Virus Antibody Survey in Different European Populations Indicates Risk Association Between Coxsackievirus B1 and Type 1 Diabetes

Oikarinen, Sami; Tauriainen, Sisko; Hober, Didier; Lucas, Bernadette; Vazeou, Andriani; Sioofy‐Khojine, Amir‐Babak; Bozas, Evangelos; Muir, Peter; Honkanen, Hanna; Ilonen, Jorma; Knip, Mikael; Keskinen, Päivi; Saha, Marja‐Terttu; Huhtala, Heini; Stanway, Glyn; Bartsocas, Christos S.; Ludvigsson, Johnny; Taylor, K. W.; Hyöty, Heikki

doi:10.2337/db13-0620

Cited by 131 publications

(145 citation statements)

References 33 publications

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“…Fourth, the observation that maternal CVB1 antibodies modulated the risk effect of CVB1 supports biological plausibility because maternal antibodies protect the child against enterovirus infections (43,44). Finally, we observed a similar risk effect of CVB1 in another study where neutralizing antibodies were analyzed in patients with newly diagnosed type 1 diabetes and control subjects in five European countries (41). In summary, the results are in line with the previous literature suggesting a link between enterovirus infections and type 1 diabetes.…”

Section: Discussionsupporting

confidence: 81%

“…In addition, CVB1 infections peaked a few months before autoantibodies first appeared, which overlaps with the previously observed peak in the frequency of enterovirus RNA in serum (41), fitting with the rapid induction of islet autoantibodies in enterovirus-infected mice (42). Second, the accumulation of risk and protective viruses to a small subgroup of phylogenically close enteroviruses supports the biological relevance of our findings.…”

Section: Discussionsupporting

confidence: 69%

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Coxsackievirus B1 Is Associated With Induction of β-Cell Autoimmunity That Portends Type 1 Diabetes

Laitinen¹,

Honkanen

Pakkanen³

et al. 2014

Diabetes

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221

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The rapidly increasing incidence of type 1 diabetes implies that environmental factors are involved in the pathogenesis. Enteroviruses are among the suspected environmental triggers of the disease, and the interest in exploring the possibilities to develop vaccines against these viruses has increased. Our objective was to identify enterovirus serotypes that could be involved in the initiation of the disease process by screening neutralizing antibodies against 41 different enterovirus types in a unique longitudinal sample series from a large prospective birth-cohort study. The study participants comprised 183 case children testing persistently positive for at least two diabetes-predictive autoantibodies and 366 autoantibody-negative matched control children. Coxsackievirus B1 was associated with an increased risk of β-cell autoimmunity. This risk was strongest when infection occurred a few months before autoantibodies appeared and was attenuated by the presence of maternal antibodies against the virus. Two other coxsackieviruses, B3 and B6, were associated with a reduced risk, with an interaction pattern, suggesting immunological cross-protection against coxsackievirus B1. These results support previous observations suggesting that the group B coxsackieviruses are associated with the risk of type 1 diabetes. The clustering of the risk and protective viruses to this narrow phylogenetic lineage supports the biological plausibility of this phenomenon.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionsupporting

confidence: 69%

Coxsackievirus B1 Is Associated With Induction of β-Cell Autoimmunity That Portends Type 1 Diabetes

Laitinen¹,

Honkanen

Pakkanen³

et al. 2014

Diabetes

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221

219

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“…Infection of some islets might trigger an antiviral response and therefore an increase in MHC-I (Foulis et al 1987b). For example, growing evidence suggests that enteroviruses (EV) or neutralizing antibodies against them can be detected in pancreata and in the serum from T1D donors (Laitinen et al 2014;Oikarinen et al 2014;Richardson et al 2013;Richardson et al 2009;Schneider and von Herrath 2014;Willcox et al 2011). EV can effectively infect beta cells, which express the coxsackievirus and adenovirus receptor (CAR) (Oikarinen et al 2008;Ylipaasto et al 2004).…”

Section: Discussionmentioning

confidence: 99%

Heterogeneity and Lobularity of Pancreatic Pathology in Type 1 Diabetes during the Prediabetic Phase

Rodríguez-Calvo

Suwandi

Amirian

et al. 2015

J Histochem Cytochem.

