review article type i diabetes mellitus: genetic factors...

Review ArticleType I Diabetes Mellitus Genetic Factors and PresumptiveEnteroviral Etiology or Protection

Jana Precechtelova Maria Borsanyiova Sona Sarmirova and Shubhada Bopegamage

Enterovirus Laboratory Faculty of Medicine Slovak Medical University Limbova 12 83303 Bratislava Slovakia

Correspondence should be addressed to Shubhada Bopegamage shubhadabopegamageszusk

Received 6 May 2014 Revised 14 July 2014 Accepted 9 November 2014 Published 10 December 2014

Academic Editor Alexander Rodriguez-Palacios

Copyright copy 2014 Jana Precechtelova et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

We review type 1 diabetes and host genetic components as well as epigenetics and viruses associated with type 1 diabetes withadded emphasis on the enteroviruses which are often associated with triggering the disease Genus Enterovirus is classified intotwelve species of which seven (Enterovirus A Enterovirus B Enterovirus C and Enterovirus D and Rhinovirus A RhinovirusB and Rhinovirus C) are human pathogens These viruses are transmitted mainly by the fecal-oral route they may alsospread via the nasopharyngeal route Enterovirus infections are highly prevalent but these infections are usually subclinicalor cause a mild flu-like illness However infections caused by enteroviruses can sometimes be serious with manifestations ofmeningoencephalitis paralysis myocarditis and in neonates a fulminant sepsis-like syndrome These viruses are often implicatedin chronic (inflammatory) diseases as chronic myocarditis chronic pancreatitis and type 1 diabetes In this review we discuss thecurrently suggested mechanisms involved in the viral induction of type 1 diabetes We recapitulate current basic knowledge anddefinitions

1 History of Diabetes

Symptoms of type 1 diabetes (T1D) have been recognizedsince approximately 1500 BC when they were described onEgyptian papyrus as indicators of a rare disease that causedpatients to lose weight rapidly and experience ldquotoo greatemptying of the urinerdquo [1 2] This was probably the firstmention of the disease At approximately the same timehowever Indian physicians realized that the urine of somepatients attracted ants These doctors classified the diseaseand named it ldquomadhumehardquo or ldquohoney urinerdquo [3] Later thedisease was called ldquodiabetesrdquo by Greek physician Aretaeuswho noted symptoms such as constant thirst excessiveurination and loss of weight ldquoDiabetesrdquo comes from theGreek word for ldquosiphonrdquo (to draw off or convey liquid) TheArabian physician Avicenna (980ndash1037) was the first to bringattention to the complexity and progression of the diseaserecognizing primary and secondary diabetes In the 17thcentury the Latin term ldquomellitusrdquo meaning ldquohoneyedrdquo orldquosweetrdquo was added byThomasWillis an English physician inhis treatise Pharmaceutice Rationalis (1674) He tested urine

samples of patients to determine the presence of diabetesthose samples with a sweet taste indicated diabetesmellitus orldquohoneyedrdquo diabetes In 1776 Matthew Dobson measured thequantity of glucose in the urine samples of diabetic patientsDr Frederick Allen a diabetes specialist in the early 20thcentury advised low calorie diets for his diabetic patientsThese diets increased the life of his patients but they oftenbecame weak and starved [4]

A critical experiment occurred in 1921 when FrederickBanting and his assistant Charles Best kept a dog withdiabetes alive for 70 days by injecting it with a turbid mixtureof an extract from a canine pancreas Dr Collip and DrMacleod then helped Banting and Best to administer amore refined extract of insulin to Leonard Thompson a boysuffering from diabetes They noted that within 24 hourshis high blood sugar had dropped to nearly normal levelsBanting and Best received the Nobel Prize in Physiology orMedicine in 1923 for their discovery of insulin Since thattime scientific interest in this disease and associated glucosemetabolism has increased Ten scientists have received NobelPrizes for diabetes-related investigations [5] Sir Harold

Hindawi Publishing CorporationJournal of PathogensVolume 2014 Article ID 738512 21 pageshttpdxdoiorg1011552014738512

2 Journal of Pathogens

Himsworth reported the existence of two types of diabetesin 1935 ldquoinsulin sensitiverdquo (type I) and ldquoinsulin insensitiverdquo(type II) His work [6] was an important landmark in theunderstanding of diabetes and treatment strategies

2 Types of Diabetes Mellitus

Diabetes mellitus (DM) is classified as a group of metabolicdiseases with a typical clinical state of hyperglycemia (highblood glucose levels) which is an outcome of defectiveinsulin secretion insulin action or both [7] Hyperglycemiais correlated with typical acute diabetic symptoms thatinclude excessive urine production (polyuria) and high urinesugar levels (glycosuria) the consequences of which arethirst increased fluid intake (polydipsia) increased eating(polyphagia) weakness fatigue blurred vision unexplainedweight loss and lethargy Chronic hyperglycemia is furtherrelated to prolonged damage dysfunction and failure ofdifferent organs Secondary complications due to fluctuationsin blood glucose arise from vascular degeneration whichresults in damage of eyes kidneys nerves blood vesselsand heart causing dysfunction and failure of the organs oreventual gangrene with a probable loss of toes feet andlegs These complications decrease the quality of life and caneventually lead to premature death Table 1 shows the recentclassification of diabetes according to the American DiabetesAssociation and World Health Organization which includesfour clinical categories of diabetes [7ndash9] In this review wefocus on type 1 diabetes because it is the most commonendocrine disorder in children with a worldwide increase inincidence

Type 1 diabetes usually develops before the age of 30 withpeaks at 2 4ndash6 and 10ndash14 years of age Type 1 diabetes patientsdepend on external insulin (usually injected subcutaneously)for survival Approximately 5ndash10 of diabetics with type1 diabetes (T1D) show gradual destruction of the insulinproducing 120573-cells in the pancreas This destruction leads toabsolute insulin deficiencyThe disease usually appears when80ndash90 of the 120573-cells are destroyed [10 11]

Autoimmune-mediated destruction of 120573-cells has beenassociated with T1D because 85ndash90 of the cases showone or more autoantibodies [12] Some of the autoanti-gens described by different authors include enzyme glu-tamic acid decarboxylase (GAD65) [13] insulin (IAA) [14]insulinoma associated antigens (identified as tyrosine phos-phatases IA-2 and IA2120573) [15 16] islet cell antigens (ICA-69) [17] enzyme carboxypeptidase-H [18] GM-gangliosides[19] 38 kD autoantigen [20] sex determining region-Y boxprotein (SOX13) [21] and zinc transporter 8 protein (ZnT8A)also known as the solute carrier family 30 member 8(SLC30A8) [22] The presence of two or more antibodieshas been suggested as predictive markers for T1D [23 24]In the present times commercial kits are available and somelaboratories have developed in-house methods for detectionof some of these antibodies The predictive value of thesemarkers would be of importance for intervention measuresHowever it is difficult to identify the right time to measurethese antibodies Another unclear aspect is whether these

antibodies are produced after the cell destruction or ifantibodies induce the cellular destruction

Treatment of T1D usually consists of insulin admin-istration via injections or pumps Insulin therapy resultsin improvements yet T1D is considered to be a chronicdisease for which there is no prevention or cure The diseaseprogresses in the majority of diabetic patients and the result-ing dysglycemia leads to microangiopathic or neuropathiccomplications

3 Type 1 Diabetes Major HistocompatibilityComplex Related Genetic Factors

Type 1 diabetes is amultifactorial disorder requiring a geneticpredisposition and a trigger for the destructive process asobserved in other autoimmune diseases [25 26] T1D has astrong genetic component Relatives of diabetic patients havea high risk of developing the disease siblings have a greaterrisk than offspring and there is a high concordance rateamong identical twins [27 28] This genetic predisposition(or lack thereof) is determined by the balance betweensusceptibility and resistance alleles Among various factorsthe major histocompatibility complex (MHC) glycoproteinsare very important in the recognition of the tissues by theimmune system

Genetic wide association studies (GWAS) help to identifyand measure the DNA variations in the human genomeand identify disease risk factors in a given populationThis is done by measuring single nucleotide polymorphism(SNP) changes occurring frequently as single base pairchanges in the DNA sequences [29 30] These variationsare identified by genotyping using the next-generationsequencing and chip based microarray [31] Epigenome wideassociation studies (EWAS) using this modern technologyhave shown that besides the HLA-A HLA-B and HLA-DP1205731 other strong markers include HLA-DR1205731 HLA-DQ1205721 and HLA-DQ1205731 The HLA-DR1205731lowast0301 haplotypescarrying HLA-DR1205733lowast0202 alleles showed a higher riskthan HLA-DR1205731lowast0301 haplotypes carrying DR1205733lowast0101 inDR1205731lowast0301lowast0301 homozygotes with twoDR1205733lowast0101 alleles[31ndash35]

The human leukocyte antigen (HLA) region of the 6p21chromosome encodes glycoprotein of the MHC which hasa function in presenting antigenic peptides to T-cells MHCis a cluster of genes that are situated on the short armof chromosome 6 and vary in length depending on theirhaplotypes The MHC locus first discovered by Snell andHiggins [36] comprises 121 functional genes which includeall of the MHC class I and MHC class II genes MHCI molecules constitutively expressed in most cells presentantigens for binding to CD8+ T-cells and display peptidesfrom proteins synthesized within the cell On the otherhand MHC II molecules constitutively expressed in antigen-presenting cells (APCs) such asmacrophages dendritic cellsand B-cells are important to the human immune responsebecause they present peptide antigens to T-helper (CD4+)cells revealing peptides from engulfed proteins present inthymic stromal cells or antigen-presenting cells [37ndash39]

Journal of Pathogens 3

Table 1 Current and former classifications of diabetes mellitus

Former classification(based on treatment) Current classification Causelowast

Insulin-dependent diabetesmellitus (IDDM) Type 1 diabetes (T1D) 120573-cell destruction that leads to total insulin deficiency

Non-insulin-dependent diabetesmellitus (NIDDM) Type 2 diabetes (T2D) A progressive defect in insulin secretion in combination

with insulin resistance

HeterogenicOther types of diabetes maturity-onsetdiabetes of the young (MODY) neonataldiabetes mellitus (NDM) geneticsyndrome associated with diabetes

