Skip to main content
Top
Published in: Seminars in Immunopathology 1/2021

01-02-2021 | Type 1 Diabetes | Review

The thymus and the science of self

Author: Vincent Geenen

Published in: Seminars in Immunopathology | Issue 1/2021

Login to get access

Abstract

The conventional perception asserts that immunology is the science of ‘discrimination’ between self and non-self. This concept is however no longer tenable as effector cells of the adaptive immune system are first conditioned to be tolerant to the body’s own antigens, collectively known as self until now. Only then attain these effectors the responsiveness to non-self. The acquisition of this essential state of tolerance to self occurs for T cells in the thymus, the last major organ of our body that revealed its intricate function in health and disease. The ‘thymus’ as an anatomical notion was first notably documented in Ancient Greece although our present understanding of the organ’s functions was only deciphered commencing in the 1960s. In the late 1980s, the thymus was identified as the site where clones of cells reactive to self, termed ‘forbidden’ thymocytes, are physically depleted as the result of a process now known as negative selection. The recognition of this mechanism further contributed to the belief that the central rationale of immunology as a science lies in the distinction between self and non-self. This review will discuss the evidence that the thymus serves as a unique lymphoid organ able to instruct T cells to recognize and be tolerant to harmless self before adopting the capacity to defend the body against potentially injurious non-self-antigens presented in the context of different challenges from infections to exposure to malignant cells. The emerging insight into the thymus’ cardinal functions now also provides an opportunity to exploit this knowledge to develop novel strategies that specifically prevent or even treat organ-specific autoimmune diseases.
Literature
1.
go back to reference Geenen V, Savino W (2019) History of the thymus – from a vestigial organ to the programming of immune self-tolerance. In: Passos GA (ed) Thymus Transcriptome and Cell Biology. Springer, London, pp 1–18 Geenen V, Savino W (2019) History of the thymus – from a vestigial organ to the programming of immune self-tolerance. In: Passos GA (ed) Thymus Transcriptome and Cell Biology. Springer, London, pp 1–18
2.
go back to reference Hammar J (1921) The new views at the morphology of the thymus gland and their hearing on the problem of the function of the thymus. Endocrinology 5:543–573 Hammar J (1921) The new views at the morphology of the thymus gland and their hearing on the problem of the function of the thymus. Endocrinology 5:543–573
3.
go back to reference Selye H (1946) The general adaptation syndrome and the diseases of adaptation. J Clin Endocrinol Metab 6:117–130PubMed Selye H (1946) The general adaptation syndrome and the diseases of adaptation. J Clin Endocrinol Metab 6:117–130PubMed
4.
go back to reference Miller JF (1961) The immune function of the thymus. Lancet 2:748–749PubMed Miller JF (1961) The immune function of the thymus. Lancet 2:748–749PubMed
5.
go back to reference Medawar PB (1963) discussion after Miller JFAP and Osoba D. role of the thymus in the origin of immune competence. In: Westenholme GEW, Knight J (eds) The immunologically competent cell: its nature and origin. Ciba Foundation Study Group, London, p 70 Medawar PB (1963) discussion after Miller JFAP and Osoba D. role of the thymus in the origin of immune competence. In: Westenholme GEW, Knight J (eds) The immunologically competent cell: its nature and origin. Ciba Foundation Study Group, London, p 70
6.
go back to reference Ehrlich P (1900) The Croonian lecture: on immunity. Proc Soc Lond Biol 66:424 Ehrlich P (1900) The Croonian lecture: on immunity. Proc Soc Lond Biol 66:424
7.
go back to reference Tonegawa S, Steinberg C, Dube S, Bernardini A (1974) Evidence for somatic generation of antibody diversity. Proc Natl Acad Sci USA 71:4027–4031PubMed Tonegawa S, Steinberg C, Dube S, Bernardini A (1974) Evidence for somatic generation of antibody diversity. Proc Natl Acad Sci USA 71:4027–4031PubMed
8.
go back to reference Malissen M, Minard K, Mjolsness et al (1984) Mouse T cell antigen receptor: structure and organization of constant and joining segments encoding the beta polypeptide. Cell 73:1101–1110 Malissen M, Minard K, Mjolsness et al (1984) Mouse T cell antigen receptor: structure and organization of constant and joining segments encoding the beta polypeptide. Cell 73:1101–1110
9.
go back to reference Ohki H, Martin C, Corbel C, Coltey M, le Douarin N (1987) Tolerance induced by thymic epithelial grafts in birds. Science 237:1032–1035PubMed Ohki H, Martin C, Corbel C, Coltey M, le Douarin N (1987) Tolerance induced by thymic epithelial grafts in birds. Science 237:1032–1035PubMed
10.
