1. Please check and comment entries here.
Table of Contents

    Topic review

    Viruses and Type 1 Diabetes

    View times: 7
    Submitted by: Ki Wook Kim

    Definition

    Type 1 diabetes (T1D) is characterised by the chronic immune-mediated destruction of pancreatic β-cells, with affected individuals requiring lifelong exogenous insulin. An interplay between genetics and environmental factors such as the virome is suggested to regulate immune tolerance, with environmental, lifestyle or dietary exposures currently being investigated as either accelerating or protective. The hypothesised role of viral infections in the initiation of IA and the progression to T1D is supported by a large body of epidemiological and animal model-based evidence, beginning almost a century ago.

    1. Type 1 Diabetes

    Type 1 diabetes (T1D) is characterised by the chronic immune-mediated destruction of pancreatic β-cells, with affected individuals requiring lifelong exogenous insulin [1][2]. Globally, over 1.1 million children and adolescents under the age of 20 are estimated to have T1D, with approximately 128,900 new cases diagnosed each year. In children 0–14 years, India and USA currently have the highest prevalence of T1D (95.6 and 94.2 thousand cases, respectively) [3]. In Australia, a recent study of T1D incidence in children 0–14 years from 2002 to 2017 found a mean incidence of 25.0 per 100,000, additionally revealing a sinusoidal pattern in incidence over time represented by 5-yearly cycles. Mean incidence also increased with age, with the highest incidence in 10–14-year-olds (224% higher than 0–4-year-olds). Wide geographical variation in the mean incidence of T1D has been described, with incidence increases of up to 6.6% per year in Poland, a levelling off reported in populations such as Finland and Sweden, and a slight decreasing trend in Australia over recent years, particularly in 0–4-year-olds. This variation both between and within countries and different ethnic populations is suggested to reflect geographical differences in genetic susceptibility and environmental risk in addition to disparities in diagnostic criteria including islet autoantibody testing requirements [2][4].
    T1D is categorised into four stages: (1) presymptomatic T1D with the presence of multiple islet autoantibodies (type 1a) but normoglycemia; (2) presymptomatic T1D with progression to dysglycaemia; (3) dysglycaemia and clinical symptoms such as polyuria, polydipsia, polyphagia, weight loss, fatigue and diabetic ketoacidosis (DKA)); (4) long-standing T1D [5][6]. Acute and long-term complications of T1D include severe hypoglycaemia, DKA, vascular disease, nephropathy, retinopathy and neuropathy; with lifespan also reduced [7][8][9].

    2. Islet Autoimmunity

    Most T1D is preceded by the development of islet autoimmunity (IA), serologically confirmed by the presence of at least one diabetes-associated islet autoantibody to insulin (IAA), glutamic acid decarboxylase 65 (GADA), protein tyrosine kinase-related islet antigen 2 (IA-2A) and zinc transporter 8 (ZnT8A). IA can appear from around six months of age with incidence peaking prior to two years of age in the genetically at risk but will be generally present months to years before symptomatic onset, reinforcing the need for early-stage interventions and increased monitoring of presymptomatic T1D. These autoantibodies typically appear sequentially rather than simultaneously, making it unclear whether multiple or single events precipitate seroconversion and eventual T1D development [10][11]. The risk of developing T1D increases as additional autoantibodies are detected [12][13][14], with the presence of a single autoantibody (‘early’ IA) conferring a 15% risk of progression to T1D [15], whereas two or more antibodies (‘established’ IA) are associated with an 80% risk of progression to T1D [16][17][18][19][20]. Early seroconversion and increased autoantibody concentrations can be observed in a high proportion of at-risk children, with over 80% of children who developed T1D seroconverting before three years of age [21]. The first-appearing or primary antibody has been proposed to represent two major IA phenotypes representing early or late diagnosis of IA [18][22]. Increasing IAA concentrations have been used to predict progression to overt T1D, with proinsulin highlighted as an important autoantigen in T1D diagnosed in early childhood. Conversely, the appearance of GADA as the primary autoantigen may result in progression at a later age, affecting the design of early interventions [21][23][24].
    T1D pathogenesis is marked by selective destruction of insulin-producing cells by effector autoreactive and bystander CD8+ T cells, directly contrasted by the action of regulatory T cells. Dendritic cells and even mast cells (although limited data are available) have also been implicated in T1D pathogenesis, as they present islet autoantigens to autoreactive T-cells, resulting in dysregulated peripheral immune tolerance [25]. However, the occurrence of the resulting islet infiltration by autoantibodies (insulitis) is heterogenous amongst islets both within lobules of a single pancreas and between individuals, following a relapsing–remitting nature during early disease and perhaps reflecting the highly variable asymptomatic period in preclinical T1D [26]. Approximately 70–95% of β-cells are usually lost at the onset of symptoms, resulting in a reduced pancreas size, although in some individuals a 40% reduction is adequate to elicit symptoms [2][16][27]. Efforts to preserve any residual β-cell function (measured by C-peptide production) using immune intervention therapies have had limited success [28][29][30][31][32]. Notably, only 15% of children displaying single IA positivity progress to T1D [33], and conversely, only 10% of individuals with T1D display single IA positivity [16]. Therefore, there is an increasing focus on the prevention of T1D progression from the early stages of non-clinical disease. Development of more economical and efficient assays of islet autoantibody detection may allow for more widespread employment of IA screening and potential for use in the general population, enabling earlier diagnosis and intervention [17][34].

