cancer

Breast cancer (BC) is the leading cause of morbidity and mortality of malignant neoplasms in women worldwide. In spite of a large number of studies devoted to the etiopathogenesis of this group of malignant tumors, many questions concerning specific mechanisms of their origin and development are still unresearched. Based on numerous studies in recent years, in addition to traditional risk factors (such as hereditary factors, hormonal disorders, environmental factors, etc.), foreign and Russian authors have identified a new risk factor for BC development - the sphere of molecular disorders affecting circadian rhythms and circadian genes, as well as metabolic and regulatory intracellular pathways regulated by them. It has been shown that the balance between oncogenes and suppressor genes and processes such as neoangiogenesis, metastasis and antitumor immune response depend on the functioning of the circadian rhythm system. One of the key metabolites in the circadian rhythm regulation system is melatonin, which physiological effects extend not only to the central nervous system, but also to peripheral tissue cells. The study of the relationship between circadian rhythm disturbances, melatonin secretion and malignant tumors is one of the important tasks of modern oncology. In the present review the following aspects of this problem are considered in detail: relationships between circadian rhythms, melatonin and BC; molecular mechanisms of melatonin antitumor action in BC; therapeutic potential of melatonin in prevention and treatment of malignant breast tumors as a direct antitumor agent, a component of accompanying treatment, and as a radiosensitizer and radioprotector for radiotherapy. The purpose of this review is to investigate the problem of the relationship between the circadian rhythm system, melatonin and molecular mechanisms of development and progression of breast malignancies, as well as the therapeutic potential of melatonin in their prevention and treatment. The review is based on the study of relevant and reliable scientific articles, reviews, meta-analyses, systematic reviews, and clinical trials published in Scopus, PubMed, Web of Science and in peer-reviewed Russian journals mainly during the last 5 years.

CAR-T Cell-Mediated B-Cell Depletion in Central Nervous System Autoimmunity.

Anti-CD20 monoclonal antibody (mAb) B-cell depletion is a remarkably successful multiple sclerosis (MS) treatment. Chimeric antigen receptor (CAR)-T cells, which target antigens in a non-major histocompatibility complex (MHC)-restricted manner, can penetrate tissues more thoroughly than mAbs. However, a previous study indicated that anti-CD19 CAR-T cells can paradoxically exacerbate experimental autoimmune encephalomyelitis (EAE) disease. We tested anti-CD19 CAR-T cells in a B-cell-dependent EAE model that is responsive to anti-CD20 B-cell depletion similar to the clinical benefit of anti-CD20 mAb treatment in MS. Anti-CD19 CAR-T cells or control cells that overexpressed green fluorescent protein were transferred into C57BL/6 mice pretreated with cyclophosphamide (Cy). Mice were immunized with recombinant human (rh) myelin oligodendrocyte protein (MOG), which causes EAE in a B-cell-dependent manner. Mice were evaluated for B-cell depletion, clinical and histologic signs of EAE, and immune modulation. Clinical scores and lymphocyte infiltration were reduced in mice treated with either anti-CD19 CAR-T cells with Cy or control cells with Cy, but not with Cy alone. B-cell depletion was observed in peripheral lymphoid tissue and in the CNS of mice treated with anti-CD19 CAR-T cells with Cy pretreatment. Th1 or Th17 populations did not differ in anti-CD19 CAR-T cell, control cell-treated animals, or Cy alone. In contrast to previous data showing that anti-CD19 CAR-T cell treatment exacerbated EAE, we observed that anti-CD19 CAR-T cells ameliorated EAE. In addition, anti-CD19 CAR-T cells thoroughly depleted B cells in peripheral tissues and in the CNS. However, the clinical benefit occurred independently of antigen specificity or B-cell depletion.

COVID-19 Heart Lesions in Children: Clinical, Diagnostic and Immunological Changes.