go back to reference Kappler JW, Roehm N, Marrack P (1987) T cell tolerance by clonal elimination in the thymus. Cell 49:273–280PubMed Kappler JW, Roehm N, Marrack P (1987) T cell tolerance by clonal elimination in the thymus. Cell 49:273–280PubMed
11.
go back to reference MacDonald HR, Glasebrook AL, Schneider R et al (1988) T-cell receptor Vβ use predicts reactivity and tolerance to Mlsa-encoded antigens. Nature 332:40–45PubMed MacDonald HR, Glasebrook AL, Schneider R et al (1988) T-cell receptor Vβ use predicts reactivity and tolerance to Mlsa-encoded antigens. Nature 332:40–45PubMed
12.
go back to reference Kisielow P, Blüthman H, Staerz UD et al (1988) Tolerance in T-cell receptor transgenic mice involves deletion of non-mature CD4 + 8+ thymocytes. Nature 333:742–746PubMed Kisielow P, Blüthman H, Staerz UD et al (1988) Tolerance in T-cell receptor transgenic mice involves deletion of non-mature CD4 + 8+ thymocytes. Nature 333:742–746PubMed
13.
go back to reference Scollay RG, Butcher EC, Weissman IL (1980) Thymus cell migration. Quantitative aspects of cellular traffic from the thymus to the periphery in mice. Eur J Immunol 10:210–218PubMed Scollay RG, Butcher EC, Weissman IL (1980) Thymus cell migration. Quantitative aspects of cellular traffic from the thymus to the periphery in mice. Eur J Immunol 10:210–218PubMed
14.
go back to reference Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chain (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155:1151–1164PubMed Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chain (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155:1151–1164PubMed
15.
go back to reference Josefowicz SZ, Liu LF, Rudensky AY (2012) Regulatory T cells: mechanisms of differentiation and function. Ann Rev Immunol 30:531–564 Josefowicz SZ, Liu LF, Rudensky AY (2012) Regulatory T cells: mechanisms of differentiation and function. Ann Rev Immunol 30:531–564
16.
go back to reference Wong JB, Tanaka A, Sakaguchi S (2019) Human FOXP3+ regulatory T cell heterogeneity and function in autoimmunity and cancer. Immunity 50:302–316 Wong JB, Tanaka A, Sakaguchi S (2019) Human FOXP3+ regulatory T cell heterogeneity and function in autoimmunity and cancer. Immunity 50:302–316
17.
go back to reference Matzinger P (1993) Why positive selection? Immunol Rev 135:81–117PubMed Matzinger P (1993) Why positive selection? Immunol Rev 135:81–117PubMed
18.
go back to reference Geenen V, Trussart C, Michaux H, Halouani A, Jaïdane H, Collée C, Renard C, Daukandt M, Ledent P, Martens H (2019) The presentation of neuroendocrine self-peptides in the thymus: an essential event for individual life and vertebrate survival. Ann NY Acad Sci 1455:113–126PubMed Geenen V, Trussart C, Michaux H, Halouani A, Jaïdane H, Collée C, Renard C, Daukandt M, Ledent P, Martens H (2019) The presentation of neuroendocrine self-peptides in the thymus: an essential event for individual life and vertebrate survival. Ann NY Acad Sci 1455:113–126PubMed
19.
go back to reference Guillemin R, Cohn M, Melnechuk T (eds) (1985) Neural Modulation of Immunity. Raven Press, New York Guillemin R, Cohn M, Melnechuk T (eds) (1985) Neural Modulation of Immunity. Raven Press, New York
20.
21.
go back to reference du Vigneaud V, Ressler C, Trippett S (1953) The sequence of amino acids in oxytocin, with a proposal for the structure of oxytocin. J Biol Chem 205:949–953 du Vigneaud V, Ressler C, Trippett S (1953) The sequence of amino acids in oxytocin, with a proposal for the structure of oxytocin. J Biol Chem 205:949–953
22.
go back to reference Gimpl G, Fahrenholz F (2001) The oxytcin receptor system: structure, function, and regulation. Physiol Rev 81:629–683PubMed Gimpl G, Fahrenholz F (2001) The oxytcin receptor system: structure, function, and regulation. Physiol Rev 81:629–683PubMed
23.
go back to reference Sue Carter C, Kenkel WM, MacLean EL, Wilson SR, Perkeybille AM et al (2020) Is oxytocin nature’s medicine. Pharmacol Rev 72:829–861PubMed Sue Carter C, Kenkel WM, MacLean EL, Wilson SR, Perkeybille AM et al (2020) Is oxytocin nature’s medicine. Pharmacol Rev 72:829–861PubMed
24.