    3. Genetics

    Comprehensive genome-wide association studies have identified over 60 genetic loci associated with increased T1D risk, with approximately half of the genetic risk attributed to the human leukocyte antigen (HLA) genotype, with notable contributions also arising from the INS, PTPN22, CTLA4 and IL2RA genes [35]. HLA-class II DR and DQ allele haplotypes DRB1*03:01-DQA1*05: 01-DQB1*02:01 and DRB1*04-DQA1*03:01-DQB1*03:02 show the highest risk, with DR3/DR4 (DQ2/DQ8) heterozygotes displaying a 30-fold increased risk of IA and T1D in the general population. Whilst a combination of islet autoantibodies has been previously used to predict increased risk of progression to T1D in first-degree relatives [36], we can now use genetic risk scores (GRS) to predict progression to T1D in IA positive children [37]. GRS are calculated using a combination of HLA and non-HLA genes, with weighted values given to both high-risk HLA class II genotypes plus a weighted value assigned to each susceptible allele of HLA class I and non-HLA single nucleotide polymorphisms (SNPs). Individuals with lower GRS experience slower progression to IA, and slower development from both single and multiple IA to T1D in The Environmental Determinants of Diabetes in the Young (TEDDY) cohort [38]. Recent improvements in T1D GRS algorithms have led to the development of T1D GRS2 for standardised use with greater predictive power [39].
    Although individuals with a first-degree relative with T1D are at approximately 15-fold increased relative lifetime risk for T1D compared to the general population, over 85% of diagnosed children have no family history, highlighting the major contribution of environmental factors in the aetiology of T1D [5][40]. T1D heritability varies depending on which family member has T1D, with the risk of T1D in the offspring higher with a T1D-affected father (~6%) compared to a T1D-affected mother (~2%). Furthermore, having a dizygotic twin imposes a slightly higher risk of T1D (~10%) compared to a non-twin sibling (~6%), highlighting the role of the intrauterine environment on T1D-risk. [41]. Interestingly, the proportion of individuals with the highest risk genotype DR3-DQ2/DR4-DQ8 has been shown to decrease over time in multiple populations in the United Kingdom, Finland and United States [2].

    4. Environmental Triggers

    An interplay between genetics and environmental factors such as the virome, microbiome and metabolome is suggested to regulate immune tolerance, with the introduction of environmental, lifestyle or dietary exposures currently being investigated as either accelerating or protective [42]. A range of potential environmental triggers has been proposed, including viruses. The hypothesised role of viral infections in the initiation of IA and the progression to T1D is supported by a large body of epidemiological and animal model-based evidence [43][44]. Multiple viruses have been associated with IA/T1D to date, including enterovirus (EV) [45][46][47][48][49][50][51][52][53][54], rotavirus [55][56][57][58][59][60][61], cytomegalovirus [62][63][64][65][66][67][68], Epstein-Barr virus [63][69][70], parechovirus [71][72][73], influenza [74][75][76], parvovirus [77][78], mumps [79][80][81], rubella [80][81][82][83][84][85] and human endogenous retrovirus [86][87][88][89]. By far, the strongest supporting evidence exists for EVs. Our previous meta-analysis of 26 molecular studies and >4400 participants revealed EV infection was 10 times greater at the onset of T1D compared to healthy controls [90]. Furthermore, T1D-specific risk alleles contained within genes involved in immune function have been shown to alter susceptibility to viral infection or affect the extent of the host antiviral response [91]. The rs1990760 SNP within IFIH1 has been associated with increased detection of EV RNA in blood [92] and separately with severe EV-A71 infection [93]. The rs2476601 SNP within PTPN22 has been associated with lower IFN production by macrophages in response to TLR ligand stimulation (as would occur during viral infection) [94], and additionally it has been suggested that PTPN22 could suppress the function of effector T cells, diminishing their response to viral infection and allowing the establishment of persistent infection [91][95].
    The timing of environmental triggers is likely to be critical, with environmental influences potentially commencing in utero and within the first year of life, emphasising the importance of longitudinal prospective cohort studies that follow at-risk children from pregnancy, such as the Environmental Determinants of Islet Autoimmunity (ENDIA) and Type 1 Diabetes Prediction and Prevention (DIPP)-novum studies [96][97]. Our recent meta-analysis of observational studies revealed maternal viral infections during pregnancy resulted in offspring that were twice more likely to develop T1D (OR 2.16, 95% CI 1.22–3.80; p = 0.008), highlighting the need to measure infections in utero as well as during early life. The adoption of large, national or international prospective birth cohort studies allows for the examination of any temporal links between infection in utero and the eventual development of IA or T1D in the offspring [46].

    5. Enteroviruses

    EVs are non-enveloped, single-stranded icosahedral RNA viruses classified within the Picornaviridae family that primarily display faecal–oral transmission, within occasional cases of vertical and respiratory transmission also possible [98]. Human EVs are ubiquitous and responsible for serious diseases such as poliomyelitis, myocarditis and aseptic meningitis [99]. However, many EV infections cause subclinical or mild disease and are thus underreported, with a small proportion proceeding to clinical identification [100]. More severe EV infection is typically seen in children and neonates, with proposed intrinsic immunity in the adult mature gut moderating the course of infection and preventing viraemia [101].
    There are more than 100 characterised genotypes of human EV, classified into four species: EV-A to -D. Also included within the EV genus are rhinoviruses, which predominately cause upper respiratory tract infections and distinct clinical presentation [102][103][104]. The linear EV RNA genome spans 7.2–8.5 kb in length, consisting of four structural (P1) capsid proteins and seven non-structural (P2 and P3) proteins, forming a single polypeptide which is cleaved by a viral 3C and 2A proteases [105][106]. The EV 5′-untranslated region (UTR) contains internal ribosome entry sites which allow for ribosome recruitment during cap-independent translation of EVs’ single polypeptide. Self-assembly of VP1-VP4 capsid proteins into empty capsid particles and transcription of the positive-strand RNA genome facilitated by non-structural proteins is followed by RNA encapsidation and formation of infectious virions. The mechanism of release is still unconfirmed but is proposed to involve changes to cell membrane integrity, lysis and apoptosis [107]. The 5′ and 3′ UTRs are highly conserved amongst all EV species and have historically formed the basis of primer and probe designs used in molecular diagnostics of general EV infection [108]. The highly variable major capsid protein VP1 codes for genotype-specific determinants of neutralisation and antigenic sites and is therefore typically used for EV genotypic classification [109][110].
    EVs invade host cells primarily via the coxsackievirus and adenovirus receptor (CAR), expressed in both α- and β-cells, with entry of genomic RNA post adsorption followed by translation and replication of sense viral RNA in the cytosol in a cap-independent manner [111]. A specific isoform of CAR with a terminal SIV motif and a unique PDZ-binding domain at the C-terminal (CAR-SIV) has been shown to be highly and selectively expressed within β-cells and is localised mainly to insulin secretory granules, which may further contribute to the sensitivity of human β-cells to EV infection [112]. Secretory granule proteins are proposed to be hijacked during exocytosis, allowing internalisation of virus particles by existing endocytic machinery. This is further supported by the identification of viral replication complexes around insulin granule membranes in coxsackievirus B (CVB)-infected human islets using electron microscopy [113][114].

