33 results on '"aire"'
Search Results
2. The single-cell transcriptome of mTECs and CD4 + thymocytes under adhesion revealed heterogeneity of mTECs and a network controlled by Aire and lncRNAs.
- Author
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Monteiro CJ, Duarte MJ, Machado MCV, Mascarenhas RS, Palma PVB, García HDM, Nakaya HI, Cunha TM, Donadi EA, and Passos GA
- Subjects
- Animals, Mice, Thymus Gland cytology, Thymus Gland immunology, Thymus Gland metabolism, Single-Cell Analysis, Gene Regulatory Networks, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, Coculture Techniques, Gene Expression Profiling, Mice, Knockout, RNA, Long Noncoding genetics, AIRE Protein, Transcription Factors genetics, Transcription Factors metabolism, Thymocytes metabolism, Thymocytes immunology, Thymocytes cytology, Cell Adhesion, Transcriptome, Epithelial Cells metabolism, Epithelial Cells immunology
- Abstract
To further understand the impact of deficiency of the autoimmune regulator ( Aire ) gene during the adhesion of medullary thymic epithelial cells (mTECs) to thymocytes, we sequenced single-cell libraries (scRNA-seq) obtained from Aire wild-type (WT) ( Aire
wt/wt ) or Aire -deficient ( Airewt/mut ) mTECs cocultured with WT single-positive (SP) CD4+ thymocytes. Although the libraries differed in their mRNA and long noncoding RNA (lncRNA) profiles, indicating that mTECs were heterogeneous in terms of their transcriptome, UMAP clustering revealed that both mTEC lines expressed their specific markers, i.e., Epcam, Itgb4 , Itga6 , and Casp3 in resting mTECs and Ccna2, Pbk , and Birc5 in proliferative mTECs. Both cocultured SP CD4+ thymocytes remained in a homogeneous cluster expressing the Il7r and Ccr7 markers. Comparisons of the two types of cocultures revealed the differential expression of mRNAs that encode transcription factors ( Zfpm2, Satb1 , and Lef1 ), cell adhesion genes ( Itgb1 ) in mTECs, and Themis in thymocytes, which is associated with the regulation of positive and negative selection. At the single-cell sequencing resolution, we observed that Aire acts on both Aire WT and Aire -deficient mTECs as an upstream controller of mRNAs, which encode transcription factors or adhesion proteins that, in turn, are posttranscriptionally controlled by lncRNAs, for example, Neat1, Malat1, Pvt1, and Dancr among others. Under Aire deficiency, mTECs dysregulate the expression of MHC-II, CD80, and CD326 (EPCAM) protein markers as well as metabolism and cell cycle-related mRNAs, which delay the cell cycle progression. Moreover, when adhered to mTECs, WT SP CD4+ or CD8+ thymocytes modulate the expression of cell activation proteins, including CD28 and CD152/CTLA4, and the expression of cellular metabolism mRNAs. These findings indicate a complex mechanism through which an imbalance in Aire expression can affect mTECs and thymocytes during adhesion., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Monteiro, Duarte, Machado, Mascarenhas, Palma, García, Nakaya, Cunha, Donadi and Passos.)- Published
- 2024
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3. Immune tolerance and the prevention of autoimmune diseases essentially depend on thymic tissue homeostasis.
- Author
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Shirafkan F, Hensel L, and Rattay K
- Subjects
- Humans, Immune Tolerance, Self Tolerance, Homeostasis, Thymus Gland, Autoimmune Diseases prevention & control
- Abstract
The intricate balance of immune reactions towards invading pathogens and immune tolerance towards self is pivotal in preventing autoimmune diseases, with the thymus playing a central role in establishing and maintaining this equilibrium. The induction of central immune tolerance in the thymus involves the elimination of self-reactive T cells, a mechanism essential for averting autoimmunity. Disruption of the thymic T cell selection mechanisms can lead to the development of autoimmune diseases. In the dynamic microenvironment of the thymus, T cell migration and interactions with thymic stromal cells are critical for the selection processes that ensure self-tolerance. Thymic epithelial cells are particularly significant in this context, presenting self-antigens and inducing the negative selection of autoreactive T cells. Further, the synergistic roles of thymic fibroblasts, B cells, and dendritic cells in antigen presentation, selection and the development of regulatory T cells are pivotal in maintaining immune responses tightly regulated. This review article collates these insights, offering a comprehensive examination of the multifaceted role of thymic tissue homeostasis in the establishment of immune tolerance and its implications in the prevention of autoimmune diseases. Additionally, the developmental pathways of the thymus are explored, highlighting how genetic aberrations can disrupt thymic architecture and function, leading to autoimmune conditions. The impact of infections on immune tolerance is another critical area, with pathogens potentially triggering autoimmunity by altering thymic homeostasis. Overall, this review underscores the integral role of thymic tissue homeostasis in the prevention of autoimmune diseases, discussing insights into potential therapeutic strategies and examining putative avenues for future research on developing thymic-based therapies in treating and preventing autoimmune conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Shirafkan, Hensel and Rattay.)
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- 2024
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4. Mitochondrial extracellular vesicles, autoimmunity and myocarditis.
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Di Florio DN, Beetler DJ, McCabe EJ, Sin J, Ikezu T, and Fairweather D
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- Humans, Autoimmunity, Enterovirus B, Human, Mitochondria metabolism, Myocarditis, Coxsackievirus Infections, Autoimmune Diseases, Extracellular Vesicles metabolism
- Abstract
For many decades viral infections have been suspected as 'triggers' of autoimmune disease, but mechanisms for how this could occur have been difficult to establish. Recent studies have shown that viral infections that are commonly associated with viral myocarditis and other autoimmune diseases such as coxsackievirus B3 (CVB3) and SARS-CoV-2 target mitochondria and are released from cells in mitochondrial vesicles that are able to activate the innate immune response. Studies have shown that Toll-like receptor (TLR)4 and the inflammasome pathway are activated by mitochondrial components. Autoreactivity against cardiac myosin and heart-specific immune responses that occur after infection with viruses where the heart is not the primary site of infection (e.g., CVB3, SARS-CoV-2) may occur because the heart has the highest density of mitochondria in the body. Evidence exists for autoantibodies against mitochondrial antigens in patients with myocarditis and dilated cardiomyopathy. Defects in tolerance mechanisms like autoimmune regulator gene (AIRE) may further increase the likelihood of autoreactivity against mitochondrial antigens leading to autoimmune disease. The focus of this review is to summarize current literature regarding the role of viral infection in the production of extracellular vesicles containing mitochondria and virus and the development of myocarditis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Di Florio, Beetler, McCabe, Sin, Ikezu and Fairweather.)
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- 2024
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5. Interferon autoantibodies as signals of a sick thymus.
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Oftedal BE, Sjøgren T, and Wolff ASB
- Subjects
- Thymus Gland, Herpesvirus 3, Human, Autoantibodies, Interferon Type I
- Abstract
Type I interferons (IFN-I) are key immune messenger molecules that play an important role in viral defense. They act as a bridge between microbe sensing, immune function magnitude, and adaptive immunity to fight infections, and they must therefore be tightly regulated. It has become increasingly evident that thymic irregularities and mutations in immune genes affecting thymic tolerance can lead to the production of IFN-I autoantibodies (autoAbs). Whether these biomarkers affect the immune system or tissue integrity of the host is still controversial, but new data show that IFN-I autoAbs may increase susceptibility to severe disease caused by certain viruses, including SARS-CoV-2, herpes zoster, and varicella pneumonia. In this article, we will elaborate on disorders that have been identified with IFN-I autoAbs, discuss models of how tolerance to IFN-Is is lost, and explain the consequences for the host., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Oftedal, Sjøgren and Wolff.)