Genetic defects in function of the 120573-cells Other factorsinclude pathophysiology of the pancreas (cystic fibrosisor pancreatitis) and drug- or chemical-induced diabetesin patientsSyndromes Down syndrome Huntingtonrsquos choreaPrader-Willi syndrome diabetes insipidusRabson-Mendenhall syndrome and immune-mediateddisorders such as systemic lupus erythematosus

Heterogenic Gestational diabetes (GD) diagnosedduring pregnancy

Related to hormonal changes low insulin levelsnutritional and genetic factors

lowastCauses or current definitions as per [7ndash9]

MHC II molecules are also inducible in some tissues bycytokines such as interferon gamma (IFN-120574) [40]

In humansMHC Imolecules comprise theHLA-A HLA-B and HLA-C while MHC II molecules include HLA-DPDQ and DR which have the strongest association with T1Das summarized in Figure 1 and Table 2 Two types of MHC IIgenes encode alpha polypeptides and beta polypeptides andtogether form the functional class II alpha-beta heterodimerThey form major DP120572 DP120573 DQ120572 DQ120573 DR120572 and DR120573plus minor DM and DO genes that encode MHC II proteinson the APCs Both the alpha and beta polypeptide genes arepolymorphic [37ndash43] These proteins are important becauseof their role in triggering of autoimmune and inflammatoryresponses

Autoimmune diseases such as systemic lupus erythe-matosus and psoriasis have been linked to MHC III andMHC IV loci [43 44] but so far association of these lociwith the T1D has not been investigated and remains a novelarea for research MHC III region is highly conserved butis more heterogeneous than MHC I and MHC II regionsThe MHC III genes are located between the MHC I andMHC II on the short arm of chromosome 6 [43] Figure 1and Table 2 summarize the location of these loci The humanMHC III region contains 61 genes which encode the MHCclass III moleculesThese are proteins which are componentsof the immune and complement system such as C2 C4and B factor Lastly MHC IV genes are involved in theproduction of several factors tumor necrosis factor alpha(TNF-120572) lymphotoxin alpha (LTA) and lymphotoxin beta(LTB) B144LST protein expressed in dendritic cells andinvolved in theirmorphogenesis 1C7 expressed in the naturalkiller (NK) cells and responsible for their activation theG1 and allograft inflammatory factor 1 (AIF1) which areinflammatorymarkers superkiller 12W (SK12W) that confersantiviral activity B associated transcript (BAT1) encodinga protein with helicase motifs heat shock proteins (HSP)related to proinflammatory cytokines and protection againstcellular inflammationapoptosis and MIC A and MIC B

genes coding for theMIC A andMIC B proteins which play arole in activation of natural killer cells [44]TheMHC III andMHC IVgenes are involved in the antigen processing (but notpresenting) and production of proinflammatory cytokines

The influence of a particular HLA molecule on suscepti-bility to any disease depends on its three-dimensional struc-ture [45 51 52] The diabetogenic and protective moleculesdiffer in structure The differences result in varied antigenpeptide selectivity binding affinity and the stability of theHLA molecule presented on the cell surface The HLAmolecules react with distinct peptide binding motifs andinteract differently with a given diabetogenic autoantigenThe disease susceptibility conferred by HLA represents thecombined effect of several genes within the MHC At leastthree major loci are involved (HLA-DR1205731 HLA-DQ1205721 andHLA-DQ1205731) but several other genes may also contribute[46 53]

Susceptibility to T1D is most strongly determined byDQ1205731 and I-A120573 equivalent chain allele for MHC in micethat encode serine alanine or valine at position 57 onboth chromosomes In contrast DQ120573 and I-A120573 in mice atposition 57 aspartic acid positive alleles mediate resistanceto T1D To some extent resistance is also mediated by DR1205731and I-E120573 in mice expressing aspartic acid at position 57 orglutamine at position 74 [47] It has been suggested thatHLA-DQ and HLA-DR polymorphism affects the susceptibility toT1D through the selectively affecting nature of the peptidespresented to T-cells [48] One copy (allele) of the DR3 orDR4is found commonly in the general population Individualssusceptible to T1D inherit two alleles DR3DR3 DR4DR4or the high risk DR3DR4 combination [49 50] (Table 2)Heterogeneity in these alleles may increase or decrease thedisease risk

4 Epigenetics

Epigenetics is a study of heritable changes which are not aconsequence ofmutations in theDNAbut occur as alterations


MHC class II MHC III and MHC IV

loci MHC class I

Complement-proteins C4A and C4BB factor

LTAB144LST1C7SK12WHSPMICAMICB

DP1205731DQ1205721DQ1205731DR1205731DR1205733 TNF-120572

Figure 1 Major histocompatibility complex loci associated with type 1 diabetes The known loci and products participating in the triggeringof type 1 diabetes are marked in blue and italics

Table 2 The major histocompatibility complex and the human leukocyte antigenslowast

HLA loci Combinations mostassociated with T1D Cell type Functions

MHC IA A24 Mainly cytotoxic CD8+

T-cells also other types ofnucleated cells

Peptide binding proteinfor antigen presentationB B8 B18 B39

C Processing of antigens

MHC II

DP DP-alpha DP1205721

Helper CD4+antigen-presenting cells(dendritic cellsmacrophages someendothelial cells thymicepithelial cells and B-cells)

Peptide binding proteinDP-beta DP1205731 DP1205731

DQ DQ-alpha DQ1205721DQ-beta DQ1205731

DR

DR-alpha

Helper activity for specificMHC II proteinsDR-beta

DR1205731 DR1205731 DQ1205731 DR-DQcombinationsDR1205731-DQ1205721-DQ1205731subset combinations

DR1205732DR1205733DR1205734

MHC III Are flanked by the MHC I and MHC IIcoding regions

Novel area forresearch Various

Components of thecomplement systems C2C4a and C4bCytokinesHeat shock proteins

MHC IV Exist at the telomeric end of MHC IIIgenes

Novel area forresearch

Dendritic cells naturalkiller cells

Morphogenesis ofdendritic cells naturalkiller cells

lowastReferences [9 29ndash36 41ndash50]

at the transcriptional level Increasing knowledge of theimmune mechanisms that have the largest impact on thedisease modern molecular technology and recent develop-ments in the understanding of meta-analysis and epigeneticsshow that the T1D risk is a combination of reactions or adialogue among four major factors (1) primary T1D-relatedgenetic susceptibility genes (2) triggering immunologicalfactors that may vary and act as stimuli (3) other factorssuch as epigenetic heterogeneity caused by environmentalfactors and (4) interactions with genes related to other(immunological and apoptotic) pathways expressed locally inpancreatic 120573-cells Each of these factors has been reviewedelsewhere in recent years [35]

In addition to inherited alleles other mechanisms reg-ulating gene expression include ldquoparent-of-origin effectsrdquo(marker from either the maternal or paternal allele) whichcan modify the inheritance andor transcription of suscep-tibility genes [54] The ldquoparent-of-origin effectsrdquo show thedifferential behavior of the genes depending on the parentfromwhom theywere inherited and relating them to differentdiseases [55]The influence of the susceptibility to T1D in theoffspring is stronger and more frequent to the father thanthe mother ranging from 6 to 9 [56ndash58] The ldquoparent-of-originrdquo susceptibility transmission also varies for differentantibodies with greater prevalence in children from diabeticfathers than mothers [59] Alteration of DLK1-MEG3 gene


region on chromosome 14q322 in the father appears toinfluence the susceptibility to T1D [60]

GWAS identified epigenetic modifications which arechanges in gene expression and gene function withoutchanges in the gene sequenceThe three mechanisms definedinclude (1) the methylation of cytosine residues in DNA atposition 5 (moving clockwise from NH

2 which is counted

as position 0) of the 6-atom ring of cytosine associated withtranscriptional repression or posttranslational modification(2) N-terminal histones that may be affected by posttrans-lational modifications through acetylation methylation orphosphorylation and (3) demethylation of miRNA Rakyanet al [61] analyzed DNA methylation variable positions(MVPs) for T1D on monocytes of monozygotic twins discor-dant for T1D The MVPs were sought in these monozygotictwins in order to rule out typical genetic factors The authors[61] showed that the methylations were not an effect of thedisease but occurred prior to the disease

5 Non-MHC Complex Genes Related to T1D

Since the first association ofMHCandT1D [26 62] a numberof other non-MHC-related genes and immune mediatorshave been associatedwith T1D Such genes include the insulingene cytotoxic T-lymphocyte antigen 4 gene (CTLA4) [2663 64] protein tyrosine phosphatase N22 gene (PTPN22)[65] IL-2 receptor alpha (IL-2RA) [66] and interferoninduced with helicase C domain 1 (IFIH1) gene [29] GWASstudies and the non-MHC genes related to T1D have beendiscussed and compared by Bakay et al [67]

Nejentsev et al [68] identified four variations in theinterferon induced with helicase C domain 1 (IFIH1) genewhich might be associated with reduced risk of developingT1D The helicase enzyme IFIH1 (also known as MDA5 ormelanoma differentiation-associated protein-5) triggers thesecretion of interferons in response to viral infection Theinterferon-regulating factor 7- (IRF7-) driven inflammatorynetwork (IDIN) genes also contribute to the risk of T1D [69]

Different non-MHC candidate gene products relatedto T1D involving the cytokine pathways are IL-12B 21015840-51015840-oligoadenylate synthetase 1 (OAS1) small ubiquitin-likemodifier 4 (SUM04) paired box gene 4 (PAX4) protein tyro-sine phosphatase N2 gene (PTPN2) regulatory and proin-flammatory T-cells macrophage-related cytokines includinginterferon gamma (IFN-120574) tumor necrosis factor alpha(TNF-120572) interleukin-4 and interleukin-10 (IL-4 and IL-10)and C-type lectin domain family 16 (CLEC16A) [29 69ndash81] Table 3 shows the overview of the non-MHC genes andgene products associated with T1D and the chromosomeson which they are located Although the functions of eachof these products are well known in the regulation of theimmune system (Table 3) their exact role inducing T1Dremains unclear