    The entry is from 10.3390/microorganisms9071519

    References

    1. Katsarou, A.; Gudbjörnsdottir, S.; Rawshani, A.; Dabelea, D.; Bonifacio, E.; Anderson, B.J.; Jacobsen, L.M.; Schatz, D.A.; Lernmark, Å. Type 1 diabetes mellitus. Nat. Rev. Dis. Primers 2017, 3, 17016.
    2. Mayer-Davis, E.J.; Kahkoska, A.R.; Jefferies, C.; Dabelea, D.; Balde, N.; Gong, C.X.; Aschner, P.; Craig, M.E. ISPAD Clinical Practice Consensus Guidelines 2018: Definition, epidemiology, and classification of diabetes in children and adolescents. Pediatr. Diabetes 2018, 19, 7–19.
    3. Diabetes Atlas, 9th ed.; International Diabetes Federation (IDF): Brussles, Belgium, 2019.
    4. Haynes, A.; Bulsara, M.K.; Bergman, P.; Cameron, F.; Couper, J.; Craig, M.E.; Demangone, K.; Johnson, S.; Lafferty, A.; Titmuss, A.; et al. Incidence of type 1 diabetes in 0 to 14 year olds in Australia from 2002 to 2017. Pediatr. Diabetes 2020, 21, 707–712.
    5. Couper, J.J.; Haller, M.J.; Greenbaum, C.J.; Ziegler, A.-G.; Wherrett, D.K.; Knip, M.; Craig, M.E. ISPAD Clinical Practice Consensus Guidelines 2018: Stages of type 1 diabetes in children and adolescents. Pediatr. Diabetes 2018, 19, 20–27.
    6. Insel, R.A.; Dunne, J.L.; Atkinson, M.A.; Chiang, J.L.; Dabelea, D.; Gottlieb, P.A.; Greenbaum, C.J.; Herold, K.C.; Krischer, J.P.; Lernmark, Å. Staging Presymptomatic Type 1 Diabetes: A Scientific Statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes Care 2015, 38, 1964–1974.
    7. Veijola, R.; Koskinen, M.; Helminen, O.; Hekkala, A. Dysregulation of glucose metabolism in preclinical type 1 diabetes. Pediatr. Diabetes 2016, 17, 25–30.
    8. Borchers, A.T.; Uibo, R.; Gershwin, M.E. The geoepidemiology of type 1 diabetes. Autoimmun. Rev. 2010, 9, A355–A365.
    9. Ferrat, L.A.; Vehik, K.; Sharp, S.A.; Lernmark, Å.; Rewers, M.J.; She, J.-X.; Ziegler, A.-G.; Toppari, J.; Akolkar, B.; Krischer, J.P.; et al. A combined risk score enhances prediction of type 1 diabetes among susceptible children. Nat. Med. 2020, 26, 1247–1255.
    10. Taplin, C.E.; Barker, J.M. Natural Evolution, Prediction, and Prevention of Type 1 Diabetes in Youth. Endocr. Res. 2008, 33, 17–33.
    11. Cossen, K.; Muir, A. Birth Cohorts in Type 1 Diabetes: Preparing for the Payoff. J. Clin. Endocrinol. Metab. 2021, 106, e1044–e1045.
    12. Ziegler, A.-G.; Pflueger, M.; Winkler, C.; Achenbach, P.; Akolkar, B.; Krischer, J.P.; Bonifacio, E. Accelerated progression from islet autoimmunity to diabetes is causing the escalating incidence of type 1 diabetes in young children. J. Autoimmun. 2011, 37, 3–7.
    13. Krischer, J.P.; Lynch, K.F.; Schatz, D.A.; Ilonen, J.; Lernmark, Å.; Hagopian, W.A.; Rewers, M.J.; She, J.-X.; Simell, O.G.; Toppari, J.; et al. The 6 year incidence of diabetes-associated autoantibodies in genetically at-risk children: The TEDDY study. Diabetologia 2015, 58, 980–987.
    14. Taplin, C.E.; Barker, J.M. Autoantibodies in type 1 diabetes. Autoimmunity 2008, 41, 11–18.
    15. Miao, D.; Steck, A.K.; Zhang, L.; Guyer, K.M.; Jiang, L.; Armstrong, T.; Muller, S.M.; Krischer, J.; Rewers, M.; Yu, L. Electrochemiluminescence Assays for Insulin and Glutamic Acid Decarboxylase Autoantibodies Improve Prediction of Type 1 Diabetes Risk. Diabetes Technol. Ther. 2015, 17, 119–127.
    16. Regnell, S.E.; Lernmark, Å. Early prediction of autoimmune (type 1) diabetes. Diabetologia 2017, 60, 1370–1381.
    17. Yu, L.; Zhao, Z.; Steck, A.K. T1D Autoantibodies: Room for improvement? Curr. Opin. Endocrinol. Diabetes Obes. 2017, 24, 285–291.
    18. Bauer, W.; Veijola, R.; Lempainen, J.; Kiviniemi, M.; Härkönen, T.; Toppari, J.; Knip, M.; Gyenesei, A.; Ilonen, J. Age at Seroconversion, HLA Genotype, and Specificity of Autoantibodies in Progression of Islet Autoimmunity in Childhood. J. Clin. Endocrinol. Metab. 2019, 104, 4521–4530.
    19. Balke, E.M.; Balti, E.V.; Van Der Auwera, B.; Weets, I.; Costa, O.; Demeester, S.; Abrams, P.; Casteels, K.; Coeckelberghs, M.; Tenoutasse, S.; et al. Accelerated Progression to Type 1 Diabetes in the Presence ofHLA-A*24and-B*18Is Restricted to Multiple Islet Autoantibody–Positive Individuals With DistinctHLA-DQand Autoantibody Risk Profiles. Diabetes Care 2018, 41, 1076–1083.
