Thymic epithelial cell

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Thymus epithelial cells play an important role in self-tolerance . Unlike all other known cells in medullary thymic epithelial cells proteins ( proteins formed), which themselves have no function for the cell. Rather, they are formed so that they are broken down into short pieces with the help of proteasomes and then presented to the T lymphocytes that are maturing in the thymus in the peptide binding pockets of histocompatibility antigens (MHC) . It is crucial for the function of the thymus epithelial cells that the proteins formed are not selected specifically but randomly. In oneThymus epithelial cells are statistically formed up to 5% of all human proteins. With around 100 thymus epithelial cells, peptides from all of a person's own proteins can be presented to the maturing T lymphocytes in the thymus. This finding supports the thesis of central self-tolerance.

Anatomy and characterization of thymic epithelial cells

Thymus epithelial cells are found in both the medulla and the cortex of the thymus . The Hassall corpuscles are formed from them in the marrow . The function of Hassall bodies was still unknown in 1991. In the few articles in the literature database PUBMED in which Hassall bodies are mentioned, a role in T-cell maturation is sporadically suspected, but beyond anatomical studies there are no attempts to identify the function of Hassall bodies.

Autoimmune regulator: AIRE

Autoimmune regulator

Existing structural data: 2KFT

Properties of human protein
Mass / length primary structure 545 amino acids; 348 amino acids
Isoforms Aire-1, Aire-2
Identifier
Gene name AIRE
External IDs

AIRE was discovered as the gene that is causally responsible for triggering autoimmune diseases such as juvenile polyglandular autoimmune syndrome (PAS type 1), also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). In this disease there are multiple autoimmune attacks that are not directed against a single endogenous antigen, as in other autoimmune diseases, but against different antigens. It is encoded on human chromosome 22. Its expression appears to be restricted to medullary thymic epithelial cells (mTEC) and those at the junction from the cortex to the medulla.

The AIRE-positive cells are free from the leukocyte surface protein CD45. On the other hand, they carry some proteins that are involved in interacting with and in stimulating T lymphocytes: MHC II; CD40 , CD80 , PD-L1 . The formal proof that the Hassall bodies contain the AIRE-positive mTEC cells is missing.

Central tolerance

In the thymus, precursor cells ( thymocytes ) mature into T lymphocytes. The most important property they acquire is the clonal antigen receptor , with the help of which target cells are recognized. Since the work of Karl Landsteiner , immunologists have known that the reactions of the immune system that emanate from individual cells can be directed against any natural or synthetic antigen. “Every antigen” also includes one's own body as a target. The fright of the reaction of an immune system against its carrier, autoimmunity or horror autotoxicus is normally prevented by the selection of non-autoimmune T lymphocytes in the thymus. Only such are allowed to leave the thymus and become active.

The self-reactive thymocytes, however, are eliminated. The process of this elimination was far from clear. Above all, there was a lack of understanding of how a thymocyte, e.g. B. is directed against peptides characteristic of nerve cells, these can already be seen in the thymus and can be eliminated because of this recognition. How should all possible endogenous peptides be present in thymus cells, which are characteristic features of highly specialized and mature cells? This did not seem possible due to cell-type-specific protein formation.

With the help of the diseases APS-1 and APECED, it was found that proteins are ectopically expressed in the thymus, i.e. in the wrong place. In addition to ectopic expression, some publications also speak of promiscuous expression. In contrast to the rest of the body tissue, the expression of many proteins in the thymus is precisely not subject to the cell-typical control. Their expression depends primarily on AIRE.

Which protein is expressed in which mTEC appears rather random. The calculated probability for the expression of a certain protein in a certain mTEC is 0.03 to 0.05. Or a certain protein can be found expressed in one of 20 to 35 mTEC cells.

The finding of a stochastic expression of a rather random part of all human proteins in thymus epithelial cells helps out of this understanding dilemma. If thymic epithelial cells express proteins only in order to introduce as many peptides as possible in the MHC molecules, then the thymocytes have the chance to have seen all possible peptides before they leave the thymus. Thymocytes that recognize self-peptide can then be screened and eliminated.

Stochastic regulation of protein expression and the role of AIRE

For the expression of a protein, the gene of this protein must be activated so that the RNA polymerase can read the RNA from the activated gene. This activation usually takes place through binding of transcription factors to the promoter of the gene. Further DNA-binding proteins are incorporated into the activation complex and the histones in the promoter are changed (acetylation, methylation or demethylation) so that the polymerase can jump up and transcribe the gene.

The gene expression mediated by AIRE is precisely not gene-specific, but rather unspecific and stochastic. Under the influence of AIRE, numerous (possibly all) proteins are expressed in the thymus, which characterize cells outside the thymus: for example, insulin and other hormone-producing cells, cells of the brain or skin, liver cells, muscle cells and many others. Without AIRE, these peripheral tissue antigens ( peripheral tissue antigens : PTA) are not expressed, which then leads to autoimmune diseases. The proteins that interact with AIRE fall into four categories: nuclear transport , chromatin binding and structure, transcription or processing of the heteronuclear RNA in messenger RNA .