In the beginning of COVID-19, the proportion of confirmed cases in the pediatric population was relatively small and there was an opinion that children often had a mild or asymptomatic course of infection. Our understanding of the immune response, diagnosis and treatment of COVID-19 is highly oriented towards the adult population. At the same time, despite the fact that COVID-19 in children usually occurs in a mild form, there is an incomplete understanding of the course as an acute infection and its subsequent manifestations such as Long-COVID-19 or Post-COVID-19, PASC in the pediatric population, correlations with comorbidities and immunological changes. In mild COVID-19 in childhood, some authors explain the absence of population decreasing T and B lymphocytes. Regardless of the patient's condition, they can have the second phase, related to the exacerbation of inflammation in the heart tissue even if the viral infection was completely eliminated-post infectious myocarditis. Mechanism of myocardial dysfunction development in MIS-C are not fully understood. It is known that various immunocompetent cells, including both resident inflammatory cells of peripheral tissues (for example macrophages, dendritic cells, resident memory T-lymphocytes and so on) and also circulating in the peripheral blood immune cells play an important role in the immunopathogenesis of myocarditis. It is expected that hyperproduction of interferons and the enhanced cytokine response of T cells 1 and 2 types contribute to dysfunction of the myocardium. However, the role of Th1 in the pathogenesis of myocarditis remains highly controversial. At the same time, the clinical manifestations and mechanisms of damage, including the heart, both against the background and after COVID-19, in children differ from adults. Further studies are needed to evaluate whether transient or persistent cardiac complications are associated with long-term adverse cardiac events.

JAK1 signaling in dendritic cells promotes peripheral tolerance in autoimmunity through PD-L1-mediated regulatory Tcell induction.

Dendritic cells (DCs) induce peripheral Tcell tolerance, but cell-intrinsic signaling cascades governing their stable tolerogenesis remain poorly defined. Janus Kinase 1 (JAK1) transduces cytokine-receptor signaling, and JAK inhibitors (Jakinibs), including JAK1-specific filgotinib, break inflammatory cycles in autoimmunity. Here, we report in heterogeneous DC populations of multiple secondary lymphoid organs that JAK1 promotes peripheral Tcell tolerance during experimental autoimmune encephalomyelitis (EAE). Mice harboring DC-specific JAK1 deletion exhibit elevated peripheral CD4+ Tcell expansion, less regulatory Tcells (Tregs), and worse EAE outcomes, whereas adoptive DC transfer ameliorates EAE pathogenesis by inducing peripheral Tregs, programmed cell death ligand 1 (PD-L1) dependently. This tolerogenic program is substantially reduced upon the transfer of JAK1-deficient DCs. DC-intrinsic IFN-γ-JAK1-STAT1 signaling induces PD-L1, which is required for DCs to convert CD4+ Tcells into Tregs invitro and attenuated upon JAK1 deficiency and filgotinib treatment. Thus, DC-intrinsic JAK1 promotes peripheral tolerance, suggesting potential unwarranted DC-mediated effects of Jakinibs in autoimmune diseases.

SNHG12 regulates biological behaviors of ox-LDL-induced HA-VSMCs through upregulation of SPRY2 and NUB1

