Enteroviruses and type 1 diabetes: towards a better understanding of the relationship.

Environmental factors, especially viruses, are involved in the initiation or the acceleration of type 1 diabetes (T1D) pathogenesis. Epidemiological data strongly suggest that enteroviruses, such as coxsackievirus B4 (CV-B4), can be associated with T1D. It has been demonstrated that enterovirus infections were significantly more prevalent in at risk individuals, such as siblings of diabetic patients, when they developed anti-beta-cell autoantibodies or T1D, and in recently diagnosed diabetic patients, compared with control subjects.

Pathogenesis of type 1 diabetes mellitus: interplay between enterovirus and host.

Enteroviruses are believed to contribute to the pathogenesis of type 1 diabetes mellitus (T1DM). In this Review, the interplay between infection with enteroviruses, the immune system and host genes is discussed. Data from retrospective and prospective epidemiological studies strongly suggest the involvement of enteroviruses, such as coxsackievirus B, in the development of T1DM.

Mechanisms and results of the antibody-dependent enhancement of viral infections and role in the pathogenesis of coxsackievirus B-induced diseases.

The mechanisms of the antibody-dependent enhancement (ADE) of viral infection are presented, particularly within the Picornaviridae family. The ADE of infection has been described in both human and animal models, worsens viral infections and compromises vaccine safety. The ADE of coxsackievirus B infection can also be implied in the pathogenesis of diseases like chronic dilated cardiomyopathy or insulin-dependent type 1 diabetes.

A part of the VP4 capsid protein exhibited by coxsackievirus B4 E2 is the target of antibodies contained in plasma from patients with type 1 diabetes.

The capsid protein VP4 was identified previously as the target of antibodies contained in plasma enhancing the coxscakievirus B4 (CV-B4) E2-induced production of IFN-alpha by peripheral blood mononuclear cells (PBMCs). The sequence of VP4 recognized by these antibodies was investigated. This sequence was identified as amino acids 11 to 30 by using synthetic overlapping peptides spanning VP4(CV-B4 E2) in competition experiments for antibodies enhancing the CV(B4 E2) induced production of IFN-alpha by PBMCs.

Role of the capsid protein VP4 in the plasma-dependent enhancement of the Coxsackievirus B4E2-infection of human peripheral blood cells.

It has been previously shown that antibodies contained in human plasma directed towards the Coxsackievirus B4 (CVB4)E2 capsid protein VP4 can enhance the CVB4E2-induced production of IFN-alpha by peripheral blood mononuclear cells (PBMC). The aim of this study was to produce a VP4 fusion protein to investigate the role of the internal capsid protein VP4 and anti-VP4 antibodies in the plasma-dependent enhancement of CVB4E2 infection of PBMC. A fusion protein MBPVP4 containing the VP4 insert of CVB4E2 and a control fusion protein MBP-beta-gal-alpha, were produced in Escherichia coli K12 TB1.

Viral protein VP4 is a target of human antibodies enhancing coxsackievirus B4- and B3-induced synthesis of alpha interferon.

Coxsackievirus B4 (CVB4)-induced production of alpha interferon (IFN-alpha) by peripheral blood mononuclear cells (PBMC) is enhanced in vitro by nonneutralizing anti-CVB4 antibodies from healthy subjects and, to a higher extent, from patients with insulin-dependent diabetes mellitus. In this study, we focused on identification of the viral target of these antibodies in CVB systems. High levels of IFN-alpha were obtained in supernatants of PBMC incubated with CVB4E2 or CVB3 and plasma from healthy subjects and, to a higher extent, from patients.