- Published
- 2024
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6. Acute irradiation causes a long-term disturbance in the heterogeneity and gene expression profile of medullary thymic epithelial cells.
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Horie K, Namiki K, Kinoshita K, Miyauchi M, Ishikawa T, Hayama M, Maruyama Y, Hagiwara N, Miyao T, Murata S, Kobayashi TJ, Akiyama N, and Akiyama T
- Subjects
- Mice, Animals, Cell Differentiation, Mice, Inbred C57BL, Epithelial Cells metabolism, Transcriptome, Transcription Factors metabolism
- Abstract
The thymus has the ability to regenerate from acute injury caused by radiation, infection, and stressors. In addition to thymocytes, thymic epithelial cells in the medulla (mTECs), which are crucial for T cell self-tolerance by ectopically expressing and presenting thousands of tissue-specific antigens (TSAs), are damaged by these insults and recover thereafter. However, given recent discoveries on the high heterogeneity of mTECs, it remains to be determined whether the frequency and properties of mTEC subsets are restored during thymic recovery from radiation damage. Here we demonstrate that acute total body irradiation with a sublethal dose induces aftereffects on heterogeneity and gene expression of mTECs. Single-cell RNA-sequencing (scRNA-seq) analysis showed that irradiation reduces the frequency of mTECs expressing AIRE, which is a critical regulator of TSA expression, 15 days after irradiation. In contrast, transit-amplifying mTECs (TA-mTECs), which are progenitors of AIRE-expressing mTECs, and Ccl21a-expressing mTECs, were less affected. Interestingly, a detailed analysis of scRNA-seq data suggested that the proportion of a unique mTEC cluster expressing Ccl25 and a high level of TSAs was severely decreased by irradiation. In sum, we propose that the effects of acute irradiation disrupt the heterogeneity and properties of mTECs over an extended period, which potentially leads to an impairment of thymic T cell selection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Horie, Namiki, Kinoshita, Miyauchi, Ishikawa, Hayama, Maruyama, Hagiwara, Miyao, Murata, Kobayashi, Akiyama and Akiyama.)
- Published
- 2023
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7. Analysis of a series of Italian APECED patients with autoimmune hepatitis and gastro-enteropathies.
- Author
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Paldino G, Faienza MF, Cappa M, Pietrobattista A, Capalbo D, Valenzise M, Lampasona V, Cudini A, Carbone E, Pagliarosi O, Maggiore G, Salerno M, Betterle C, and Fierabracci A
- Subjects
- Humans, Male, Child, Female, Mutation, Italy epidemiology, Hepatitis, Autoimmune diagnosis, Hepatitis, Autoimmune genetics, Polyendocrinopathies, Autoimmune diagnosis, Polyendocrinopathies, Autoimmune genetics, Intestinal Diseases
- Abstract
Introduction: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome is a rare monogenic disease determined by biallelic mutations in AIRE gene, which encodes a transcription factor essential for central immune tolerance. Classic diagnosis is determined by the presence of two of the main APECED clinical diseases: chronic mucocutaneous candidiasis, chronic hypoparathyroidism, and Addison's disease. Non-endocrine autoimmunity, involving the liver, intestine, eyes, and kidneys, is generally reported in a minority of European patients, while American APECED patients have a higher tendency of developing organ-specific non-endocrine manifestations early in life. This observation led to the revision of the diagnostic criteria to permit earlier diagnosis based on the appearance of one classic triad symptom or one non-classical manifestation at a young age in the presence of IFNωAbs or AIRE mutations (Ferre-Lionakis criteria)., Patients and Methods: We analyzed the clinical, genetic, and autoantibody (Ab) profiles in a series of 14 pediatric Italian APECED patients with gastrointestinal manifestations (seven male and seven female patients). Ten patients presented hepatitis (APECED-associated hepatitis (APAH)), while seven were affected by constipation, diarrhea, and malabsorption. Four patients had developed APAH before classic triad symptoms., Results: Based on the age of appearance of non-endocrine manifestations including APAH and gastro-enteropathy, the Ferre-Lionakis criteria would have allowed an expedited diagnosis in 11/14 patients. Abs to tryptophan hydroxylase (TPHAb) and hepatic aromatic l-amino acid decarboxylase (AADC) were significantly associated with APECED patients of the present series. Abs to cP4501A2 were detectable in the serum of 4/8 patients with APAH, and Abs to cP4502A6 were detectable in 3/8 patients. AADC Abs tested positive in 5/7 patients, which is indicative of gastrointestinal dysfunction in APECED and TPHAb in 5/7 patients with gastrointestinal dysfunction. IFNAb was significantly associated with the syndrome., Conclusion: Although Ferre-Lionakis expanded criteria applied to the American cohorts of APECED patients would require validation in independent large cohorts of European patients, the results of this study emphasize the importance to evaluate the presence and the age of appearance of APAH and autoimmune enteropathy even in European cohorts for an earlier APECED diagnosis. An earlier APECED diagnosis would also allow the prevention of episodes of life-threatening hypocalcemic seizures and adrenal crisis, which are the main manifestations of undiagnosed APECED., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Paldino, Faienza, Cappa, Pietrobattista, Capalbo, Valenzise, Lampasona, Cudini, Carbone, Pagliarosi, Maggiore, Salerno, Betterle and Fierabracci.)
- Published
- 2023
- Full Text
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8. Revisiting Aire and tissue-restricted antigens at single-cell resolution.
- Author
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Matsumoto M, Yoshida H, Tsuneyama K, Oya T, and Matsumoto M
- Subjects
- Mice, Animals, Mice, Inbred C57BL, T-Lymphocytes, Autoantigens metabolism, Thymus Gland, Epithelial Cells metabolism
- Abstract
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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Matsumoto, Yoshida, Tsuneyama, Oya and Matsumoto.)
- Published
- 2023
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9. The AIRE G228W mutation disturbs the interaction of AIRE with its partner molecule SIRT1.
- Author
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Santos JC, Dametto M, Masson AP, Faça VM, Bonacin R, Donadi EA, and Passos GA
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- Chromatin, Gene Expression Regulation, Mutation, Peptides, RNA Polymerase II, Sirtuin 1 genetics
- Abstract
The autoimmune regulator (AIRE) protein functions as a tetramer, interacting with partner proteins to form the "AIRE complex," which relieves RNA Pol II stalling in the chromatin of medullary thymic epithelial cells (mTECs). AIRE is the primary mTEC transcriptional controller, promoting the expression of a large set of peripheral tissue antigen genes implicated in the negative selection of self-reactive thymocytes. Under normal conditions, the SIRT1 protein temporarily interacts with AIRE and deacetylates K residues of the AIRE SAND domain. Once the AIRE SAND domain is deacetylated, the binding with SIRT1 is undone, allowing the AIRE complex to proceed downstream with the RNA Pol II to the elongation phase of transcription. Considering that the in silico and in vitro binding of the AIRE SAND domain with SIRT1 provides a powerful model system for studying the dominant SAND G228W mutation mechanism, which causes the autoimmune polyglandular syndrome-1, we integrated computational molecular modeling, docking, dynamics between the whole SAND domain with SIRT1, and surface plasmon resonance using a peptide harboring the 211 to 230 residues of the SAND domain, to compare the structure and energetics of binding/release between AIRE G228 (wild-type) and W228 (mutant) SAND domain to SIRT1. We observed that the G228W mutation in the SAND domain negatively influences the AIRE-SIRT1 interaction. The disturbed interaction might cause a disruption in the binding of the AIRE SAND domain with the SIRT1 catalytic site, impairing the AIRE complex to proceed downstream with RNA Pol II., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Santos, Dametto, Masson, Faça, Bonacin, Donadi and Passos.)