    20. Michels, A.; Zhang, L.; Khadra, A.; Kushner, J.A.; Redondo, M.J.; Pietropaolo, M. Prediction and prevention of type 1 diabetes: Update on success of prediction and struggles at prevention. Pediatr. Diabetes 2015, 16, 465–484.
    21. Parikka, V.; Nanto-Salonen, K.; Saarinen, M.; Simell, T.; Ilonen, J.; Hyoty, H.; Veijola, R.; Knip, M.; Simell, O. Early seroconversion and rapidly increasing autoantibody concentrations predict prepubertal manifestation of type 1 diabetes in children at genetic risk. Diabetologia 2012, 55, 1926–1936.
    22. Lönnrot, M.; Lynch, K.F.; Elding Larsson, H.; Lernmark, Å.; Rewers, M.J.; Törn, C.; Burkhardt, B.R.; Briese, T.; Hagopian, W.A.; She, J.-X.; et al. Respiratory infections are temporally associated with initiation of type 1 diabetes autoimmunity: The TEDDY study. Diabetologia 2017, 60, 1931–1940.
    23. Bosi, E.; Boulware, D.C.; Becker, D.J.; Buckner, J.H.; Geyer, S.; Gottlieb, P.A.; Henderson, C.; Kinderman, A.; Sosenko, J.M.; Steck, A.K.; et al. Impact of Age and Antibody Type on Progression From Single to Multiple Autoantibodies in Type 1 Diabetes Relatives. J. Clin. Endocrinol. Metab. 2017, 102, 2881–2886.
    24. Knip, M.; Simell, O. Environmental triggers of type 1 diabetes. Cold Spring Harb. Perspect. Med. 2012, 2, a007690.
    25. Frizinsky, S.; Haj-Yahia, S.; Machnes Maayan, D.; Lifshitz, Y.; Maoz-Segal, R.; Offengenden, I.; Kidon, M.; Agmon-Levin, N. The innate immune perspective of autoimmune and autoinflammatory conditions. Rheumatology 2019, 58, vi1–vi8.
    26. Schneider, D.A.; von Herrath, M.G. Potential viral pathogenic mechanism in human type 1 diabetes. Diabetologia 2014, 57, 2009–2018.
    27. Morgan, N.G.; Richardson, S.J. Fifty years of pancreatic islet pathology in human type 1 diabetes: Insights gained and progress made. Diabetologia 2018, 61, 2499–2506.
    28. Atkinson, M.A.; Eisenbarth, G.S.; Michels, A.W. Type 1 diabetes. Lancet 2014, 383, 69–82.
    29. Ludvigsson, J.; Routray, I.; Vigård, T.; Hanås, R.; Rathsman, B.; Carlsson, A.; Särnblad, S.; Albin, A.K.; Arvidsson, C.G.; Samuelsson, U.; et al. Combined Etanercept, GAD-alum and vitamin D treatment: An open pilot trial to preserve beta cell function in recent onset type 1 diabetes. Diabetes Metab. Res. Rev. 2021, e3440.
    30. Simmons, K.M.; Gottlieb, P.A.; Michels, A.W. Immune Intervention and Preservation of Pancreatic Beta Cell Function in Type 1 Diabetes. Curr. Diabetes Rep. 2016, 16, 97.
    31. Eisenbarth, G.S. Prevention of Type 1A Diabetes Mellitus. Endocr. Pract. 2012, 18, 745–749.
    32. Beik, P.; Ciesielska, M.; Kucza, M.; Kurczewska, A.; Kuźmińska, J.; Maćkowiak, B.; Niechciał, E. Prevention of Type 1 Diabetes: Past Experiences and Future Opportunities. J. Clin. Med. 2020, 9, 2805.
    33. Ziegler, A.G.; Rewers, M.; Simell, O.; Simell, T.; Lempainen, J.; Steck, A.; Winkler, C.; Ilonen, J.; Veijola, R.; Knip, M.; et al. Seroconversion to Multiple Islet Autoantibodies and Risk of Progression to Diabetes in Children. JAMA 2013, 309, 2473.
    34. Yi, L.; Swensen, A.C.; Qian, W.-J. Serum biomarkers for diagnosis and prediction of type 1 diabetes. Transl. Res. 2018, 201, 13–25.
    35. Thomson, G.; Valdes, A.M.; Noble, J.A.; Kockum, I.; Grote, M.N.; Najman, J.; Erlich, H.A.; Cucca, F.; Pugliese, A.; Steenkiste, A.; et al. Relative predispositional effects of HLA class II DRB1-DQB1 haplotypes and genotypes on type 1 diabetes: A meta-analysis. Tissue Antigens 2007, 70, 110–127.
    36. Verge, C.F.; Gianani, R.; Kawasaki, E.; Yu, L.; Pietropaolo, M.; Chase, H.P.; Eisenbarth, G.S.; Jackson, R.A. Prediction of Type I Diabetes in First-Degree Relatives Using a Combination of Insulin, GAD, and ICA512bdc/IA-2 Autoantibodies. Diabetes 1996, 45, 926–933.
    37. Redondo, M.J.; Geyer, S.; Steck, A.K.; Sharp, S.; Wentworth, J.M.; Weedon, M.N.; Antinozzi, P.; Sosenko, J.; Atkinson, M.; Pugliese, A.; et al. A Type 1 Diabetes Genetic Risk Score Predicts Progression of Islet Autoimmunity and Development of Type 1 Diabetes in Individuals at Risk. Diabetes Care 2018, 41, 1887–1894.
    38. Beyerlein, A.; Bonifacio, E.; Vehik, K.; Hippich, M.; Winkler, C.; Frohnert, B.I.; Steck, A.K.; Hagopian, W.A.; Krischer, J.P.; Lernmark, Å.; et al. Progression from islet autoimmunity to clinical type 1 diabetes is influenced by genetic factors: Results from the prospective TEDDY study. J. Med. Genet. 2019, 56, 602–605.