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SummaryType 1 diabetes (T1D) is an autoimmune disease in which insulin-producing beta cells are destroyed in the islets of Langerhans. One of its main pathological manifestations is the hyper-expression of Major Histocompatibility Complex I (MHC-I) by beta cells, which was first described over 3 decades ago yet its cause remains unknown. It might not only be a sign of beta cell dysfunction but could also render the cells susceptible to autoimmune destruction; for example, by islet-infiltrating CD8 T cells. In this report, we studied pancreas tissue from a 22-year-old non-diabetic male cadaveric organ donor who had been at high risk of developing T1D, in which autoantibodies against GAD and IA-2 were detected. Pancreas sections were analyzed for signs of inflammation. Multiple insulin-containing islets were identified, which hyper-expressed MHC-I. However, islet density and MHC-I expression exhibited a highly lobular and heterogeneous pattern even within the same section. In addition, many islets with high expression of MHC-I presented higher levels of CD8 T cell infiltration than normal islets. These results demonstrate the heterogeneity of human pathology that occurs early during the pre-diabetic, autoantibody positive phase, and should contribute to the understanding of human T1D. (J Histochem Cytochem 63:626-636, 2015)

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“…If endogenous antigens are released as a consequence of tissue damage in the presence of proinflammatory mediators, it could facilitate activation of self-reactive T cells, a process called bystander activation. Antibodies against Coxsackie B virus, indicating a previous infection, are associated with increased risk of T1D development [32]. There is potential molecular mimicry between parts of the P2-C protein expressed by Coxsackie B virus and peptides within the 247-279 amino acid region of human glutamic acid decarboxylase (GAD 65 ), which could explain mechanistically how infection leads to autoimmunity [33].…”

Section: Environmental Risk Factorsmentioning

confidence: 99%

Regin in Blood Immune Regulation in Type 1 Diabetes

Pihl¹

2013

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Type 1 Diabetes (T1D) is an autoimmune disease resulting in insulin deficiency as a result of autoimmune destruction of pancreatic β-cells. Preserving β-cell function in patients with T1D would be of great benefit since patients with sustained endogenous insulin secretion are known to suffer less from secondary complications due to hyperglycemia. Glutamic acid decarboxylase 65 (GAD 65 ) is a major autoantigen targeted by self-reactive lymphocytes in T1D, and has been used in several attempts at treating T1D by inducing tolerance to β-cell antigens. We showed positive clinical effects of GAD 65 formulated with aluminium hydroxide (GAD-alum) on preservation of C-peptide secretion in a phase II clinical trial. Unfortunately, a phase III clinical trial in a larger population failed to confirm this finding. Regulatory T cells (Treg) are instrumental in maintaining peripheral tolerance to self-antigens. Deficiencies in Treg function are thought to influence the pathogenesis of autoimmune diseases, including T1D. One proposed mechanism of achieving tolerance to β-cell antigens in T1D is the induction of antigen-specific Treg through immunomodulation. The general aim of this thesis was to study immune regulation in T1D, the role of Treg and immunomodulatory effects of GAD-alum treatment in particular. Our hypothesis was that Treg biology is altered in T1D and pre-diabetes, and that an induction of GAD 65 -specific Treg contributes to the clinical efficacy of GAD-alum treatment. We demonstrated that T cells expressing Treg-associated markers were increased in number in patients with recent-onset T1D, as well as in children with high risk of developing T1D. We found that antigen recall 4 years after GAD-alum treatment induced cells with both regulatory and effector phenotypes in GAD-alum treated patients. Furthermore there was no effect on Treg-mediated suppression in GAD-alum treated patients, while patients with T1D, regardless of treatment, exhibited deficient Treg-mediated suppression of Teff that was intrinsic to the Treg population. We followed patients participating in a phase III trial of GAD-alum, and using an extended antibody panel we risk, but found no effects of variant alleles on the risk of developing T1D, or on the efficacy of GAD-alum treatment. We show small effects on C-peptide secretion and autoantibody positivity in patients with T1D. In conclusion, we find that while Treg are deficient in patients with T1D, induction of Treg is an unlikely mechanism of action of GAD-alum treatment. SUPERVISOR

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Virus Antibody Survey in Different European Populations Indicates Risk Association Between Coxsackievirus B1 and Type 1 Diabetes

Cited by 131 publications

References 33 publications

Coxsackievirus B1 Is Associated With Induction of β-Cell Autoimmunity That Portends Type 1 Diabetes

Coxsackievirus B1 Is Associated With Induction of β-Cell Autoimmunity That Portends Type 1 Diabetes

Heterogeneity and Lobularity of Pancreatic Pathology in Type 1 Diabetes during the Prediabetic Phase

Regin in Blood Immune Regulation in Type 1 Diabetes

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