aire transcription factor

Weak binding to the MHC results in lower effective avidity that allows escape from deletion. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Mol Cell Biochem (2010) 342(1–2):21–8. AIRE activated tissue specific genes have histone modifications associated with inactive chromatin. The results showed that AIRE+ cells always co-expressed HLA-DR and fascin and usually expressed the myeloid DC markers CD11c and S100. Mature DCs induce effective immune responses via the expression of co-stimulatory molecules and high levels of MHC II molecules, whereas immature DCs usually exert immune suppressive functions because they lack co-stimulatory molecules and have low levels of MHC II molecule expression. doi:10.1182/blood-2014-08-597245, 128. Perniola R. Expression of the autoimmune regulator gene and its relevance to the mechanisms of central and peripheral tolerance. Found inside – Page iiiThis book provides a molecular explanation how our genome is connected with environmental signals. It outlines that epigenetic programming is a learning process that results in epigenetic memory in each of the cells forming our body. 12. After DNA-PKcs silencing, TLR1, TLR3, and TLR8 expression was down-regulated in macrophages transiently transfected with pEGFPC1/AIRE. Bredenkamp N, Nowell CS, Blackburn CC. Given that Liston et al., employing mice in which one Aire allele was deleted, found that PGE affects in quantitative terms the magnitude of self-reactive T cells escaping negative selection (296), it has been hypothesized that conditions of partial AIRE deficiency may represent a risk for non-syndromic autoimmunity when acting in synergy with other susceptibility factors. Lopes N, Sergé A, Ferrier P, Irla M. Thymic crosstalk coordinates medulla organization and T-cell tolerance induction. doi:10.1021/pr100044d, 62. Colomé N, Collado J, Bech-Serra JJ, Liiv I, Antón LC, Peterson P, et al. Gene (2014) 549(2):286–94. Autoimmune regulator (AIRE) is an important transcriptional regulator that is mainly expressed in medullary thymic epithelial cells (mTECs) in the central immune system. doi:10.4049/jimmunol.176.7.3995, 89. Adrenal failure requires hydrocortisone replacement. doi:10.4049/jimmunol.1200119, 112. doi:10.4049/jimmunol.177.1.290, 80. Here’s why Greenspan’s is an essential tool for learning how to manage endocrine patients: • The Tenth Edition is enhanced by updated content throughout each chapter • NEW CHAPTERS on Transgender Endocrinology and Disorders of ... Identification of a bipotent epithelial progenitor population in the adult thymus. Immunity (2012) 36(3):427–37. doi:10.1182/blood-2009-05-223198, 126. Finnish patients with APS-1 often have ectodermal and enamel hypoplasia.58 Calcium deficiency secondary to hypoparathyroidism should not be the primary cause for enamel dystrophy, because in Finnish patients, ectodermal and enamel hypoplasia occurs in APS-1 patients with or without hypoparathyroidism.58,130 In addition, those non-Finnish patients with APS-1 who had hypoparathyroidism are seldom seen with enamel hypoplasia.114,118 Background genes or genes with epistatic effects may be responsible for variations in the expressed phenotype.116 Alternatively, more than one gene may be responsible for the development of APS-1, although this possibility is becoming increasingly unlikely. doi:10.1084/jem.188.1.1, 331. J Leukoc Biol (2012) 91(3):417–26. Macedo C, Oliveira EH, Almeida RS, Donate PB, Fornari TA, Pezzi N, et al. doi:10.4049/jimmunol.1500558, 206. Sci Rep (2015) 5:e12895. The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator. Trends Immunol (2010) 31(2):71–9. The thymic epithelial microRNA network elevates the threshold for infection-associated thymic involution via the miR-29a mediated suppression of the IFN-α receptor. The autoimmune regulator directly controls the expression of genes critical for thymic epithelial function. Finally, interaction with the human heterogeneous