Biology:Promiscuous gene expression

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Promiscuous gene expression (PGE), formerly referred to as ectopic expression, is a process specific to the thymus that plays a pivotal role in the establishment of central tolerance. This phenomenon enables generation of self-antigens, so called tissue-restricted antigens (TRAs), which are in the body expressed only by one or few specific tissues (antigens rank among TRAs if they are expressed by less than five tissues from the sixty tested [1]). These antigens are represented for example by insulin from the pancreas or defensins from the gastrointestinal tract.[2] Antigen-presenting cells (APCs) of the thymus, namely medullary thymic epithelial cells (mTECs), dendritic cells (DCs) and B cells are capable to present peptides derived from TRAs to developing T cells (thymus is the major origin of T cell development[3]) and hereby test, whether their T cell receptors (TCRs) engage self entities and therefore their occurrence in the body can potentially lead to the development of autoimmune disease. In that case, thymic APCs either induce apoptosis in these autoreactive T cells (negative selection) or they deviate them to become T regulatory cells (Treg selection), which suppress self-reactive T cells in the body that escaped negative selection in the thymus.[4] Thus, PGE is crucial for tissues protection against autoimmunity.

Characteristics of PGE in distinct cell types

The usual level of gene expression in the peripheral tissues (e.g. spleen, kidney, liver etc.) reaches about 60% of the mouse coding genome. Some peripheral tissues, including lungs, brain and testis, reveal the repertoire of expressed genes about 10% broader. Importantly, PGE in the thymus, which is mediated by unique subset of epithelial cells called mTECs, triggers expression of vast majority of the genes from the whole genome (~85%). Such a broad repertoire of expressed genes wasn't shown in any other tissue of the body.[5]

mTECs

The process of PGE in the thymus was discovered in late 80's [6] however, it took a decade to find that the cell subset that mediates PGE and therefore provides a "library" of TRAs are mTECs.[7] These cells were shown to uniquely express a protein called autoimmune regulator (Aire), which drives the expression of approximately 40% TRAs, referred to as Aire-dependent, and is so far the only well characterized driver of PGE.[8] Defects in the expression of Aire lead to multiorgan autoimmunity in mice and cause a severe autoimmune syndrome called APECED in human.[9][10] Because Aire is not the exclusive PGE regulator, more than half of TRAs are Aire-independent and it isn't still known how their PGE is orchestrated.[11]

mTECs are very heterogenous population and at least should be subdivided to MHCII low expressing subset (mTECsLO) and MHCII high expressing subset (mTECsHI) which is considered to be mature.[12] Aire is expressed only by 30% from the latter.[5]

PGE was found to act in a stochastic manner, which means that each mTEC expresses distinct set of Aire-dependent and Aire-independent TRAs.[13] Despite its stochasticity, TRAs are co-expressed in clusters which however, rather mirror their co-localization on chromosomes than co-expression patterns from particular tissues. Even though TRAs involved in each cluster were found to be consistent, the PGE of whole cluster is transient and changes during mTEC development.[14] Moreover, these clusters are highly variable between individuals.[15] PGE is distinct from the expression of TRAs in the peripheral tissues also by its monoalelic or bialelic course.[16] On the other hand, the level of TRA expression and numbers of alternative-splicing protein variants in the thymus correspond to the peripheral tissues.[17][5]

PGE is highly conserved between mice and human.[18]

B cells

Although thymic B cells were shown to induce either negative selection or Treg selection, their importance for the establishment of central tolerance remains elusive.[19][20] It is assumed however, that B cells in the thymus are licensed by CD40-CD40L interaction with autoreactive T cells to activate the expression of Aire and upregulate levels of MHCII and CD80. Moreover, Aire drives the PGE of Aire-dependent TRAs in B cells and because their repertoire is non-overlaping with that of mTECs it should broaden the scope of peripheral antigens displayed in the thymus.[21]