The multigenic nature of T1D has been recognizedthrough meta-analysis studies [73 82] and genetic epidemi-ology [83 84] To date several MHC and immune-relatedgenes associated with antigen presentation and inflammatoryregulation appear to serve as risk factors for T1D

6 Genetic Mechanisms for T1D Predispositionor Protection

The interaction between cellular immune and genetic fac-tors determines if a particular (experimental) system isprone to protection or predisposition to T1D Studies onthe involvement of B-cells in the induction of diabetes arelimited B-cells are common in inflamed insulin producingpancreatic islets [85ndash87] Single nucleotide polymorphismanalysis indicates the following variants are associated withT1D and B-cell receptor (BCR) and B-cell differentiationPTPN22 PTPN2 Src homology 2B3 adapter gene (SH2B3)and immunoregulatory cytokines IL-10 IL-19 and IL-20 [8889] Peripheral B-cell proliferation was shown to be relatedto the cytokine IL-10 and the ldquoIL2-IL21 T1Drdquo locus wasassociated with IL-10 production by the memory B-cells andthe autoreactive T-cells [89] B-cell subsets that might belinked to autoimmune diseases and related views have beendiscussed by Yang et al [90] The regulatory B-cells (B-reg) influence the responses of regulatory T-cells effectorcells and invariant natural killer T-cells (iNKT) and activatethe dendritic cells through cytokines These cytokines aremainly the IL-10 and tumor growth factors (TGF) togetherinfluencing T1D Research related to B-cell subtypes and T1Dis increasingly accumulating

Normally islet 120573-cells express low levels of IFNs butviral infections may result in high levels of IFN produc-tion which further increase MHC I expression leading tohigh susceptibility to cytotoxic CD8+ T-cell recognition anddestruction [91] Therefore normal IFIH1 gene-mediatedimmune responses activated by some viruses may stimulateautoimmunity against pancreatic120573-cellsHowevermutationsin IFIH1 gene disrupt this mechanism inducing protectionagainst T1D by production of protein product MDA5 with animpaired function [68 92]

Interferons can be identified as type I (IFN-120572 and IFN-120573)type II (IFN-120574) and type III (IFN-120582) Among type 1 interfer-ons the best studied ones are interferons alpha (IFN-120572) andbeta (IFN-120573) These interferons are induced via stimulationof different transmembrane and cytosolic receptors Themain receptors responsible for type I interferon induction inresponse to infections and double stranded RNAs (dsRNAs)are the RNA helicases retinoic acid inducible gene 1 (RIG-1) and melanoma differentiation-associated gene 5 (MDA-5) Type 1 interferons are produced by most cell typesincluding plasmacytoid dendritic cells [93] IFN-120572 usuallylimits viral replication but on the other hand together withinflammatory cytokines IL-1120573 and TNF-120572 these interleukinscan cause direct cellular damage [94]120573-cells of the pancreaticislets express IFN-120572 [95] Sera of T1D patients have increasedtiters of IFN-120572 [96] Of epidemiological relevance IFN-120572 inthe plasma of patients with detectable enteroviral-RNA [97]has been found to be in high concentrations

Type II interferons (IFN-120574) are produced by different cellstypes They enhance the MHC class I and class II expressionvia the protein tyrosine kinase of the Janus family (Jak 1 andJak 2) leading to phosphorylation of the tyrosine in STAT1[98 99] Interferon gamma (IFN-120574) interacts with IFN-120572In autoimmune diseases type I interferons induced by the


Table 3 Nonmajor histocompatibility complex genes and gene products associated with type 1 diabetes by genome wide association studies

Chromosomelowastnumber Genelowast Function of the gene product

Chromosome 1 Protein tyrosine phosphatase nonreceptor 22 gene(PTPN22) Plays a role in T-cell receptor signaling

Chromosome 1 Interleukin-10 (IL-10)Downregulates expression of MHC II antigensandTh1 cytokines and is involved in cellmediated and cytotoxic inflammatory response

Chromosome 2 Including cytotoxic T-lymphocyte antigen 4(CTLA4)

Expressed by CD4+ and CD8+ T-cells anddownregulates T-cell proliferation andcytokine production

Chromosome 2 Interferon induced with helicase C domain 1(IFIH1MDA-5)

Triggers the secretion of interferons inresponse to viral infections

Chromosome 5 Interleukin-4 (IL-4)Induces differentiation of naive T-cells toT-helper cells but suppresses interferon-120574 andIL-2 producingTh1 cells

Chromosome 5 Interleukin-12 beta also known as interleukin-12p40(IL-12B)

Produced by antigen-presenting cells anddrives the differentiation of CD4+ T-cells intoTh1 cells

Chromosome 6 Small ubiquitin-like modifier 4 (SUM04) Polymorphism in this gene leads to activationof nuclear factor kappa B

Chromosome 6 Tumor necrosis factor alpha (TNF-120572) Stimulates inflammatory reactions andphagocytosis

Chromosome 7 Paired box gene 4 (PAX4) Plays a role in tissue development and is foundon pancreatic islet cells

Chromosome 10 IL-2 receptor-alpha (IL-2RA) Its expression on T-cells is necessary forsuppressing T-cell response

Chromosome 11 Insulin (INS) Controls glucose levels in the blood

Chromosome 12 21015840-51015840-Oligoadenylate synthetase 1 (OAS1)Enzyme involved in the innate immuneresponse induced by interferons against viralinfections

Chromosome 12 Interferon gamma (IFN-120574)Cytokine involved in the inflammatoryresponses produced by different natural killercells CD4+ and CD8+ T-cells

Chromosome 13 Interferon-regulating factor 7- (IRF7-) driveninflammatory network (IDIN)

Present in monocytes and regulated by viralresponses

Chromosome 16 C-type lectin domain family 16 (CLEC16A) Expressed in most of the immune cells andplays a role in the antigen uptake

Chromosome 18 Tyrosine protein phosphate nonreceptor 2 gene(PTPN2) Regulates proinflammatory cytokines

lowastReferences [25ndash27 29 63ndash81]

plasmacytoid dendritic cells may upregulate or downregulatethe IFN-120574 which in turn affects the MHC expression andapoptosis [100] Whereas type III interferons also knownas interferon lambda (IFN-120582) are restricted only to few celltypes they may affect the viral replication and reduce viralinduced damage to tissues This was observed in primaryhuman pancreatic islet cells recently [101] leading to theirprotection from coxsackievirus infection The IFN-120582 and itsassociation with T1D could be a new area for investigation

The relevance of genetic factors modulating the expres-sion and function of various types of interferons and otherimmune-related cytokines is related to their critical impor-tance in controlling infections Among the various possibleinfections agents viruses have been the most studied and

consistently associated with the mechanisms and predispo-sition to T1D A growing body of literature on in vitro and invivo experiments indicates that viruses may drive unspecificinflammatory or immune responses against pancreatic cellscritical in blood glucose homeostasis

7 Viruses and Predisposition toType 1 Diabetes

Viruses with their potential to induce innate and adap-tive immune responses and local inflammation in targetorgans are suspected of initiating autoimmune processesThe etiologic link between T1D and viruses is based on


epidemiological serological and histological findings as wellas experimental in vivo and in vitro studiesThese include theDNA viruses from families Herpesviridae and Parvoviridaeand RNA viruses of families Togaviridae ParamyxoviridaeRetroviridae and Picornaviridae (Tables 4 and 5) The viralgenetics host genetics host immunological status age atthe time of exposure to the virus and the pancreaticmicroenvironment may influence triggering of T1D relatedto 120573-cell damage A systematic review and meta-analysisof observational molecular studies in 2011 showed a strongassociation between T1D and enteroviruses [82] Tables 4 and5 show the different viruses and themechanisms of inductionof T1D Also the proposed mechanisms related to the virus-induced impact on the pancreatic beta cells have been studiedusing animalin vitromodels and enteroviruses

71 Human Cytomegalovirus In 1979 the human cytomega-lovirus (HCMV) also known as human herpes virus-5(HHV-5) was first linked to T1D [124] onset following a con-genital infection by this virusThese findings were confirmedby detection of cytomegalovirus genome in 22 of diabeticpatients correlating with the presence of islet cell antibodies(ICA) [102] The same group showed cross-reactivity of anti-cytomegalovirus antibodies with 38 kD human pancreaticislet-specific protein [125] The virus infected human fetalislets in vitro yet direct destruction of 120573-cells was absent[126] The different mechanisms suggested for the role ofhuman cytomegalovirus in diabetogenesis maybe related to(1) molecular mimicry induced by T-cell cross-reactivitybetween human cytomegalovirus and GAD65 (glutamic aciddecarboxylase exists as two isoforms GAD65 and GAD67a major enzyme required for the production of the gammaamino butyric acid which regulates the glucagon secretion)in pancreatic islet 120573-cells [102 103] (2) the persistence ofHCMV specific CD4+ T-cells or a bystander activity [104]and (3) persistent infection in 120573-cells [127] However othergroups [128 129] failed to find a link between the virus andT1D no human cytomegalovirus DNA was found in theformalin-fixed pancreases of patients with T1D [130 131]Thecontribution of human cytomegalovirus to the diabetogenicprocess is not clear yet and controversial more clinical andmodel studies related to this virus and T1D are required

72 Parvovirus Parvovirus B19 belongs to family Parvoviri-dae genus Erythroparvovirus The virus may affect individu-als of any age but the infections are common in children agedsix to ten Typical syndromes are headache nausea diarrheaand fever with red rash and chronic anemia in HIV patientsElevated serum anti-parvovirus B19 IgM and antibodies tothe autoantigen IA-2 have been described with a homologyin amino acid sequences between B19 and the extracellulardomain of IA-2 [105] The autoantigen IA-2 (islet cell antigen512) is amember of the protein tyrosine phosphatase secretedby the pancreatic endocrine cells and a regulator of insulinsynthesis A link between acute parvovirus B19 infection andT1D has been shown [132] Parvovirus B19 can stimulate T-cell-mediated proliferative response It activates autoimmu-nity by presentation of HLA class II antigen to CD4+ T-cells