nuclear ribonucleoprotein L suggests that AIRE enhances mRNA diversity by favoring alternative mRNA splicing (184), as confirmed in murine mTECs (185, 186). doi:10.4161/epi.3.6.7182, 161. Pitkänen J, Doucas V, Sternsdorf T, Nakajima T, Aratani S, Jensen K, et al. Autoimmune regulator (aire) is a transcription factor that controls the self-reactivity of the T cell repertoire. J Biol Chem (1999) 274(18):12555–66. Liston A. In the theory of avidity, the amount of antigen determines the outcome of the interaction. Cell Rep (2016) 17(2):448–57. This presentation imparts deletional tolerance, and Aire deficiency results in multiorgan autoimmune disease in both human patients and KO mice. deleted Ins2 in CD11c-expressing cells of Ins1−/− mice. Analysis of the autoimmune regulator gene in patients with autoimmune non-APECED polyendocrinopathies. Brennecke P, Reyes A, Pinto S, Rattay K, Nguyen M, Küchler R, et al. Werdelin O, Cordes U, Jensen T. Aberrant expression of tissue-specific proteins in the thymus: a hypothesis for the development of central tolerance. Martins V, Boehm T, Bleul CC. The autoimmune regulator gene AIRE (21q22.3) codes for a transcription factor. This disorder is caused by mutations in the gene encoding the autoimmune regulator protein (AIRE), a transcription factor that is important in controlling the ectopic expression of self-antigens in the thymus. Fierabracci A. Gibson TJ, Ramu C, Gemünd C, Aasland R. The APECED polyglandular autoimmune syndrome protein, AIRE-1, contains the SAND domain and is probably a transcription factor. The rate of mRNA translation into the respective proteins is even lower, so that each ts-ag is traceable in about 1–3% of mTECs (211). Fujicado N, Mann AO, Bansal K, Romito KR, Ferre EMN, Rosenzweig SD, et al. doi:10.1182/blood-2012-12-474759, 127. Only Aire−/− recipients, independently from the donor condition, exhibited organ damage, underlining that the property of preventing the autoimmune process is inherent to wild-type (Aire-sufficient) thymic stroma. Evidence suggests that central tolerance is incomplete because autoreactive cells can be found in the peripheral repertoire and autoimmune diseases do arise in humans and animal models (Haskins and McDuffie, 1990; Nagata et al., 1994; Verdaguer et al., 1997; Wong et al., 1999). Later, Lkhagvasuren et al. AIRE is not a canonical transcription factor that recognizes specific DNA sequence motifs (Mathis and Benoist, 2009), and so there is considerable interest in understanding how AIRE functions in inducing promiscuous expression and other processes. Semin Immunol (1997) 9(6):375–80. Gäbler J, Arnold J, Kyewski B. Promiscuous gene expression and the developmental dynamics of medullary thymic epithelial cells. Zhang B, Wang Z, Ding J, Peterson P, Gunning WT, Ding H-F. NF-κB2 is required for the control of autoimmunity by regulating the development of medullary thymic epithelial cells. doi:10.1126/science.272.5263.886, 66. doi:10.1126/scitranslmed.3000284, 275. Tykocinski L-O, Sinemus A, Rezavandy E, Weiland Y, Baddeley D, Cremer C, et al. Analogously, clustered Aire-dependent genes are expressed stochastically in small groups of murine mTECshi, with a significant degree of diversity between individuals (215, 216). Guerau-de-Arellano M, Mathis D, Benoist C. Trascriptional impact of Aire varies with cell type. doi:10.1210/jcem.85.2.6369, 298. doi:10.1016/S0968-0004(00)88957-4, 157. Peterson P, Org T, Rebane A. Transcriptional regulation by AIRE: molecular mechanisms of central tolerance. Sun, H. Fu, J. Wu, W. Zhu, Y. Li, and W. Yang, “Macrophages overexpressing Aire induce CD4, Y. S. Choi, R. Kageyama, D. Eto et al., “ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl 6,”, H. Qi, “T follicular helper cells in space-time,”, E. Lindmark, Y. Chen, A.