PGE in the periphery

Except the thymus, Aire is expressed also in the periphery, namely in the secondary lymphoid organs. However, the search for particular Aire-expressing cell type still continues due to conflicting results.[22][23] What seems to be clear is that these cells express Aire-dependent TRAs, that are distinct from those in mTECs.[22] In line with their high expression of MHCII and very limited expression of costimulatory molecules, these cells were shown to establish tolerance by inactivation of autoreactive T cells rather than inducing apoptosis in them.[23]

Master-regulators of PGE

Aire and its partners

Aire is not classical transcription factor, because instead of recognition of specific consensus sequences, Aire seeks after genes marked by specific histone marks, such as the absence of H3K4me3 and presence of H3K27me3, which indicate transcriptionally inactive chromatin.[24][25][26] This type of gene recognition logically explains the high numbers of genes whose expression is affected by Aire. There is available also alternative explanation, that Aire recognizes silenced chromatin thanks to interaction with molecular complex ATF7ip- MBD1 which binds methylated CpG di-nucleotides.[27]

After the recognition of Aire dependent genes, Aire recruits topoisomerase II to perform double-strand DNA breaks at their transcriptional start sites (TSSs).[28] These brakes attract DNA PK and other DNA damage response proteins which relax the surrounding chromatin and repair the breaks.[29][30] Subsequently, Aire recruits elongation complex p-TEFb to the TSSs,[31] which releases stalled RNA II polymerases and therefore activates transcription (PGE) of Aire-dependent genes.[32] Interaction between Aire and p-TEFb is enabled by another partner molecule Brd4, which stabilizes this molecular complex.[33]

Altogether, Aire requires around fifty partner molecules to properly activate PGE.[30] Among these molecules further rank acetylase Creb-binding protein (CBP), which enhances stability of Aire, however dampens its transactivation properties and deacetylase Sirtuin 1 (Sirt1), which is essential for activation of PGE of Aire-dependent TRAs.[34][35] Worth mentioning is also Hipk2, which phosphorylates Aire and CBP however, its absence affects mostly PGE of Aire-independent genes, suggesting that this kinase might cooperate with other unknown transcriptional regulator.[36]

Recently, molecular complexes of Aire and its partners were shown to localize to specific parts of chromatin called super-enhancers.[37]

By contrast, little is known about transcription of Aire itself. Nevertheless, several studies suggest that major role in triggering of Aire expression plays NF-κB signaling pathway,[38][39] similarly as in the development of mTECs.[40] Aire expression and PGE of Aire-dependent TRAs is also affected by sex hormones. Androgens enhance these processes, whereas impact by estrogens is completely opposite and results in less efficient PGE.[41][42]

Fezf2

Fezf2 (forebrain embryonic zinc-finger-like protein 2) was recently discovered as the second regulator of PGE.[43] Even though little is known about its operation in the thymus, Fezf2, in marked contrast with Aire, plays role in different physiological processes than central tolerance, e.g. development of the brain, and acts as a classical transcription factor. In the thymus however, Fezf2 is expressed by nearly 80% of mTECs and not other cells. The repertoire of TRAs involved in Fezf2-driven PGE is nonoverlapping with that of Aire and comprises genes previously defined as Aire-independent, e.g. Fabp9 (TRA of testis). This fact is also bolstered by different manifestations of autoimmunity in Fezf2 knockout mouse, in comparison with Aire KO mouse.[44]

The expression of Fezf2 was found to be independent on Aire however, was found to be triggered also by the receptor of NF-κB signaling pathway, namely by LtβR.[43]

The expression of Aire and Fezf2 was found to be upregulated after mTEC adhesion to developing T cells which points to the fact that functional PGE requires direct contact with T cells.[45]