[106 133] Studies on the Kilham rat virus (KRV) belongingto the same genus have suggested molecular mimicry [134]and initiation of innate immunity in the pancreatic lymphnodes [135] In vivo in vitro and epidemiological evidenceare required to define further the role of these viruses in T1Dinduction

73 Rotavirus Species Rotavirus A is the most commoncause of childhood gastroenteritis and is suspected of trig-gering T1D Association between rotavirus and T1D wasshown by Honeyman et al [136] who demonstrated spe-cific seroconversion and increase in autoantibodies in T1Dpatients In the experimental model rotavirus infectioncaused inflammation of the insulin producing cells andinduction of diabetes which was attributed to 120573-cell autoim-munity [137] The authors suggested a possible mechanismwhich involves increased exposure of 120573-cells to immunerecognition and activation of autoreactive T-cells by proin-flammatory cytokines Rotavirus could induce or affect theislet autoimmunity by molecular mimicry because rotaviruscontains peptide sequences in VP7 (viral protein 7) highlysimilar to T-cell epitopes in the islet autoantigens glutamicacid decarboxylase-65 and tyrosine phosphatase IA-2 [107]The published literature is insufficient tomake any conclusiveremarks with respect to the inductive role which rotaviruseshave on T1D [138]

74 Rubella Virus Infection by rubella virus during preg-nancy has been related to increased risk of diabetes inthe offspring suffering from congenital rubella syndromeCongenital rubella was associated with induction of isletautoantibodies in 10 to 20 of congenital rubella cases withpatients 5 to 25 years of age [108 139] Children who haverubella antibodies present before measles-mumps-rubellavaccination have been shown to have higher levels of isletcell autoantibodies than do seronegative children [140 141]Molecular mimicry has been suggested as the mechanism forthe association of rubella virus with T1D induction where thecross-reaction between glutamic acid decarboxylase and vari-ous rubella peptides byT-cells is involved [109] Experimentalin vitro studies and in vivo hamster models suggest direct120573-cell infection and cytolysis Rubella may fit the classicalpicture of viruses involved in the triggering of T1D Howeverthe reduced rubella infections after the introduction of themeasles-mumps-rubella vaccination and the increase in T1Dcases (an inverse relationship) in the world seem to becontradictory The measles-mumps-rubella vaccination andautoantibody induction hypotheses are more likely to berelated to T1D than are direct infection and cytolysis Morefactors likely play a role in the onset but more studies arerequired in this regard

75 Mumps Virus Mumps virus has demonstrated the abilityto infect 120573-cells leading to a decrease in insulin secretionin the human fetal cultured islet The infection is associatedwith an increase of the HLA class I molecule expressionwhich could influence the autoimmune process in prediabeticindividuals by increasing the activity of autoreactive cytotoxic


Table 4 An overview of the viruses associated with T1D and their classification

Viruses Species Genus Family GenomeHuman cytomegalovirus Human cytomegalovirus Cytomegalovirus Herpesviridae dsDNAParvovirus B19 Primate erythroparvovirus 1 Erythroparvovirus Parvoviridae ssDNAKilham rat virus Rodent protoparvovirus 1 Protoparvovirus Parvoviridae ssDNARotavirus Rotavirus A Rotavirus Reoviridae dsRNARubella virus Rubella virus Rubivirus Togaviridae Positive ssRNAMumps virus Mumps virus Rubulavirus Paramyxoviridae Negative ssRNAHuman endogenous retrovirus Retroviridae ssRNAEncephalomyocarditis virus-K Encephalomyocarditis virus Cardiovirus Picornaviridae Positive ssRNAParechovirus Human parechovirus Parechovirus Picornaviridae Positive ssRNAEchovirus Enterovirus B Enterovirus Picornaviridae Positive ssRNACoxsackievirus Enterovirus B Enterovirus Picornaviridae Positive ssRNA

Table 5 Viruses linked with type 1 diabetes in humans

Virus Family Mechanism of the T1D induction Model system

Humancytomegalovirus Herpesviridae

Persistent infection [102] Lymphocytes and autoantibodies (clinical study)

Molecular mimicry [103] GAD65-specific T-cells cross-react with a peptide ofthe HCMV (in vitro)

Bystander activation [104] Activation of CD4+ and CD8+ T-cells (clinicalstudy)

Parvovirus Parvoviridae Molecular mimicry [105] Elevated serum anti-parvovirus B19 IgM andautoantibodies (clinical study)

Induction of autoimmunity [106] Prolonged autoimmune alterations (clinical study)

Rotavirus Reoviridae Molecular mimicry [107]Correlation in the proliferative responses of T-cellsto the similar peptides in rotavirus and isletautoantigens (in vitro)

Rubella virus Togaviridae Congenital infection [108] Children with congenital rubella-autoantibodies(clinical study)

Molecular mimicry [109] T-cell response to viral and beta cell peptides (invitro)

Mumps virus ParamyxoviridaeLoss of tolerance toward 120573-cells [110] Human insulinoma cell line infected with mumps (in

vitro)

Molecular mimicry [111] Antibodies in serum of vaccinated andnonvaccinated children (clinical study)

Humanendogenousretrovirus

Retroviridae Influence of the immune response [112] Presence of antigen in T-cell subsets of patients(clinical study)

Humanparechovirus Picornaviridae Induction of autoimmunity [113] Stool samples and autoantibodies (clinical study)

Echovirus Picornaviridae Molecular mimicry [114] Echovirus 9 isolated from baby was destructive forhuman islets (in vitro)

Coxsackievirus Picornaviridae

Direct cellular injury [115] CVB4 and SJLJ mice (in vivo)Delayed viral clearance [116] Serum of prediabetic children (clinical study)

Molecular mimicry [117] Autoantibodies in human blood samples (clinicalstudy)

Bystander activation [118] CVB4 and NOD and BDC25 mice (in vivo)Antibody-dependent enhancement[119]

CVB4 and human serum-PBMC and monocyte (invitro)

Phagocytosis of infected 120573-cells [120] CVB3-infected human and porcine pancreatic islets(in vitro)

Loss of regulatory T-cells [121] CVB4-E2 infection of human thymic epithelial cells(in vitro)

Increased intestine permeability [122] Virus presence in the small intestine biopsy samplesDisruption in 120573-cells neogenesis [123] CVB4-E2 or CVB4-JVB and SJLJ mice


T-cells [142] Cavallo et al [110] showed that the mumpsvirus infection was related to IL-1 and IL-6 release so mumpscould induce diabetes by decreasing tolerance toward 120573-cells and making them more sensitive to immune-mediateddestruction

A high number of children with mumps showed isletcell antigens for 2ndash15 months following the infection withthis virus [143] Another study associated the virus with anincrease in the incidence of T1D [144] A shared epitope 7-amino-acid-long in the mumps virus nucleocapsid and inMHC class II molecule has been suggested as the causeof immunological cross-reactivity between these molecules[111] Regarding the rubella virus and measles-mumps-rubella vaccination a similar suggestion has been mademumps infections have decreased while TD1 incidence hasincreased [144]More investigations are required to shed lighton the mumps virus studies

76 Human Endogenous Retroviruses Endogenous retro-viruses (ERVs) represent the proviral phase of exogenousretroviruses that have integrated into the host cells Inhumans the most active endogenous retroviruses are mem-bers of Human endogenous retroviruses which are notincluded in the classification of the family Retroviridae[145] forming a part of the human genome Retrovirusescan integrate with the human genome so their genes areeither inherited (derived from old viral infections of thegerm cells) or acquired after birth Environmental factors(diet common viral infections andor the sex-hormonechanges) may activate endogenous retrovirus genes whichthen work as a triggering factor [112] Human endogenousretrovirus genes could be transcribed expressed in proteinand responsible for the development of autoantibodies thatmight react against host proteins and these mechanismscould lead to T1D Human endogenous retrovirus-K mayinfluence the immune response through insertion close toor in neighboring genes involved in immune epigeneticregulation Human endogenous retroviruses are known toinduce proinflammatory cytokines production as IL-1120573 IL-6 or TNF-120572 through cells such as monocytes [146] Thisvirus may involve a combination of the epigenetic factor withother components in the triggering of T1D

8 Special Viral Family Picornaviridae

Of the viral agents involved in presumptive triggering of T1Dthemost studied ones belong to the familyPicornaviridaeWewill first describe the viruses that are linked to the inductionof T1D in experimental animals (natural nonhuman hosts)but have the potential to infect humans in rare conditionsThen we will describe the viruses that are shown to beassociated with T1D in human clinical cases Figure 2 showsa schematic representation of the different viruses of thisfamily and the suggested mechanisms for the destruction ofpancreatic islets and function

81 Encephalomyocarditis Virus Encephalomyocarditis virusbelongs to the genusCardiovirus of the Picornaviridae family

The common hosts of these viruses are rodents and pigsalthough the virus can infect any mammal Recently theseviruses were shown to circulate naturally in humans in SouthAmerica [147] The clinical symptoms in humans usually gounnoticed but in serious cases symptoms include high fevernausea headache rigidity delirium vomiting photophobiaand pleocytosis

These viruses are able to induce the rapid onset ofdiabetes in mice Twomain variants of encephalomyocarditisvirus have been determined the nondiabetogenic variantencephalomyocarditis virus-B and the diabetogenic vari-ant encephalomyocarditis virus-D both with tropism forpancreatic 120573-cells There are differences in 14 nucleotidesand in the 776th amino acid alanine (Ala-776) of theencephalomyocarditis virus polyprotein located at majorcapsid protein VP1 These changes are seen only among alldiabetogenic variants In contrast threonine in this position(Thr-776) is observed particularly in all nondiabetogenicvirusesThe tyrosine kinase-2 gene expression prevented betacell destruction by encephalomyocarditis virus-D in knock-out mice [148] The prevention of macrophage-related celldestruction was shown to be induced by knocking out thetyrosine kinase pathway