- Published
- 2022
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10. Effects of sex steroids on thymic epithelium and thymocyte development.
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Taves MD and Ashwell JD
- Subjects
- Atrophy, Epithelium, Estrogens, Gonadal Steroid Hormones, Humans, Progestins, Receptors, Antigen, T-Cell, Androgens, Thymocytes
- Abstract
Sex steroid hormones have major effects on the thymus. Age-related increases in androgens and estrogens and pregnancy-induced increases in progestins all cause dramatic thymic atrophy. Atrophy can also be induced by treatment with exogenous sex steroids and reversed by ablation of endogenous sex steroids. Although these observations are frequently touted as evidence of steroid lymphotoxicity, they are often driven by steroid signaling in thymic epithelial cells (TEC), which are highly steroid responsive. Here, we outline the effects of sex steroids on the thymus and T cell development. We focus on studies that have examined steroid signaling in vivo , aiming to emphasize the actions of endogenous steroids which, via TEC, have remarkable programming effects on the TCR repertoire. Due to the dramatic effects of steroids on TEC, especially thymic involution, the direct effects of sex steroid signaling in thymocytes are less well understood. We outline studies that could be important in addressing these possibilities, and highlight suggestive findings of sex steroid generation within the thymus itself., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 At least a portion of this work is authored by Jonathan D. Ashwell on behalf of the U.S. Government and as regards Dr. Ashwell and the U.S. Government, is not subject to copyright protection in the United States. Foreign and other copyrights may apply.)
- Published
- 2022
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11. Aire and Fezf2, two regulators in medullary thymic epithelial cells, control autoimmune diseases by regulating TSAs: Partner or complementer?
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Qi Y, Zhang R, Lu Y, Zou X, and Yang W
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- Animals, Central Tolerance, Epithelial Cells, Gene Expression Regulation, Humans, Mice, AIRE Protein, Autoimmune Diseases metabolism, Transcription Factors metabolism
- Abstract
The expression of tissue-specific antigens (TSAs) in medullary thymic epithelial cells (mTECs) is believed to be responsible for the elimination of autoreactive T cells, a critical process in the maintenance of central immune tolerance. The transcription factor autoimmune regulator (Aire) and FEZ family zinc finger 2(Fezf2) play an essential role in driving the expression of TSAs in mTECs, while their deficiency in humans and mice causes a range of autoimmune manifestations, such as type 1 diabetes, Sjögren's syndrome and rheumatoid arthritis. However, because of their regulatory mechanisms, the expression profile of TSAs and their relationship with special autoimmune diseases are still in dispute. In this review, we compare the roles of Aire and Fezf2 in regulating TSAs, with an emphasis on their molecular mechanisms in autoimmune diseases, which provides the foundation for devising improved diagnostic and therapeutic approaches for patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Qi, Zhang, Lu, Zou and Yang.)
- Published
- 2022
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12. SARS-CoV-2 Spike Protein-Directed Monoclonal Antibodies May Ameliorate COVID-19 Complications in APECED Patients.
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Ferré EMN, Schmitt MM, Ochoa S, Rosen LB, Shaw ER, Burbelo PD, Stoddard JL, Rampertaap S, DiMaggio T, Bergerson JRE, Rosenzweig SD, Notarangelo LD, Holland SM, and Lionakis MS
- Subjects
- Adult, COVID-19 complications, COVID-19 genetics, COVID-19 immunology, Female, Humans, Interferons genetics, Interferons immunology, Male, Mutation, Polyendocrinopathies, Autoimmune complications, Polyendocrinopathies, Autoimmune genetics, Polyendocrinopathies, Autoimmune immunology, SARS-CoV-2 genetics, Spike Glycoprotein, Coronavirus genetics, Transcription Factors genetics, Transcription Factors immunology, AIRE Protein, Antibodies, Monoclonal, Humanized administration & dosage, Polyendocrinopathies, Autoimmune drug therapy, SARS-CoV-2 immunology, Spike Glycoprotein, Coronavirus immunology, COVID-19 Drug Treatment
- Abstract
Patients with the monogenic immune dysregulatory syndrome autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), which is caused by loss-of-function mutations in the autoimmune regulator ( AIRE ) gene, uniformly carry neutralizing autoantibodies directed against type-I interferons (IFNs) and many develop autoimmune pneumonitis, both of which place them at high risk for life-threatening COVID-19 pneumonia. Bamlanivimab and etesevimab are monoclonal antibodies (mAbs) that target the SARS-CoV-2 spike protein and block entry of SARS-CoV-2 in host cells. The use of bamlanivimab and etesevimab early during infection was associated with reduced COVID-19-associated hospitalization and death in patients at high risk for progressing to severe disease, which led the US Food and Drug Administration to issue an emergency use authorization for their administration in non-hypoxemic, non-hospitalized high-risk patients. However, the safety and efficacy of these mAbs has not been evaluated in APECED patients. We enrolled two siblings with APECED on an IRB-approved protocol (NCT01386437) and admitted them prophylactically at the NIH Clinical Center for evaluation of mild-to-moderate COVID-19. We assessed the safety and clinical effects of early treatment with bamlanivimab and etesevimab. The administration of bamlanivimab and etesevimab was well tolerated and was associated with amelioration of COVID-19 symptoms and prevention of invasive ventilatory support, admission to the intensive care, and death in both patients without affecting the production of antibodies to the nucleocapsid protein of SARS-CoV-2. If given early in the course of COVID-19 infection, bamlanivimab and etesevimab may be beneficial in APECED and other high-risk patients with neutralizing autoantibodies directed against type-I IFNs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ferré, Schmitt, Ochoa, Rosen, Shaw, Burbelo, Stoddard, Rampertaap, DiMaggio, Bergerson, Rosenzweig, Notarangelo, Holland and Lionakis.)
- Published
- 2021
- Full Text
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13. Editorial: Defects in Regulation: How, Where and When the Immune System Can Go Wrong.
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Rijkers GT, Riccardi C, and Kroese FGM
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- Animals, Humans, Immune System, Immune System Diseases
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Published
- 2021
- Full Text
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14. AIRE Gene Mutation Presenting at Age 2 Years With Autoimmune Retinopathy and Steroid-Responsive Acute Liver Failure: A Case Report and Literature Review.