References

  1. ↑ Hogquist, Kristin A.; Paul M. Allen; Kyewski, Bruno; Klein, Ludger (June 2014). "Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see)". Nature Reviews Immunology 14 (6): 377–391. doi:10.1038/nri3667. ISSN 1474-1741. PMID 24830344. 
  2. ↑ Filipp, Dominik; Brabec, Tomáš; Vobořil, Matouš; Dobeš, Jan (2018-02-01). "Enteric α-defensins on the verge of intestinal immune tolerance and inflammation". Seminars in Cell & Developmental Biology 88: 138–146. doi:10.1016/j.semcdb.2018.01.007. ISSN 1084-9521. PMID 29355606. 
  3. ↑ Zúñiga-Pflücker, Juan Carlos (January 2004). "T-cell development made simple". Nature Reviews Immunology 4 (1): 67–72. doi:10.1038/nri1257. ISSN 1474-1741. PMID 14704769. 
  4. ↑ Perry, Justin S. A.; Hsieh, Chyi-Song (2016). "Development of T-cell tolerance utilizes both cell-autonomous and cooperative presentation of self-antigen". Immunological Reviews 271 (1): 141–155. doi:10.1111/imr.12403. ISSN 1600-065X. PMID 27088912. 
  5. ↑ 5.0 5.1 5.2 Danan-Gotthold, Miri; Guyon, Clotilde; Giraud, Matthieu; Levanon, Erez Y.; Abramson, Jakub (2016-10-24). "Extensive RNA editing and splicing increase immune self-representation diversity in medullary thymic epithelial cells". Genome Biology 17 (1): 219. doi:10.1186/s13059-016-1079-9. ISSN 1474-760X. PMID 27776542. 
  6. ↑ Linsk, R.; Gottesman, M.; Pernis, B. (1989-10-13). "Are tissues a patch quilt of ectopic gene expression?". Science 246 (4927): 261. doi:10.1126/science.2799388. ISSN 0036-8075. PMID 2799388. Bibcode: 1989Sci...246..261L. 
  7. ↑ Klein, Ludger; Bruno Kyewski; Schulte, Antje; Derbinski, Jens (November 2001). "Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self". Nature Immunology 2 (11): 1032–1039. doi:10.1038/ni723. ISSN 1529-2916. PMID 11600886. 
  8. ↑ Perniola, Roberto (2018). "Twenty Years of AIRE". Frontiers in Immunology 9: 98. doi:10.3389/fimmu.2018.00098. ISSN 1664-3224. PMID 29483906. 
  9. ↑ Benoist, Christophe; Mathis, Diane; Bronson, Roderick; Anderson, Mark S.; Jiang, Wenyu (2005-09-19). "Modifier loci condition autoimmunity provoked by Aire deficiency". Journal of Experimental Medicine 202 (6): 805–815. doi:10.1084/jem.20050693. ISSN 0022-1007. PMID 16172259. 
  10. ↑ Kisand, Kai; Peterson, Pärt (2015-07-01). "Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy". Journal of Clinical Immunology 35 (5): 463–478. doi:10.1007/s10875-015-0176-y. ISSN 1573-2592. PMID 26141571. 
  11. ↑ Kyewski, Bruno; Walter, Jörn; Peltonen, Leena; Hergenhahn, Manfred; Jonnakuty, Sunitha; Tierling, Sascha; Brors, Benedikt; Gäbler, Jana et al. (2005-07-04). "Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels". Journal of Experimental Medicine 202 (1): 33–45. doi:10.1084/jem.20050471. ISSN 0022-1007. PMID 15983066. 
  12. ↑ Amit, Ido; Abramson, Jakub; Zimmermann, Valérie S.; Jay, Philippe; Taylor, Naomi; Itzkovitz, Shalev; Goldberg, Ori; Tóth, Beáta et al. (July 2018). "Single-cell mapping of the thymic stroma identifies IL-25-producing tuft epithelial cells". Nature 559 (7715): 622–626. doi:10.1038/s41586-018-0346-1. ISSN 1476-4687. PMID 30022162. Bibcode: 2018Natur.559..622B. 