    39. Sharp, S.A.; Rich, S.S.; Wood, A.R.; Jones, S.E.; Beaumont, R.N.; Harrison, J.W.; Schneider, D.A.; Locke, J.M.; Tyrrell, J.; Weedon, M.N.; et al. Development and Standardization of an Improved Type 1 Diabetes Genetic Risk Score for Use in Newborn Screening and Incident Diagnosis. Diabetes Care 2019, 42, 200–207.
    40. Steck, A.K.; Rewers, M.J. Genetics of type 1 diabetes. Clin. Chem. 2011, 57, 176–185.
    41. VanBuecken, D.; Lord, S.; Greenbaum, C.J. Changing the Course of Disease in Type 1 Diabetes. In Endotext; Feingold, K.R., Anawalt, B., Boyce, A., Chrousos, G., de Herder, W.W., Dhatariya, K., Dungan, K., Grossman, A., Hershman, J.M., Hofland, J., et al., Eds.; MDText.com, Inc.: South Dartmouth, MA, USA, 2000.
    42. Siljander, H.; Honkanen, J.; Knip, M. Microbiome and type 1 diabetes. EBioMedicine 2019, 46, 512–521.
    43. Gamble, D.R.; Kinsley, M.L.; FitzGerald, M.G.; Bolton, R.; Taylor, K.W. Viral antibodies in diabetes mellitus. Br. Med. J. 1969, 3, 627–630.
    44. KimpimȧKi, T.; Kupila, A.; HȧMȧLȧInen, A.M.; Kukko, M.; Kulmala, P.; Savola, K.; Simell, T.; Keskinen, P.; Ilonen, J.; Simell, O.; et al. The First Signs of β-Cell Autoimmunity Appear in Infancy in Genetically Susceptible Children from the General Population: The Finnish Type 1 Diabetes Prediction and Prevention Study. J. Clin. Endocrinol. Metab. 2001, 86, 4782–4788.
    45. Richardson, S.J.; Willcox, A.; Bone, A.J.; Foulis, A.K.; Morgan, N.G. The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes. Diabetologia 2009, 52, 1143–1151.
    46. Allen, D.W.; Kim, K.W.; Rawlinson, W.D.; Craig, M.E. Maternal virus infections in pregnancy and type 1 diabetes in their offspring: Systematic review and meta-analysis of observational studies. Rev. Med. Virol. 2018, 28, e1974.
    47. Roth, R.; Lynch, K.; Hyöty, H.; Lönnrot, M.; Driscoll, K.A.; Bennett Johnson, S. The association between stressful life events and respiratory infections during the first 4 years of life: The Environmental Determinants of Diabetes in the Young study. Stress Health 2019, 35, 289–303.
    48. Rodriguez-Calvo, T. Enterovirus infection and type 1 diabetes: Unraveling the crime scene. Clin. Exp. Immunol. 2019, 195, 15–24.
    49. Lin, H.-C.; Wang, C.-H.; Tsai, F.-J.; Hwang, K.-P.; Chen, W.; Lin, C.-C.; Li, T.-C. Enterovirus infection is associated with an increased risk of childhood type 1 diabetes in Taiwan: A nationwide population-based cohort study. Diabetologia 2015, 58, 79–86.
    50. Simonen-Tikka, M.L.; Pflueger, M.; Klemola, P.; Savolainen-Kopra, C.; Smura, T.; Hummel, S.; Kaijalainen, S.; Nuutila, K.; Natri, O.; Roivainen, M.; et al. Human enterovirus infections in children at increased risk for type 1 diabetes: The Babydiet study. Diabetologia 2011, 54, 2995–3002.
    51. Dahlquist, G.; Frisk, G.; Ivarsson, S.A.; Svanberg, L.; Forsgren, M.; Diderholm, H. Indications that maternal coxsackie B virus infection during pregnancy is a risk factor for childhood-onset IDDM. Diabetologia 1995, 38, 1371–1373.
    52. Lönnrot, M.; Salminen, K.; Knip, M.; Savola, K.; Kulmala, P.; Leinikki, P.; Hyypiä, T.; Akerblom, H.K.; Hyöty, H. Enterovirus RNA in serum is a risk factor for beta-cell autoimmunity and clinical type 1 diabetes: A prospective study. Childhood Diabetes in Finland (DiMe) Study Group. J. Med. Virol. 2000, 61, 214–220.
    53. Viskari, H.R.; Roivainen, M.; Reunanen, A.; Pitkaniemi, J.; Sadeharju, K.; Koskela, P.; Hovi, T.; Leinikki, P.; Vilja, P.; Tuomilehto, J.; et al. Maternal First-Trimester Enterovirus Infection and Future Risk of Type 1 Diabetes in the Exposed Fetus. Diabetes 2002, 51, 2568–2571.
    54. Faulkner, C.L.; Luo, Y.X.; Isaacs, S.; Rawlinson, W.D.; Craig, M.E.; Kim, K.W. The virome in early life and childhood and development of islet autoimmunity and type 1 diabetes: A systematic review and meta-analysis of observational studies. Rev. Med. Virol. 2020, e2209.
    55. Glanz, J.M.; Clarke, C.L.; Xu, S.; Daley, M.F.; Shoup, J.A.; Schroeder, E.B.; Lewin, B.J.; McClure, D.L.; Kharbanda, E.; Klein, N.P.; et al. Association Between Rotavirus Vaccination and Type 1 Diabetes in Children. JAMA Pediatr. 2020, 174, 455.
