ABSTRACT
Regulatory T cells (Tregs) are produced in the thymus to establish self-tolerance, and agonistic stimuli by self-Ags play a pivotal role in this process. Although two types of APCs, medullary thymic epithelial cells (mTECs) and dendritic cells (DCs), are responsible for presenting self-Ags together with costimulatory/cytokine signals, the distinct role of each APC in producing Tregs remains enigmatic. We have approached this issue by depleting the mTECs and DCs using mice expressing diphtheria toxin receptors driven by Aire and CD11c promoters, respectively. Depletion of mTECs showed an effect on Treg production quantitatively and qualitatively more profound than that of DCs followed by the development of distinct organ-specific autoimmune lesions in the hosts. Because self-Ags produced by mTECs are transferable to DCs through a process known as Ag transfer, we monitored the process of Ag transfer using mice expressing GFP from TECs. Although GFP expressed from total TECs was effectively transferred to DCs, GFP expressed from cortical TECs was not, suggesting that mTECs are the predominant source of self-Ags. We also found that GFP expressed not only from mature mTECs but also from immature mTECs was transferred to DCs, suggesting that a broad spectrum of molecules were subjected to Ag transfer during mTEC development. Interestingly, the numbers of recirculating non-Tregs producing IL-2, an important source for Treg expansion in the thymus, were reduced only in the mTEC-depleted mice. These results suggested the cooperative but distinct role of mTECs and DCs in the production of Tregs to avoid autoimmunity.
Subject(s)
T-Lymphocytes, Regulatory , Thymus Gland , Mice , Animals , Mice, Inbred C57BL , Epithelial Cells , Dendritic Cells , Cell DifferentiationABSTRACT
The deficiency of Aire, a transcriptional regulator whose defect results in the development of autoimmunity, is associated with reduced expression of tissue-restricted self-Ags (TRAs) in medullary thymic epithelial cells (mTECs). Although the mechanisms underlying Aire-dependent expression of TRAs need to be explored, the physical identification of the target(s) of Aire has been hampered by the low and promiscuous expression of TRAs. We have tackled this issue by engineering mice with augmented Aire expression. Integration of the transcriptomic data from Aire-augmented and Aire-deficient mTECs revealed that a large proportion of so-called Aire-dependent genes, including those of TRAs, may not be direct transcriptional targets downstream of Aire. Rather, Aire induces TRA expression indirectly through controlling the heterogeneity of mTECs, as revealed by single-cell analyses. In contrast, Ccl25 emerged as a canonical target of Aire, and we verified this both in vitro and in vivo. Our approach has illuminated the Aire's primary targets while distinguishing them from the secondary targets.
Subject(s)
Autoantigens/immunology , Autoimmunity/immunology , Chemokines, CC/metabolism , Thymus Gland/immunology , Transcription Factors/metabolism , Animals , Autoimmunity/genetics , Chemokines, CC/genetics , Epithelial Cells/immunology , Gene Expression Regulation , Gene Knock-In Techniques , Gene Knockout Techniques , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, Transgenic , Thymus Gland/cytology , Transcription Factors/genetics , Transcription, Genetic/genetics , AIRE ProteinABSTRACT
One of the difficulties in studying the pathogenesis of autoimmune diseases is that the disease is multifactorial involving sex, age, MHC, environment, and some genetic factors. Because deficiency of Aire, a transcriptional regulator, is an autoimmune disease caused by a single gene abnormality, Aire is an ideal research target for approaching the enigma of autoimmunity, e.g., the mechanisms underlying Aire deficiency can be studied using genetically modified animals. Nevertheless, the exact mechanisms of the breakdown of self-tolerance due to Aire's dysfunction have not yet been fully clarified. This is due, at least in part, to the lack of information on the exact target genes controlled by Aire. State-of-the-art research infrastructures such as single-cell analysis are now in place to elucidate the essential function of Aire. The knowledge gained through the study of Aire-mediated tolerance should help our understanding of the pathogenesis of autoimmune disease in general.