-M. Georgoudaki et al., “AIRE expressing marginal zone dendritic cells balances adaptive immunity and T-follicular helper cell recruitment,”. Through the peripheral expression of different TSA groups, eTACs can lead to the tolerance of central antigen-specific T cells that have not been cleared [22]. doi:10.4049/jimmunol.179.12.8069, 82. doi:10.1038/ni.2820, 190. Cellular localization of somatomedin (insulin-like growth factor) messenger RNA in the human fetus. Human AIRE is encoded by a gene located in the region 22q.3 of chromosome 21 (129, 130). Autoimmune regulator (aire) is a transcription factor that controls the self-reactivity of the T cell repertoire. Interestingly, mTEC differentiation may be reproduced in vitro by three-dimensional organotypic co-cultures engineered for dermal equivalent and based on the close relationship between skin and thymic stroma (128). Ucar O, Rattay K. Promiscuous gene expression in the thymus: a matter of epigenetics, miRNA, and more? doi:10.1074/jbc.274.18.12555, 148. Immunobiology (2015) 220(1):93–102. There are three or four stages of maturation of the SP thymocytes, which finally reach the perivascular space as pre-recent thymic emigrants (pre-RTEs). Bennett AR, Farley A, Blair NF, Gordon J, Sharp L, Blackburn CC. Keratinocyte growth factor and androgen blockade work in concert to protect against conditioning regimen-induced thymic epithelial damage and enhance T-cell reconstitution after murine bone marrow transplantation. Science (2005) 308(5719):248–51. Derbinski J, Schulte A, Kyewski B, Klein L. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Akirav EM, Xu Y, Ruddle NH. We use cookies to help provide and enhance our service and tailor content and ads. Johnnidis JB, Venanzi ES, Taxman DJ, Ting JP-Y, Benoist CO, Mathis DJ. There are four stages (DN1–DN4) of DN condition, during which thymocytes move from the cortico-medullary junction to the subcapsular zone of the gland. Found insideWritten by world experts, this books follows upon the monumental success of the first edition of The Parathyroids, which was universally acclaimed as the best text on the subject. In the last few years, the researchers have focused their attention on TEPC characterization in the thymus of adult (at least 4-week-old) mice, applying different experimental settings and marker panels (40–45). Lymphotoxin pathway directs thymic Aire expression. The neuroendocrine thymus: coexistence of oxytocin and neurophysin in the human thymus. doi:10.1006/bbrc.1999.0308, 134. There is a bulk of experimental data from the studies on the role and consequences of loss and gain of function of these molecules in the embryonic and postnatal/adult thymus (76–114). A smaller number of PHD fingers displays preference for histone H3 tails trimethylated at Lys9 (H3K9me3) (49,50) and Lys36 (H3K36me3) (51) or acetylated at Lys9 (H3K9ac) and Lys14 (H3K14ac). Found insideThe last ten years have witnessed a remarkable increase in our awareness of the importance of events subsequent to transcriptional initiation in terms of the regulation and control of gene expression. Proc R Soc Lond B Biol Sci (1962) 156(964):415–28. Although previous results indicate that it exerts this function in part by . Ucar A, Ucar O, Klug P, Matt S, Brunk F, Hofmann TG, et al. Aire-independent manner,or the existence of binding partners to Aire that modify target recognition (Abramson et al., 2010). Figure 5. A novel mutation of the autoimmune regulator gene in an Italian kindred with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, acting in a dominant fashion and strongly cosegregating with hypothyroid autoimmune thyroiditis. doi:10.1155/2012/207403, 136. Schematic representation of thymocyte maturation and the processes of positive and negative selection. Mol Cell Biol (2012) 32(8):1354–62. One LXXLL motif is contained between the PHDs in a proline-rich region, while the fourth LXXLL is present in the transcriptional activating domain at the C-terminus. Matsumoto M, Nishikawa Y, Nishijima H, Morimoto J, Matsumoto M, Mouri Y. Schaller CE, Wang CL, Beck-Engeser G, Goss L, Scott HS, Anderson MS, et al. Not all