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Thymus Dysfunction in the Development of Type 1 Diabetes and Endocrine Autoimmune Diseases

Published Online: June 6th 2011 European Endocrinology, 2009; 5:24-6; DOI: http://doi.org/10.17925/EE.2009.05.00.24
Authors: Olivier Dardenne, Vincent Geenen
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Abstract
The discovery that thymic epithelium from many species expresses a large repertoire of genes encoding neuroendocrine and other tissuerestricted antigens has radically changed our knowledge of the pathogenic mechanisms underlying the development of organ-specific autoimmune diseases such as type 1 diabetes and autoimmune endocrine diseases. Rather than a breakdown of immunological selftolerance in periphery, there is mounting evidence that the diabetogenic autoimmune response may first arise from a thymus dysfunction in the central programming of β-cell self-tolerance. Insulin-like growth factor 2 (IGF-2) is the dominant member of the insulin gene/protein family expressed in thymic epithelial cells (TECs) from different species, and Igf2-/- mice fail to programme complete tolerance to insulin. Based on the homology between insulin, the primary and immunogenic auto-antigen of type 1 diabetes, and IGF-2, the tolerogenic selfantigen of the insulin family, the design of a regulatory/negative self-vaccination for prevention against type 1 diabetes has been proposed and is under development.

KeywordsThymus, type 1 diabetes, self-tolerance, insulin-like growth factor 2, insulin

Disclosure: These studies were supported by the Fund of Scientific Medical Research of Belgium (convention 3.4508.04), the Fonds Leon Fredericq (Liège University Hospital), the Walloon Region (Waleo 2 convention Tolediab), the European Association for the Study of Diabetes (EASD, Düsseldorf, Germany) and the EU FP6 Integrated Project Euro- Thymaide (contract LSHB-CT-2003-503410/www.eurothymaide.org).
Received: 6 May 2009 Accepted: 17 July 2009
Correspondence: Vincent Geenen, Centre of Immunoendocrinology, Institute of Pathology CHU-B23, B-4000 Liège-Sart Tilman, Belgium. E: vgeenen@ulg.ac.be

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In distant species and invertebrates, the foundations of the neuroendocrine and immune systems have co-existed until now without any apparent problem. Some 470 millions years ago, while gene conversion already determined some rudiments of immune diversity in primitive vertebrates (such as jawless fishes), adaptive immunity emerged in lymphoid cells of cartilaginous fishes (i.e. sharks and rays).

In distant species and invertebrates, the foundations of the neuroendocrine and immune systems have co-existed until now without any apparent problem. Some 470 millions years ago, while gene conversion already determined some rudiments of immune diversity in primitive vertebrates (such as jawless fishes), adaptive immunity emerged in lymphoid cells of cartilaginous fishes (i.e. sharks and rays). Adaptive immune response is characterised by enzymatic machinery specialising in the random recombination of gene segments encoding the variable parts of B-cell receptor (BCR) and T-cell receptor (TCR) for antigens. The emergence of this sophisticated defence system exerted a very potent pressure for the appearance of lymphoid structures and pathways necessary to impose immunological self-tolerance, i.e. the inability of the immune system to react against the host organism. The first thymus appeared in cartilaginous fishes concomitantly or very shortly after adaptive immunity. This organ is not an endocrine gland, but it stands at the crucial intersection between the immune and neuroendocrine systems. Among all lymphoid tissues, the thymus is unique in that it is the only place where there is a permanent confrontation between ancient, almost constant, neuroendocrine principles and a more recently evolved system equipped with machinery that stochastically generates diversity of the adaptive immune response. The progressive rise in the level of immune diversity and complexity may explain why failures in self-tolerance (systemic and organ-specific autoimmune diseases) are increasingly detected during evolution, with most such failures observed in the human species. Because the intrathymic education is so complex, mistakes easily occur, leading to thymic output of self-reactive T lymphocytes orientated against components of the neuroendocrine system and other peripheral tissues. Contrary to the assumption that has prevailed for a very long time, the thymus operates throughout life, and it plays a fundamental role in generating the peripheral repertoire of T lymphocytes that are diverse, selftolerant and competent against non-self antigens.

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