- Author
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Sakaguchi H, Mizuochi T, Haruta M, Takase R, Yoshida S, Yamashita Y, and Nishikomori R
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- Administration, Intravenous, Autoantibodies blood, Autoimmune Diseases diagnosis, Autoimmune Diseases genetics, Autoimmune Diseases immunology, Azathioprine administration & dosage, Child, Preschool, Drug Therapy, Combination, Female, Genetic Predisposition to Disease, Humans, Immunosuppressive Agents administration & dosage, Liver Failure, Acute diagnosis, Liver Failure, Acute genetics, Liver Failure, Acute immunology, Phenotype, Polyendocrinopathies, Autoimmune diagnosis, Polyendocrinopathies, Autoimmune genetics, Polyendocrinopathies, Autoimmune immunology, Pulse Therapy, Drug, Recoverin immunology, Retinal Diseases diagnosis, Retinal Diseases genetics, Retinal Diseases immunology, Treatment Outcome, AIRE Protein, Adrenal Cortex Hormones administration & dosage, Autoimmune Diseases drug therapy, Liver Failure, Acute drug therapy, Methylprednisolone administration & dosage, Mutation, Polyendocrinopathies, Autoimmune drug therapy, Retinal Diseases drug therapy, Transcription Factors genetics
- Abstract
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare monogenic autosomal recessive disorder caused by mutation in the autoimmune regulator (AIRE) gene. Patients usually are diagnosed at ages between 5 and 15 years when they show 3 or more manifestations, most typically mucocutaneous candidiasis, Addison's disease, and hypoparathyroidism. APECED-associated hepatitis (APAH) develops in only 10% to 40% of patients, with severity varying from subclinical chronic active hepatitis to potentially fatal acute liver failure (ALF). Ocular abnormalities are fairly common, most often keratopathy but sometimes retinopathy. Here we report a 2-year-old Japanese girl with an AIRE gene mutation who developed APAH with ALF, preceded by autoimmune retinopathy associated with anti-recoverin antibody before major symptoms suggested a diagnosis of APECED. Intravenous pulse methylprednisolone therapy followed by a corticosteroid combined with azathioprine treatment resolved ALF and achieved control of APAH. To our knowledge, our patient is the youngest reported to have ALF resulting from an AIRE gene mutation. Pulse methylprednisolone induction therapy followed by treatment with corticosteroid plus azathioprine may well be effective in other children with APAH and AIRE gene mutations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sakaguchi, Mizuochi, Haruta, Takase, Yoshida, Yamashita and Nishikomori.)
- Published
- 2021
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15. Post-Aire Medullary Thymic Epithelial Cells and Hassall's Corpuscles as Inducers of Tonic Pro-Inflammatory Microenvironment.
- Author
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Laan M, Salumets A, Klein A, Reintamm K, Bichele R, Peterson H, and Peterson P
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- Animals, Calgranulin A metabolism, Calgranulin B metabolism, Child, Preschool, Epithelial Cells immunology, Humans, Infant, Mice, Proteome, Proteomics, Thymus Gland immunology, Toll-Like Receptor 4 metabolism, AIRE Protein, Cell Differentiation, Cellular Microenvironment, Central Tolerance, Epithelial Cells metabolism, Inflammation Mediators metabolism, Thymus Gland metabolism, Transcription Factors metabolism
- Abstract
While there is convincing evidence on the role of Aire-positive medullary thymic epithelial cells (mTEC) in the induction of central tolerance, the nature and function of post-Aire mTECs and Hassall's corpuscles have remained enigmatic. Here we summarize the existing data on these late stages of mTEC differentiation with special focus on their potential to contribute to central tolerance induction by triggering the unique pro-inflammatory microenvironment in the thymus. In order to complement the existing evidence that has been obtained from mouse models, we performed proteomic analysis on microdissected samples from human thymic medullary areas at different differentiation stages. The analysis confirms that at the post-Aire stages, the mTECs lose their nuclei but maintain machinery required for translation and exocytosis and also upregulate proteins specific to keratinocyte differentiation and cornification. In addition, at the late stages of differentiation, the human mTECs display a distinct pro-inflammatory signature, including upregulation of the potent endogenous TLR4 agonist S100A8/S100A9. Collectively, the study suggests a novel mechanism by which the post-Aire mTECs and Hassall's corpuscles contribute to the thymic microenvironment with potential cues on the induction of central tolerance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Laan, Salumets, Klein, Reintamm, Bichele, Peterson and Peterson.)
- Published
- 2021
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16. The Role of AIRE Deficiency in Infertility and Its Potential Pathogenesis.
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Zou X, Zhang Y, Wang X, Zhang R, and Yang W
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- Animals, Female, Infertility genetics, Male, Mice, Infertility immunology, Polyendocrinopathies, Autoimmune complications
- Abstract
The increasing number of patients with infertility is recognized as an emerging problem worldwide. However, little is known about the cause of infertility. At present, it is believed that infertility may be related to genetic or abnormal immune responses. It has long been indicated that autoimmune regulator (AIRE), a transcription factor, participates in immune tolerance by regulating the expression of thousands of promiscuous tissue-specific antigens in medullary thymic epithelial cells (mTECs), which play a pivotal role in preventing autoimmune diseases. AIRE is also expressed in germ cell progenitors. Importantly, the deletion of AIRE leads to severe oophoritis and age-dependent depletion of follicular reserves and causes altered embryonic development in female mice. AIRE-deficient male mice exhibit altered apoptosis during spermatogenesis and have a significantly decreased breeding capacity. These reports suggest that AIRE deficiency may be responsible for infertility. The causes may be related to the production of autoantibodies against sperm, poor development of germ cells, and abnormal ovarian function, which eventually lead to infertility. Here, we focus on the potential associations of AIRE deficiency with infertility as well as the possible pathogenesis, providing insight into the significance of AIRE in the development of infertility., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zou, Zhang, Wang, Zhang and Yang.)
- Published
- 2021
- Full Text
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17. Exploring the Origin and Antigenic Specificity of Maternal Regulatory T Cells in Pregnancy.
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Ahn SH, Nguyen SL, and Petroff MG
- Subjects
- Antigens immunology, Female, Fetus immunology, Humans, Immune Tolerance, Lymphocyte Activation immunology, Pregnancy Outcome, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, T-Lymphocytes, Regulatory cytology, T-Lymphocytes, Regulatory metabolism, Cell Differentiation immunology, Epitopes immunology, Lymphopoiesis immunology, Pregnancy immunology, T-Lymphocytes, Regulatory immunology
- Abstract
Successful pregnancy outcome is partially determined by the suppression of reactive effector T cells by maternal regulatory T cells (T
Regs ) at the maternal-fetal interface. While a large area of research has focused on the regulation of peripherally-induced TReg (pTReg ) distribution and differentiation using transgenic mouse models and human samples, studies focusing on the role of TRegs derived from the thymus (tTRegs ), and the potential role of central tolerance in maternal-fetal tolerance is less explored. The genome of the fetus is composed of both the tissue-specific and paternally-inherited antigens, and a break in maternal immune tolerance to either antigen may result in adverse pregnancy outcomes. Notably, "self"-antigens, including antigens that are highly restricted to the fetus and placenta, are promiscuously expressed by medullary thymic epithelial cells under the control of Autoimmune Regulator (Aire), which skews the tTReg T cell receptor (TCR) repertoire to be specific toward these antigens. TRegs that circulate in mothers during pregnancy may be comprised of TRegs that stem from the thymus as well as those induced in the periphery. Moreover, despite a wealth of research dedicated to elucidating the function of TRegs in maternal-fetal tolerance, little is understood about the origin of these cells, and whether/how tTRegs may contribute. Investigation into this question is complicated by the absence of reliable markers to distinguish between the two. In this review, we discuss how distinct types of fetal/placental antigens may determine the generation of different subtypes of TReg cells in the mother, and in turn how these may promote maternal tolerance to the fetus in pregnancy., (Copyright © 2020 Ahn, Nguyen and Petroff.)- Published