patients with APS-1 express all of the three core component diseases or the frequently accompanied diseases. Finnish-German APECED Consortium. Other evidences have been called into question, such as the small percentage of mTECs in which each ts-ag is detectable (335); the dependency on Aire of differentiation-associated genes and genes encoding master transcription factors (21–23, 336, 337); and the ultrastructure of Aire−/− thymus, in which expansion of the K8+ subset indicates mTEC inability to differentiate into distinct epithelial lineages (338, 339). In addition, the mRNA expression levels of TLR1, TLR3, and TLR8 increased in mouse peritoneal macrophages with transient AIRE expression. doi:10.1172/JCI28326, 81. The PHD2 finger of CHD4 prefers H3K9me3 or H3K9ac (43,47), whereas the tandem PHD finger of Trends Immunol (2007) 28(7):321–7. doi:10.1038/ni.3675, 178. Hidaka K, Nitta T, Sugawa R, Shirai M, Schwartz RJ, Amagai T, et al. Heino M, Peterson P, Sillanpää N, Guérin S, Wu L, Anderson G, et al. The role of Aire in clonal selection. Homozygous inheritance of mutant AIRE, expressed particularly in stromal cells in the thymic medulla, curtails the establishment of central immune tolerogenesis because the AIRE protein facilitates intrathymic expression of normally organ-specific “cryptic” autoantigens [123]. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Impact Factor 7.561 | CiteScore 8.1More on impact ›, Vlaams Instituut voor Biotechnologie, Belgium. Pommier Y, Sun Y, Huang SN, Nitiss JL. Dertschnig S, Nusspaumer G, Ivanek R, Hauri-Hohl MM, Holländer GA, Krenger W. Epithelial cytoprotection sustains ectopic expression of tissue-restricted antigens in the thymus during murine acute GVHD. There and back again: autoimmune polyendocrinopathy syndrome type I and the Aire knockout mouse. The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. From this perspective, it has been possible to elaborate a model of cTEC/mTEC commitment in which mTEC sublineage diverges from a defaulted program of cTEC differentiation (38), as shown in Figure 1. Lymph node-resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation. J Immunol (2007) 178(11):7173–89. AIRE expands: new roles in immune tolerance and beyond. Hum Mol Genet (1998) 7(10):1547–53. doi:10.4049/jimmunol.0804133, 255. The expression of Aire and most ts-ag-encoding genes, in turn, is restricted to the mature, MHCIIhi or CD80hi, mTECs (14, 53, 56). Thymic medullary epithelial cell differentiation, thymocyte emigration, and the control of autoimmunity require lympho-epithelial cross talk via LTβR. Endocrinology (2009) 150(6):2948–56. Homeostatic properties and phenotypic maturation of murine CD4+ pre-thymic emigrants in the thymus. Immunity (2008) 29(3):438–50. doi:10.1038/ni723, 15. Proc Natl Acad Sci U S A (1998) 95(20):11822–7. Later, one of these research groups revised the phenotype of the extra-thymic Aire+ cells, identifying them in unconventional CD45loEpcam+MHCIIhiCD80lo bone marrow-derived APCs (323). PHD fingers are cysteine-rich domains characterized by a four-cysteine, one-histidine, three-cysteine motif, which coordinates two zinc ions (156). J Proteome Res (2010) 9(5):2600–9. Mittaz L, Rossier C, Heino M, Peterson P, Krohn KJE, Gos A, et al. doi:10.1002/eji.201243209, 34. PHD1 disruption abrogates the transcription of a part of human AIRE-dependent genes (159), while a histone H3-specific demethylase does not enlarge their number (187), so that the hypothesis that promoters of AIRE-dependent and AIRE-independent genes merely differ in chromatin marks is unsatisfying (188). An aberrant prostate antigen-specific immune response causes prostatitis in mice and is associated with chronic prostatitis in humans. Projection of an immunological self shadow within the thymus by the Aire protein. Overlapping gene coexpression patterns in human medullary thymic epithelial cells generate self-antigen diversity. Proc Natl Acad Sci U S A (2008) 105(41):15878–83. Repressors