  13. ↑ Kyewski, Bruno; Hexel, Klaus; Rösch, Stefanie; Pinto, Sheena; Derbinski, Jens (2008-01-15). "Promiscuous gene expression patterns in single medullary thymic epithelial cells argue for a stochastic mechanism". Proceedings of the National Academy of Sciences 105 (2): 657–662. doi:10.1073/pnas.0707486105. ISSN 0027-8424. PMID 18180458. Bibcode: 2008PNAS..105..657D. 
  14. ↑ Kyewski, Bruno; Derbinski, Jens; Willecke, Klaus; Sonntag, Stephan; Cremer, Christoph; Baddeley, David; Weiland, Yanina; Rezavandy, Esmail et al. (2010-11-09). "Epigenetic regulation of promiscuous gene expression in thymic medullary epithelial cells". Proceedings of the National Academy of Sciences 107 (45): 19426–19431. doi:10.1073/pnas.1009265107. ISSN 0027-8424. PMID 20966351. Bibcode: 2010PNAS..10719426T. 
  15. ↑ Benoist, Christophe; Diane Mathis; Zemmour, David; Meredith, Matthew (September 2015). "Aire controls gene expression in the thymic epithelium with ordered stochasticity". Nature Immunology 16 (9): 942–949. doi:10.1038/ni.3247. ISSN 1529-2916. PMID 26237550. 
  16. ↑ Mathis, Diane; Benoist, Christophe; Besse, Whitney; Villaseñor, Jennifer (2008-10-14). "Ectopic expression of peripheral-tissue antigens in the thymic epithelium: Probabilistic, monoallelic, misinitiated". Proceedings of the National Academy of Sciences 105 (41): 15854–15859. doi:10.1073/pnas.0808069105. ISSN 0027-8424. PMID 18836079. Bibcode: 2008PNAS..10515854V. 
  17. ↑ Steinmetz, Lars M.; Kyewski, Bruno; Huber, Wolfgang; Küchler, Rita; Nguyen, Michelle; Rattay, Kristin; Pinto, Sheena; Reyes, Alejandro et al. (September 2015). "Single-cell transcriptome analysis reveals coordinated ectopic gene-expression patterns in medullary thymic epithelial cells". Nature Immunology 16 (9): 933–941. doi:10.1038/ni.3246. ISSN 1529-2916. PMID 26237553. 
  18. ↑ Rattay, Kristin; Meyer, Hannah Verena; Herrmann, Carl; Brors, Benedikt; Kyewski, Bruno (2016-02-01). "Evolutionary conserved gene co-expression drives generation of self-antigen diversity in medullary thymic epithelial cells". Journal of Autoimmunity 67: 65–75. doi:10.1016/j.jaut.2015.10.001. ISSN 0896-8411. PMID 26481130. 
  19. ↑ Huang, Haochu; Meng, Fanyong; Meng, Liping; Perera, Jason (2013-10-15). "Autoreactive thymic B cells are efficient antigen-presenting cells of cognate self-antigens for T cell negative selection". Proceedings of the National Academy of Sciences 110 (42): 17011–17016. doi:10.1073/pnas.1313001110. ISSN 0027-8424. PMID 24082098. Bibcode: 2013PNAS..11017011P. 
  20. ↑ Grey, Shane T.; Daley, Stephen; Webster, Kylie E.; Walters, Stacey N. (2014-07-01). "A Role for Intrathymic B Cells in the Generation of Natural Regulatory T Cells". The Journal of Immunology 193 (1): 170–176. doi:10.4049/jimmunol.1302519. ISSN 0022-1767. PMID 24872190. 