82 Human parechoviruses Both species Human pare-chovirus (some of which are former echovirus serotypes)and Ljungan virus which belong to genus Parechovirus havebeen implicated in the development of T1D [113] Theseviruses can naturally infect bank voles but are also knownto cause infections in humans T1D was described in theanimals after one month of observation in the laboratoryThe symptoms were persistent hyperglycemia with weightloss ketosis and hyperlipidemia as well as specific 120573-celldestruction associatedwith signs of autoimmunity (increasedlevels of autoantibodies to glutamic acid decarboxylase-65 autoantigen IA-2 (islet cell antigen 512) and insulin)The disease was correlated with Ljungan virus antibodiesAntibodies to Ljungan virus have been shown in childrenwith onset of T1D and a possible zoonotic infection has beenproposed [149] The virus could be involved in T1D but moreepidemiological and experimental studies are required toelucidate the mechanisms involved

83 Enteric Cytopathic Human Orphan Viruses Theseviruses commonly referred to as echoviruses belong togenus Enterovirus Enterovirus B species An enteric cyto-pathic human orphan virus strain isolated from a 6-week-oldbaby suffering from acute T1D [114] was shown to be moredestructive in human islets in vitro than the echovirus 9and 30 other prototype strains [150] Cabrera-Rode et al[151] detected the presence of insulin antibodies glutamicacid decarboxylase antibodies and autoantigen IA-2 (isletcell antigen 512) in the serum indicating that the isletcell autoimmunity was associated with infection in theyear 2003 aseptic-meningitis Cuban epidemic caused byechovirus 16 During an echovirus 30 epidemic in CubaCabrera-Rode et al [152] reported the case of an adolescentwho developed pancreatic autoantibodies (ICA and IA2A)


Virus Mechanisms

Direct cellular injury

Delayed viral clearance

Increased intestine permeability

Bystander activation

Molecular mimicry

Antibody-dependent

Phagocytosis of enterovirus-

Loss of regulatory T-cells

Neogenesis

Encephalomyocarditis virus (EMCV)

Human parechovirus(HPeV)

Enteric cytopathic human orphan viruses (echoviruses)

Coxsackieviruses

Pancreatic cell destruction

enhancement (ADE)

infected pancreatic 120573-cells

Figure 2 Putative mechanisms suggested for the induction bymembers of the family Picornaviridae (Viruses linked to the induction of T1Din experimental animals (natural nonhuman hosts) or through clinical studies having a potential to infect humans in rare conditions) Factorsinfluencing the mechanisms involved in the beta cell destruction by these viruses (a) Genes related to infection putatively influencing themechanisms HLA-DR melanoma differentiation-associated protein-5 and interferon induced helicase 1 (b) Innate immunity interferonstumor necrosis factor and interleukins (c) T- and B-lymphocytes viral antibodies islet cell antibodies glutamic acid decarboxylaseantibodies antibody against insulin and tyrosine phosphatase-related IA2-A antibodies

and T1D after infection Diaz-Horta et al [153] provide alist of autoantibodies produced following various echovirusinfection In short islet cell autoantibodies were related toechoviruses 3 6 9 16 and 30 Glutamic acid decarboxylase-65 was related to echoviruses 6 and 16 autoantigen IA-2(islet cell antigen 512) was linked to echoviruses 3 and 16and insulin antibodies were related to echoviruses 9 and 16[114 116 151 152 154ndash156] The published literature showsstrong association between echoviruses and T1D onset

84 Coxsackieviruses Coxsackieviruses belong to the genusEnterovirus species Enterovirus A and Enterovirus B Thecoxsackievirus type B consists of 6 serotypes that have beeninvestigated in vivo and in vitro to establish associationwith chronic diseases since an early report of a link amongcoxsackievirus infections myocarditis [157] and T1D [158]The most often studied enteroviruses are coxsackievirusesB as they have been diagnosed frequently from clinicalsamples of patients with T1D (or high risk thereof) com-pared to a healthy population Several seroepidemiologicalstudies have demonstrated that recent-onset diabetic patientshad increased levels of coxsackievirus-specific antibodies orcoxsackievirus-RNA compared to control populations [116159ndash161] Sarmiento et al [162] also found this correlationin Cuba where the incidence of T1D is low [163] butcoxsackieviral infections incidence is high Coxsackievirus

B4 (CVB4) has also been directly isolated from the pancreasautopsy of a recent-onset T1D patient [164]

85 Enteroviral Mechanisms for T1D Predisposition or Pro-tection Coxsackieviruses are under intense scrutiny afterthe first isolation reported in 1979 [164] They have beendemonstrated to accelerate diabetes in genetically susceptiblemousemodels [117 118 165ndash167] Different in vivo and in vitrocoxsackievirus models are described in Table 5 Prospectiveand cross-sectional studies of patients published in the year2014 from Finland England France Greece and Sweden[168 169] showed two different mechanisms within thedifferent serotypes of coxsackieviruses One was destructiveand the other protective consistent with results from thenonobese diabetic (NOD) mouse model of coxsackievirus B-associated T1D Coxsackievirus B1 (CVB1) was shown to berelated to autoimmune destruction of pancreatic120573-cellsTheyhave shown that virus neutralizing antibodies appeared onlya few months before the autoantibodies and were related tothe presence of maternal antibody modification whereas theother prevalent viruses CVB3 and CVB6 showed a protectiveeffect

Experimental in vivo and in vitromodels show protectionor destruction of the pancreatic islets and the endocrinefunction in response to virus infection In these models theinfluencing factors in vivo are the hostrsquos age at the time of


infection host and virus genetics and dose of infectionIn our experimental coxsakievirus serotype B4 strain E2(CVB4-E2) infection model using outbred gravid mice [170]we showed gross infiltration of the endocrine pancreas andglycemia in the virus-challenged pups weaned from damsinfected at the 1st and 3rd weeks of gestation Another groupshowed that maternal infection conferred protection to theoffspring fromdiabetes in a transgenic Socs1-tgmousemodelwith nonobese diabetic (NOD) genetic background [171]Evidence indicated that the time of infection during thepregnancy and age of the pups at time of challenge areimportant factors To determine the conditions for protectiveor destructive outcomes further studies are required toelucidate the mechanisms

86 Coxsackievirus In Vitro Studies Coxsackievirus sero-types have been shown to replicate and destroy human 120573-cells [150 172 173] and mouse islet 120573-cells [174] in vitroProlonged persistence of the virus in human pancreatic isletcells has also been shown in vitro [126 175] Rodent120573-cells areresistant to metabolic disturbances caused by the prototypestrain CVB4 [115 176 177] Porcine endocrine cells have alsobeen used as models for virus infection and for studyingthe pathogenesis of T1D [176] (due to their cost) Porcineislet cells are susceptible to virus-induced impairment but arerelatively resistant to oxidative toxins and cytokine-induceddamage [178] Direct cytolysis of the islet cells which involvesinfection of the 120573-cells replication of the virus resulting inlysis of the cells depends on the genetics of the virus

87 Coxsackieviruses in Human Samples of T1D Coxsackie Bviruses were linked to T1Dwhen a coxsackievirus B4 (CVB4)strain was isolated from the pancreas during the autopsy of a10-year-old child who had died from diabetic ketoacidosisIn the pancreatic tissue necrosis of 120573-cells with infiltrationof lymphocytes was seen Inoculation of mice with the viralisolate resulted in hyperglycemia on day 5 after infection andinflammation of the islets of Langerhans and necrosis to day14 after infection only in SJL mice after two passages of thevirus in vivo [164]

There is also serological evidence in pregnant womenwith coxsackievirus (incidence of anti-enteroviral antibodiesin the sera of pregnant women) and subsequent developmentof T1D in the children [179ndash181] There is however one reportthat does not support this finding [182] These differencesmaybe related to the time of infection during gestation

The enterovirus (EV) genome and antibodies againstCVB1-B6 can be found in sera of prediabetic children severalyears before the onset of diabetic symptoms which havebeen associated with induction of autoimmunity Studies ofsera from newly diagnosed diabetics have revealed increasedlevels of anti-EV neutralizing antibodies (as compared withcontrols) [183ndash186] and elevated T-cell responses to coxsack-ievirus antigen [187]

Numerous researchers have detected antiviral antibodiesand viral-RNA in bloodserumperipheral blood mononu-clear cells by PCR sequencing methods or in tissues ofpostmortem pancreatic specimens with in situ hybridization

and identification of viral proteins by immunohistochemicalstaining from T1D patients

Enteroviral-RNA was associated with an increase inantibodies against islet cells (ICA) and glutamic acid decar-boxylase (GAD) [116 162] as well as antibodies against insulin(IAA) or the tyrosine phosphatase-related IA-2 protein (IA-2) [188] The enteroviral infections are prevalent in childrenwho became positive for 120573-cell autoantibodies compared tohealthy controls [116 160 162 188ndash190]

Enteroviral-RNA has also been shown in the whole bloodof patients at the onset or during the course of T1D butwas not shown in healthy subjects and patients with T2DSequencing of circulating enteroviral-RNAs in T1D patientshas confirmed systemic viral coxsackievirus infection [159]In another study the presence of IFN-120572mRNA was detectedby reverse transcriptase polymerase chain reaction (RT-PCR)in whole blood and sera of the T1D patients but in noneof controls Enteroviral-RNA was detected in patientsrsquo bloodsamples with IFN-120572 but not in patients without any IFN-120572Circulating enterovirus-RNA was sequenced by Chehadehet al [97] Enteroviral-RNA in blood spots (taken on days2ndash4 after birth for screening analysis of inherited metabolicdiseases) showed increased prevalence of enteroviral-RNA inchildren preceding the T1D [191] Coxsackievirus B4-specificRNA was found in the sera of diabetic children [186 192193] and a significant proportion of diabetic children with apositive RT-PCR were even less than one year old [194 195]In the peripheral blood mononuclear cells enteroviral-RNAwas detected by RT-PCR [196] and enteroviral capsid anti-gens were detected by immunofluorescence [197] Prolongedenterovirus infections could be found in patients who werepositive for the detection of viral-RNA in peripheral bloodmononuclear cells andor plasma together with the absenceof viral-RNA in stool and throat swabs [198]