- 2020
- Full Text
- View/download PDF
18. Aire Gene Influences the Length of the 3' UTR of mRNAs in Medullary Thymic Epithelial Cells.
- Author
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Oliveira EH, Assis AF, Speck-Hernandez CA, Duarte MJ, and Passos GA
- Subjects
- Algorithms, Animals, Antigens genetics, Binding Sites genetics, Computer Simulation, Epithelial Cells immunology, Epithelial Cells metabolism, Gene Expression Regulation, Mice, Mice, Knockout, MicroRNAs genetics, Polyadenylation genetics, Polyendocrinopathies, Autoimmune genetics, RNA-Seq, Sequence Alignment, Thymus Gland cytology, Thymus Gland immunology, Transcription Factors deficiency, AIRE Protein, 3' Untranslated Regions, RNA, Messenger genetics, Thymus Gland metabolism, Transcription Factors genetics
- Abstract
Aire is a transcriptional controller in medullary thymic epithelial cells (mTECs) modulating a set of peripheral tissue antigens (PTAs) and non-PTA mRNAs as well as miRNAs. Even miRNAs exerting posttranscriptional control of mRNAs in mTECs, the composition of miRNA-mRNA networks may differ. Under reduction in Aire expression, networks exhibited greater miRNA diversity controlling mRNAs. Variations in the number of 3'UTR binding sites of Aire-dependent mRNAs may represent a crucial factor that influence the miRNA interaction. To test this hypothesis, we analyzed through bioinformatics the length of 3'UTRs of a large set of Aire-dependent mRNAs. The data were obtained from existing RNA-seq of mTECs of wild type or Aire-knockout (KO) mice. We used computational algorithms as FASTQC, STAR and HTSEQ for sequence alignment and counting reads, DESEQ2 for the differential expression, 3USS for the alternative 3'UTRs and TAPAS for the alternative polyadenylation sites. We identified 152 differentially expressed mRNAs between these samples comprising those that encode PTAs as well as transcription regulators. In Aire KO mTECs, most of these mRNAs featured an increase in the length of their 3'UTRs originating additional miRNA binding sites and new miRNA controllers. Results from the in silico analysis were statistically significant and the predicted miRNA-mRNA interactions were thermodynamically stable. Even with no in vivo or in vitro experiments, they were adequate to show that lack of Aire in mTECs might favor the downregulation of PTA mRNAs and transcription regulators via miRNA control. This could unbalance the overall transcriptional activity in mTECs and thus the self-representation., (Copyright © 2020 Oliveira, Assis, Speck-Hernandez, Duarte and Passos.)
- Published
- 2020
- Full Text
- View/download PDF
19. IL-22 Paucity in APECED Is Associated With Mucosal and Microbial Alterations in Oral Cavity.
- Author
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Kaleviste E, Rühlemann M, Kärner J, Haljasmägi L, Tserel L, Org E, Trebušak Podkrajšek K, Battelino T, Bang C, Franke A, Peterson P, and Kisand K
- Subjects
- Adolescent, Adult, Autoantibodies immunology, Biopsy, Child, Female, Gene Expression Regulation immunology, Humans, Inflammation, Interferon-alpha immunology, Male, Mouth pathology, Mutation, Saliva immunology, Young Adult, Interleukin-22, Interleukins deficiency, Interleukins immunology, Microbiota immunology, Mouth immunology, Mouth microbiology, Polyendocrinopathies, Autoimmune immunology
- Abstract
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by recessive mutations in the AIRE gene. The hallmark of the disease is the production of highly neutralizing autoantibodies against type I interferons and IL-22. Considering the importance of IL-22 in maintaining mucosal barrier integrity and shaping its microbial community, we sought to study potential changes in the oral cavity in this model of human IL-22 paucity. We found that besides known Th22 cell deficiency, APECED patients have significantly fewer circulating MAIT cells with potential IL-22 secreting capacity. Saliva samples from APECED patients revealed local inflammation, the presence of autoantibodies against IFN-α and IL-22, and alterations in the oral microbiota. Moreover, gene expression data of buccal biopsy samples suggested impaired antimicrobial response and cell proliferation, both of which are processes regulated by IL-22. Our data complement the knowledge gained from mouse models and support the concept of IL-22 being a critical homeostatic cytokine in human mucosal sites., (Copyright © 2020 Kaleviste, Rühlemann, Kärner, Haljasmägi, Tserel, Org, Trebušak Podkrajšek, Battelino, Bang, Franke, Peterson and Kisand.)
- Published
- 2020
- Full Text
- View/download PDF
20. The Rheumatoid Arthritis Risk Gene AIRE Is Induced by Cytokines in Fibroblast-Like Synoviocytes and Augments the Pro-inflammatory Response.
- Author
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Bergström B, Lundqvist C, Vasileiadis GK, Carlsten H, Ekwall O, and Ekwall AH
- Subjects
- Cells, Cultured, Chemokine CXCL10 metabolism, Humans, Inflammation immunology, Interferon-gamma immunology, Interleukin-1beta immunology, Membrane Glycoproteins metabolism, Polymorphism, Single Nucleotide genetics, RNA Interference, RNA, Small Interfering genetics, Tumor Necrosis Factor-alpha immunology, AIRE Protein, Arthritis, Rheumatoid genetics, Arthritis, Rheumatoid immunology, Synovial Membrane immunology, Synoviocytes metabolism, Transcription Factors genetics
- Abstract
The autoimmune regulator AIRE controls the negative selection of self-reactive T-cells as well as the induction of regulatory T-cells in the thymus by mastering the transcription and presentation of tissue restricted antigens (TRAs) in thymic cells. However, extrathymic AIRE expression of hitherto unknown clinical significance has also been reported. Genetic polymorphisms of AIRE have been associated with rheumatoid arthritis (RA), but no specific disease-mediating mechanism has been identified. Rheumatoid arthritis is characterized by a systemic immune activation and arthritis. Activated fibroblast-like synoviocytes (FLS) are key effector cells, mediating persistent inflammation, and destruction of joints. In this study, we identified AIRE as a cytokine-induced RA risk gene in RA FLS and explored its role in these pathogenic stroma cells. Using RNA interference and RNA sequencing we show that AIRE does not induce TRAs in FLS, but augments the pro-inflammatory response induced by tumor necrosis factor and interleukin-1β by promoting the transcription of a set of genes associated with systemic autoimmune disease and annotated as interferon-γ regulated genes. In particular, AIRE promoted the production and secretion of a set of chemokines, amongst them CXCL10, which have been associated with disease activity in RA. Finally, we demonstrate that AIRE is expressed in podoplanin positive FLS in the lining layer of synovial tissue from RA patients. These findings support a novel pro-inflammatory role of AIRE at peripheral inflammatory sites and provide a potential pathological mechanism for its association with RA.