go back to reference Geenen V, Legros JJ, Franchimont P, Baudrihaye M, Defresne M, Boniver J (1986) The thymus as a neuroendocrine organ: Coexistence of oxytocin and neurophysin in the human thymus. Science 232:508–511PubMed Geenen V, Legros JJ, Franchimont P, Baudrihaye M, Defresne M, Boniver J (1986) The thymus as a neuroendocrine organ: Coexistence of oxytocin and neurophysin in the human thymus. Science 232:508–511PubMed
25.
go back to reference Geenen V, Legros JJ, Franchimont P et al (1987) The thymus as a neuroendocrine organ. Synthesis of vasopressin and oxytocin in human thymic epithelium. Ann NY Acd Sci 496:56–66 Geenen V, Legros JJ, Franchimont P et al (1987) The thymus as a neuroendocrine organ. Synthesis of vasopressin and oxytocin in human thymic epithelium. Ann NY Acd Sci 496:56–66
26.
go back to reference Geenen V, Defresne MP, Robert F, Legros JJ, Franchimont P, Boniver J (1988) The neurohormonal thymic microenvironment: immunocytochemical evidence that thymic nurse cells are neuroendocrine cells. Neuroendocrinology 47:365–368PubMed Geenen V, Defresne MP, Robert F, Legros JJ, Franchimont P, Boniver J (1988) The neurohormonal thymic microenvironment: immunocytochemical evidence that thymic nurse cells are neuroendocrine cells. Neuroendocrinology 47:365–368PubMed
27.
go back to reference Nakagawa Y, Ohigashi I, Nitta T, Sakata M, Tanaka K, Murata S, Kanagawa O, Takahama Y (2012) Thymic nurse cells provide microenvironment for secondary T cell receptor a rearrangement in cortical thymocytes. Proc Natl Acad Sci U S A 109:20572–20577PubMedPubMedCentral Nakagawa Y, Ohigashi I, Nitta T, Sakata M, Tanaka K, Murata S, Kanagawa O, Takahama Y (2012) Thymic nurse cells provide microenvironment for secondary T cell receptor a rearrangement in cortical thymocytes. Proc Natl Acad Sci U S A 109:20572–20577PubMedPubMedCentral
28.
go back to reference Hansenne I, Rasier G, Péqueux C, Brilot F, Renard C, Breton C, Greimers R, Legros JJ, Geenen V, Martens HJ (2005) Ontogenesis and functional aspects of oxytocin and vasopressin gene expression in the thymus network. J Neuroimmunol 158:67–75PubMed Hansenne I, Rasier G, Péqueux C, Brilot F, Renard C, Breton C, Greimers R, Legros JJ, Geenen V, Martens HJ (2005) Ontogenesis and functional aspects of oxytocin and vasopressin gene expression in the thymus network. J Neuroimmunol 158:67–75PubMed
29.
go back to reference Martens H, Kecha O, Charlet-Renard C, Defresne MP, Geenen V (1998) Neurohypophysial peptides activate phosphorylation of focal adhesion kinases in immature thymocytes. Neuroendocrinology 67:282–289PubMed Martens H, Kecha O, Charlet-Renard C, Defresne MP, Geenen V (1998) Neurohypophysial peptides activate phosphorylation of focal adhesion kinases in immature thymocytes. Neuroendocrinology 67:282–289PubMed
30.
go back to reference Reichardt P, Dornbach B, Gunzer M (2010) APC, T cells and the immune synapse. Curr Top Microbiol Immunol 340:229–249PubMed Reichardt P, Dornbach B, Gunzer M (2010) APC, T cells and the immune synapse. Curr Top Microbiol Immunol 340:229–249PubMed
31.
go back to reference Martens H, Goxe GV (1996) The thymic repertoire of neuroendocrine self-peptides in T-cell life and death. Immunol Today 17:312–317PubMed Martens H, Goxe GV (1996) The thymic repertoire of neuroendocrine self-peptides in T-cell life and death. Immunol Today 17:312–317PubMed
32.
go back to reference Geenen V, Kecha O, Martens H (1998) Thymic expression of neuroendocrine self-peptide precursors: role in T-cell survival and self-tolerance. J Neuroendocrinol 10:811–822PubMed Geenen V, Kecha O, Martens H (1998) Thymic expression of neuroendocrine self-peptide precursors: role in T-cell survival and self-tolerance. J Neuroendocrinol 10:811–822PubMed
33.
go back to reference Geenen V, Kroemer G (1993) Multiple ways to cellular immune tolerance. Immunol Today 14:573–575PubMed Geenen V, Kroemer G (1993) Multiple ways to cellular immune tolerance. Immunol Today 14:573–575PubMed
35.