decrease transcription. Pöntynen N, Miettinen A, Arstila TP, Kämpe O, Alimohammadi M, Vaarala O, et al. Pitkänen J, Vähämurto P, Krohn K, Peterson P. Subcellular localization of the autoimmune regulator protein. Immunol Rev (2002) 189:20–7. doi:10.1016/j.jaut.2005.08.006, 314. Additionally, AIRE induces Treg development. Rizzi M, Ferrera F, Filaci G, Indiveri F. Disruption of immunological tolerance: role of AIRE gene in autoimmunity. Danso-Abeam D, Humblet-Baron S, Dooley J, Liston A. Jenkinson WE, McCarthy NI, Dutton EE, Cowan JE, Parnell SM, White AJ, et al. Finally, AIRE seems to replicate its action in the secondary lymphoid organs, albeit the cell lineage detaining such property has not been fully characterized. Nat Rev Immunol (2016) 16(4):247–58. This volume examines a wide array of vital technologies for advancing our understanding of the receptor-mediated actions of estrogen. Furthermore, as a novel T cell subtype, TFH participates in humoral immunity and exerts its function mainly by regulating the composition of germinal centres and cell responses in germinal centres. the Aire transcription factor. doi:10.7554/eLife.28131, 24. Front Immunol (2013) 4:e210. During lymphocyte maturation in the thymus, the random rearrangement of antigen-specific receptor genes produces a vast and diverse repertoire of receptors, some of which mistakenly recognize "self" as "non-self". These principles were applied in a following study. J Immunol (2010) 184(12):6865–73. Front Immunol (2012) 3:e278. JCI Insight (2017) 2(18):e93265. doi:10.1172/JCI38332, 273. doi:10.1016/j.celrep.2014.07.029, 42. Although previous results indicate that it exerts this function in part by promoting ectopic expression of a battery of peripheral-tissue antigens in epithelial cells of the thymic medulla, recent data argue for additional roles in negative selection of thymocytes by medullary cells. However, recent studies have set out some basic principles, highlighting that LtβR and Rank cooperate in the embryonic thymus to switch TEPCs to mTEC sublineage, while in the following step mTEC precursors become Rankhi (92, 95, 106). Ilmarinen T, Melén K, Kangas H, Julkunen I, Ulmanen I, Eskelin P. The monopartite nuclear localization signal of autoimmune regulator mediates its nuclear import and interaction with multiple importin α molecules. In addition, the specific mechanisms of AIRE in the periphery and whether AIRE has other functions in peripheral tolerance are not clear; therefore, more relevant research is needed in this area. doi:10.1093/nar/gks933, 164. Although not fully known, there is a strict regulation of TEC ontogenesis. doi:10.1038/ng0397-293, 8. Immunobiology (2011) 216(5):591–603. Found insideThis book represents a synergic effort of an international team of specialists in immunology to expand the scientific achievements in the field of lymphocytes. Chignola F, Gaetani M, Rebane A, Org T, Mollica L, Zucchelli C, et al. Aire unleashes stalled mRNA polymerase to induce ectopic gene expression in thymic epithelial cells. Eur J Immunol (2013) 43(3):589–94. Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation. Across-tissue expression and evolution of genes controlled by the Aire transcription factor Austin L. Hughesa,⁎, Robert Friedmanb a Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA b Bioinformatics Center, University of Connecticut, Storrs, CT 06269, USA Received 31 January 2006; accepted 18 May 2006 UEA1 labeling, in turn, was related to the co-stimulatory cluster of differentiation CD80, and, to a lesser degree, to class-II major histocompatibility complex (MHCII) antigens. J Immunol (2006) 177(1):290–7. Front Immunol (2014) 5:e51. The results showed that in the stable AIRE-expressing RAW264.7 cells, the expression of TLR1, TLR3, and TLR8 increased, especially that of TLR8. Laan M, Kisand K, Kont V, Möll K, Tserel L, Scott HS, et al. Poliani et al. doi:10.3389/fimmu.2015.00365, 122. Nat Immunol (2017) 