    56. Honeyman, M.C.; Coulson, B.S.; Stone, N.L.; Gellert, S.A.; Goldwater, P.N.; Steele, C.E.; Couper, J.J.; Tait, B.D.; Colman, P.G.; Harrison, L.C. Association between rotavirus infection and pancreatic islet autoimmunity in children at risk of developing type 1 diabetes. Diabetes 2000, 49, 1319–1324.
    57. Honeyman, M.C.; Stone, N.L.; Falk, B.A.; Nepom, G.; Harrison, L.C. Evidence for Molecular Mimicry between Human T Cell Epitopes in Rotavirus and Pancreatic Islet Autoantigens. J. Immunol. 2010, 184, 2204–2210.
    58. Perrett, K.P.; Jachno, K.; Nolan, T.M.; Harrison, L.C. Association of Rotavirus Vaccination With the Incidence of Type 1 Diabetes in Children. JAMA Pediatr. 2019, 173, 280.
    59. Graham, K.L.; Sanders, N.; Tan, Y.; Allison, J.; Kay, T.W.; Coulson, B.S. Rotavirus infection accelerates type 1 diabetes in mice with established insulitis. J. Virol. 2008, 82, 6139–6149.
    60. Blomqvist, M.; Juhela, S.; Erkkilä, S.; Korhonen, S.; Simell, T.; Kupila, A.; Vaarala, O.; Simell, O.; Knip, M.; Ilonen, J. Rotavirus infections and development of diabetes-associated autoantibodies during the first 2 years of life. Clin. Exp. Immunol. 2002, 128, 511–515.
    61. Rogers, M.A.M.; Basu, T.; Kim, C. Lower Incidence Rate of Type 1 Diabetes after Receipt of the Rotavirus Vaccine in the United States, 2001–2017. Sci. Rep. 2019, 9, 7727.
    62. Gugliesi, F.; Pasquero, S.; Griffante, G.; Scutera, S.; Albano, C.; Pacheco, S.F.C.; Riva, G.; Dell’Oste, V.; Biolatti, M. Human Cytomegalovirus and Autoimmune Diseases: Where Are We? Viruses 2021, 13, 260.
    63. Chen, T.; Hudnall, S.D. Anatomical mapping of human herpesvirus reservoirs of infection. Mod. Pathol. 2006, 19, 726–737.
    64. Aarnisalo, J.; Veijola, R.; Vainionpää, R.; Simell, O.; Knip, M.; Ilonen, J. Cytomegalovirus infection in early infancy: Risk of induction and progression of autoimmunity associated with type 1 diabetes. Diabetologia 2008, 51, 769–772.
    65. Pak, C.; McArthur, R.; Eun, H.-M.; Yoon, J.-W. Association Of Cytomegalovirus Infection With Autoimmune Type 1 Diabetes. Lancet 1988, 332, 1–4.
    66. Hiltunen, M.; Hyöty, H.; Karjalainen, J.; Leinikki, P.; Knip, M.; Lounamaa, R.; Kerblom, H.K. Serological evaluation of the role of cytomegalovirus in the pathogenesis of IDDM: A prospective study. Diabetologia 1995, 38, 705–710.
    67. Ivarsson, S.A.; Lindberg, B.; Nilsson, K.O.; Ahlfors, K.; Svanberg, L. The prevalence of type 1 diabetes mellitus at follow-up of Swedish infants congenitally infected with cytomegalovirus. Diabet Med. 1993, 10, 521–523.
    68. Jenson, A.B.; Rosenberg, H.S.; Notkins, A.L. Pancreatic Islet-Cell Damage In Children With Fatal Viral Infections. Lancet 1980, 316, 354–358.
    69. Hyöty, H.; Räasäanen, L.; Hiltunen, M.; Lehtinen, M.; Huupponen, T.; Leinikki, P. Decreased antibody reactivity to Epstein-Barr virus capsid antigen in type 1 (insulin-dependent) diabetes mellitus. APMIS 1991, 99, 359–363.
    70. Bian, X.; Wallstrom, G.; Davis, A.; Wang, J.; Park, J.; Throop, A.; Steel, J.; Yu, X.; Wasserfall, C.; Schatz, D.; et al. Immunoproteomic Profiling of Anti-Viral Antibodies in New-Onset Type 1 Diabetes Using Protein Arrays. Diabetes 2015, 65, db150179.
    71. Nilsson, A.L.; Vaziri-Sani, F.; Broberg, P.; Elfaitouri, A.; Pipkorn, R.; Blomberg, J.; Ivarsson, S.A.; Elding Larsson, H.; Lernmark, Å. Serological evaluation of possible exposure to Ljungan virus and related parechovirus in autoimmune (type 1) diabetes in children. J. Med. Virol. 2015, 87, 1130–1140.
    72. Niklasson, B.; Heller, K.E.; Schønecker, B.; Bildsøe, M.; Daniels, T.; Hampe, C.S.; Widlund, P.; Simonson, W.T.; Schaefer, J.B.; Rutledge, E.; et al. Development of Type 1 Diabetes in Wild Bank Voles Associated With Islet Autoantibodies and the Novel Ljungan Virus. Exp. Diabesity Res. 2003, 4, 35–44.
    73. Kolehmainen, P.; Koskiniemi, M.; Oikarinen, S.; Veijola, R.; Simell, O.; Ilonen, J.; Knip, M.; Hyöty, H.; Tauriainen, S. Human parechovirus and the risk of type 1 diabetes. J. Med. Virol. 2013, 85, 1619–1623.
    74. Ruiz, P.L.D.; Tapia, G.; Bakken, I.J.; Håberg, S.E.; Hungnes, O.; Gulseth, H.L.; Stene, L.C. Pandemic influenza and subsequent risk of type 1 diabetes: A nationwide cohort study. Diabetologia 2018, 61, 1996–2004.
    75. Piccini, B.; Toni, S.; Lenzi, L.; Guasti, M.; Barm, F.; De Martino, M. Type 1 Diabetes Onset and Pandemic Influenza A (H1N1). Int. J. Immunopathol. Pharmacol. 2012, 25, 547–549.