By influencing chromatin binding and structure, AIRE could trigger a stochastic activation of many genes with the help of epigenetic mechanisms; if it z. B. the promoter activation is replaced by gene-specific transcription factors. By influencing the chromatin state, it could stimulate the cracking of the RNA polymerase unspecifically, so that not one specific, but many different RNAs are read (transcribed) and rewritten (translated) into protein. As a result, a cell type- non- specific gene expression is achieved. Up to 5% of all proteins are expressed per thymus epithelial cell (i.e. around 1000 to 1500 different ones). The proteins expressed differ from cell to cell. In 100 cells, the protein repertoire is then available five times in purely mathematical terms, sufficient to assume that all proteins are expressed and can then be presented as peptides.

literature

Bruno Kyewski from the German Cancer Research Center in Heidelberg and Ludger Klein from the Institute for Immunology, LMU Munich, have researched this topic over the past 10 years:

  • Christian Koble, Bruno Kyewski: The thymic medulla: a unique microenvironment for intercellular self-antigen transfer . In: Journal of Experimental Medicine . tape 206 , no. 7 , 2009, p. 1505–1513 , doi : 10.1084 / jem.20082449 .
  • B. Kyewski, R. Taubert: How promiscuity promotes tolerance: the case of myasthenia gravis . In: Ann NY Acad Sci . tape 1132 , 2008, p. 157-162 , doi : 10.1196 / annals.1405.026 .
  • J. Derbinski, S. Pinto, S. Rösch, K. Hexel, B. Kyewski: Promiscuous gene expression patterns in single medullary thymic epithelial cells argue for a stochastic mechanism . In: Proc Natl Acad Sci USA . tape 105 , no. 2 , 2008, p. 657-662 , PMC 2206592 (free full text).
  • B. Kyewski, L. Klein: A central role for central tolerance . In: Annu Rev Immunol . tape 24 , 2006, pp. 571-606 , doi : 10.1146 / annurev.immunol.23.021704.115601 .
  • J. Derbinski, A. Schulte, B. Kyewski, L. Klein: Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self . In: Nat Immunol . tape 2 , no. 11 , 2001, p. 1032-1039 , doi : 10.1038 / ni723 , PMID 11600886 ( PDF ).
  • L. Klein, M. Hinterberger, G. Wirnsberger, B. Kyewski: Antigen presentation in the thymus for positive selection and central tolerance induction . In: Nat Rev Immunol . tape 9 , no. 12 , 2009, p. 833-844 .

Individual evidence

  1. ^ RV Krstic: Human Microanatomy . Springer-Verlag, Berlin / Heidelberg / New York 1991, ISBN 0-387-53666-3 , p. 112-113 .
  2. ↑ M. Raica, S. Encică, A. Motoc, AM Cîmpean, T. Scridon, M. Bârsan: Structural heterogeneity and immunohistochemical profile of Hassall corpuscles in normal human thymus. In: Ann Anat . tape 188 , no. 4 , 2006, p. 345-352 , PMID 16856599 .
  3. ↑ K. Nagamine, P. Peterson, HS Scott, J. Kudoh, S. Minoshima, M. Heino, KJ ​​Krohn, MD Lalioti, PE Mullis, SE Antonarakis, K. Kawasaki, S. Asakawa, F. Ito, N. Shimizu: Positional cloning of the APECED gene . In: Nat Genet . tape 17 , no. 4 , 1997, p. 393-398 , doi : 10.1038 / ng1297-393 .
  4. ↑ S. Zuklys, G. Balciunaite, A. Agarwal, E. Fasler-Kan, E. Palmer, GA Holländer: Normal thymic architecture and negative selection are associated with Aire expression, the gene defective in the autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) . In: J Immunol . tape 165 , no. 4 , 2000, pp. 1976-1983 .
  5. ^ A b F. X. Hubert, SA Kinkel, KE Webster, P. Cannon, PE Crewther, AI Proeitto, L. Wu, WR Heath, HS Scott: A specific anti-Aire antibody reveals aire expression is restricted to medullary thymic epithelial cells and not expressed in periphery . In: J Immunol . tape 180 , no. 6 , 2008, p. 3824-3832 ( PDF, 606 KB ).
  6. ^ D. Mathis, C. Benoist: AIRE . In: Annu Rev Immunol . tape 27 , 2009, p. 287-312 .
  7. ↑ J. Abramson, M. Giraud, C. Benoist, D. Mathis: Aire's partners in the molecular control of immunological tolerance . In: Cell . tape 140 , no. 1 , 2010, p. 132-135 .