Enteroviral-RNA is commonly found in stool samplesof T1D children [190 199 200] but a direct connection tothe onset of T1D and acute coxsackievirus infection and thepresence of enterovirus in the stool remains uncertain

Different virological methods have been used to deter-mine whether enteroviruses can be found in small intestinalmucosa of T1D patients undergoing intestinal biopsies Viral-RNA was found by RT-PCR in a frozen sample In thesesamples protein VP1 was localized in the epithelium byimmunohistochemistry and enteroviral-RNA was detectedby in situ hybridization in the cells of lamina propria [122]

Enterovirus-positive cells have been detected in numer-ous pancreatic islets and some duct cells with nondestructiveinsulitis and natural killer cell infiltration but were not seenin the exocrine pancreas [201] Using electron microscopyDotta et al [202] observed viral inclusions and signs ofpyknosis and loss of 120573-cell function In different studies usingimmunohistochemistry for VP1 protein was demonstrated inendocrine cells of the pancreatic islets during autopsies ofdiabetic children [119 202ndash204] Although the enteroviruseshave been found in the pancreatic islets of patients withrecent-onset of diabetes [202 204 205] 120573-cell destructionin patients with fatal diabetes was not a direct outcome of


the virus-mediated cytopathic effect Viruses induce 120573-cellsdestruction through an autoimmunity mechanism

9 Viruses Mechanism ofProtection Hypothesis

Type 1 diabetes cases are increasing worldwide especiallyin highly industrialized countries and urban regions Suchstatistics have given rise to the ldquohygiene hypothesisrdquo whichwas originally proposed to explain increases in asthma andallergic diseases [206] Since the year 1989 the hygienehypothesis has also been suggested as an explanation ofincreased rates of other autoimmune diseases including T1D[207] A lack of exposure to a wide range of infectiousagents in industrialized or developed countries is presumedto increase the rates of some diseases especially those whichare transmitted by the fecal-oral route While the incidenceof various infectious diseases has decreased over the lastfew decades the occurrence of autoimmune disorders hasincreased rapidly [207] Several authors have discussed theprotective effect of the enteroviruses on T1D [208ndash211]Serological and epidemiological studies and in vivoin vitromodels indicate that the effect of virus on the pancreatic isletcells afflictionprotection depends on several factors

10 Viruses Mechanism of 120573-Cells Destruction

Enterovirus infections often go unnoticed and humans maybe infected several times during their lifetime with differententeroviruses Recent studies show that viral-RNA may per-sist over a long period of time These viruses have a widerange of tropism they induce interferons their teratogeniccharacter is vague as compared with other viruses and theymay cause multiple infections and immune imbalances in thedefence system Epigenetics and other factors such as age ofhost at the time of infection multiple infections maternalinfections circulating viruses genetics and a combination ofother factors have resulted in differentcontroversial opin-ions The actual mechanism could be a destructive path-way which is a combination of different factors One hasto consider that the methodologies applied here are fordetection of RNAs or for analyzing viral genome persistenceIn situ hybridization and VP1 detection need standardizedmethodology Different mechanisms related to enterovirusare described below

101 Direct Cellular Injury Human and prototype laboratorycoxsackieviruses A and B strains can infect mouse islet cellsin vitro [174] In addition human islet 120573-cell infection invitro and its destruction by enteroviruses and clinical isolateshave been recorded [85 150 212ndash215] Pathogens mainlyviruses that infect pancreatic islet cells may induce T1Dthrough direct cytopathic effects and cause destruction ofthe insulin-secreting 120573-cells by cytolysis enteroviruses areknown to be highly cytolytic [172 216] Direct infectioncauses disruption of cells and release of autoantigens which

activate the innate and adaptive immune systems The ensu-ing inflammation and development of autoimmune reactionsfurther contribute to 120573-cell destruction and T1D

102 Delayed Viral Clearance Delayed viral clearance isbased on evidence that individuals with high genetic riskfor T1D have impaired defence mechanisms against virusclearance [217] Virus persistence in the pancreatic 120573-cellscan result in the induction of autoimmunity In enterovirus-infected individuals the viremia is short yet enteroviral-RNA has been found in the blood of patients with newlydiagnosedT1Dwhichmay be a result of prolonged enteroviralpersistence in blood cells [198] Enteroviruses detected at theonset of T1D were not found in plasma but were presentin peripheral blood mononuclear cells The viruses mightuse monocytes andor lymphocytes as viral reservoirs andvehicles for viral dissemination [218] T-cells from dia-betic patients show reduced activation and cytokine pro-duction when challenged in vitro with coxsackievirus B4[217] Patients with coxsackievirus infection with insufficientimmune response to provide total protection maybe at ahigh risk of delayed virus clearance viral persistence andincreased pancreatic islet damage are high risk patientsMany T1D patients show detectable levels of viral-RNAsuggesting that a delayed clearancemay bemore relevant thanviral persistence to the progression of T1D [116]

103 Molecular Mimicry Molecular mimicry is based onthe observation that some microbialviral proteins and hostproteins have sequence or structural homology and there-fore go unrecognized as self-proteins A normal immuneresponse against the viral antigen becomes cross-reactiveagainst the homologous sequence of the 120573-cells host protein[219] Glutamic acid decarboxylase-65 (GAD65) expressedin pancreatic 120573-cells is the important islet cell autoantigenwhich can be recognized as nonself in T1D [114] There isa structural similarity between P2-C protein sequence ofCVB and an epitope derived from the humans and NODmice the GAD65 [220] Therefore both autoreactive andantiviral T-cells activated upon CVB infection might act asstrong enhancers of the autoimmune process Enteroviralinfections can activate the antienteroviral T-lymphocyteswhich via cross-reactivity contribute to the damage of120573-cellspersistently infected by another enterovirus [154] Some invivo and in vitro studies [118 221 222] do not support thetheory of molecular mimicry due to lack of cross-reactingglutamic acid decarboxylase epitopes and viral antigens

104 Bystander Activation Infection of cells neighboring the120573-cells (eg ductal cells) may stimulate local inflammationAs a consequence CD8+ T-cells and inflammatory cells(macrophages) release cytokines such as tumor necrosisfactor alpha lymphotoxin and nitric oxide which canlead to bystander killing of 120573-cells [223] The inflammationprovokes cell damage and release of segregated antigensThrough bystander activation the T-lymphocytes directedagainst these self-antigens are responsible for pancreaticislet destruction and T1D development [224ndash226] Diabetes


develops when the damage gets out of control In contrastto molecular mimicry initial tissue injury via bystanderactivation is not antigen specific as the T-cells have notbeen shown to respond to the coxsackievirus The injuryis due to inflammation via the bystander activation ofcells [118] Viral infection can also lead to the activationof antigen-presenting cells namely dendritic cells (DCs)Activated APCs then increase T-helper density at the siteof infectioninflammation [227] Horwitz et al [228] andSerreze et al [117] suggested that the number of autoreactiveT-cells is important for T1D induction after coxsackievirus B4infection for initiation of bystander activation

105 Antibody-Dependent Enhancement (ADE) of EnterovirusInfection Antibodies are essential in limiting clearing andinfluencing the severity of enteroviral infections This mech-anism is mediated by anti-coxsackievirus antibodies lackingneutralizing activityThese antibodies bind to the cell surfacemembrane of the monocytesmacrophages via the coxsackie-adenovirus receptor (CAR) and increase the replication ofCVB4 in the cellsThe infectedmonocytesmacrophages helpvirus dissemination in the host as well as viral replicationtarget sites enhancing pathological responses known asantibody-dependent enhancementThis pathological severitywas shown to be enhanced (in vitro)whenplasmaor IgG frompatients with T1D was used as compared to those of healthyindividuals [229] Coxsackievirus B4 induces interferon-120572 inperipheral blood mononuclear cells in vitro [230 231] andchronic IFN-120572 synthesis or its abnormal activation can beassociated with disorders leading to autoimmune diseases[97] These antibodies target the EV-protein VP4 and it hasbeen shown that the prevalence and anti-VP4 antibody titresare in higher concentrations in patients with T1D than thosein control subjects [232 233]

106 Phagocytosis of Enterovirus-Infected Pancreatic 120573-CellsAnother suggested mechanism in which virus infected isletsmay affect the local immune balance has been shown invitro in human islets [120] where coxsackievirus-infectedislets were efficiently phagocytosed by human monocyte-derived dendritic cells Phagocytosis induces an antiviral statethat protects dendritic cells from subsequent coxsackievirusinfection This antiviral state of protected dendritic cellsdepends on the presence of intracellular viral-RNA in thecoxsackievirus-infected cells and type 1 interferons producedby the dendritic cells It has been suggested that these virus-induced effectsmay alter dendritic cells therefore influencingthe development of regulatory T-cells andor effector T-cellpopulations

107 Loss of Regulatory T-Cells The failure of immunologicaltolerance towards 120573-cell antigens after the T-cell and B-cell maturation is due to abnormalities of the T-regulatorylymphocytes (Tregs) in the periphery This occurs outsidethe primary lymphoid tissues alongonly with the centraltolerance and involves the thymus [234] Coxsackievirus B4replicates andpersists in human thymic epithelial cells in vitro[121] as well as mouse in vitro and in vivo models [235 236]

which disturbs maturationdifferentiation of T-lymphocytesEnteroviral infection of thymus has been suggested to resultin defective T-lymphocyte subpopulations which have beenfound in diabetic and prediabetic patients [237]

108 Increased Intestinal Permeability Enteroviruses havebeen detected in small intestinal biopsies of T1D patientsmore frequently than in healthy controls suggesting per-sistence of enterovirus infections and replication in the gutfor prolonged periods [122] Increased intestinal permeabilityas an outcome of prolonged infections which could beassociated with an increased susceptibility to T1D has alsobeen suggested [122 238] Enteroviral infections lead tochanges in gut permeability and increased viral access to thepancreas allowing other environmental factors tomodify T1Dsusceptibility

109 Neogenesis Pancreatic ductal cells can differentiate intofunctioning adult 120573-cell mass [239] Normally a stable rateof recirculation of ldquoapoptotic 120573-cell replacementrdquo takes placeduring the differentiation of progenitor cells [240] It hasbeen suggested that coxsackievirus infections afflict 120573-cellneogenesis causing depletion of 120573-cell mass which wouldhave a role in diabetes development [123]