go back to reference Geenen V, Vandersmissen E, Cormann-Goffin N, Martens H, Legros JJ, Degiovanni G, Benhida A, Martial J, Franchimont P (1993) Membrane translocation and relationship with MHC class I of a human thymic neurophysin-like molecule. Thymus 22:55–66PubMed Geenen V, Vandersmissen E, Cormann-Goffin N, Martens H, Legros JJ, Degiovanni G, Benhida A, Martial J, Franchimont P (1993) Membrane translocation and relationship with MHC class I of a human thymic neurophysin-like molecule. Thymus 22:55–66PubMed
36.
go back to reference Martens H, Malgrange B, Robert F, Charlet C, de Groote D, Heymann D, Godard A, Soulillou JP, Moonen G, Geenen V (1996) Cytokine production by human thymic epithelial cells: Control by the immune recognition of the neurohypophysial self-antigen. Regul Pept 67:39–45PubMed Martens H, Malgrange B, Robert F, Charlet C, de Groote D, Heymann D, Godard A, Soulillou JP, Moonen G, Geenen V (1996) Cytokine production by human thymic epithelial cells: Control by the immune recognition of the neurohypophysial self-antigen. Regul Pept 67:39–45PubMed
37.
go back to reference Rammensee HG, Falk K, Rötschke O (1993) Peptides naturally presented by MHC class I molecules. Ann Rev Immunol 11:213–244 Rammensee HG, Falk K, Rötschke O (1993) Peptides naturally presented by MHC class I molecules. Ann Rev Immunol 11:213–244
38.
go back to reference Vanneste Y, Ntodou-Thomé A, Vandersmissen E et al (1997) Identification of neurotensin-related peptides in human thymic epithelial cell membranes and relationship with major histocompatibility complex class I molecules. J Neuroimmunol 76:161–166PubMed Vanneste Y, Ntodou-Thomé A, Vandersmissen E et al (1997) Identification of neurotensin-related peptides in human thymic epithelial cell membranes and relationship with major histocompatibility complex class I molecules. J Neuroimmunol 76:161–166PubMed
39.
go back to reference Kyewski BA, Fathman CG, Kaplan HS (1984) Intrathymic presentation of circulating non-major histocompatibility complex antigens. Nature 308:196–199PubMed Kyewski BA, Fathman CG, Kaplan HS (1984) Intrathymic presentation of circulating non-major histocompatibility complex antigens. Nature 308:196–199PubMed
40.
go back to reference Geenen V, Bodart G, Henry S et al (2013) Programming of neuroendocrine self in the thymus and its defect in the development of neuroendocrine autoimmunity. Front Neurosc 7:e187 Geenen V, Bodart G, Henry S et al (2013) Programming of neuroendocrine self in the thymus and its defect in the development of neuroendocrine autoimmunity. Front Neurosc 7:e187
41.
go back to reference Jolicœur C, Hanahan D, Smith KM (1994) T-cell tolerance toward a transgenic beta-cell antigen and transcription of endogenous pancreatic genes in the thymus. Proc Natl Acad Sci U S A 5:6707–6711 Jolicœur C, Hanahan D, Smith KM (1994) T-cell tolerance toward a transgenic beta-cell antigen and transcription of endogenous pancreatic genes in the thymus. Proc Natl Acad Sci U S A 5:6707–6711
42.
go back to reference Smith KM, Olson DC, Hirose R, Hanahan D (1997) Pancreatic gene expression in rare cells of thymic medulla: evidence for functional contribution to T-cell tolerance. Int Immunol 9:1355–1365PubMed Smith KM, Olson DC, Hirose R, Hanahan D (1997) Pancreatic gene expression in rare cells of thymic medulla: evidence for functional contribution to T-cell tolerance. Int Immunol 9:1355–1365PubMed
43.
go back to reference Klein L, Kyewski B (2000) “Promiscuous” expression of tissue antigens in the thymus: a key to T-cell tolerance and autoimmunity. J Mol Med 78:483–494PubMed Klein L, Kyewski B (2000) “Promiscuous” expression of tissue antigens in the thymus: a key to T-cell tolerance and autoimmunity. J Mol Med 78:483–494PubMed
44.
go back to reference Derbinsky J, Schulte A, Kyewski B, Klein L (2001) Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat Immunol 2:1032–1039 Derbinsky J, Schulte A, Kyewski B, Klein L (2001) Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat Immunol 2:1032–1039
45.
go back to reference Gotter J, Brors B, Hergenhahn M, Kyewski B (2004) Medullary epithelial cells of the thymus express a highly diverse selection of tissue-specific genes co-localized in chromosomal clusters. J Exp Med 199:155–165PubMedPubMedCentral Gotter J, Brors B, Hergenhahn M, Kyewski B (2004) Medullary epithelial cells of the thymus express a highly diverse selection of tissue-specific genes co-localized in chromosomal clusters. J Exp Med 199:155–165PubMedPubMedCentral
46.
