An Enterovirus Attacking the Thymus May Play a Key Role in Triggering Type 1 Diabetes

An Enterovirus Attacking the Thymus May Play a Key Role in Triggering Type 1 Diabetes

As part of the European FP6 Eurothymaide project, and, in close collaboration with Lille’s CHRU hospital (Didier Hober), the Centre d’Immunologie de Marseille-Luminy (Philippe Naquet) and the University of Tunis, Vincent Geenen and his team have discovered that infection of the thymus by the diabetogenic CV-B4 virus leads to a decrease in the transcription of the IGF2 gene (Insulin-like Growth Factor 2).

This is noteworthy because IGF2 plays an important role in establishing immunological tolerance to the insulin protein/gene family. This drastic reduction in thymic IGF2 could render the immune system intolerant to insulin, the hormone secreted by the pancreas whose deficiency causes autoimmune T1D.

The results of this study have been published in the 2012 October issue of Journal of Virology.

Although both T1D and type 2 diabetes (T2D) are both characterized by chronic hyperglycaemia, they are two very different diseases. The former, which is of autoimmune origin, affects children, teenagers and young adults and represents approximately 10% of all cases of diabetes. The latter involves 90% of people affected by diabetes and occurs later in life and is mainly due to a resistance to insulin and is associated with excess weight as well as a lack of physical exercise.

In people with T1D, formerly known as juvenile or insulin-dependent diabetes, insulin deficiency results from autoimmunity selectively directed against the beta cells located in the islets of Langerhans of the pancreas.

The origin of this selective autoimmunity has never been resolved. The thymus gland is the safeguard organ of the adaptive immune system against the high risk of autoimmunity inherent to this system. The thymus gland determines not only which T-lymphocytes will be selected but also which ones are released into the body.

The thymus eliminates self-reactive T cells, also called ‘forbidden’ clones. This involves 95% of T cells generated at random in this primary lymphoid organ. The thymus filters and lets through a mere 5% of cells, those that are self-tolerant. It is also capable of generating natural regulatory T (nTreg) cells that inhibit in periphery forbidden self-reactive T cells that have escaped the thymus filter. Through this double control, the thymus prevents the adaptive immune system from turning against the body. An increasing number of experimental arguments now reinforce this new concept according to which defect in the intra-thymic programming of central tolerance favors the development of organ-specific autoimmunity.

Autoimmune type 1 diabetes develops in people who are genetically predisposed to this disease and about 40 genetic loci determining susceptibility to T1D have been identified. But other factors favor the emergence of T1D, in particular, environmental factors and, among those, different viruses including those from the family of enteroviruses, such as CVs. In Scandinavian countries, the incidence of T1D is approximately 50 cases/100,000 inhabitants compared with only 8/100,000 in Belgium, the lowest incidence is observed in African countries.

The frequency of infection by enteroviruses is greater in the northern hemisphere versus the southern hemisphere which could partially explain the existence of this gradient. While CVs do indeed seem to play a role in the development of autoimmune T1D, the mechanisms by which they act remain unknown.

While an increasing number of studies, mainly epidemiological, indicate that coxsackie viruses (CVs) play a role in the pathogenesis of autoimmune type 1 diabetes (T1D), the mechanisms of action of these viruses remain elusive.

The hypothesis that Vincent Geenen and Didier Hober from the University of Lille have been investigating for more than 13 years, mainly as part of the Eurothymaide programme, is as follows: CVs could infect the thymus and cause secondly an imbalance in the tolerogenic function of the latter. In their study, Vincent Geenen, Didier Hober and their colleagues provide new experimental evidence supporting this hypothesis.

They have revealed that infection of thymus epithelial cells by CV-B4 leads to a clear decrease in the transcription of the IGF2 gene, a gene of the insulin family that intervenes in programming immunological self-tolerance towards the entire family, especially during foetal life. Thymic infection by CV-B4 would therefore be responsible for a breakdown of central self-tolerance to insulin and to islet beta cells that secrete this hormone. In addition, these new findings are unifying the major working hypotheses of those laboratories:

– Role of a thymus dysfunction in the development of the diabetogenic autoimmune response,

– Role of thymic IGF2 as the major tolerogenic factor of the insulin family, and

– The involvement of thymus infection by CV-B4 in the development of T1D.

The team is now focusing on the development of a new type of vaccine, a ‘negative or tolerogenic self-vaccine’ based on IGF2 that would reprogram immune tolerance to islet beta cells and thus could contribute to both the prevention and cure of T1D (see  Geenen V et al., Curr Opin Pharmacol, 2010, 10:461).

SOURCE:  J Virol. 2012 Oct;86(20):11151-62. Epub 2012 Aug 1.

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Source: Cover Image: Thymus gland. Wikimedia Commons.

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