    76. Sadeghi, K.; Salimi, V.; Rezaei, F.; Jalilian, F.A.; Ghavami, N.; Azad, T.M. Potential of H1N1 influenza A virus as an air borne pathogen to induce infectivity in pancreas: A mouse model study. J. Environ. Health Sci. Eng. 2020, 18, 303–310.
    77. Kasuga, A. Insulin-Dependent Diabetes Mellitus Associated with Parvovirus B19 Infection. Ann. Intern. Med. 1996, 125, 700.
    78. Munakata, Y.; Kodera, T.; Saito, T.; Sasaki, T. Rheumatoid arthritis, type 1 diabetes, and Graves’ disease after acute parvovirus B19 infection. Lancet 2005, 366, 780.
    79. Hyoty, H.; Leinikki, P.; Reunanen, A.; Ilonen, J.; Surcel, H.M.; Rilva, A.; Kaar, M.L.; Huupponen, T.; Hakulinen, A.; Makela, A.L.; et al. Mumps infections in the etiology of type 1 (insulin-dependent) diabetes. Diabetes Res. 1988, 9, 111–116.
    80. Ramondetti, F.; Sacco, S.; Comelli, M.; Bruno, G.; Falorni, A.; Iannilli, A.; D’Annunzio, G.; Iafusco, D.; Songini, M.; Toni, S.; et al. Type 1 diabetes and measles, mumps and rubella childhood infections within the Italian Insulin-dependent Diabetes Registry. Diabet. Med. 2012, 29, 761–766.
    81. Hyöty, H.; Hiltunen, M.; Reunanen, A.; Leinikki, P.; Vesikari, T.; Lounamaa, R.; Tuomilehto, J.; Akerblom, H.K. Decline of mumps antibodies in type 1 (insulin-dependent) diabetic children and a plateau in the rising incidence of type 1 diabetes after introduction of the mumps-measles-rubella vaccine in Finland. Childhood Diabetes in Finland Study Group. Diabetologia 1993, 36, 1303–1308.
    82. Gale, E.A.M. Congenital rubella: Citation virus or viral cause of type 1 diabetes? Diabetologia 2008, 51, 1559–1566.
    83. Ginsberg-Fellner, F.; Witt, M.E.; Yagihashi, S.; Dobersen, M.J.; Taub, F.; Fedun, B.; McEvoy, R.C.; Roman, S.H.; Davies, T.F.; Cooper, L.Z.; et al. Congenital rubella syndrome as a model for Type 1 (insulin-dependent) diabetes mellitus: Increased prevalence of islet cell surface antibodies. Diabetologia 1984, 27, 87–89.
    84. Rayfield, E.J. Effects of rubella virus infection on islet function. Curr. Top. Microbiol. Immunol. 1990, 156, 63–74.
    85. Menser, M.; Dods, L.; Harley, J.D. A Twenty-Five-Year Follow-Up Of Congenital Rubella. Lancet 1967, 290, 1347–1350.
    86. Conrad, B.; Weissmahr, R.N.; Böni, J.; Arcari, R.; Schüpbach, J.; Mach, B. A human endogenous retroviral superantigen as candidate autoimmune gene in type I diabetes. Cell 1997, 90, 303–313.
    87. Carding, S.R.; Davis, N.; Hoyles, L. Review article: The human intestinal virome in health and disease. Aliment. Pharmacol. Ther. 2017, 46, 800–815.
    88. Dechaumes, A.; Bertin, A.; Sane, F.; Levet, S.; Varghese, J.; Charvet, B.; Gmyr, V.; Kerr-Conte, J.; Pierquin, J.; Arunkumar, G.; et al. Coxsackievirus-B4 Infection Can Induce the Expression of Human Endogenous Retrovirus W in Primary Cells. Microorganisms 2020, 8, 1335.
    89. Levet, S.; Charvet, B.; Bertin, A.; Deschaumes, A.; Perron, H.; Hober, D. Human Endogenous Retroviruses and Type 1 Diabetes. Curr. Diabetes Rep. 2019, 19.
    90. Yeung, W.C.; Rawlinson, W.D.; Craig, M.E. Enterovirus infection and type 1 diabetes mellitus: Systematic review and meta-analysis of observational molecular studies. BMJ 2011, 342, d35.
    91. Blanter, M.; Sork, H.; Tuomela, S.; Flodström-Tullberg, M. Genetic and Environmental Interaction in Type 1 Diabetes: A Relationship Between Genetic Risk Alleles and Molecular Traits of Enterovirus Infection? Curr. Diabetes Rep. 2019, 19, 82.
    92. Cinek, O.; Tapia, G.; Witsø, E.; Kramna, L.; Holkova, K.; Rasmussen, T.; Stene, L.C.; Rønningen, K.S. Enterovirus RNA in Peripheral Blood May Be Associated with the Variants of rs1990760, a Common Type 1 Diabetes Associated Polymorphism in IFIH1. PLoS ONE 2012, 7, e48409.
    93. Pang, L.; Gong, X.; Liu, N.; Xie, G.; Gao, W.; Kong, G.; Li, X.; Zhang, J.; Jin, Y.; Duan, Z. A polymorphism in melanoma differentiation-associated gene 5 may be a risk factor for enterovirus 71 infection. Clin. Microbiol. Infect. 2014, 20, O711–O717.
    94. Wang, Y.; Shaked, I.; Stanford, S.M.; Zhou, W.; Curtsinger, J.M.; Mikulski, Z.; Shaheen, Z.R.; Cheng, G.; Sawatzke, K.; Campbell, A.M. The Autoimmunity-Associated Gene PTPN22 Potentiates Toll-like Receptor-Driven, Type 1 Interferon-Dependent Immunity. Immunity 2013, 39, 111–122.