Subject(s)
Autoimmune Diseases , Polyendocrinopathies, Autoimmune , Animals , Transcription Factors/genetics , Transcription Factors/metabolism , Autoimmune Diseases/genetics , Autoimmune Diseases/metabolism , Autoimmunity/genetics , Polyendocrinopathies, Autoimmune/genetics , Polyendocrinopathies, Autoimmune/metabolism , Learning , Thymus GlandABSTRACT
While the interaction of cells such as macrophages and hepatic stellate cells is known to be involved in the generation of fibrosis in nonalcoholic steatohepatitis (NASH), the mechanism remains unclear. This study employed a high-fat/cholesterol/cholate (HFCC) diet to generate a model of NASH-related fibrosis to investigate the pathogenesis of fibrosis. Two mouse strains: C57BL/6J, the one susceptible to obesity, and A/J, the one relatively resistant to obesity, developed hepatic histologic features of NASH, including fat deposition, intralobular inflammation, hepatocyte ballooning, and fibrosis, after 9 weeks of HFCC diet. The severity of hepatic inflammation and fibrosis was greater in A/J mice than in the C57BL/6J mice. A/J mice fed HFCC diet exhibited characteristic CD204-positive lipid-laden macrophage aggregation in hepatic parenchyma. Polarized light was used to visualize the Maltese cross, cholesterol crystals within the aggregated macrophages. Fibrosis developed in a ring shape from the periphery of the aggregated macrophages such that the starting point of fibrosis could be visualized histologically. Matrix-assisted laser desorption/ionization mass spectrometry imaging analysis detected a molecule at m/z 772.462, which corresponds to the protonated ion of phosphatidylcholine [P-18:1 (11Z)/18:0] and phosphatidylethanolamine [18:0/20:2 (11Z, 14Z)], in aggregated macrophages adjacent to the fibrotic lesions. In conclusion, the HFCC diet-fed A/J model provides an ideal tool to study fibrogenesis and enables novel insights into the pathophysiology of NASH-related fibrosis.
Subject(s)
Lipids/chemistry , Macrophages/metabolism , Non-alcoholic Fatty Liver Disease/pathology , Animals , Body Weight , Disease Models, Animal , Energy Intake , Gene Expression Regulation , Lipids/blood , Liver/pathology , Male , Mice, Inbred C57BL , Models, Biological , Non-alcoholic Fatty Liver Disease/blood , Non-alcoholic Fatty Liver Disease/genetics , Organ Size , Spectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationABSTRACT
Autoimmune regulator+ (Aire) medullary thymic epithelial cells (mTECs) play a critical role in tolerance induction. Several studies demonstrated that Aire+ mTECs differentiate further into Post-Aire cells. Yet, the identification of terminal stages of mTEC maturation depends on unique fate-mapping mouse models. Herein, we resolve this limitation by segmenting the mTEChi (MHCIIhi CD80hi ) compartment into mTECA/hi (CD24- Sca1- ), mTECB/hi (CD24+ Sca1- ), and mTECC/hi (CD24+ Sca1+ ). While mTECA/hi included mostly Aire-expressing cells, mTECB/hi contained Aire+ and Aire- cells and mTECC/hi were mainly composed of cells lacking Aire. The differential expression pattern of Aire led us to investigate the precursor-product relationship between these subsets. Strikingly, transcriptomic analysis of mTECA/hi , mTECB/hi , and mTECC/hi sequentially mirrored the specific genetic program of Early-, Late- and Post-Aire mTECs. Corroborating their Post-Aire nature, mTECC/hi downregulated the expression of tissue-restricted antigens, acquired traits of differentiated keratinocytes, and were absent in Aire-deficient mice. Collectively, our findings reveal a new and simple blueprint to survey late stages of mTEC differentiation.