Background and aimsHuman vascular smooth muscle cells (HA-VSMCs) are an important cell type involved in atherosclerosis. Low density lipoprotein (LDL) is a lipoprotein particle that carries cholesterol into peripheral tissue cells, and oxidized modified LDL (ox-LDL) is a well-known inducer of the atherosclerosis-related phenotype switch in VSMCs, leading to the occurrence of atherosclerosis. Accumulating studies have revealed that long non-coding RNAs (lncRNAs) mediate the effect of ox-LDL on the atherosclerosis-related biological activities of HA-VSMCs, including proliferation, migration, and apoptosis. However, the mechanism of small nucleolar RNA host gene 12 (SNHG12) in ox-LDL-induced phenotype switch of VSMCs remains unclear. Thus, this research dug in whether SNHG12 mediated the influence of ox-LDL on HA-VSMCs and the potential mechanism. MethodsFundamental experiments and functional assays were performed to measure the function of SNHG12 on HA-VSMCs. Then, mechanism assays and rescue assays were performed to study the regulatory mechanism of SNHG12 in HA-VSMCs. ResultsSNHG12 reversed the influence of ox-LDL treatment in enhancing cell proliferative and migratory abilities and weakening apoptotic ability in HA-VSMCs. SNHG12 was a competitive endogenous RNA (ceRNA) competing with sprouty RTK signaling antagonist 2 (SPRY2) to bind to miR-1301-3p, thus up-regulating SPRY2 expression in ox-LDL-treated HA-VSMCs. Besides, SNHG12 recruited serine and arginine rich splicing factor 1 (SRSF1) to stabilize negative regulator of ubiquitin like proteins 1 (NUB1) expression. ConclusionsThis study illustrated that SNHG12 inhibited cell proliferation, migration and facilitated cell apoptosis in ox-LDL-induced HA-VSMCs by up-regulating SPRY2 and NUB1.

The Effects of Trained Innate Immunity on T Cell Responses; Clinical Implications and Knowledge Gaps for Future Research.

The burgeoning field of innate immune training, also called trained immunity, has given immunologists new insights into the role of innate responses in protection against infection and in modulating inflammation. Moreover, it has led to a paradigm shift in the way we think about immune memory and the interplay between innate and adaptive immune systems in conferring immunity against pathogens. Trained immunity is the term used to describe the medium-term epigenetic and metabolic reprogramming of innate immune cells in peripheral tissues or in the bone marrow stem cell niche. It is elicited by an initial challenge, followed by a significant period of rest that results in an altered response to a subsequent, unrelated challenge. Trained immunity can be associated with increased production of proinflammatory mediators, such as IL-1β, TNF and IL-6, and increased expression of markers on innate immune cells associated with antigen presentation to T cells. The microenvironment created by trained innate immune cells during the secondary challenge may have profound effects on T cell responses, such as altering the differentiation, polarisation and function of T cell subtypes, including Th17 cells. In addition, the Th1 cytokine IFN-γ plays a critical role in establishing trained immunity. In this review, we discuss the evidence that trained immunity impacts on or can be impacted by T cells. Understanding the interplay between innate immune training and how it effects adaptive immunity will give insights into how this phenomenon may affect the development or progression of disease and how it could be exploited for therapeutic interventions or to enhance vaccine efficacy.

The Crosstalk Between Dendritic Cells, Cytokine-Induced Killer Cells And Cancer Cells From The Perspective Of Combination Therapy

Dendritic cells (DCs) are considered the most potent professional antigen-presenting cells (APCs) that elicit adaptive antitumour immunity. DCs integrate multiple environmental signals by efficiently processing tumour-associated antigens (TAAs) and migrating to draining lymph nodes (dLNs), where they present foreign antigens to T cells for priming. DCs thus serve as a major link between innate and adaptive immunity. Although DCs (mostly monocyte-derived DCs [mo-DCs]) have already been used in cancer therapies, such approaches have shown limited efficacy. Mo-DCs have the unique ability to present antigens to T cells in peripheral tissues. CD3+CD56+ cytokine-induced killer (CIK) cells are characterized by both MHC-restricted and MHC-unrestricted antitumour cytotoxicity against a broad range of cancer cells. This review presents an overview of the mechanisms by which mo-DCs and CIK cells’ interact with each other and with tumours. The maturation of DCs was identified as a crucial step in the development of effective DC-based vaccines against cancer. A further improved adoptive immunotherapy strategy involves a combination of mature mo-DCs and CIK cells. Combination therapy presents many opportunities for cancer treatment, as reported by a number of clinical trials. However, there is a lack of fundamental studies on the interaction of in vitro-generated mo-DCs with CIK cells. We discuss several methods of boosting DC-based vaccines and review the current knowledge of contact-dependent and cytokine-induced interactions of mo-DCs with CIK cells. We highlight that the combination of mo-DCs with CIK cells activates MHC-restricted and MHC-unrestricted immune responses.