- Published
- 2019
- Full Text
- View/download PDF
21. Maturing Human CD127+ CCR7+ PDL1+ Dendritic Cells Express AIRE in the Absence of Tissue Restricted Antigens.
- Author
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Fergusson JR, Morgan MD, Bruchard M, Huitema L, Heesters BA, van Unen V, van Hamburg JP, van der Wel NN, Picavet D, Koning F, Tas SW, Anderson MS, Marioni JC, Holländer GA, and Spits H
- Subjects
- B7-H1 Antigen metabolism, Cell Communication immunology, Cells, Cultured, Child, Preschool, Dendritic Cells metabolism, Humans, Infant, Infant, Newborn, Interleukin-7 Receptor alpha Subunit metabolism, Lymphocyte Activation, Palatine Tonsil immunology, Palatine Tonsil metabolism, Primary Cell Culture, Receptors, CCR7 metabolism, T-Lymphocytes immunology, Transcription Factors immunology, AIRE Protein, Dendritic Cells immunology, Palatine Tonsil cytology, Transcription Factors metabolism
- Abstract
Expression of the Autoimmune regulator (AIRE) outside of the thymus has long been suggested in both humans and mice, but the cellular source in humans has remained undefined. Here we identify AIRE expression in human tonsils and extensively analyzed these "extra-thymic AIRE expressing cells" (eTACs) using combinations of flow cytometry, CyTOF and single cell RNA-sequencing. We identified AIRE+ cells as dendritic cells (DCs) with a mature and migratory phenotype including high levels of antigen presenting molecules and costimulatory molecules, and specific expression of CD127, CCR7, and PDL1. These cells also possessed the ability to stimulate and re-stimulate T cells and displayed reduced responses to toll-like receptor (TLR) agonists compared to conventional DCs. While expression of AIRE was enriched within CCR7+CD127+ DCs, single-cell RNA sequencing revealed expression of AIRE to be transient, rather than stable, and associated with the differentiation to a mature phenotype. The role of AIRE in central tolerance induction within the thymus is well-established, however our study shows that AIRE expression within the periphery is not associated with an enriched expression of tissue-restricted antigens (TRAs). This unexpected finding, suggestive of wider functions of AIRE, may provide an explanation for the non-autoimmune symptoms of APECED patients who lack functional AIRE.
- Published
- 2019
- Full Text
- View/download PDF
22. Comprehensively Profiling the Chromatin Architecture of Tissue Restricted Antigen Expression in Thymic Epithelial Cells Over Development.
- Author
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Handel AE, Shikama-Dorn N, Zhanybekova S, Maio S, Graedel AN, Zuklys S, Ponting CP, and Holländer GA
- Subjects
- Animals, Antigens metabolism, Cell Differentiation genetics, Chromatin metabolism, Histones metabolism, Mice, Inbred C57BL, Thymocytes metabolism, Thymus Gland cytology, Thymus Gland metabolism, Transcription Factors genetics, Transcription Factors metabolism, AIRE Protein, Antigens genetics, Chromatin genetics, Epithelial Cells metabolism, Gene Expression Profiling methods
- Abstract
Thymic epithelial cells (TEC) effect crucial roles in thymopoiesis including the control of negative thymocyte selection. This process depends on their capacity to express promiscuously genes encoding tissue-restricted antigens. This competence is accomplished in medullary TEC (mTEC) in part by the presence of the transcriptional facilitator AutoImmune REgulator, AIRE. AIRE-regulated gene transcription is marked by repressive chromatin modifications, including H3K27me3. When during TEC development these chromatin marks are established, however, remains unclear. Here we use a comprehensive ChIP-seq dataset of multiple chromatin modifications in different TEC subtypes to demonstrate that the chromatin landscape is established early in TEC differentiation. Much of the chromatin architecture found in mature mTEC was found to be present already over earlier stages of mTEC lineage differentiation as well as in non-TEC tissues. This was reflected by the fact that a machine learning approach accurately classified genes as AIRE-induced or AIRE-independent both in immature and mature mTEC. Moreover, analysis of TEC specific enhancer elements identified candidate transcription factors likely to be important in mTEC development and function. Our findings indicate that the mature mTEC chromatin landscape is laid down early in mTEC differentiation, and that AIRE is not required for large-scale re-patterning of chromatin in mTEC.
- Published
- 2018
- Full Text
- View/download PDF
23. The Role of AIRE in the Immunity Against Candida Albicans in a Model of Human Macrophages.
- Author
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de Albuquerque JAT, Banerjee PP, Castoldi A, Ma R, Zurro NB, Ynoue LH, Arslanian C, Barbosa-Carvalho MUW, Correia-Deur JEM, Weiler FG, Dias-da-Silva MR, Lazaretti-Castro M, Pedroza LA, Câmara NOS, Mace E, Orange JS, and Condino-Neto A
- Subjects
- Candida albicans physiology, Candidiasis genetics, Candidiasis immunology, Candidiasis microbiology, Cytokines immunology, Cytokines metabolism, HEK293 Cells, Humans, Hyphae physiology, Lectins, C-Type genetics, Lectins, C-Type immunology, Lectins, C-Type metabolism, Macrophages microbiology, Mutation, Phagocytosis genetics, Phagocytosis immunology, Polyendocrinopathies, Autoimmune genetics, Polyendocrinopathies, Autoimmune immunology, Polyendocrinopathies, Autoimmune microbiology, RNA Interference, THP-1 Cells, Transcription Factors genetics, Transcription Factors metabolism, AIRE Protein, Candida albicans immunology, Hyphae immunology, Macrophages immunology, Transcription Factors immunology
- Abstract
Autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a primary immunodeficiency caused by mutations in the autoimmune regulator gene ( AIRE ). Patients with AIRE mutations are susceptible to Candida albicans infection and present with autoimmune disorders. We previously demonstrated that cytoplasmic AIRE regulates the Syk-dependent Dectin-1 pathway. In this study, we further evaluated direct contact with fungal elements, synapse formation, and the response of macrophage-like THP-1 cells to C. albicans hyphae to determine the role of AIRE upon Dectin receptors function and signaling. We examined the fungal synapse (FS) formation in wild-type and AIRE-knockdown THP-1 cells differentiated to macrophages, as well as monocyte-derived macrophages from APECED patients. We evaluated Dectin-2 receptor signaling, phagocytosis, and cytokine secretion upon hyphal stimulation. AIRE co-localized with Dectin-2 and Syk at the FS upon hyphal stimulation of macrophage-like THP-1 cells. AIRE-knockdown macrophage-like THP-1 cells exhibited less Dectin-1 and Dectin-2 receptors accumulation, decreased signaling pathway activity at the FS, lower C. albicans phagocytosis, and less lysosome formation. Furthermore, IL-1β, IL-6, or TNF-α secretion by AIRE-knockdown macrophage-like THP-1 cells and AIRE-deficient patient macrophages was decreased compared to control cells. Our results suggest that AIRE modulates the FS formation and hyphal recognition and help to orchestrate an effective immune response against C. albicans .