Subject(s)
Cell Differentiation/genetics , Cell Differentiation/immunology , Epithelial Cells/immunology , Keratinocytes/immunology , Thymus Gland/immunology , Transcription Factors/genetics , Animals , Down-Regulation/genetics , Down-Regulation/immunology , Gene Expression Profiling/methods , Gene Expression Regulation/genetics , Gene Expression Regulation/immunology , Mice , Mice, Inbred C57BL , Transcription Factors/immunology , AIRE ProteinABSTRACT
Deficiency for AIRE/Aire in both humans and mice results in the development of organ-specific autoimmune disease. We tested whether augmented and/or dysregulated AIRE/Aire expression might be also prone to the breakdown of self-tolerance. To define the effect of augmented Aire expression on the development of autoimmunity, antigen-specific clonal deletion and production of clonotypic regulatory T cells (Tregs) in the thymus were examined using mice expressing two additional copies of Aire in a heterozygous state (3xAire-knockin mice: 3xAire-KI). We found that both clonal deletion of autoreactive T cells and production of clonotypic Tregs in the thymus from 3xAire-KI were impaired in a T-cell receptor-transgenic system. Furthermore, 3xAire-KI females showed higher scores of experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein than wild-type littermates, suggesting that augmented Aire expression exacerbates organ-specific autoimmunity under disease-prone conditions. In humans, we found that one patient with amyopathic dermatomyositis showed CD3- CD19- cells expressing AIRE in the peripheral blood before the treatment but not during the remission phase treated with immunosuppressive drugs. Thus, not only loss of function of AIRE/Aire but also augmented and/or dysregulated expression of AIRE/Aire should be considered for the pathogenesis of organ-specific autoimmunity. We suggest that further analyses should be pursued to establish a novel link between organ-specific autoimmune disease and dysregulated AIRE expression in clinical settings.
Subject(s)
Autoimmunity , Encephalomyelitis, Autoimmune, Experimental , Animals , Clonal Deletion , Female , Humans , Immune Tolerance , Mice , Myelin-Oligodendrocyte Glycoprotein , Thymus GlandABSTRACT
Tissue-specific autoimmune diseases are assumed to arise through malfunction of two checkpoints for immune tolerance: defective elimination of autoreactive T cells in the thymus and activation of these T cells by corresponding autoantigens in the periphery. However, evidence for this model and the outcome of such alterations in each or both of the tolerance mechanisms have not been sufficiently investigated. We studied these issues by expressing human AIRE (huAIRE) as a modifier of tolerance function in NOD mice wherein the defects of thymic and peripheral tolerance together cause type I diabetes (T1D). Additive huAIRE expression in the thymic stroma had no major impact on the production of diabetogenic T cells in the thymus. In contrast, huAIRE expression in peripheral antigen-presenting cells (APCs) rendered the mice resistant to T1D, while maintaining other tissue-specific autoimmune responses and antibody production against an exogenous protein antigen, because of the loss of Xcr1+ dendritic cells, an essential component for activating diabetogenic T cells in the periphery. These results contrast with our recent demonstration that huAIRE expression in both the thymic stroma and peripheral APCs resulted in the paradoxical development of muscle-specific autoimmunity. Our results reveal that tissue-specific autoimmunity is differentially controlled by a combination of thymic function and peripheral tolerance, which can be manipulated by expression of huAIRE/Aire in each or both of the tolerance mechanisms.