18(3):263–73. doi:10.1210/jcem.81.4.8636356, 317. Following studies suggested that Ac by CBP stabilizes the subcellular distribution of AIRE, albeit data on targeted lysine residues and functional consequences were conflicting (169, 170). J Immunol (2012) 189(12):5519–26. J Immunol (2008) 181(8):5225–32. In transfected cells, AIRE has two expression patterns: a punctate nuclear pattern along the cytoskeleton and a fibrous staining pattern [7, 9, 18]; AIRE mutants in patients were transfected into COS-1 cells and the results showed that mutations of AIRE are associated with changes in these staining patterns [19, 20]. Proc Natl Acad Sci U S A (2010) 107(29):13016–21. The vertebrate immune system defends the organism against invading pathogens while at the same time being self-tolerant to the body’s own constituents thus preserving its integrity. Extensive RNA editing and splicing increase immune self-representation diversity in medullary thymic epithelial cells. Down arrows indicate NF-κB-inducing kinase in thymic stroma establishes central tolerance by orchestrating cross-talk with not only thymocytes but also dendritic cells. Identification and characterization of thymic epithelial progenitor cells. With regard to PGE, which is only in part dependent on Aire, author refers the kind readers to excellent reviews that delineate its extent and principles (15–17). At the cellular level, peripheral AIRE expression mainly occurs in one group of cells with a phenotype similar to DCs. Found insideThis book addresses this gap by providing an understanding of dental genetics and its developmental biology counterpart. Akiyama N, Takizawa N, Miyauchi M, Yanai H, Tateishi R, Shinzawa M, et al. Peterson P, Nagamine K, Scott H, Heino M, Kudoh J, Shimizu N, et al. Int J Immunogenet (2005) 32(6):393–400. Bingjie Zhao, Lu Chang, Haiying Fu, Guangyu Sun, Wei Yang, "The Role of Autoimmune Regulator (AIRE) in Peripheral Tolerance", Journal of Immunology Research, vol. AIRE recruits P-TEFb for transcriptional elongation of target genes in medullary thymic epithelial cells. showed that 10–20% of the AIRE-expressing cells in human lymph nodes expressed CD83, which was consistent with the DC phenotype [12]. The N-terminal of the protein contains the homogenously staining region (HSR; also called caspase-recruiting domain), which is important for the regulation of AIRE multimerization and the Sp100, AIRE-1, NucP41/75, and DEAF-1 (SAND) domain, which is involved in oligomerization (Zumer et al., 2013). Nevertheless, studies on Aire−/− mice have made it possible to identify, with proven or potential connection to the human field, several targets of autoimmunity (271–278). Shum AK, Alimohammadi M, Tan CL, Cheng MH, Metzger TC, Law CS, et al. Interesting data are available when, taking into consideration a set of functionally connected genes, thymic PGE is compared with the corresponding expression in the relevant peripheral tissue. Nat Commun (2016) 7:e11350. Heino M, Peterson P, Kudoh J, Nagamine K, Lagerstedt A, Ovod D, et al. Kelly RM, Goren EM, Taylor PA, Mueller SN, Stefanski HE, Osborn MJ, et al. Nat Immunol (2014) 15(3):258–65. Biochim Biophys Acta (2008) 1783(1):74–83. doi:10.1016/S0167-5699(98)01293-6, 138. Mutational analysis of the autoimmune regulator (AIRE) gene in sporadic autoimmune Addison’s disease can reveal patients with unidentified autoimmune polyendocrine syndrome type I. Eur J Endocrinol (2002) 146(4):519–22. When the body produces antibodies against . Eur J Immunol (2014) 44(5):1313–9. Poliani et al. Mol Immunol (2016) 77:157–73. AIRE. Similar studies supplied valuable data on thymic PGE and led to identify several markers of autoimmunity, but did not realize the extent of the phenomenon (8–10). doi:10.1002/eji.200737275, 32. doi:10.3389/fimmu.2012.00019, 64. Aire inhibits the generation of a perinatal population of interleukin-17A-producing γδ T cells to promote immunologic tolerance. The interaction with P-TEFb seals