- Published
- 2018
- Full Text
- View/download PDF
24. Autoimmune Regulator Deficiency Results in a Decrease in STAT1 Levels in Human Monocytes.
- Author
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Zimmerman O, Rosen LB, Swamydas M, Ferre EMN, Natarajan M, van de Veerdonk F, Holland SM, and Lionakis MS
- Abstract
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare primary immunodeficiency disorder typically caused by biallelic autoimmune regulator ( AIRE ) mutations that manifests with chronic mucocutaneous candidiasis (CMC) and autoimmunity. Patients with STAT1 gain-of-function (GOF) mutations also develop CMC and autoimmunity; they exhibit increased STAT1 protein levels at baseline and STAT1 phosphorylation (pSTAT1) upon interferon (IFN)-γ stimulation relative to healthy controls. AIRE interacts functionally with a protein that directly regulates STAT1, namely protein inhibitor of activated STAT1, which inhibits STAT1 activation. Given the common clinical features between patients with AIRE and STAT1 GOF mutations, we sought to determine whether APECED patients also exhibit increased levels of STAT1 protein and phosphorylation in CD14
+ monocytes. We obtained peripheral blood mononuclear cells from 8 APECED patients and 13 healthy controls and assessed the levels of STAT1 protein and STAT1 tyrosine phosphorylation at rest and following IFN-γ stimulation, as well as the levels of STAT1 mRNA. The mean STAT1 protein levels in CD14+ monocytes exhibited a ~20% significant decrease in APECED patients both at rest and after IFN-γ stimulation relative to that of healthy donors. Similarly, the mean peak value of IFN-γ-induced pSTAT1 level was ~20% significantly lower in APECED patients compared to that in healthy controls. The decrease in STAT1 and peak pSTAT1 in APECED patients was not accompanied by decreased STAT1 mRNA or anti-IFN-γ autoantibodies; instead, it correlated with the presence of autoantibodies to type I IFN and decreased AIRE- / - monocyte surface expression of IFN-γ receptor 2. Our data show that, in contrast to patients with STAT1 GOF mutations, APECED patients show a moderate but consistent and significant decrease in total STAT1 protein levels, associated with lower peak levels of pSTAT1 molecules after IFN-γ stimulation.- Published
- 2017
- Full Text
- View/download PDF
25. Aire Downregulation Is Associated with Changes in the Posttranscriptional Control of Peripheral Tissue Antigens in Medullary Thymic Epithelial Cells.
- Author
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Oliveira EH, Macedo C, Collares CV, Freitas AC, Donate PB, Sakamoto-Hojo ET, Donadi EA, and Passos GA
- Abstract
Autoimmune regulator (Aire) is a transcriptional regulator of peripheral tissue antigens (PTAs) and microRNAs (miRNAs) in medullary thymic epithelial cells (mTECs). In this study, we tested the hypothesis that Aire also played a role as an upstream posttranscriptional controller in these cells and that variation in its expression might be associated with changes in the interactions between miRNAs and the mRNAs encoding PTAs. We demonstrated that downregulation of Aire in vivo in the thymuses of BALB/c mice imbalanced the large-scale expression of these two RNA species and consequently their interactions. The expression profiles of a large set of mTEC miRNAs and mRNAs isolated from the thymuses of mice subjected (or not) to small-interfering-induced Aire gene knockdown revealed that 87 miRNAs and 4,558 mRNAs were differentially expressed. The reconstruction of the miRNA-mRNA interaction networks demonstrated that interactions between these RNAs were under Aire influence and therefore changed when this gene was downregulated. Prior to Aire-knockdown, only members of the miR-let-7 family interacted with a set of PTA mRNAs. Under Aire-knockdown conditions, a larger set of miRNA families and their members established this type of interaction. Notably, no previously described Aire-dependent PTA interacted with the miRNAs, indicating that these PTAs were somehow refractory. The miRNA-mRNA interactions were validated by calculating the minimal free energy of the pairings between the miRNA seed regions and the mRNA 3' UTRs and within the cellular milieu using the luciferase reporter gene assay. These results suggest the existence of a link between transcriptional and posttranscriptional control because Aire downregulation alters the miRNA-mRNA network controlling PTAs in mTEC cells.
- Published
- 2016
- Full Text
- View/download PDF
26. Thymic B Cells and Central T Cell Tolerance.
- Author
-
Yamano T, Steinert M, and Klein L
- Abstract
Central T cell tolerance is believed to be mainly induced by thymic dendritic cells and medullary thymic epithelial cells. The thymus also harbors substantial numbers of B cells. These may arise though intrathymic B lymphopoiesis or immigration from the bloodstream. Importantly, and in contrast to resting "mainstream" B cells in the periphery, thymic B cells display elevated levels of MHC class II and constitutively express CD80. Arguably, their most unexpected feature is the expression of autoimmune regulator. These unique features of thymic B cells result from a licensing process that involves cross-talk with CD4 single-positive T cells and CD40 signaling. Together, these recent findings suggest that B cells play a more prominent role as thymic APCs than previously appreciated.
- Published
- 2015
- Full Text
- View/download PDF
27. The Thymic Orchestration Involving Aire, miRNAs, and Cell-Cell Interactions during the Induction of Central Tolerance.
- Author
-
Passos GA, Mendes-da-Cruz DA, and Oliveira EH
- Abstract
Developing thymocytes interact sequentially with two distinct structures within the thymus: the cortex and medulla. Surviving single-positive and double-positive thymocytes from the cortex migrate into the medulla, where they interact with medullary thymic epithelial cells (mTECs). These cells ectopically express a vast set of peripheral tissue antigens (PTAs), a property termed promiscuous gene expression that is associated with the presentation of PTAs by mTECs to thymocytes. Thymocyte clones that have a high affinity for PTAs are eliminated by apoptosis in a process termed negative selection, which is essential for tolerance induction. The Aire gene is an important factor that controls the expression of a large set of PTAs. In addition to PTAs, Aire also controls the expression of miRNAs in mTECs. These miRNAs are important in the organization of the thymic architecture and act as posttranscriptional controllers of PTAs. Herein, we discuss recent discoveries and highlight open questions regarding the migration and interaction of developing thymocytes with thymic stroma, the ectopic expression of PTAs by mTECs, the association between Aire and miRNAs and its effects on central tolerance.
- Published
- 2015
- Full Text
- View/download PDF
28. Promiscuous Gene Expression in the Thymus: A Matter of Epigenetics, miRNA, and More?
- Author
-
Ucar O and Rattay K
- Abstract
The induction of central tolerance in the course of T cell development crucially depends on promiscuous gene expression (pGE) in medullary thymic epithelial cells (mTECs). mTECs express a genome-wide variety of tissue-restricted antigens (TRAs), preventing the escape of autoreactive T cells to the periphery, and the development of severe autoimmunity. Most of our knowledge of how pGE is controlled comes from studies on the autoimmune regulator (Aire). Aire activates the expression of a large subset of TRAs by interacting with the general transcriptional machinery and promoting transcript elongation. However, further factors regulating Aire-independent TRAs must be at play. Recent studies demonstrated that pGE in general and the function of Aire in particular are controlled by epigenetic and post-transcriptional mechanisms. This mini-review summarizes current knowledge of the regulation of pGE by miRNA and epigenetic regulatory mechanisms such as DNA methylation, histone modifications, and chromosomal topology.
- Published
- 2015
- Full Text
- View/download PDF
29. Lymphopenia-induced proliferation in aire-deficient mice helps to explain their autoimmunity and differences from human patients.