go back to reference Koble C, Kyewski B (2009) The thymic medulla: a unique microenvironment for intercellular self-antigen transfer. J Exp Med 206:1505–1513PubMedPubMedCentral Koble C, Kyewski B (2009) The thymic medulla: a unique microenvironment for intercellular self-antigen transfer. J Exp Med 206:1505–1513PubMedPubMedCentral
47.
go back to reference Mathis D, Benoist C (2014) Back to central tolerance. Immunity 20:509–516 Mathis D, Benoist C (2014) Back to central tolerance. Immunity 20:509–516
48.
go back to reference Kyewski B, Klein L (2016) A central role for central tolerance. Ann Rev Immunol 24:571–606 Kyewski B, Klein L (2016) A central role for central tolerance. Ann Rev Immunol 24:571–606
49.
go back to reference Hansenne I, Charlet-Renard C, Greimers R, Geenen V (2006) Dendritic cell differentiation and immune tolerance to insulin-related peptides in Igf2-deficient mice. J Immunol 176:4651–4657PubMed Hansenne I, Charlet-Renard C, Greimers R, Geenen V (2006) Dendritic cell differentiation and immune tolerance to insulin-related peptides in Igf2-deficient mice. J Immunol 176:4651–4657PubMed
50.
go back to reference Burnet FM (1973) A reassessment of the forbidden clone hypothesis of autoimmune diseases. Aust J Exp Biol Med 50:1–9 Burnet FM (1973) A reassessment of the forbidden clone hypothesis of autoimmune diseases. Aust J Exp Biol Med 50:1–9
51.
go back to reference Geenen V (2012) Thymus and type 1 diabetes: an update. Diabetes Res Clin Pract 98:26–32PubMed Geenen V (2012) Thymus and type 1 diabetes: an update. Diabetes Res Clin Pract 98:26–32PubMed
52.
go back to reference Kecha-Kamoun O, Achour I, Martens H, Collette J, Lefebvre PJ, Greiner DL, Geenen V (2001) Thymic expression of insulin-related genes in an animal model of type 1 diabetes. Diab Metab Res Rev 17:146–152 Kecha-Kamoun O, Achour I, Martens H, Collette J, Lefebvre PJ, Greiner DL, Geenen V (2001) Thymic expression of insulin-related genes in an animal model of type 1 diabetes. Diab Metab Res Rev 17:146–152
53.
go back to reference Vafiadis P, Bennett ST, Todd JA, Nadeau J, Grabs R, Goodyer CG, Wickramasinghe S, Colle E, Polychronakos C (1997) Insulin expression in human thymus is modulated by INS VTNR alleles at the IDDM2 locus. Nat Genet 15:289–292PubMed Vafiadis P, Bennett ST, Todd JA, Nadeau J, Grabs R, Goodyer CG, Wickramasinghe S, Colle E, Polychronakos C (1997) Insulin expression in human thymus is modulated by INS VTNR alleles at the IDDM2 locus. Nat Genet 15:289–292PubMed
54.
go back to reference Pugliese A, Zeller M, Fernandez A Jr et al (1997) The insulin gene is transcribed in human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nat Genet 15:293–297PubMed Pugliese A, Zeller M, Fernandez A Jr et al (1997) The insulin gene is transcribed in human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nat Genet 15:293–297PubMed
55.
go back to reference Chentoufi AA, Polychronakos C (2002) Insulin expression levels in the thymus modulate insulin-specific autoreactive T-cell tolerance. Diabetes 51:1383–1390PubMed Chentoufi AA, Polychronakos C (2002) Insulin expression levels in the thymus modulate insulin-specific autoreactive T-cell tolerance. Diabetes 51:1383–1390PubMed
56.
go back to reference Noso S, Kataoka K, Kawabata Y, Babaya N, Hiromine Y, Yamaji K, Fujisawa T, Aramata S, Kudo T, Takahashi S, Ikegami H (2010) Insulin transactivator Mafa regulates intrathymic expression of insulin and affects susceptibility to type 1 diabetes. Diabetes 59:2579–2587PubMedPubMedCentral Noso S, Kataoka K, Kawabata Y, Babaya N, Hiromine Y, Yamaji K, Fujisawa T, Aramata S, Kudo T, Takahashi S, Ikegami H (2010) Insulin transactivator Mafa regulates intrathymic expression of insulin and affects susceptibility to type 1 diabetes. Diabetes 59:2579–2587PubMedPubMedCentral
57.