11 Conclusion

The incidence of T1D has increased rapidly in recent yearsWhether the increase is an outcome of synergistic influ-ence(s) of different factors is unclear The onset of T1D isa coordination of multiple factors Several riskprotectiveelements are however associated with the incidence of T1Dfamily history host genetics immunological status sex ageobesity ethnicity and social group characteristics as wellas behavioral lifestyle psychological and clinical factorsFurthermore the T1D process may start in the early neonatalstage or even in utero and the environmental factors encoun-tered in early childhood might also induce or accelerate thedisease [155] Among such influential conditions are exposureto intrauterine infections nutrition and consumption oftoxic material The time of exposure during gravidity anddelivery conditions may also be relevant [241]

The genetic predisposition depends mainly on the MHCand non-MHC genes which are proven major factors infavoring T1D induction These genes direct the immuneresponses which are important in autoimmune diseases

Suggestedmechanisms for triggering T1D consider director indirect interaction of viruses and immune system ingenetically predisposed individuals Viruses may cause vari-ation in certain genes of the MHC loci and may upregulateor dysregulate inflammatory or proinflammatory cytokinesleading to destructive or protective effect on pancreaticislet cells Numerous investigations on the pathogenesis ofT1D and the involvement of viruses have been carried outHowever the onset of T1D and the triggering factors andmechanisms involved remain unsolved Together varioustypes of studies (observational and experimental) indicate


that the mechanism of T1D indication via genetic-viralinteractions is complex

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Authorsrsquo Contribution

Jana Precechtelova wrote the primary draft Maria Bor-sanyiova and Sona Sarmirova contributed to proofreadingand editing and Shubhada Bopegamage contributed to con-ception reviewing editing and finalization All authors havereviewed the final draft and agreed to the contents

Acknowledgments

The authors thank the Norwegian financial support mech-anism Mechanism EEA and Slovak Government ProjectSK0082 and project of the Ministry of Health Project MZSR200613-SZU-08 both granted to Shubhada BopegamageThey are grateful to Professor Steven Tracy MS PhDUniversity of Nebraska Medical Centre USA for reading thedocument and for valuable suggestions They appreciate thetechnical support of Ms Brigita Benkoova (MSc student)They thank Bill Coleman of Far Out Books and Educa-tionPontiac Michigan USA for editorial assistance

References

[1] N S Papaspyros ldquoThe history of diabetesrdquo in The History ofDiabetes Mellitus G T Verlag Ed p 4 Thieme StuttgartGermany 1964

[2] httpwwwcrystalinkscomegyptmedicinehtml[3] J Zajac A Shrestha P Patel and L Poretsky ldquoThe main events

in the history of diabetes mellitusrdquo in Principles of DiabetesMellitus L Poretsky Ed pp 3ndash16 Springer New York NYUSA 2nd edition 2010

[4] F Allen ldquoStudies concerning diabetesrdquo Journal of AmericanMedical Association vol 63 pp 939ndash943 1914

[5] httpwwwnobelprizeorgnobel prizesmedicine[6] H P Himsworth ldquoThe mechanism of diabetes mellitusrdquo The

Lancet vol 234 no 6047 pp 171ndash176 1939[7] American Diabetes Association ldquoStandards of medical care in

diabetesmdash2014rdquo Diabetes Care vol 37 no 1 pp 14ndash80 2014[8] World Health Organization ldquoDiagnostic criteria and clas-

sification of hyperglycaemia first detected in pregnancyrdquoWHONMHMND132 World Health Organization 2013

[9] ldquoDefinition and diagnosis of diabetes mellitus and intermediatehyperglycaemiardquo Report of a WHOIDF Consultation 2006

[10] W Gepts ldquoPathologic anatomy of the pancreas in juvenilediabetes mellitusrdquo Diabetes vol 14 no 10 pp 619ndash633 1965

[11] A K Foulis C N Liddle M A Farquharson J A Richmondand R S Weir ldquoThe histopathology of the pancreas in typeI (insulin-dependent) diabetes mellitus a 25-year review ofdeaths in patients under 20 years of age in theUnitedKingdomrdquoDiabetologia vol 29 no 5 pp 267ndash274 1986

[12] American Diabetes Association ldquoDiagnosis and classificationof diabetes mellitusrdquo Diabetes Care vol 36 no 1 pp 67ndash742013

[13] S Baekkeskov H-J Aanstoot S Christgau et al ldquoIdentifica-tion of the 64K autoantigen in insulin-dependent diabetes asthe GABA-synthesizing enzyme glutamic acid decarboxylaserdquoNature vol 347 no 6289 pp 151ndash156 1990

[14] J P Palmer C M Asplin P Clemons et al ldquoInsulin antibodiesin insulin-dependent diabetics before insulin treatmentrdquo Sci-ence vol 222 no 4630 pp 1337ndash1339 1983

[15] E Bonifacio V Lampasona S Genovese M Ferrari and EBosi ldquoIdentification of protein tyrosine phosphatase-like IA2(islet cell antigen 512) as the insulin-dependent diabetes-related3740K autoantigen and a target of islet-cell antibodiesrdquo TheJournal of Immunology vol 155 no 11 pp 5419ndash5426 1995

[16] J Lu Q Li H Xie et al ldquoIdentification of a second transmem-brane protein tyrosine phosphatase IA-2120573 as an autoantigenin insulin-dependent diabetes mellitus Precursor of the 37-kDa tryptic fragmentrdquo Proceedings of the National Academy ofSciences of the United States of America vol 93 no 6 pp 2307ndash2311 1996

[17] M Pietropaolo L Castano S Babu et al ldquoIslet cell autoantigen69 kD (ICA69) molecular cloning and characterization of anovel diabetes-associated autoantigenrdquo The Journal of ClinicalInvestigation vol 92 no 1 pp 359ndash371 1993

[18] L Castano E Russo L Zhou M A Lipes and G S Eisen-barth ldquoIdentification and cloning of a granule autoantigen(carboxypeptidase-H) associated with type I diabetesrdquo Journalof Clinical Endocrinology and Metabolism vol 73 no 6 pp1197ndash1201 1991

[19] R C Nayak M A Omar A Rabizadeh S Srikanta and G SEisenbarth ldquoldquoCytoplasmicrdquo islet cell antibodies Evidence thatthe target antigen is a sialoglycoconjugaterdquoDiabetes vol 34 no6 pp 617ndash619 1985

[20] S D Arden B O Roep P I Neophytou et al ldquoImogen 38 anovel 38-kD islet mitochondrial autoantigen recognized by Tcells fromanewly diagnosed type 1 diabetic patientrdquoThe Journalof Clinical Investigation vol 97 no 2 pp 551ndash561 1996

[21] H Kasimiotis M A Myers A Argentaro et al ldquoSex-determining region Y-related protein SOX13 is a diabetesautoantigen expressed in pancreatic isletsrdquoDiabetes vol 49 no4 pp 555ndash561 2000

[22] JMWenzlau K Juhl L Yu et al ldquoThe cation efflux transporterZnT8 (Slc30A8) is a major autoantigen in human type 1diabetesrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 104 no 43 pp 17040ndash17045 2007

[23] T Kimpimaki A Kupila A-M Hamalainen et al ldquoThe firstsigns of 120573-cell autoimmunity appear in infancy in geneticallysusceptible children from the general population the finnishtype 1 diabetes prediction and prevention studyrdquo Journal ofClinical Endocrinology andMetabolism vol 86 no 10 pp 4782ndash4788 2001

[24] C F Verge R Gianani E Kawasaki et al ldquoPrediction of type Idiabetes in first-degree relatives using a combination of insulinGAD and ICA512bdcIA-2 autoantibodiesrdquo Diabetes vol 45no 3 pp 926ndash933 1996

[25] G F BottazzoA F Christensen andDDoniach ldquoIslet cell anti-bodies in diabetes mellitus with autoimmune polyendocrinedeficienciesrdquoThe Lancet vol 2 no 7892 pp 1279ndash1283 1974

[26] D P Singal and M A Blajchman ldquoHistocompatibility (HL-A)antigens lymphocytotoxic antibodies and tissue antibodies in


patients with diabetesmellitusrdquoDiabetes vol 22 no 6 pp 429ndash432 1973

[27] A G Cudworth and J CWoodrow ldquoLetter HL-A antigens anddiabetes mellitusrdquoThe Lancet vol 2 no 7889 article 1153 1974

[28] L Zhang and G S Eisenbarth ldquoPrediction and prevention oftype 1 diabetes mellitusrdquo Journal of Diabetes vol 3 no 1 pp48ndash57 2011

[29] D J Smyth J D Cooper R Bailey et al ldquoA genome-wideassociation study of nonsynonymous SNPs identifies a type1 diabetes locus in the interferon-induced helicase (IFIH1)regionrdquo Nature Genetics vol 38 no 6 pp 617ndash619 2006

[30] Genomes Project Consortium ldquoA map of human genomevariation from population-scale sequencingrdquo Nature vol 467no 7319 pp 1061ndash1073 2010

[31] I Kockum C B Sanjeevi S Eastman M Landin-Olsson GDahlquist and A Lernmark ldquoComplex interaction betweenHLA DR and DQ in conferring risk for childhood type 1diabetesrdquo European Journal of Immunogenetics vol 26 no 5pp 361ndash372 1999

[32] B P C Koeleman B A Lie D E Undlien et al ldquoGenotypeeffects and epistasis in type 1 diabetes andHLA-DQ trans dimerassociations with diseaserdquoGenes and Immunity vol 5 no 5 pp381ndash388 2004

[33] O L Griffith S B Montgomery B Bernier et al ldquoORegAnnoan open-access community-driven resource for regulatoryannotationrdquo Nucleic Acids Research vol 36 no 1 pp D107ndashD113 2008

[34] J K Distefano and D M Taverna ldquoTechnological issues andexperimental design of gene association studiesrdquo Methods inMolecular Biology vol 700 pp 3ndash16 2011