Subject(s)
Autoimmunity/immunology , Peripheral Tolerance/immunology , Thymus Gland/immunology , Transcription Factors/immunology , Animals , Autoantigens/immunology , Diabetes Mellitus, Type 1/immunology , Disease Models, Animal , Humans , Islets of Langerhans/immunology , Mice , Mice, Inbred NOD , Mice, Knockout , Mice, SCID , Mice, Transgenic , T-Lymphocytes/immunology , Transcription Factors/genetics , AIRE ProteinABSTRACT
Metabolic syndrome (MS) is a risk factor for type 2 diabetes mellitus, vascular inflammation, atherosclerosis, and renal, liver, and heart diseases. Non-alcoholic steatohepatitis (NASH) is a progressive representative liver disease and may lead to the irreversible calamities of cirrhosis and hepatocellular carcinoma. Metabolic disorders such as hyperglycemia have been broadly reported to be related to hepatocarcinogenesis in NASH; however, direct evidence of a link between hyperglycemia and carcinogenesis is still lacking. Tsumura Suzuki Obese Diabetic (TSOD) mice spontaneously develop metabolic syndrome, including obesity, insulin resistance, and NASH-like liver phenotype, and eventually develop hepatocellular carcinomas. TSOD mice provide a spontaneous human MS-like model, even with significant individual variations. In this study, we monitored mice in terms of their changes in blood glucose levels, body weights, and pancreatic and liver lesions over time. As a result, liver carcinogenesis was delayed in non-hyperglycemic TSOD mice compared to hyperglycemic mice. Moreover, at the termination point of 40 weeks, liver tumors appeared in 18 of 24 (75%) hyperglycemic TSOD mice; in contrast, they only appeared in 5 of 24 (20.8%) non-hyperglycemic mice. Next, we investigated three kinds of oligosaccharide that could lower blood glucose levels in hyperglycemic TSOD mice. We monitored the levels of blood and urinary glucose and assessed pancreatic lesions among the experimental groups. As expected, significantly lower levels of blood and urinary glucose and smaller deletions of Langerhans cells were found in TSOD mice fed with milk-derived oligosaccharides (galactooligosaccharides and lactosucrose). At the age of 24 weeks, mild steatohepatitis was found in the liver but there was no evidence of liver carcinogenesis. Steatosis in the liver was alleviated in the milk-derived oligosaccharide-administered group. Taken together, suppressing the increase in blood glucose level from a young age prevented susceptible individuals from diabetes and the onset of NAFLD/NASH, as well as carcinogenesis. Milk-derived oligosaccharides showed a lowering effect on blood glucose levels, which may be expected to prevent liver carcinogenesis.
Subject(s)
Blood Glucose/metabolism , Liver Neoplasms/blood , Metabolic Syndrome/blood , Metabolic Syndrome/diet therapy , Animals , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/diet therapy , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/pathology , Disease Models, Animal , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Male , Metabolic Syndrome/metabolism , Metabolic Syndrome/pathology , Mice , Mice, Obese , Non-alcoholic Fatty Liver Disease/blood , Non-alcoholic Fatty Liver Disease/diet therapy , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/pathology , Obesity/blood , Oligosaccharides/pharmacologyABSTRACT
Medullary thymic epithelial cells (mTECs), which express a wide range of tissue-restricted Ags (TRAs), contribute to the establishment of self-tolerance by eliminating autoreactive T cells and/or inducing regulatory T cells. Aire controls a diverse set of TRAs within Aire-expressing cells by employing various transcriptional pathways. As Aire has a profound effect on transcriptomes of mTECs, including TRAs not only at the single-cell but also the population level, we suspected that Aire (Aire+ mTECs) might control the cellular composition of the thymic microenvironment. In this study, we confirmed that this is indeed the case by identifying a novel mTEC subset expressing Ly-6 family protein whose production was defective in Aire-deficient thymi. Reaggregated thymic organ culture experiments demonstrated that Aire did not induce the expression of Ly-6C/Ly-6G molecules from mTECs as Aire-dependent TRAs in a cell-intrinsic manner. Instead, Aire+ mTECs functioned in trans to maintain Ly-6C/Ly-6G+ mTECs. Thus, Aire not only controls TRA expression transcriptionally within the cell but also controls the overall composition of mTECs in a cell-extrinsic manner, thereby regulating the transcriptome from mTECs on a global scale.