go back to reference Paschke R, Geenen V (1995) Messenger RNA expression for a TSH receptor variant in the thymus of a 2-yr old child. J Mol Med 73:577–580PubMed Paschke R, Geenen V (1995) Messenger RNA expression for a TSH receptor variant in the thymus of a 2-yr old child. J Mol Med 73:577–580PubMed
58.
go back to reference Sospedra M, Ferrer-Francesch X, Dominguez O et al (1998) Transcription of a broad range of self-antigens in human thymus suggesting a role for central mechanisms in tolerance towards peripheral antigens. J Immunol 161:5918–5929PubMed Sospedra M, Ferrer-Francesch X, Dominguez O et al (1998) Transcription of a broad range of self-antigens in human thymus suggesting a role for central mechanisms in tolerance towards peripheral antigens. J Immunol 161:5918–5929PubMed
59.
go back to reference Murakami M, Hosoi Y, Negishi T, Kamiya Y, Miyashita K, Yamada M, Iriuchijima T, Yokoo H, Yoshida I, Tsushima Y, Mori M (1996) Thymic hyperplasia in patients with Graves’ disease. Identification of thyrotropin receptor in human thymus. J Clin Invest 98:2228–2234PubMedPubMedCentral Murakami M, Hosoi Y, Negishi T, Kamiya Y, Miyashita K, Yamada M, Iriuchijima T, Yokoo H, Yoshida I, Tsushima Y, Mori M (1996) Thymic hyperplasia in patients with Graves’ disease. Identification of thyrotropin receptor in human thymus. J Clin Invest 98:2228–2234PubMedPubMedCentral
60.
go back to reference Colobran R, del Pilar AM, Faner R et al (2011) Association of an SNP with intrathymic expression and Graves’ disease: a role for defective tolerance. Hum Mol Genet 20:3415–3423PubMed Colobran R, del Pilar AM, Faner R et al (2011) Association of an SNP with intrathymic expression and Graves’ disease: a role for defective tolerance. Hum Mol Genet 20:3415–3423PubMed
61.
go back to reference Lv H, Havari E, Pinto S, Gottumukkala RVSRK, Cornivelli L, Raddassi K, Matsui T, Rosenzweig A, Bronson RT, Smith R, Fletcher AL, Turley SJ, Wucherpfennig K, Kyewski B, Lipes MA (2011) Impaired thymic tolerance to a-myosin directs autoimmunity to the heart in mice and humans. J Clin Invest 121:1561–1573PubMedPubMedCentral Lv H, Havari E, Pinto S, Gottumukkala RVSRK, Cornivelli L, Raddassi K, Matsui T, Rosenzweig A, Bronson RT, Smith R, Fletcher AL, Turley SJ, Wucherpfennig K, Kyewski B, Lipes MA (2011) Impaired thymic tolerance to a-myosin directs autoimmunity to the heart in mice and humans. J Clin Invest 121:1561–1573PubMedPubMedCentral
62.
go back to reference Handel AE, Sarosh R, Holländer GA (2018) The role of thymic tolerance in CNS autoimmune disease. Nat Rev Neurosci 14:723–734 Handel AE, Sarosh R, Holländer GA (2018) The role of thymic tolerance in CNS autoimmune disease. Nat Rev Neurosci 14:723–734
63.
go back to reference Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, von Boehmer H, Bronson R, Dierich A, Benoist C, Mathis D (2002) Projection of an immune self-shadow within the thymus by the Aire protein. Science 298:1395–1401PubMed Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, von Boehmer H, Bronson R, Dierich A, Benoist C, Mathis D (2002) Projection of an immune self-shadow within the thymus by the Aire protein. Science 298:1395–1401PubMed
64.
go back to reference The Finnish-German APECED Consortium (1997) An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PhD-type zinc-finger domains. Nat Genet 17:399–403 The Finnish-German APECED Consortium (1997) An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PhD-type zinc-finger domains. Nat Genet 17:399–403
65.
go back to reference Nagamine K, Peterson P, Scott H et al (1997) Positional cloning of the APECED gene. Nat Genet 17:393–398PubMed Nagamine K, Peterson P, Scott H et al (1997) Positional cloning of the APECED gene. Nat Genet 17:393–398PubMed
66.
go back to reference Irla M, Hugues S, Gill J, Nitta T, Hirosaka Y et al (2008) Autoantigen-specific interactions with CD4+ thymocytes control medullary thymic epithelial cell cellularity. Immunity 29:451–463PubMed Irla M, Hugues S, Gill J, Nitta T, Hirosaka Y et al (2008) Autoantigen-specific interactions with CD4+ thymocytes control medullary thymic epithelial cell cellularity. Immunity 29:451–463PubMed
67.