The molecular basis and cellular effects of distinct CD103 expression on CD4 and CD8 T cells.

Integrin CD103 mediates the adhesion and tissue retention of T cells by binding to E-cadherin which is abundant on epithelial cells. Notably, CD103 is highly expressed on CD8 T cells but conspicuously absent on most CD4 T cells. The mechanism controlling such lineage-specific expression of CD103 remains unclear. Using a series of genetically engineered mouse models, here, we demonstrate that the regulatory mechanism of CD103 expression is distinct between CD4 and CD8 T cells, and that the transcription factor Runx3 plays an important but not an essential role in this process. We further found that the availability of integrin β7 which heterodimerizes with CD103 was necessary but also constrained the surface expression of CD103. Notably, the forced surfaceexpression of CD103 did not significantly alter the thymic development of conventional T cells but severely impaired the generation of MHC-II-restricted TCR transgenic T cells, revealing previously unappreciated aspects of CD103 in the selection and maturation of CD4 T cells. Unlike its effect on CD4 T cell development, however, CD103 overexpression did not significantly affect CD4 T cells in peripheral tissues. Moreover, the frequency and number of CD4 T cells in the small intestine epithelium did not increase even though E-cadherin is highly expressed in this tissue. Collectively, these results suggest that most mature CD4 T cells are refractory to the effects of CD103 expression, and that they presumably utilize CD103-independent pathways to control their tissue retention and residency.

Neuroimmune interactions in peripheral tissues

Neuroimmune interactions have been revealed to be at the centre stage of tissue defence, organ homeostasis, and organismal physiology. Neuronal and immune cell subsets have been shown to colocalize in discrete tissue environments, forming neuroimmune cell units that constitute the basis for bidirectional interactions. These multitissue units drive coordinated neuroimmune responses to local and systemic signals, which represents an important challenge to our current views of mucosal physiology and immune regulation. In this review, we focus on the impact of reciprocal neuroimmune interactions, focusing on the anatomy of neuronal innervation and on the neuronal regulation of immune cells in peripheral tissues. Finally, we shed light on recent studies that explore how neuroimmune interactions maximise sensing and integration of environmental aggressions, modulating immune function in health and disease.

Transcriptome analysis of reactivated T H 1 cells reveal distinct differences between priming and reactivation processes

As a key player of the adaptive immune system CD4+ T cells play a critical role in orchestrating an effective immune response during infections, autoimmunity or cancer. Few studies have addressed antigen-mediated reactivation of T effector cells in peripheral tissues, as opposed to the well-studied primary activation (priming) in lymph nodes. We hypothesize that T effector cell reactivation is distinct from naïve T cell priming beyond linage differentiation, focusing on TH1 effector cells. We employed OT-II/Nur77GFP mice that allowed direct identification of T cell receptor (TCR) activated cells as Nur77 expression is up-regulated by TCR stimulation and correlates with the strength of TCR stimulation. Isolated naïve CD4 T cells (naïve resting), were either stimulated (naïve stimulated) or differentiated into TH1 (effector resting) and consecutively reactivated in an in vitro restimulation assay (effector stimulated). We correlated Nur77-GFP expression to the expression of TH1 lead cytokine IFNγ via qRT-PCR and flow cytometry and found that the maximum of restimulation is reached after 6-8 hours. While Nur77-GFP expression declines slowly after 4 hours in effector cells, IFNγ expression increases for up to 8 hours. In naïve T cells we correlated Nur77-GFP expression to IL2 expression and found that after 4 hours of stimulation IL2 expression reaches a saturation and nearly 90% of cells are Nur77-GFP positive. Transcriptome analysis of sorted naïve (CD62L+, CD44-, CD69-, Nur77-GFP-), active naïve (CD62Lint, CD44-, CD69+, Nur77-GFP+), TH1 (CD62L+, CD44+, Nur77-GFP-) and reactivated TH1 cells (CD62L+, CD44+, Nur77-GFP+) revealed 11899 significantly differentially expressed genes of overall T cell differentiation and activation (naïve vs reactivated effector), 10840 of naïve T cell activation (naïve vs active naïve), 11583 of TH1 differentiation (naïve vs effector) and 10736 of TH1 reactivation (effector vs reactivated effector). Furthermore 3107 genes were predominantly specifically regulated in reactivated TH1 cells. Of these, 447 are solely regulated in reactivated TH1 cells and do not appear in the other comparisons. We here report a unique signature to T effector cell reactivation that goes beyond lineage alterations.