Subject(s)
Epithelial Cells/pathology , Thymus Gland/physiology , Transcription Factors/metabolism , Animals , Antigens, Ly/metabolism , Cells, Cultured , Cellular Microenvironment , Humans , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , Organ Culture Techniques , Transcription Factors/genetics , Transcriptional Activation , AIRE ProteinABSTRACT
A 26-year-old man visited our hospital with a complaint of macrohematuria. Cystoscopy revealed a nodular tumor around the right ureteral orifice. Transurethral resection of bladder tumor was performed, and the tumor was pathologically diagnosed as the nested variant of urothelial carcinoma (NVUC). Radical cystectomy and modified Studer orthotopic neobladder reconstruction were performed. The pathological stage was pT2a, pN2. The patient received 2 courses of adjuvant chemotherapy consisting of gemcitabine and cisplatin. The patient is currently free from disease at 31 months after the treatment. To our knowledge, this case report represents the youngest case of NVUC.
Subject(s)
Carcinoma, Transitional Cell , Urinary Bladder Neoplasms , Adult , Carcinoma, Transitional Cell/surgery , Cystectomy , Humans , Male , Patients , Urinary Bladder Neoplasms/surgeryABSTRACT
Aire controls the fate of autoreactive thymocytes (i.e., clonal deletion or development into regulatory T cells [Tregs]) through transcriptional control of the expression of tissue-restricted self-antigens (TRAs) from medullary thymic epithelial cells (mTECs) and bone marrow (BM)-derived cells. Although TRAs expressed by mTECs and BM-derived cells are suggested to complement each other to generate a full spectrum of TRAs, little is known about the relative contribution of TRAs from each component for establishment of self-tolerance. Furthermore, the precise role of Aire in specific types of Aire-expressing APCs remains elusive. We have approached these issues by generating two different types of transgenic mouse (Tg) model, which express a prefixed model self-antigen driven by the insulin promoter or the Aire promoter. In the insulin-promoter Tg model, mTECs alone were insufficient for clonal deletion, and BM-derived APCs were required for this action by utilizing Ag transferred from mTECs. In contrast, mTECs alone were able to induce Tregs, although at a much lower efficiency in the absence of BM-derived APCs. Importantly, lack of Aire in mTECs, but not in BM-derived APCs, impaired both clonal deletion and production of Tregs. In the Aire-promoter Tg model, both mTECs and BM-derived APCs could independently induce clonal deletion without Aire, and production of Tregs was impaired by the lack of Aire in mTECs, but not in BM-derived APCs. These results suggest that the fate of autoreactive thymocytes together with the requirement for Aire depend on the cell types that express self-antigens and the types of APCs involved in tolerance induction.
Subject(s)
Antigen Presentation , Antigen-Presenting Cells/immunology , Autoantigens/immunology , Clonal Deletion/immunology , T-Lymphocytes, Regulatory/immunology , Thymus Gland/immunology , Transcription Factors/immunology , Animals , Autoantigens/biosynthesis , Autoantigens/genetics , Epithelial Cells/immunology , Epithelial Cells/metabolism , Female , Gene Expression Regulation/immunology , Gene Knock-In Techniques , Genes, Synthetic , Insulin/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Ovalbumin/biosynthesis , Ovalbumin/genetics , Ovalbumin/immunology , Promoter Regions, Genetic , Rats , Specific Pathogen-Free Organisms , Thymus Gland/cytology , Transcription Factors/deficiency , Transcription Factors/genetics , Transgenes , AIRE ProteinABSTRACT
Autoimmunity is prevented by the function of the autoimmune regulator [AIRE (Aire in mice)], which promotes the expression of a wide variety of tissue-restricted antigens (TRAs) from medullary thymic epithelial cells (mTECs) and from a subset of peripheral antigen-presenting cells (APCs). We examined the effect of additive expression of human AIRE (huAIRE) in a model of autoimmune diabetes in NOD mice. Unexpectedly, we observed that mice expressing augmented AIRE/Aire developed muscle-specific autoimmunity associated with incomplete maturation of mTECs together with impaired expression of Aire-dependent TRAs. This led to failure of deletion of autoreactive T cells together with dramatically reduced production of regulatory T cells in the thymus. In peripheral APCs, expression of costimulatory molecules was augmented. We suggest that levels of Aire expression need to be tightly controlled for maintenance of immunological tolerance. Our results also highlight the importance of coordinated action between central tolerance and peripheral tolerance under the common control of Aire.