go back to reference Akiyama T, Shino Y, Yanai H, Qin J, Oshima D et al The tumor necrosis factor family receptor RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity 29:423–437 Akiyama T, Shino Y, Yanai H, Qin J, Oshima D et al The tumor necrosis factor family receptor RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity 29:423–437
68.
go back to reference Gardner JM, Metzger TC, Mc Mahon EJ, Au-Yeung BB, Krawisz AK et al (2013) Extrathymic Aire-expressing cells are a distinct bone marrow-derived population that induces functional inactivation of CD4+ T cells. Immunity 39:560–572PubMedPubMedCentral Gardner JM, Metzger TC, Mc Mahon EJ, Au-Yeung BB, Krawisz AK et al (2013) Extrathymic Aire-expressing cells are a distinct bone marrow-derived population that induces functional inactivation of CD4+ T cells. Immunity 39:560–572PubMedPubMedCentral
69.
go back to reference Handel AE, Shakama-Dorn N, Zhanybekova S, Maio S, Graedel AN et al (2018) Comprehensively profiling the chromatin architecture of tissue-restricted antigen expression in thymic epithelial cells over development. Front Immunol 9:2120PubMedPubMedCentral Handel AE, Shakama-Dorn N, Zhanybekova S, Maio S, Graedel AN et al (2018) Comprehensively profiling the chromatin architecture of tissue-restricted antigen expression in thymic epithelial cells over development. Front Immunol 9:2120PubMedPubMedCentral
70.
go back to reference Sansom SN, Shikana-Dorn N, Zhanybekova S, Nusspaumer G, Macaulay K et al (2014) Population and single-cell genomics reveal the Aire dependency, relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia. Genome Res 24:1918–1931PubMedPubMedCentral Sansom SN, Shikana-Dorn N, Zhanybekova S, Nusspaumer G, Macaulay K et al (2014) Population and single-cell genomics reveal the Aire dependency, relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia. Genome Res 24:1918–1931PubMedPubMedCentral
71.
go back to reference Takaba H, Morishita Y, Tomfuji Y et al (2015) Fezf2 orchestrates a thymic program of self-antigen expression for immune tolerance. Cell 163:975–987PubMed Takaba H, Morishita Y, Tomfuji Y et al (2015) Fezf2 orchestrates a thymic program of self-antigen expression for immune tolerance. Cell 163:975–987PubMed
73.
go back to reference Eckler MJ, Larkan KA, McKennan WL, Katzman S, Guo C et al (2014) Multiple conserved regulatory domains promte Fezf2 expression in the developing cerebral cortex. Neural Dev 9:6PubMedPubMedCentral Eckler MJ, Larkan KA, McKennan WL, Katzman S, Guo C et al (2014) Multiple conserved regulatory domains promte Fezf2 expression in the developing cerebral cortex. Neural Dev 9:6PubMedPubMedCentral
74.
go back to reference Baran-Gale J, Morgan MD, Maio S, Dhalla F, Calvo-Asensio I, Deadman ME, Handel AE, Maynard A, Chen S, Green F, Sit RV, Neff NF, Darmanis S, Tan W, May AP, Marioni JC, Ponting CP, Holländer GA (2020) Ageing compromises mouse thymus function and remodels epithelial cell differentiation. eLife 9:e56221PubMedPubMedCentral Baran-Gale J, Morgan MD, Maio S, Dhalla F, Calvo-Asensio I, Deadman ME, Handel AE, Maynard A, Chen S, Green F, Sit RV, Neff NF, Darmanis S, Tan W, May AP, Marioni JC, Ponting CP, Holländer GA (2020) Ageing compromises mouse thymus function and remodels epithelial cell differentiation. eLife 9:e56221PubMedPubMedCentral
75.
go back to reference Fourlanos S, Perry C, Gellert SA, Martinuzzi F, Mallone R et al (2011) Evidence that nasal insulin induces immune tolerance to insulin in adults with autoimmune diabetes. Diabetes 60:1237–1245PubMedPubMedCentral Fourlanos S, Perry C, Gellert SA, Martinuzzi F, Mallone R et al (2011) Evidence that nasal insulin induces immune tolerance to insulin in adults with autoimmune diabetes. Diabetes 60:1237–1245PubMedPubMedCentral
76.
go back to reference Roep BO, Solvason N, Gottlieb PA, Abreu JRF, Harrison LC et al (2013) Plasmid-encoding proinsulin preserves C-peptide while specifically reducing proinsulin-specific CD8+ T cells. Sci Transl Med 5:191ra82PubMedPubMedCentral Roep BO, Solvason N, Gottlieb PA, Abreu JRF, Harrison LC et al (2013) Plasmid-encoding proinsulin preserves C-peptide while specifically reducing proinsulin-specific CD8+ T cells. Sci Transl Med 5:191ra82PubMedPubMedCentral
77.