IL-9 regulates type-2 CD4 tissue resident memory cell mediated allergic airway recall responses

Abstract Allergic asthma is a chronic inflammatory lung disease with intermittent flares where patients experience symptoms mediated by memory T cells. Allergen-specific CD4+ tissue resistant memory (Trm) cells in peripheral tissues have been reported to facilitate mucosal barrier immunity. However, the precise role of Trm CD4+ T cells in allergic exacerbations is not clearly defined. In this study we identified interleukin-9 (IL-9)-secreting allergen-specific CD4 T cells with a memory phenotype that regulate recall response to Aspergillus fumigatus. Inhibition of circulating T cells by administering FTY720 in the last month of rest, diminished the total CD4 T cells population in the lung, while the IL-9 secreting CD4 tissue resident cells remained stable. Single-cell RNA-seq and ATAC-seq confirmed the presence of multi-cytokine producing IL-9 secreting CD4 Trms in early recall responses to the allergen. Blockade of IL-9 prior to recall challenge phase reduced overall allergic lung inflammation observed through both flow-cytometry and single cell-RNA-seq analysis. IL-9 neutralization reduced cellularity of several populations in the lung including granulocytes and lymphocytes. Moreover, the expression of genes associated with mucus metaplasia including Muc2, Muc5ac, Muc5b, and Bpifb1 were significantly reduced in type-2 alveolar and epithelial cells with anti-IL-9 treatment. These findings demonstrate that IL-9-producing Trms play an important role in mediating allergic memory responses. IL-9 could be a promising therapeutic target specifically in patients showing symptoms of intermittent allergic response.

Effective Prediction of Diabetes Mellitus using Nine different Machine Learning Techniques and their Performances

Diabetes is a disease where the predominant finding is high blood sugar. The high blood sugar may either be because of deficient insulin production (Type 1) or insulin resistance in peripheral tissue cells (Type 2). Many problems occur if diabetes remains untreated and unidentified. It is additional inventor of various varieties of disorders for example: coronary failure, blindness, urinary organ diseases etc. Nine different machine learning techniques are used in this research work for prediction of diabetes. A dataset of diabetic patient’s is taken and nine different machine learning techniques are applied on the dataset. Positive likelihood ratio, Negative likelihood ratio, Positive predictive value, Negative predictive value, Disease prevalence, Specificity, Precision, Recall, F1-Score ,True positive rate, False positive rate of the applied algorithms is discussed and compared. Diabetes is growing at an increasing in the world and it requires continuous monitoring. To check this we use Logical regression, Random forest, Logical regression CV, Support Vector Machine, Artificial Neural Network (ANN), Decision Tree, k-nearest neighbors (KNN), XGB classifier

The molecular mechanisms of copper metabolism and its roles in human diseases.