Subject(s)
Diabetes Mellitus, Type 1/immunology , Muscles/immunology , Polymyositis/immunology , Thymus Gland/immunology , Transcription Factors/metabolism , Animals , Autoantigens/metabolism , Autoimmunity , Disease Models, Animal , Humans , Immune Tolerance , Mice , Mice, Inbred NOD , Mice, Transgenic , Organ Specificity , Transcription Factors/genetics , AIRE ProteinABSTRACT
Metabolic syndrome (MS) is a worldwide healthcare issue and a dominant risk factor for the development of incurable diseases affecting the entire body. The hepatic manifestations of MS include nonalcoholic fatty liver disease (NAFLD) and its progressive variant, nonalcoholic steatohepatitis (NASH). NASH is known to progress to liver cirrhosis and hepatocellular carcinoma (HCC). Excellent animal models for determining the mechanism of pathogenesis and establishing therapeutic treatment of NASH/HCC are strongly required worldwide. We recently reported that two previously established mouse models of obesity and diabetes mellitus, namely, Tsumura-Suzuki Obese Diabetes (TSOD) mice and MSG mice, developed MS-associated NASH and that their clinical course and pathological characteristics closely mimicked those of human MS-NASH patients. Interestingly, most of the mice developed HCC with advancing age, and the pathological and functional characteristics of this condition were identical to those of human HCC. We further established a novel mouse model of HCC based on type 1 diabetes (DIAR-nSTZ mice) and reported its histopathological features. By comparing various aspects of these mouse models, specific and useful characteristics in a suitable model of MS-associated liver diseases, including hepato-carcinogenesis, can be highlighted.
Subject(s)
Disease Models, Animal , Liver Diseases/etiology , Liver Diseases/pathology , Metabolic Syndrome/complications , Animals , MiceABSTRACT
Understanding the cellular dynamics of Aire-expressing lineage(s) among medullary thymic epithelial cells (AEL-mTECs) is essential for gaining insight into the roles of Aire in establishment of self-tolerance. In this study, we monitored the maturation program of AEL-mTECs by temporal lineage tracing, in which bacterial artificial chromosome transgenic mice expressing tamoxifen-inducible Cre recombinase under control of the Aire regulatory element were crossed with reporter strains. We estimated that the half-life of AEL-mTECs subsequent to Aire expression was â¼7-8 d, which was much longer than that reported previously, owing to the existence of a post-Aire stage. We found that loss of Aire did not alter the overall lifespan of AEL-mTECs, inconsistent with the previous notion that Aire expression in medullary thymic epithelial cells (mTECs) might result in their apoptosis for efficient cross-presentation of self-antigens expressed by AEL-mTECs. In contrast, Aire was required for the full maturation program of AEL-mTECs, as exemplified by the lack of physiological downregulation of CD80 during the post-Aire stage in Aire-deficient mice, thus accounting for the abnormally increased CD80(high) mTECs seen in such mice. Of interest, increased CD80(high) mTECs in Aire-deficient mice were not mTEC autonomous and were dependent on cross-talk with thymocytes. These results further support the roles of Aire in the differentiation program of AEL-mTECs.
