How Does Thymus Infection by Coxsackievirus Contribute to the Pathogenesis of Type 1 Diabetes?

Abstract

Through synthesis and presentation of neuroendocrine self-antigens by major histocompatibility complex proteins, thymic epithelial cells (TECs) play a crucial role in programing central immune self-tolerance to neuroendocrine functions. Insulin-like growth factor-2 (IGF-2) is the dominant gene/polypeptide of the insulin family that is expressed in TECs from different animal species and humans. Igf2 transcription is defective in the thymus of diabetes-prone bio-breeding rats, and tolerance to insulin is severely decreased in Igf2−/− mice. For more than 15 years now, our group is investigating the hypothesis that, besides a pancreotropic action, infection by coxsackievirus B4 (CV-B4) could implicate the thymus as well, and interfere with the intrathymic programing of central tolerance to the insulin family and secondarily to insulin-secreting islet β cells. In this perspective, we have demonstrated that a productive infection of the thymus occurs after oral CV-B4 inoculation of mice. Moreover, our most recent data have demonstrated that CV-B4 infection of a murine medullary (m) TEC line induces a significant decrease in Igf2 expression and IGF-2 production. In these conditions, Igf1 expression was much less affected by CV-B4 infection, while Ins2 transcription was not detected in this cell line. Through the inhibition of Igf2 expression in TECs, CV-B4 infection could lead to a breakdown of central immune tolerance to the insulin family and promote an autoimmune response against insulin-secreting islet β cells. Our major research objective now is to understand the molecular mechanisms by which CV-B4 infection of TECs leads to a major decrease in Igf2 expression in these cells.

Murine uterine decidualization is a novel function of autoimmune regulator—beyond immune tolerance

“…In addition, AIRE also is known to control transcription of insulin gene family proteins, viz. Igf1, Igf2, Ins1, and Ins2 . Insulin‐like growth factor‐1 (IGF‐1) is reported to cause increased vascular permeability, Bmp2 expression, and decidualization .…”

T cell thymic selection and peripheral homeostatic proliferation in infectious diseases

“…При этом Т-клетки становятся толерантными к антигенам вируса [19]. Инфицирование in utero HBV индуцирует толерантность к вирусу [24], и такие дети становятся хроническими носителями вируса [36]. Скорее всего, толерантность в указанных случаях развивается в результате инфицирования стромальных клеток тимуса [19,20].…”

Is Cytomegalovirus Involved in Recurring Periods of Higher than Expected Death and Medical Admissions, Occurring as Clustered Outbreaks in the Northern and Southern Hemispheres?

“…One further route is via infection of the thymus. Infection of the thymic epithelial cells by Coxsackievirus in the mouse initiates a cascade of immune changes which can lead to Type I diabetes [142]. CMV is able to infect the same thymic tissues in humans [1,21] and this potential relationship requires further study.…”