AIRE participation in the post-initiation events of gene transcription (173). As discussed above, the same arguments have been used to build and support the well-defined theory that places Aire onto the high point of mTEC differentiation. Baik S, Sekai M, Hamazaki Y, Jenkinson WE, Anderson G. Relb acts downstream of medullary thymic epithelial stem cells and is essential for the emergence of RANK+ medullary epithelial progenitors. Rossi S, Blazar BR, Farrell CL, Danilenko DM, Lacey DL, Weinberg KI, et al. According to the authors’ comment, this diversity may be beneficial in preventing uniform holes in central tolerance, but at the price of an unpredictable individual predisposition to autoimmunity. Autoimmune regulator is expressed in the cells regulating immune tolerance in thymus medulla. Abbott JK, Huoh Y-S, Reynolds PR, Yu L, Rewers M, Reddy M, et al. Two LXXLL motifs, known to mediate protein–protein interactions between nuclear receptors, and coactivators are contained within the HSR. J Immunol (2008) 180(3):1338–43. Mouse embryonic stem cell-derived thymic epithelial cell progenitors enhance T-cell reconstitution after allogeneic bone marrow transplantation. Finally, immature cTECs and mTECs deal with the differentiation program leading to full maturity. Dominant-negative loss of function arises from a second, more frequent variant within the SAND domain of autoimmune regulator (AIRE). The cited studies are those that, on a targeted basis, have evaluated the impact of these changes on the generation and differentiation of Aire+ mTECs. Eur J Immunol (2014) 44(10):2918–24. Lomada D, Liu B, Coghlan L, Hu Y, Richie ER. Org T, Rebane A, Kisand K, Laan M, Haljasorg U, Andreson R, et al. Eur J Immunol (2000) 30(7):1884–93. J Immunol (2005) 175(7):4331–7. J Biol Chem (2017) 292(16):6542–54. At the C-terminus, AIRE is completed by two PHD fingers, named PHD1 (aa 299–340) and PHD2 (aa 434–475), which are separated by a proline-rich region. Both polymorphic variable number of tandem repeats and autoimmune regulator modulate differential expression of insulin in human thymic epithelial cells. There is still no definite answer to this question, but, in author opinion, Aire mandate remains unchanged: to accomplish the largest PGE for self-tolerance induction. These results indicated that AIRE up-regulated the expression of various TSAs in the dendritic cell line DC2.4, the macrophage cell line RAW264.7, and primary bone marrow DCs, whereas the expression of various TSAs was absent in BMDCs from AIRE−/− mice [21, 28, 29]. In summary, it is best to use the monoclonal anti-AIRE Abs, especially if joined to other methods, such as flow cytometry, which can improve the purity of the cell samples [14]. doi:10.1126/science.1105677, 88. Surface receptors, enzymes, hormones, structural proteins, and other molecules act as self-antigens (self-ags) and are susceptible to autoimmune targeting in adverse circumstances. The notion that ts-ag-encoding genes are transcribed and translated into their respective proteins within the thymus, the so-called promiscuous gene expression (PGE), dates back to the eighties, when neurohypophyseal hormones, insulin-like growth factors, and other ts-ags were found in the human and animal gland (1–4). Geenen V, Legros J-J, Franchimont P, Baudrihaye M, Defresne M-P, Boniver J. Chakravarty S, Zeng L, Zhou M-M. In The Teenage Brain, Dr. Jensen brings to readers the astonishing findings that previously remained buried in academic journals. Aire is a transcription factor that is expressed by a subset of medullary thymic epithelial cells (mTECs) and mediates expression of self-peptides that are presented by mTECs and thymic dendritic cells (DCs) to nascent lymphocytes, enabling negative selection of self-reactive lymphocytes . Single-cell transcriptome analysis reveals coordinated ectopic gene-expression patterns in medullary thymic epithelial cells.

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