- Author
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Kisand K, Peterson P, and Laan M
- Abstract
Studies on autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) and its mouse model - both caused by mutant AIRE - have greatly advanced the understanding of thymic processes that generate a self-tolerant T-cell repertoire. Much is now known about the molecular mechanisms by which AIRE induces tissue-specific antigen expression in thymic epithelium, and how this leads to negative selection of auto-reactive thymocytes. However, we still do not understand the processes that lead to the activation of any infrequent naïve auto-reactive T-cells exported by AIRE-deficient thymi. Also, the striking phenotypic differences between APECED and its mouse models have puzzled researchers for years. The aim of this review is to suggest explanations for some of these unanswered questions, based on a fresh view of published experiments. We review evidence that auto-reactive T-cells can be activated by the prolonged neonatal lymphopenia that naturally develops in young Aire-deficient mice due to delayed export of mature thymocytes. Lymphopenia-induced proliferation (LIP) helps to fill the empty space; by favoring auto-reactive T-cells, it also leads to lymphocyte infiltration in the same tissues as in day 3 thymectomized animals. The LIP becomes uncontrolled when loss of Aire is combined with defects in genes responsible for anergy induction and Treg responsiveness, or in signaling from the T-cell receptor and homeostatic cytokines. In APECED patients, LIP is much less likely to be involved in activation of naïve auto-reactive T-cells, as humans are born with a more mature immune system than in neonatal mice. We suggest that human AIRE-deficiency presents with different phenotypes because of additional precipitating factors that compound the defective negative selection of potentially autoaggressive tissue-specific thymocytes.
- Published
- 2014
- Full Text
- View/download PDF
30. The many faces of aire in central tolerance.
- Author
-
Laan M and Peterson P
- Abstract
Although the role that Autoimmune Regulator (Aire) plays in the induction of central tolerance is well known, the precise cellular and molecular mechanisms are still unclear and debated. In the prevailing view, Aire serves mainly as a direct inducer of tissue-specific antigens. However, there is a growing amount of evidence suggesting that Aire modulates the differentiation program of medullary thymic epithelial cells, which may directly contribute to the negative selection of self-reactive thymocytes. In addition, Aire has been shown to regulate the expression of many intrathymic chemokines that are required for the proper localization of thymocytes and dendritic cells, and thus are potentially important for direct and indirect self-antigen presentation in the thymic medulla. Further, recent evidence suggests that the induction of certain antigen-specific regulatory T-cells that translocate to tumors and peripheral tissues can be Aire dependent and may contribute to tissue-specific tolerance. This review summarizes the current understanding of the effects of Aire on these alternative mechanisms for the induction of Aire-induced central tolerance.
- Published
- 2013
- Full Text
- View/download PDF
31. Human APECED; a Sick Thymus Syndrome?
- Author
-
Arstila TP and Jarva H
- Abstract
Loss-of-function mutations in the Autoimmune Regulator (AIRE) gene cause a rare inherited form of autoimmune disease, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, also known as autoimmune polyglandular syndrome type 1. The patients suffer from multiple endocrine deficiencies, the most common manifestations being hypoparathyroidism, Addison's disease, hypogonadism, and secondary amenorrhea, usually accompanied by typical autoantibodies against the target tissues. Chronic mucocutaneous candidiasis is also a prominent part of the disease. The highest expression of AIRE is found in medullary thymic epithelial cells (mTECs). Murine studies suggest that it promotes ectopic transcription of self antigens in mTECs and is thus important for negative selection. However, failed negative selection alone is not enough to explain key findings in human patients, necessitating the search for alternative or additional pathogenetic mechanisms. A striking feature of the human AIRE-deficient phenotype is that all patients develop high titers of neutralizing autoantibodies against type I interferons, which have been shown to downregulate the expression of interferon-controlled genes. These autoantibodies often precede clinical symptoms and other autoantibodies, suggesting that they are a reflection of the pathogenetic process. Other cytokines are targeted as well, notably those produced by Th17 cells; these autoantibodies have been linked to the defect in anti-candida defenses. A defect in regulatory T cells has also been reported in several studies and seems to affect already the recent thymic emigrant population. Taken together, these findings in human patients point to a widespread disruption of T cell development and regulation, which is likely to have its origins in an abnormal thymic milieu. The absence of functional AIRE in peripheral lymphoid tissues may also contribute to the pathogenesis of the disease.
- Published
- 2013
- Full Text
- View/download PDF
32. APECED: is this a model for failure of T cell and B cell tolerance?
- Author
-
Kluger N, Ranki A, and Krohn K
- Abstract
In APECED, the key abnormality is in the T cell defect that may lead to tissue destruction chiefly in endocrine organs. Besides, APECED is characterized by high-titer antibodies against a wide variety of cytokines that could partly be responsible for the clinical symptoms during APECED, mainly chronic mucocutaneous candidiasis, and linked to antibodies against Th17 cells effector molecules, IL-17 and IL-22. On the other hand, the same antibodies, together with antibodies against type I interferons may prevent the patients from other immunological diseases, such as psoriasis and systemic lupus erythematous. The same effector Th17 cells, present in the lymphocytic infiltrate of target organs of APECED, could be responsible for the tissue destruction. Here again, the antibodies against the corresponding effector molecules, anti-IL-17 and anti-IL-22 could be protective. The occurrence of several effector mechanisms (CD4(+) Th17 cell and CD8(+) CTL and the effector cytokines IL-17 and IL-22), and simultaneous existence of regulatory mechanisms (CD4(+) Treg and antibodies neutralizing the effect of the effector cytokines) may explain the polymorphism of APECED. Almost all the patients develop the characteristic manifestations of the complex, but temporal course and severity of the symptoms vary considerably, even among siblings. The autoantibody profile does not correlate with the clinical picture. One could speculate that a secondary homeostatic balance between the harmful effector mechanisms, and the favorable regulatory mechanisms, finally define both the extent and severity of the clinical condition in the AIRE defective individuals. The proposed hypothesis that in APECED, in addition to strong tissue destructive mechanisms, a controlling regulatory mechanism does exist, allow us to conclude that APECED could be treated, and even cured, with immunological manipulation.
- Published
- 2012
- Full Text
- View/download PDF
33. Models of aire-dependent gene regulation for thymic negative selection.
- Author
-
Danso-Abeam D, Humblet-Baron S, Dooley J, and Liston A
- Abstract
Mutations in the autoimmune regulator (AIRE) gene lead to autoimmune polyendocrinopathy syndrome type 1 (APS1), characterized by the development of multi-organ autoimmune damage. The mechanism by which defects in AIRE result in autoimmunity has been the subject of intense scrutiny. At the cellular level, the working model explains most of the clinical and immunological characteristics of APS1, with AIRE driving the expression of tissue-restricted antigens (TRAs) in the epithelial cells of the thymic medulla. This TRA expression results in effective negative selection of TRA-reactive thymocytes, preventing autoimmune disease. At the molecular level, the mechanism by which AIRE initiates TRA expression in the thymic medulla remains unclear. Multiple different models for the molecular mechanism have been proposed, ranging from classical transcriptional activity, to random induction of gene expression, to epigenetic tag recognition effect, to altered cell biology. In this review, we evaluate each of these models and discuss their relative strengths and weaknesses.
- Published
- 2011
- Full Text
- View/download PDF
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