  21. ↑ Klein, Ludger; Kyewski, Bruno; Brors, Benedikt; Busslinger, Meinrad; Ishimaru, Naozumi; Lutgens, Esther; Gerdes, Norbert; Pinto, Sheena et al. (2015-06-16). "Thymic B Cells Are Licensed to Present Self Antigens for Central T Cell Tolerance Induction" (in English). Immunity 42 (6): 1048–1061. doi:10.1016/j.immuni.2015.05.013. ISSN 1074-7613. PMID 26070482. 
  22. ↑ 22.0 22.1 Anderson, Mark S.; Krummel, Matthew F.; Chang, Howard Y.; Su, Maureen A.; Johannes, Kellsey P.; Zhou, Xuyu; Tan, Ying X.; Wong, David J. et al. (2008-08-08). "Deletional Tolerance Mediated by Extrathymic Aire-Expressing Cells". Science 321 (5890): 843–847. doi:10.1126/science.1159407. ISSN 0036-8075. PMID 18687966. Bibcode: 2008Sci...321..843G. 
  23. ↑ 23.0 23.1 Anderson, Mark S.; Weiss, Arthur; Tarbell, Kristin V.; Murphy, Kenneth M.; Satpathy, Ansuman T.; Johannes, Kellsey P.; Price, Jeffrey D.; Lu, Wen et al. (2013-09-19). "Extrathymic Aire-Expressing Cells Are a Distinct Bone Marrow-Derived Population that Induce Functional Inactivation of CD4+ T Cells" (in English). Immunity 39 (3): 560–572. doi:10.1016/j.immuni.2013.08.005. ISSN 1074-7613. PMID 23993652. 
  24. ↑ Peterson, Pärt; Musco, Giovanna; Bottomley, Matthew J.; Mollica, Luca; Maran, Uko; Liiv, Ingrid; Rebane, Ana; Gaetani, Massimiliano et al. (2008-04-01). "The autoimmune regulator PHD finger binds to non‐methylated histone H3K4 to activate gene expression". EMBO Reports 9 (4): 370–376. doi:10.1038/embor.2008.11. ISSN 1469-221X. PMID 18292755. 
  25. ↑ Mathis, Diane; Benoist, Christophe; Kingston, Robert E.; Gozani, Or; Shoelson, Steven E.; Carney, Dylan; Bua, Dennis; Abramson, Jakub et al. (2008-10-14). "Aire employs a histone-binding module to mediate immunological tolerance, linking chromatin regulation with organ-specific autoimmunity". Proceedings of the National Academy of Sciences 105 (41): 15878–15883. doi:10.1073/pnas.0808470105. ISSN 0027-8424. PMID 18840680. Bibcode: 2008PNAS..10515878K. 
  26. ↑ Holländer, Georg A.; Ponting, Chris P.; Heger, Andreas; Deadman, Mary E.; Macaulay, Iain C.; Nusspaumer, Gretel; Zhanybekova, Saule; Shikama-Dorn, Noriko et al. (2014-12-01). "Population and single-cell genomics reveal the Aire dependency, relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia". Genome Research 24 (12): 1918–1931. doi:10.1101/gr.171645.113. ISSN 1088-9051. PMID 25224068. 
  27. ↑ Anderson, Mark S.; Su, Maureen; Erle, David J.; Pollack, Joshua L.; Martinez-Llordella, Marc; Kayla Fasano; Greer, Alexandra; Metzger, Todd et al. (March 2014). "The transcriptional regulator Aire coopts the repressive ATF7ip-MBD1 complex for the induction of immunotolerance". Nature Immunology 15 (3): 258–265. doi:10.1038/ni.2820. ISSN 1529-2916. PMID 24464130. 
  28. ↑ Peterson, Pärt; Milani, Lili; Metspalu, Andres; Tasa, Tõnis; Haljasorg, Uku; Liiv, Ingrid; Kisand, Kai; Maslovskaja, Julia et al. (2017-04-21). "DNA breaks and chromatin structural changes enhance the transcription of autoimmune regulator target genes". Journal of Biological Chemistry 292 (16): 6542–6554. doi:10.1074/jbc.M116.764704. ISSN 0021-9258. PMID 28242760. 