Subject(s)
Cell Differentiation/immunology , Cell Lineage/immunology , Epithelial Cells/immunology , Transcription Factors/immunology , Animals , Apoptosis/genetics , Apoptosis/immunology , Autoantigens/immunology , Autoantigens/metabolism , B7-1 Antigen/immunology , B7-1 Antigen/metabolism , Cell Differentiation/genetics , Cell Lineage/genetics , Cells, Cultured , Cross-Priming/genetics , Cross-Priming/immunology , Epithelial Cells/metabolism , Flow Cytometry , Immunohistochemistry , Kinetics , Luminescent Proteins/genetics , Luminescent Proteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Thymocytes/cytology , Thymocytes/immunology , Thymocytes/metabolism , Thymus Gland/cytology , Time Factors , Transcription Factors/genetics , Transcription Factors/metabolism , AIRE ProteinABSTRACT
The purpose of this study was to clarify the time course of the stretching-induced decrease in maximal isometric plantar flexion torque. Nineteen women participated in 2 randomly ordered experimental trials: static 5-minute stretching or control with no stretching. The participants performed isometric maximal voluntary contractions (MVCs) of the right plantar flexor muscles, whereas electromyographic (EMG) amplitude (root mean square) was calculated for the medial and lateral gastrocnemius muscles. Measurements were conducted preintervention; immediately after intervention; and 5, 10, 15, and 30 minutes postintervention. The static 5-minute stretching trial consisted of dorsiflexion to the end range of motion and holding that position for 1 minute, 5 times, whereas the control trial consisted of 5 minutes of resting. As a result, the MVC torque was significantly decreased immediately after, and 5 minutes after the static 5-minute stretching intervention compared with the preintervention value (p < 0.05), and this change recovered within 10 minutes. However, the EMG amplitude did not change from preintervention to postintervention under any conditions. These results suggest that the deficits of static stretching are disabled in a short time after static stretching.
Subject(s)
Isometric Contraction/physiology , Muscle Stretching Exercises/adverse effects , Muscle, Skeletal/physiopathology , Warm-Up Exercise/physiology , Electromyography , Female , Foot , Humans , Recovery of Function , Time Factors , Torque , Young AdultABSTRACT
The thymus is a highly specialized organ that plays an indispensable role in the establishment of self-tolerance, a process characterized by the "education" of developing T-cells. To provide competent T-cells tolerant to self-antigens, medullary thymic epithelial cells (mTECs) orchestrate negative selection by ectopically expressing a wide range of genes, including various tissue-restricted antigens (TRAs). Notably, recent advancements in the high-throughput single-cell analysis have revealed remarkable heterogeneity in mTECs, giving us important clues for dissecting the mechanisms underlying TRA expression. We overview how recent single-cell studies have furthered our understanding of mTECs, with a focus on the role of Aire in inducing mTEC heterogeneity to encompass TRAs.
Subject(s)
Epithelial Cells , Thymus Gland , Mice , Animals , Mice, Inbred C57BL , Epithelial Cells/metabolism , T-Lymphocytes , Autoantigens/metabolismABSTRACT
Reports on pleomorphic type of undifferentiated sarcoma (PUS) originating from the gastrointestinal tract, especially the stomach, are extremely rare. We herein report a case of pleomorphic type undifferentiated gastric sarcoma. The patient was a 67-year-old woman. The chief complaint was upper abdominal pain. Upper gastrointestinal endoscopy, ultrasonography, and contrast-enhanced computed tomography showed two submucosal tumors at the greater curvature of the fundus and the lesser curvature of the gastric angle. Endoscopic ultrasound-guided fine-needle aspiration revealed a c-kit-negative spindle cell tumor at the greater curvature of the fundus. Total gastrectomy, splenectomy, and partial resection of the diaphragm and liver were performed. One lesion had invaded the lateral segment of the liver, left diaphragm and spleen. The postoperative course was uneventful. Histopathological and immunohistochemical examinations of the resected specimen revealed PUS. Peritoneal dissemination was detected at 8 months after surgery. However, no effective therapeutic agents were adopted for chemotherapy. The patient had poor performance status due to disease progression and underwent best supportive care. The patient died 10 months after surgery. This case highlights the imaging, histological diagnosis, and treatment strategy for PUS originating from the stomach. Surgeons should be aware of PUS as a differential diagnosis in cases with submucosal tumor of the stomach.
