Immunology in the clinic review series; focus on type 1 diabetes and viruses: the innate immune response to enteroviruses and its possible role in regulating type 1 diabetes.

Department of Medicine HS, The Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
Clinical & Experimental Immunology (Impact Factor: 3.28). 04/2012; 168(1):30-8. DOI: 10.1111/j.1365-2249.2011.04557.x
Source: PubMed

ABSTRACT Type 1 diabetes (T1D) is an autoimmune disease arising as a consequence of a misdirected T cell response to the pancreatic beta cell. In recent years, there has been a growing interest in the innate immune system as a regulator of disease development. Genome-wide association studies have identified diabetes-associated polymorphisms in genes encoding proteins with functions related to the innate immune response. Moreover, enteroviruses, known to activate a strong innate immune response, have been implicated in the disease pathogenesis. In this review, we discuss the innate immune response elicited by enteroviruses and how this response may regulate T1D development.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cells and Receptors CVB can infect a large range of cells. It is generally understood that the virus entry follows the binding to its cellular receptor, the Coxsackie and Adenovirus Receptor (CAR). The most common process to CVB internalisation into cells is similar to macropinocytosis. However, several findings indicated that the mechanism of the entry of CVB into the cell depends on the cell type. Indeed, CVB can enter in cells that express Fc receptors (e.g. those of the immune system, such as macrophages, monocytes, B-cells and granulocytes), when bound to CVB-specific antibodies. 8 This virus entry, dependant on FcR, is the most described of ADE mechanisms. In this scenario, immune complexes constituted by virus-bound antibodies recognise at least one of the receptors for the Fc part of antibodies on the cell surface, providing a bridge that enhances the attachment of viruses to the cells. 6, 7 The ADE phenomenon has been described with various viruses that replicate in monocytes and macrophages. 9 Using peripheral blood mononuclear cells, it was shown that CD14+ monocytes were target cells in the ADE of CVB4 infection. 10 The ADE of CVB infection was also observed in murine macrophagic cell lines J774.1 and P388D1. 11 Previous studies by our team reported that the ADE was dependent on FcγRII and FcγRIII. In addition, CAR (Coxsackie and Adenovirus Receptor), the cellular receptor of CVB, was also needed, 10-12 unlike some viruses for which ADE enables emancipation from their cellular receptor for infection. For these viruses, primary non-susceptible cells could then be infected if they express Fc receptors. 7 Antibodies Several factors such as the class, the concentration and the epitope specificity of the antibody seem to be essential for ADE of CVB4 infection. Antibodies involved in the facilitation of CVB4 infection have been identified as IgG antibodies directed against VP4, a viral capsid protein. The target amino acid sequence of these antibodies was shown to be localised between amino acids 11 and 30 of the VP4 protein (69 amino acids in total). 13, 14 According to X-ray crystallography datas obtained at – 196°C, VP4 is buried in the capsid and is not accessible at the virion surface; however it is thought that in physiological conditions, conformational changes may expose a part of this protein, making it
    Treatment Strategies -Diabetes, Edited by Hannah Corby, 11/2013: chapter Enteroviral Pathogenesis of Type 1 Diabetes: A Role for Enhancing Antibodies?: pages 65-68; Cambridge Research Centre.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Type 1 diabetes (T1D) is an autoimmune disease that is thought to be triggered by environmental factors in genetically susceptible individuals. Enteroviruses have been mentioned as the most probable induction component of the disease. Nevertheless, the literature is controversial regarding the association of T1D with viral infection and first-line antiviral defence components, e.g. type I interferons (IFNs). Our aim was to test the hypothesis that an abnormality in IFN-stimulated gene patterns may cause a failure in immunological tolerance and, thereby, initiate T1D as an autoimmune disorder. We studied material from 64 T1D and 36 control subjects, divided into two age groups: <10 years and ≥10 years old. Using a relative gene expression method, we observed a lower expression of interferon-induced helicase 1 (IFIH1) and other type I IFN-induced genes in the blood cells of T1D subjects, especially subjects under 10 years old, in spite of their higher IFN levels as measured by the pSTAT1-inducing capacity of their sera. Likewise, freshly purified CpG-stimulated cells from T1D patients showed significantly lower upregulation of IFN-induced genes, i.e. IFIH1 and CXCL10, compared to cells from the control group. The identified dysregulation in the IFN-α–induced antiviral response in T1D patients, especially in early childhood, could be one of the factors affecting T1D development.This article is protected by copyright. All rights reserved.
    Scandinavian Journal of Immunology 06/2014; · 1.88 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Enterovirus infections are usually mild but can also cause severe illnesses and play a role in chronic diseases, such as cardiomyopathies and type 1 diabetes. Host response to the invading virus can markedly modulate the course of the infection, and this response varies between individuals due to the polymorphism of immune response genes. However, it is currently not known if virus strains also differ in their ability to stimulate the host immune system. Coxsackievirus B1 (CBV1) causes severe epidemics in young infants and it has recently been connected with type 1 diabetes in seroepidemiological studies. This study evaluated the ability of different field isolates of CBV1 to induce innate immune responses in PBMCs. CBV1 strains differed markedly in their capacity to induce innate immune responses. Out of the 18 tested CBV1 strains two induced exceptionally strong alpha interferon (IFN-α) response in PBMC cultures. The responding cell type was found to be the plasmacytoid dendritic cell. Such a strong innate immune response was accompanied by an up-regulation of several other immune response genes and secretion of cytokines, which modulate inflammation, and adaptive immune responses. These results suggest that enterovirus-induced immune activation depends on the virus strain. It is possible that the immunotype of the virus modulates the course of the infection and plays a role in the pathogenesis of chronic immune-mediated enterovirus diseases. J. Med. Virol. © 2014 Wiley Periodicals, Inc.
    Journal of Medical Virology 02/2014; · 2.22 Impact Factor

Full-text (2 Sources)

Available from
May 19, 2014