Copper is an essential element in cells; it can act as either a recipient or a donor of electrons, participating in various reactions. However, an excess of copper ions in cells is detrimental as these copper ions can generate free radicals and increase oxidative stress. In multicellular organisms, copper metabolism involves uptake, distribution, sequestration, and excretion, at both the cellular and systemic levels. Mammalian enterocytes take in bioavailable copper ions from the diet in a Ctr1-dependent manner. After incorporation, cuprous ions are delivered to ATP7A, which pumps Cu+ from enterocytes into the blood. Copper ions arrive at the liver through the portal vein and are incorporated into hepatocytes by Ctr1. Then, Cu+ can be secreted into the bile or the blood via the Atox1/ATP7B/ceruloplasmin route. In the bloodstream, this micronutrient can reach peripheral tissues and is again incorporated by Ctr1. In peripheral tissue cells, cuprous ions are either sequestrated by molecules such as metallothioneins or targeted to utilization pathways by chaperons such as Atox1, Cox17, and CCS. Copper metabolism must be tightly controlled in order to achieve homeostasis and avoid disorders. A hereditary or acquired copper unbalance, including deficiency, overload, or misdistribution, may cause or aggravate certain diseases such as Menkes disease, Wilson disease, neurodegenerative diseases, anemia, metabolic syndrome, cardiovascular diseases, and cancer. A full understanding of copper metabolism and its roles in diseases underlies the identification of novel effective therapies for such diseases.

Obesity-Induced Changes in Bone Marrow Homeostasis.

Obesity is characterized by low-grade inflammation, which is accompanied by increased accumulation of immune cells in peripheral tissues including adipose tissue (AT), skeletal muscle, liver and pancreas, thereby impairing their primary metabolic functions in the regulation of glucose homeostasis. Obesity has also shown to have a detrimental effect on bone homeostasis by altering bone marrow and hematopoietic stem cell differentiation and thus impairing bone integrity and immune cell properties. The origin of immune cells arises in the bone marrow, which has been shown to be affected with the obesogenic condition via increased cellularity and shifting differentiation and function of hematopoietic and bone marrow mesenchymal stem cells in favor of myeloid progenitors and increased bone marrow adiposity. These obesity-induced changes in the bone marrow microenvironment lead to dramatic bone marrow remodeling and compromising immune cell functions, which in turn affect systemic inflammatory conditions and regulation of whole-body metabolism. However, there is limited information on the inflammatory secretory factors creating the bone marrow microenvironment and how these factors changed during metabolic complications. This review summarizes recent findings on inflammatory and cellular changes in the bone marrow in relation to obesity and further discuss whether dietary intervention or physical activity may have beneficial effects on the bone marrow microenvironment and whole-body metabolism.

A Defect in Thymic Tolerance Causes T Cell-Mediated Autoimmunity in a Murine Model of COPA Syndrome.

COPA syndrome is a recently described Mendelian autoimmune disorder caused by missense mutations in the coatomer protein complex subunit α (COPA) gene. Patients with COPA syndrome develop arthritis and lung disease that presents as pulmonary hemorrhage or interstitial lung disease (ILD). Immunosuppressive medications can stabilize the disease, but many patients develop progressive pulmonary fibrosis, which requires life-saving measures, such as lung transplantation. Because very little is understood about the pathogenesis of COPA syndrome, it has been difficult to devise effective treatments for patients. To date, it remains unknown which cell types are critical for mediating the disease as well as the mechanisms that lead to autoimmunity. To explore these issues, we generated a CopaE241K/+ germline knock-in mouse bearing one of the same Copa missense mutations in patients. Mutant mice spontaneously developed ILD that mirrors lung pathology in patients, as well as elevations of activated cytokine-secreting T cells. In this study, we show that mutant Copa in epithelial cells of the thymus impairs the thymic selection of T cells and results in both an increase in autoreactive T cells and decrease in regulatory T cells in peripheral tissues. We demonstrate that T cells from CopaE241K/+ mice are pathogenic and cause ILD through adoptive transfer experiments. In conclusion, to our knowledge, we establish a new mouse model of COPA syndrome to identify a previously unknown function for Copa in thymocyte selection and demonstrate that a defect in central tolerance is a putative mechanism by which COPA mutations lead to autoimmunity in patients.