    95. Crabtree, J.N.; He, W.; Guan, W.; Flage, M.; Miller, M.S.; Peterson, E.J. Autoimmune VariantPTPN22C1858T Is Associated With Impaired Responses to Influenza Vaccination. J. Infect. Dis. 2016, 214, 248–257.
    96. Craig, M.E.; Kim, K.W.; Isaacs, S.R.; Penno, M.A.; Hamilton-Williams, E.E.; Couper, J.J.; Rawlinson, W.D. Early-life factors contributing to type 1 diabetes. Diabetologia 2019, 62, 1823–1834.
    97. Penno, M.A.; Couper, J.J.; Craig, M.E.; Colman, P.G.; Rawlinson, W.D.; Cotterill, A.M.; Jones, T.W.; Harrison, L.C. Environmental determinants of islet autoimmunity (ENDIA): A pregnancy to early life cohort study in children at-risk of type 1 diabetes. BMC Pediatr. 2013, 13, 124.
    98. Ehrenfeld, E.; Domingo, E.; Roos, R.P. The Picornaviruses; ASM Press: Washington, DC, USA, 2010.
    99. Sells, C.J.; Carpenter, R.L.; Ray, C.G. Sequelae of Central-Nervous-System Enterovirus Infections. N. Engl. J. Med. 1975, 293, 1–4.
    100. Onkamo, P.; Vaananen, S.; Karvonen, M.; Tuomilehto, J. Worldwide increase in incidence of Type I diabetes—The analysis of the data on published incidence trends. Diabetologia 1999, 42, 1395–1403.
    101. Bopegamage, S.; Kovacova, J.; Vargova, A.; Motusova, J.; Petrovicova, A.; Benkovicova, M.; Gomolcak, P.; Bakkers, J.; Van Kuppeveld, F.; Melchers, W.J.G.; et al. Coxsackie B virus infection of mice: Inoculation by the oral route protects the pancreas from damage, but not from infection. J. Gen. Virol. 2005, 86, 3271–3280.
    102. Craig, M.E.; Nair, S.; Stein, H.; Rawlinson, W.D. Viruses and type 1 diabetes: A new look at an old story. Pediatr. Diabetes 2013, 14, 149–158.
    103. Oberste, M.S.; Maher, K.; Kilpatrick, D.R.; Pallansch, M.A. Molecular evolution of the human enteroviruses: Correlation of serotype with VP1 sequence and application to picornavirus classification. J. Virol. 1999, 73, 1941–1948.
    104. Palmenberg, A.C.; Gern, J.E. Classification and evolution of human rhinoviruses. Methods Mol. Biol. 2015, 1221, 1–10.
    105. Hober, D.; Sauter, P. Pathogenesis of type 1 diabetes mellitus: Interplay between enterovirus and host. Nat. Rev. Endocrinol. 2010, 6, 279–289.
    106. Solomon, T.; Lewthwaite, P.; Perera, D.; Cardosa, M.J.; McMinn, P.; Ooi, M.H. Virology, epidemiology, pathogenesis, and control of enterovirus 71. Lancet Infect. Dis. 2010, 10, 778–790.
    107. Petzold, A.; Solimena, M.; Knoch, K.-P. Mechanisms of Beta Cell Dysfunction Associated With Viral Infection. Curr. Diabetes Rep. 2015, 15, 73.
    108. Zhou, F.; Wang, Q.; Sintchenko, V.; Gilbert, G.L.; O’Sullivan, M.V.; Iredell, J.R.; Dwyer, D.E. Use of the 5’ untranslated region and VP1 region to examine the molecular diversity in enterovirus B species. J. Med. Microbiol 2014, 63, 1339–1355.
    109. Muir, P.; Kammerer, U.; Korn, K.; Mulders, M.N.; Poyry, T.; Weissbrich, B.; Kandolf, R.; Cleator, G.M.; van Loon, A.M. Molecular typing of enteroviruses: Current status and future requirements. The European Union Concerted Action on Virus Meningitis and Encephalitis. Clin. Microbiol. Rev. 1998, 11, 202–227.
    110. Craig, M.E.; Robertson, P.; Howard, N.J.; Silink, M.; Rawlinson, W.D. Diagnosis of enterovirus infection by genus-specific PCR and enzyme-linked immunosorbent assays. J. Clin. Microbiol. 2003, 41, 841–844.
    111. Ylipaasto, P.; Klingel, K.; Lindberg, A.M.; Otonkoski, T.; Kandolf, R.; Hovi, T.; Roivainen, M. Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells. Diabetologia 2004, 47, 225–239.
    112. Ifie, E.; Russell, M.A.; Dhayal, S.; Leete, P.; Sebastiani, G.; Nigi, L.; Dotta, F.; Marjomäki, V.; Eizirik, D.L.; Morgan, N.G.; et al. Unexpected subcellular distribution of a specific isoform of the Coxsackie and adenovirus receptor, CAR-SIV, in human pancreatic beta cells. Diabetologia 2018, 61, 2344–2355.
    113. Hodik, M.; Skog, O.; Lukinius, A.; Isaza-Correa, J.M.; Kuipers, J.; Giepmans, B.N.G.; Frisk, G. Enterovirus infection of human islets of Langerhans affects β-cell function resulting in disintegrated islets, decreased glucose stimulated insulin secretion and loss of Golgi structure. BMJ Open Diabetes Res. Care 2016, 4, e000179.
    114. Richardson, S.J.; Morgan, N.G. Enteroviral infections in the pathogenesis of type 1 diabetes: New insights for therapeutic intervention. Curr. Opin. Pharm. 2018, 43, 11–19.
    More