  29. ↑ Liiv, Ingrid; Rebane, Ana; Org, Tõnis; Saare, Mario; Maslovskaja, Julia; Kisand, Kai; Juronen, Erkki; Valmu, Leena et al. (2008-01-01). "DNA-PK contributes to the phosphorylation of AIRE: Importance in transcriptional activity". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1783 (1): 74–83. doi:10.1016/j.bbamcr.2007.09.003. ISSN 0167-4889. PMID 17997173. 
  30. ↑ 30.0 30.1 Mathis, Diane; Benoist, Christophe; Giraud, Matthieu; Abramson, Jakub (2010-01-08). "Aire's Partners in the Molecular Control of Immunological Tolerance" (in English). Cell 140 (1): 123–135. doi:10.1016/j.cell.2009.12.030. ISSN 0092-8674. PMID 20085707. 
  31. ↑ Peterlin, B. Matija; Narat, Mojca; Vaupotič, Tomaž; Kohoutek, Jiri; Brdičková, Naděžda; Oven, Irena (2007-12-15). "AIRE Recruits P-TEFb for Transcriptional Elongation of Target Genes in Medullary Thymic Epithelial Cells". Molecular and Cellular Biology 27 (24): 8815–8823. doi:10.1128/MCB.01085-07. ISSN 0270-7306. PMID 17938200. 
  32. ↑ Benoist, Christophe; Mathis, Diane; Young, Richard A.; Rahl, Peter B.; Abramson, Jakub; Yoshida, Hideyuki; Giraud, Matthieu (2012-01-10). "Aire unleashes stalled RNA polymerase to induce ectopic gene expression in thymic epithelial cells". Proceedings of the National Academy of Sciences 109 (2): 535–540. doi:10.1073/pnas.1119351109. ISSN 0027-8424. PMID 22203960. Bibcode: 2012PNAS..109..535G. 
  33. ↑ Mathis, Diane; Benoist, Christophe; Tarakhovsky, Alexander; Prinjha, Rab K.; Anderson, Mark S.; Proekt, Irina; Rioja, Inmaculada; Chapman, Trevor et al. (2015-08-11). "Brd4 bridges the transcriptional regulators, Aire and P-TEFb, to promote elongation of peripheral-tissue antigen transcripts in thymic stromal cells". Proceedings of the National Academy of Sciences 112 (32): E4448–E4457. doi:10.1073/pnas.1512081112. ISSN 0027-8424. PMID 26216992. Bibcode: 2015PNAS..112E4448Y. 
  34. ↑ Saare, Mario; Rebane, Ana; Rajashekar, Balaji; Vilo, Jaak; Peterson, Pärt (2012-08-15). "Autoimmune regulator is acetylated by transcription coactivator CBP/p300". Experimental Cell Research 318 (14): 1767–1778. doi:10.1016/j.yexcr.2012.04.013. ISSN 0014-4827. PMID 22659170. 
  35. ↑ Abramson, Jakub; Husebye, Eystein S.; McBurney, Michael W.; Giraud, Matthieu; Sagi, Irit; Cohen, Haim Y.; Rathaus, Moran; Guyon, Clotilde et al. (July 2015). "The deacetylase Sirt1 is an essential regulator of Aire-mediated induction of central immunological tolerance". Nature Immunology 16 (7): 737–745. doi:10.1038/ni.3194. ISSN 1529-2916. PMID 26006015. 
  36. ↑ Derbinski, Jens; Kyewski, Bruno; Hofmann, Thomas G.; Matt, Sonja; Rezavandy, Esmail; Claude, Janine; Rattay, Kristin (2015-02-01). "Homeodomain-Interacting Protein Kinase 2, a Novel Autoimmune Regulator Interaction Partner, Modulates Promiscuous Gene Expression in Medullary Thymic Epithelial Cells". The Journal of Immunology 194 (3): 921–928. doi:10.4049/jimmunol.1402694. ISSN 0022-1767. PMID 25552543. 