go back to reference Geenen V, Mottet M, Dardenne O, Kermani H, Martens H, Francois JM, Galleni M, Hober D, Rahmouni S, Moutschen M (2010) Thymic self-antigens for the design of a negative/tolerogenic self-vaccination against type 1 diabetes. Curr Opin Pharmacol 10:461–472PubMed Geenen V, Mottet M, Dardenne O, Kermani H, Martens H, Francois JM, Galleni M, Hober D, Rahmouni S, Moutschen M (2010) Thymic self-antigens for the design of a negative/tolerogenic self-vaccination against type 1 diabetes. Curr Opin Pharmacol 10:461–472PubMed
78.
go back to reference Geenen V, Lefèbvre PJ (1998) The intrathymic expression of insulin-related genes: implications for pathophysiology and prevention of type 1 diabetes. Diab Metab Rev 14:95–103 Geenen V, Lefèbvre PJ (1998) The intrathymic expression of insulin-related genes: implications for pathophysiology and prevention of type 1 diabetes. Diab Metab Rev 14:95–103
79.
go back to reference Jaïdane H, Caloone D, Lobert PE et al (2012) Persistent infection of thymic epithelial cells with coxsackievirus B4 results in decreased expression of type 2 insulin-like growth factor. J Virol 86:11151–11162PubMedPubMedCentral Jaïdane H, Caloone D, Lobert PE et al (2012) Persistent infection of thymic epithelial cells with coxsackievirus B4 results in decreased expression of type 2 insulin-like growth factor. J Virol 86:11151–11162PubMedPubMedCentral
80.
go back to reference Geenen V, Louis C, Martens H, The Belgian Diabetes Registry (2004) An insulin-like growth factor 2-derived self-antigen inducing a regulatory cytokine profile after presentation to peripheral blood mononuclear cells from DQ8+ type 1 diabetic adolescents: preliminary design of a thymus-based tolerogenic self-vaccination. Ann NY Acad Sci 1037:59–64PubMed Geenen V, Louis C, Martens H, The Belgian Diabetes Registry (2004) An insulin-like growth factor 2-derived self-antigen inducing a regulatory cytokine profile after presentation to peripheral blood mononuclear cells from DQ8+ type 1 diabetic adolescents: preliminary design of a thymus-based tolerogenic self-vaccination. Ann NY Acad Sci 1037:59–64PubMed
81.
go back to reference Yang G, Geng XR, Song JP, Wu Y, Yan H, Zhan Z, Yang L, He W, Liu ZQ, Qiu S, Liu Z, Yang PC (2014) Insulin-like growth factor 2 enhances regulatory T-cell functions and suppresses food allergy in an experimental model. J Allergy Clin Immunol 133:1702–1708PubMed Yang G, Geng XR, Song JP, Wu Y, Yan H, Zhan Z, Yang L, He W, Liu ZQ, Qiu S, Liu Z, Yang PC (2014) Insulin-like growth factor 2 enhances regulatory T-cell functions and suppresses food allergy in an experimental model. J Allergy Clin Immunol 133:1702–1708PubMed
82.
go back to reference Geng XR, Yang G, Li M, Song JP, Liu ZQ, Qiu S, Liu Z, Yang PC (2014) Insulin-like growth factor 2 enhances functions of antigen-specific regulatory B cells. J Biol Chem 289:17941–17950PubMedPubMedCentral Geng XR, Yang G, Li M, Song JP, Liu ZQ, Qiu S, Liu Z, Yang PC (2014) Insulin-like growth factor 2 enhances functions of antigen-specific regulatory B cells. J Biol Chem 289:17941–17950PubMedPubMedCentral
83.
go back to reference Boehm T, Mccurley N, Sutoh Y et al (2012) VLR-based adaptive immunity. Ann Rev Immunol 30:203–220 Boehm T, Mccurley N, Sutoh Y et al (2012) VLR-based adaptive immunity. Ann Rev Immunol 30:203–220
85.
go back to reference Bajoghli B, Guo P, Aghaalei N et al (2011) A thymus candidate in lampreys. Nature 470:90–94PubMed Bajoghli B, Guo P, Aghaalei N et al (2011) A thymus candidate in lampreys. Nature 470:90–94PubMed
Metadata
Title
The thymus and the science of self
Author
Vincent Geenen
Publication date
01-02-2021
Publisher
Springer Berlin Heidelberg
Keyword
Type 1 Diabetes
Published in
Seminars in Immunopathology / Issue 1/2021
Print ISSN: 1863-2297
Electronic ISSN: 1863-2300
DOI
https://doi.org/10.1007/s00281-020-00831-y

Other articles of this Issue 1/2021

Seminars in Immunopathology 1/2021 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.