Abstract:For over a century, viruses have left a long trail of evidence implicating them as frequent suspects in the development of type 1 diabetes. Through vigorous interrogation of viral infections in individuals with islet autoimmunity and type 1 diabetes using serological and molecular virus detection methods, as well as mechanistic studies of virus-infected human pancreatic β-cells, the prime suspects have been narrowed down to predominantly human enteroviruses. Here, we provide a comprehensive overview of evidenc… Show more
“…Despite the evolving knowledge on the subject, the pathological mechanisms that trigger the initiation and progression of CVB-induced autoimmunity against islet antigens in T1DM are not yet fully elucidated. Experimental data suggest various mechanisms to explain the initiation of autoimmunity by CVB; for example, molecular mimicry between the conserved enteroviral protein 2C and glutamic acid decarboxylase, or bystander activation of pre-existing autoreactive T cells through the initiation of inflammation 11 , 22 . Fig.…”
Enteroviruses are believed to trigger or accelerate islet autoimmunity in genetically susceptible individuals, thereby resulting in loss of functional insulin-producing β-cells and type 1 diabetes mellitus (T1DM). Although enteroviruses are primarily involved in acute and lytic infections in vitro and in vivo, they can also establish a persistent infection. Prospective epidemiological studies have strongly associated the persistence of enteroviruses, especially coxsackievirus B (CVB), with the appearance of islet autoantibodies and an increased risk of T1DM. CVB can persist in pancreatic ductal and β-cells, which leads to structural or functional alterations of these cells, and to a chronic inflammatory response that promotes recruitment and activation of pre-existing autoreactive T cells and β-cell autoimmune destruction. CVB persistence in other sites, such as the intestine, blood cells and thymus, has been described; these sites could serve as a reservoir for infection or reinfection of the pancreas, and this persistence could have a role in the disturbance of tolerance to β-cells. This Review addresses the involvement of persistent enterovirus infection in triggering islet autoimmunity and T1DM, as well as current strategies to control enterovirus infections for preventing or reducing the risk of T1DM onset.
“…Despite the evolving knowledge on the subject, the pathological mechanisms that trigger the initiation and progression of CVB-induced autoimmunity against islet antigens in T1DM are not yet fully elucidated. Experimental data suggest various mechanisms to explain the initiation of autoimmunity by CVB; for example, molecular mimicry between the conserved enteroviral protein 2C and glutamic acid decarboxylase, or bystander activation of pre-existing autoreactive T cells through the initiation of inflammation 11 , 22 . Fig.…”
Enteroviruses are believed to trigger or accelerate islet autoimmunity in genetically susceptible individuals, thereby resulting in loss of functional insulin-producing β-cells and type 1 diabetes mellitus (T1DM). Although enteroviruses are primarily involved in acute and lytic infections in vitro and in vivo, they can also establish a persistent infection. Prospective epidemiological studies have strongly associated the persistence of enteroviruses, especially coxsackievirus B (CVB), with the appearance of islet autoantibodies and an increased risk of T1DM. CVB can persist in pancreatic ductal and β-cells, which leads to structural or functional alterations of these cells, and to a chronic inflammatory response that promotes recruitment and activation of pre-existing autoreactive T cells and β-cell autoimmune destruction. CVB persistence in other sites, such as the intestine, blood cells and thymus, has been described; these sites could serve as a reservoir for infection or reinfection of the pancreas, and this persistence could have a role in the disturbance of tolerance to β-cells. This Review addresses the involvement of persistent enterovirus infection in triggering islet autoimmunity and T1DM, as well as current strategies to control enterovirus infections for preventing or reducing the risk of T1DM onset.
“…Like the rest of the world, Montenegro has been affected by the ongoing worldwide pandemic (COVID-19 pandemic) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus since its first case was confirmed on 17 March 2020. For more than 50 years, viruses are considered potential triggers for autoimmune diseases such as T1D (21,22). Furthermore, some authors reported an increased incidence of new-onset T1D during the first year of the COVID-19 pandemic (23)(24)(25).…”
Significant and unexplained variations in type 1 diabetes (T1D) incidence through the years were observed all around the world. The update on this disorder’s incidence is crucial for adequate healthcare resource planning and monitoring of the disease. The aim of this study was to give an update on the current incidence of pediatric T1D in Montenegro and to analyze incidence changes over time and how the exposure to different factors might have affected it. This retrospective cohort study included a total of 582 patients younger than 15 years who were newly diagnosed with T1D during the past 30 years. The average age at diagnosis was 8.4 ± 3.91 years. The mean annual incidence of T1D in the Montenegro population during the whole study period of 30 years was 15.2/100,000 person-years. Slightly higher incidence rates were observed in male compared to female individuals, and the incidence increased with age, with the highest incidence in the 10–14 age group. If the model is observed as one without jointpoints, the annual percentage change (APC) for the total population is 3.1 (1.8–4.4); for male individuals, 3.8 (2.1–5.5); and for female individuals, 2.1 (0.6–3.5). In 2020, the first year of the coronavirus disease of 2019 (COVID-19) pandemic, in comparison to 2019, the incidence rate increased from 19.7/100,000 to 21.5/100,000, with the highest increase in the age group of 5–9 years. This is the first nationwide report on a 30-year period of T1D incidence trend in Montenegro. It suggests that T1D incidence among Montenegrin children is rising again and that there is a short-term influence of COVID-19 on new-onset T1D.
“…A possible infectious origin (in this particular case, the mumps virus) for T1DM was already proposed near a century ago (Gundersen 1927). To date, many studies have dealt with the possible involvement of different enteroviruses (more speci cally, coxsackievirus) in T1DM (for two recent comprehensive reviews, see Isaacs et al 2021 andLloyd et al 2022). Another factor supporting an infectious basis for T1DM is seasonality (Gamble et al 1969).…”
Type 1diabetes mellitus (T1DM) has been increasing in prevalence in the last decades and has become a global burden. Autoantibodies against human glutamate decarboxylase (GAD65) are among the first to be detected at the onset of T1DM. Diverse viruses have been proposed to be involved in the triggering of T1DM because of molecular mimicry, i.e., similarity between some viral proteins and one or more epitopes of GAD65. However, the possibility that bacterial proteins might also be responsible of GAD65 mimicry has been seldom investigated. To date, many genomes of Streptococcus pneumoniae (the pneumococcus), a prominent human pathogen particularly among children and the elderly, have been sequenced. A dataset of more than 9000 pneumococcal genomes were mined and two different (albeit related) genes (gadA and gadB), presumably encoding two glutamate decarboxylases similar to GAD65, were found. The various gadASpn alleles were present only in serotype 3 pneumococci belonging to the global lineage GPSC83, although some paralogs have also been discovered in two subspecies of Streptococcus constellatus (pharyngis and viborgensis), an isolate of the group B streptococci, and several strains of Lactobacillus delbrueckii. Besides, gadBSpn alleles are present in > 10% of the isolates in our dataset and represent 16 GPSCs with 123 sequence types and 20 different serotypes. Sequence analyses indicated that gadA- and gadB-like genes have been mobilized among different bacteria either by prophage(s) or by integrative and conjugative element(s), respectively. Substantial similarities appear to exist between the putative pneumococcal glutamate decarboxylases and well-known epitopes of GAD65. These results deserve upcoming studies on the possible involvement of S. pneumoniae in the etiopathogenesis and clinical onset of T1DM.
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