Subject(s)
Liver Neoplasms , Sarcoma , Stomach Neoplasms , Female , Humans , Aged , Stomach Neoplasms/diagnosis , Stomach Neoplasms/surgery , Stomach Neoplasms/pathology , Gastrectomy , Sarcoma/diagnostic imaging , Sarcoma/surgery , Endoscopy, Digestive System , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/surgeryABSTRACT
Despite the clear distinction between cortical (cTECs) and medullary thymic epithelial cells (mTECs) in physiology, the cell of origin of thymic carcinomas (TCs) and other thymic epithelial tumors remained enigmatic. We addressed this issue by focusing on AIRE, an mTEC-specific transcriptional regulator that is required for immunological self-tolerance. We found that a large proportion of TCs expressed AIRE with typical nuclear dot morphology by immunohistochemistry. AIRE expression in TCs was supported by the RNA-seq data in the TCGA-THYM database. Furthermore, our bioinformatics approach to the recent single-cell RNA-seq data on human thymi has revealed that TCs hold molecular characteristics of multiple mTEC subpopulations. In contrast, TCs lacked the gene signatures for cTECs. We propose that TCs are tumors derived from mTECs.
Subject(s)
Thymoma , Thymus Neoplasms , Humans , Cell Differentiation/genetics , Epithelial Cells/metabolism , Thymoma/pathology , Thymus Gland , Thymus Neoplasms/genetics , Thymus Neoplasms/pathology , Transcription Factors/genetics , Transcription Factors/metabolism , AIRE ProteinABSTRACT
Aire, the defect of which is responsible for the development of autoimmunity, is predominantly expressed in medullary thymic epithelial cells, and it controls a wide variety of genes, including those of tissue-restricted Ags, for establishing thymic tolerance. Aire is also expressed from APCs in the periphery, called extrathymic Aire-expressing cells (eTACs), and their complementing role to thymic tolerance has been suggested. eTACs are composed of two distinct classes of APCs, conventional dendritic cell (cDC)-type and group 3 innate lymphoid cell (ILC3)-like-type expressing retinoic acid receptor-related orphan receptor γt (RORγt). Although the essential role of Aire in the latter in the Th17-mediated immune response against Candida albicans has been reported, the role of Aire in the cDC-type eTACs for this action has not been examined. Furthermore, the significance of Aire in the production of the transcriptome of the cDC-type eTACs remains unknown. We have approached these issues using a high-fidelity Aire-reporter mouse strain. We found that although the cDC-type eTACs dominated ILC3-like-type eTACs in number and they served as efficient APCs for the immune response against an exogenous Ag as well as for the C. albicans-specific Th17 immune response, loss of Aire in cDC-type eTACs showed no clear effect on these functions. Furthermore, loss of Aire showed no major impact on the transcriptome from cDC-type eTACs. These results suggested that Aire in cDC-type eTACs may not have a cell-intrinsic role in the immune response in contrast to the role of Aire in ILC3-like-type eTACs.
Subject(s)
Antigen Presentation , Transcriptome , Animals , Mice , Dendritic Cells , Immunity, Innate , Lymphocytes , CD11c Antigen/immunologyABSTRACT
BACKGROUND: Epidermoid cysts in intrapancreatic accessory spleen (ECIPAS) are a rare lesion. Its pathogenesis, including the origin of cystic epithelium, is not well established. We aimed to elucidate new aspects of the pathological features of ECIPAS to clarify its pathogenesis. METHODS: Six cases of ECIPAS were included in this study. As well as histopathological analysis, to elucidate the features and nature of cystic epithelial cells, immunohistochemical analysis including Pbx1 and Tlx1 and imaging mass spectrometry was performed. RESULTS: Histologically, the cysts were covered by either monolayered or multilayered epithelium. Immunohistochemistry revealed that the epithelial cells in multilayered epithelium exhibited different attributes between the basal and superficial layers. Few epithelial cells had abundant clear cytoplasm and were immunohistochemically positive for adipophilin, suggesting lipid-excreting function. The intracystic fluid contained cholesterol clefts and foamy macrophages, and imaging mass spectrometry revealed the accumulation of lipids. Immunohistochemical analysis indicated that the epithelial cells were positive for Pbx1 in some cases. CONCLUSION: Novel histological features of epithelial cells of ECIPAS were indicated. Although more cases need to be evaluated, we propose that the cause of ECIPAS may be different from that of pancreatic ductal origin. J. Med. Invest. 70 : 251-259, February, 2023.