  37. ↑ Mathis, Diane; Christophe Benoist; Yoshida, Hideyuki; Bansal, Kushagra (March 2017). "The transcriptional regulator Aire binds to and activates super-enhancers". Nature Immunology 18 (3): 263–273. doi:10.1038/ni.3675. ISSN 1529-2916. PMID 28135252. 
  38. ↑ Haljasorg, Uku; Bichele, Rudolf; Saare, Mario; Guha, Mithu; Maslovskaja, Julia; Kõnd, Karin; Remm, Anu; Pihlap, Maire et al. (2015). "A highly conserved NF-κB-responsive enhancer is critical for thymic expression of Aire in mice". European Journal of Immunology 45 (12): 3246–3256. doi:10.1002/eji.201545928. ISSN 1521-4141. PMID 26364592. 
  39. ↑ Anderson, Mark S.; Vijayanand, Pandurangan; Proekt, Irina; Waterfield, Michael; Fasano, Kayla J.; Lwin, Wint; Miller, Corey N.; Seumois, Grégory et al. (2015-11-16). "Identification of a novel cis-regulatory element essential for immune tolerance". Journal of Experimental Medicine 212 (12): 1993–2002. doi:10.1084/jem.20151069. ISSN 0022-1007. PMID 26527800. 
  40. ↑ Delft, Myrthe A. M. van; Huitema, Leonie F. A.; Tas, Sander W. (2015). "The contribution of NF-κB signalling to immune regulation and tolerance". European Journal of Clinical Investigation 45 (5): 529–539. doi:10.1111/eci.12430. ISSN 1365-2362. PMID 25735405. 
  41. ↑ Su, Maureen A.; Wilson, Elizabeth M.; Starmer, Joshua; Martin, Aaron; Free, Meghan; Nelson, Jennifer S.; Conley, Bridget; Bakhru, Pearl et al. (2016-04-13). "Sex bias in CNS autoimmune disease mediated by androgen control of autoimmune regulator". Nature Communications 7: 11350. doi:10.1038/ncomms11350. ISSN 2041-1723. PMID 27072778. Bibcode: 2016NatCo...711350Z. 
  42. ↑ Berrih-Aknin, Sonia; Panse, Rozen Le; Barkats, Martine; Cumano, Ana; Klatzmann, David; Nottin, Rémi; Serraf, Alain; Berthault, Claire et al. (2016-04-01). "Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseases". The Journal of Clinical Investigation 126 (4): 1525–1537. doi:10.1172/JCI81894. ISSN 0021-9738. PMID 26999605. 
  43. ↑ 43.0 43.1 Takayanagi, Hiroshi; Kodama, Tatsuhiko; Komatsu, Noriko; Nitta, Takeshi; Danks, Lynett; Tomofuji, Yoshihiko; Morishita, Yasuyuki; Takaba, Hiroyuki (2015-11-05). "Fezf2 Orchestrates a Thymic Program of Self-Antigen Expression for Immune Tolerance" (in English). Cell 163 (4): 975–987. doi:10.1016/j.cell.2015.10.013. ISSN 0092-8674. PMID 26544942. 
  44. ↑ Takayanagi, Hiroshi; Takaba, Hiroyuki (2017-11-01). "The Mechanisms of T Cell Selection in the Thymus" (in English). Trends in Immunology 38 (11): 805–816. doi:10.1016/j.it.2017.07.010. ISSN 1471-4906. PMID 28830733. https://www.cell.com/trends/immunology/abstract/S1471-4906(17)30148-5. 
  45. ↑ Passos, Geraldo A.; Giuliatti, Silvana; Bombonato-Prado, Karina F.; Lopes, Gabriel S.; Pezzi, Nicole; Cotrim-Sousa, Larissa; Felicio, Rafaela F.; Assis, Amanda F. et al. (2018). "Aire Disruption Influences the Medullary Thymic Epithelial Cell Transcriptome and Interaction With Thymocytes" (in English). Frontiers in Immunology 9: 964. doi:10.3389/fimmu.2018.00964. ISSN 1664-3224. PMID 29867946. 



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