News & Articles

Liege, 3 December 2007

Comments to USA Today article « Mysteries of autoimmune diseases unravel »

Author: Vincent GEENEN, MD, PhD – University of Liege Center of Immunology. Coordinator of FP6 Integrated Project Euro-Thymaide

The knowledge of the cellular and molecular mechanisms leading to autoimmunity (immune aggression turning to self) constitutes an important challenge addressed to the medico-scientific community. The recent development of whole genome association studies and subsequent public databases has lead to the identification of gene alleles responsible for susceptibility (or protection) to a large number of autoimmune diseases.

The most significant advances in this field of research concern two devastating organ-specific autoimmune diseases, type 1 diabetes and multiple sclerosis. Interestingly also, these studies revealed some shared susceptibility genes (such as CTLA4) that control common facets of the autoimmune response.

Despite their powerfulness, these studies have not significantly contributed to the deciphering of the fundamental mechanisms responsible for the development of autoimmunity. Besides diversity, specificity, and memory, self-tolerance is a cornerstone of immune physiology. An inborn deficiency or a later breakdown of immune self-tolerance may often result in the development of autoimmune diseases. During evolution, the thymus appeared as a new lymphoid structure necessary for the establishment of central immune self-tolerance as required by the development of immune diversity. Thymus-dependent self-tolerance results from two interconnected mechanisms:

1. Clonal deletion of self-reactive T cells that emerge in the thymus during random recombination of gene segments encoding the variable part of the T-cell receptor for the antigen (TCR); and
2. Generation of self-antigen specific regulatory T cells (Treg) that inactivate in periphery self-reactive T cells having escaped thymic deletion and censorship. Consequently, a failure in thymus-dependent self-tolerance is now more and more regarded as a major event in immune dysregulation and pathogenesis of organ-specific autoimmune diseases.

Two major genes, the AutoImmune REgulator (AIRE) and the forkhead box protein 3 (FoxP3), intimately control the mechanisms of central self-tolerance. Mutations of AIRE are responsible for a very rare congenital autoimmune syndrome (APECED, i.e. Autoimmune Polyendocrinopathy Candidiasis and Ectodermal Dystrophy or APS-I, i.e. Autoimmune Polyglandular Syndrome type I). AIRE encodes a transcription factor-like protein, and AIRE expression is maximal in the thymus epithelium where it controls the transcription of many tissue-specific antigens (TSA). Mutations of FoxP3 lead to another very rare congenital autoimmune syndrome (IPEX, i.e. Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked). The protein FoxP3 is a transcription factor essential for intrathymic differentiation of natural self-antigen specific Treg (nTreg).

From January 2004, the research activities conducted in the FP6 Integrated Project Euro-Thymaide have provided a large and very significant amount of data (see http://www.eurothymaide.org/common/ScientificPublication.asp) that further support a central role for thymus-dependent self-tolerance in protection from autoimmunity. These findings now pave the way for novel therapeutic approaches aiming at self-tolerance restoration.

Briefly, these data include the following deliverables/milestones:

• Establishment of a European database of TSA synthesized in thymic epithelium, under AIRE control or not.
• Confirmation that a major function of AIRE is the transcriptional control of many TSA in medullary thymic epithelial cells.
• Characterization of thymic epithelial stem cells in the embryo endoderm.
• Identification of the cbl-b pathway in the control of the immune self-tolerance.
• Demonstration that intrathymic expression of self-antigens controls the differentiation of self-antigen specific nTreg.
• Preliminary assessment of a new type of tolerogenic/regulatory self-vaccination against type 1 diabetes based on thymic expression of insulin-related genes/proteins.

By concentrating on these findings as the most early events in initiation of the autoimmune response, the Euro-Thymaide consortium do hope to develop original and innovating therapies for the prevention and treatment of organ-specific autoimmune diseases, in particular type 1 diabetes.

Ref: USA Today - http://www.usatoday.com/news/health/2007-09-03-autoimmune-advances_N.htm