[35] HA Erlich AMValdes S LMcDevitt et al ldquoNext generationsequencing reveals the association of DRB3lowast0202 with type 1diabetesrdquo Diabetes vol 62 no 7 pp 2618ndash2622 2013

[36] G D Snell and G F Higgins ldquoAlleles at the histocompatibility-2 locus in the mouse as determined by tumor transplantationrdquoGenetics vol 36 no 3 pp 306ndash310 1951

[37] J A Noble and H A Erlich ldquoGenetics of type 1 diabetesrdquo ColdSpring Harbor Perspectives in Medicine vol 2 no 1 Article IDa007732 2012

[38] I Santin and D L Eizirik ldquoCandidate genes for type 1 diabetesmodulate pancreatic islet inflammation and 120573-cell apoptosisrdquoDiabetes Obesity and Metabolism vol 15 no 3 pp 71ndash81 2013

[39] The MHC sequencing consortium ldquoComplete sequence andgene map of a human major histocompatibility complexrdquoNature vol 401 no 6756 pp 921ndash923 1999

[40] B Mach V Steimle E Martinez-Soria and W Reith ldquoRegu-lation of MHC class II genes lessons from a diseaserdquo AnnualReview of Immunology vol 14 pp 301ndash331 1996

[41] V Radha K S Vimaleswaran R Deepa and V MohanldquoThe genetics of diabetes mellitusrdquo Indian Journal of MedicalResearch vol 117 pp 225ndash238 2003

[42] H A Erlich R L Griffith T L Bugawan R Ziegler C Alperand G Eisenbarth ldquoImplication of specific DQB1 alleles ingenetic susceptibility and resistance by identification of IDDMsiblings with novel HLA-DQB1 allele and unusual DR2 andDR1haplotypesrdquo Diabetes vol 40 no 4 pp 478ndash481 1991

[43] D J Penn ldquoMajor Histocompatibility Complex (MHC)rdquo inEncyclopedia of Life Sciences Macmillan Publishers Ltd NaturePublishing Group 2002

[44] J R Gruen and S M Weissman ldquoHuman MHC class III andIV genes and disease associationsrdquo Frontiers in Bioscience vol6 pp D960ndashD972 2001

[45] J Bell ldquoPerinatal diagnosis current approaches and futuretrendsrdquo inHumanGenetic Information Science Law and EthicsCIBA Foundation Symposium 149 pp 18ndash36 John Wiley ampSons Chichester UK 1990

[46] R Redon S Ishikawa K R Fitch et al ldquoGlobal variation incopy number in the human genomerdquo Nature vol 444 no 7118pp 444ndash454 2006

[47] R Tisch and H McDevitt ldquoInsulin-dependent diabetes melli-tusrdquo Cell vol 85 no 3 pp 291ndash297 1996

[48] E-P Reich H von Grafenstein A Barlow K E Swenson KWilliams and C A Janeway Jr ldquoSelf peptides isolated fromMHC glycoproteins of non-obese diabetic micerdquoThe Journal ofImmunology vol 152 no 5 pp 2279ndash2288 1994

[49] A P Lambert K M Gillespie G Thomson et al ldquoAbsoluterisk of childhood-onset type 1 diabetes defined by humanleukocyte antigen class II genotype a population-based studyin the United Kingdomrdquo Journal of Clinical Endocrinology andMetabolism vol 89 no 8 pp 4037ndash4043 2004

[50] J A Noble A M Valdes M Cook W Klitz G Thom-son and H A Erlich ldquoThe role of HLA class II genes ininsulin-dependent diabetes mellitus Molecular analysis of 180Caucasian multiplex familiesrdquo American Journal of HumanGenetics vol 59 no 5 pp 1134ndash1148 1996

[51] J C Gorga and D Monos ldquoHLA and disease molecularbasisrdquo in MHC Molecules Expression Assembly and FunctionJ C Gorga Ed pp 135ndash162 Springer eBook R G LandesCompany Austin Tex USA 1996

[52] R Horton R Gibson P Coggill et al ldquoVariation analysis andgene annotation of eightMHChaplotypes theMHCHaplotypeprojectrdquo Immunogenetics vol 60 no 1 pp 1ndash18 2008

[53] D F Conrad T D Andrews N P Carter M E Hurles and J KPritchard ldquoA high-resolution survey of deletion polymorphismin the human genomerdquoNature Genetics vol 38 no 1 pp 75ndash812006

[54] H Beyan R C Drexhage L V D H Nieuwenhuijsen et alldquoMonocyte gene-expression profiles associated with childhood-onset type 1 diabetes and disease risk a study of identical twinsrdquoDiabetes vol 59 no 7 pp 1751ndash1755 2010

[55] C Sapienza and J G Hall ldquoGenetic imprinting in humandiseaserdquo in The Metabolic and Molecular Bases of InheritedDisease C R Scriver A L BeaudetW S Sly andD Valle Edsvol 1 chapter 7 pp 437ndash458McGraw-Hill NewYorkNYUSA7th edition 1995

[56] J H Warram A S Krolewski M S Gottlieb and C R KahnldquoDifferences in risk of insulin-dependent diabetes in offspringof diabetic mothers and diabetic fathersrdquo The New EnglandJournal of Medicine vol 311 no 3 pp 149ndash152 1984

[57] H Tillil and J Kobberling ldquoAge-corrected empirical genetic riskestimates for first-degree relatives of IDDM patientsrdquo Diabetesvol 36 no 1 pp 93ndash99 1987

[58] D Bleich M Polak G S Eisenbarth and R A JacksonldquoDecreased risk of type I diabetes in offspring of mothers whoacquire diabetes during adrenarchyrdquoDiabetes vol 42 no 10 pp1433ndash1439 1993

[59] L YuH P Chase A FalorniM Rewers A Lernmark andG SEisenbarth ldquoSexual dimorphism in transmission of expressionof islet autoantibodies to offspringrdquoDiabetologia vol 38 no 11pp 1353ndash1357 1995

[60] C Wallace D J Smyth M Maisuria-Armer N M Walker JA Todd and D G Clayton ldquoThe imprinted DLK1-MEG3 generegion on chromosome 14q322 alters susceptibility to type 1diabetesrdquo Nature Genetics vol 42 no 1 pp 68ndash71 2010


[61] V K Rakyan H Beyan T A Down et al ldquoIdentification of type1 diabetes-associated DNA methylation variable positions thatprecede disease diagnosisrdquo PLoS Genetics vol 7 no 9 ArticleID e1002300 2011

[62] J Nerup P Platz O O Andersen et al ldquoHL A antigens anddiabetes mellitusrdquo The Lancet vol 2 no 7885 pp 864ndash8661974

[63] G I Bell S Horita and J H Karam ldquoA polymorphic locus nearthe human insulin gene is associated with insulin-dependentdiabetes mellitusrdquo Diabetes vol 33 no 2 pp 176ndash183 1984

[64] L Nistico R Buzzetti L E Pritchard et al ldquoThe CTLA-4 generegion of chromosome 2q33 is linked to and associated withtype 1 diabetes Belgian diabetes registryrdquo Human MolecularGenetics vol 5 no 7 pp 1075ndash1080 1996

[65] N Bottini L Musumeci A Alonso et al ldquoA functional variantof lymphoid tyrosine phosphatase is associated with type Idiabetesrdquo Nature Genetics vol 36 no 4 pp 337ndash338 2004

[66] A Vella J D Cooper C E Lowe et al ldquoLocalization of atype 1 diabetes locus in the IL2RACD25 region by use of tagsingle-nucleotide polymorphismsrdquoAmerican Journal of HumanGenetics vol 76 no 5 pp 773ndash779 2005

[67] M Bakay R Pandey and H Hakonarson ldquoGenes involved intype 1 diabetes an updaterdquoGenes vol 4 no 4 pp 499ndash521 2013

[68] S Nejentsev N Walker D Riches M Egholm and J A ToddldquoRare variants of IFIH1 a gene implicated in antiviral responsesprotect against type 1 diabetesrdquo Science vol 324 no 5925 pp387ndash389 2009

[69] M Heinig E Petretto C Wallace and S A Cook ldquoA trans-acting locus regulates an anti-viral expression network and type1 diabetes riskrdquo Nature vol 467 no 7314 pp 460ndash464 2010

[70] H Hakonarson S F A Grant J P Bradfield et al ldquoA genome-wide association study identifies KIAA0350 as a type 1 diabetesgenerdquo Nature vol 448 no 7153 pp 591ndash594 2007

[71] J A ToddNMWalker JDCooper et al ldquoRobust associationsof four new chromosome regions from genome-wide analysesof type 1 diabetesrdquo Nature Genetics vol 39 no 7 pp 857ndash8642007

[72] TheWellcome Trust Case Control Consortium ldquoGenome-wideassociation study of 14000 cases of seven common diseases and3000 shared controlsrdquo Nature vol 447 no 7145 pp 661ndash6782007

[73] J D Cooper D J Smyth A M Smiles et al ldquoMeta-analysis ofgenome-wide association study data identifies additional type 1diabetes risk locirdquoNature Genetics vol 40 no 12 pp 1399ndash14012008

[74] D J Smyth V Plagnol N MWalker et al ldquoShared and distinctgenetic variants in type 1 diabetes and celiac diseaserdquo The NewEnglend Journal of Medicine vol 359 no 26 pp 2767ndash27772008

[75] J C Barrett DG Clayton P Concannon et al ldquoType 1DiabetesGenetics Consortium Genome-wide association study andmeta-analysis find that over 40 loci affect risk of type 1 diabetesrdquoNature Genetics vol 41 no 6 pp 703ndash707 2009

[76] S F Grant H Q Qu J P Bradfield et al ldquoFollow-up analysisof genome-wide association data identifies novel loci for type 1diabetesrdquo Diabetes vol 58 no 1 pp 290ndash295 2009


[78] J P Bradfield H Q Qu and K Wang ldquoA genome-widemeta-analysis of six type 1 diabetes cohorts identifies multipleassociated locirdquo PLoS Genetics vol 7 no 9 Article ID e10022932011

[79] V Plagnol J M M Howson D J Smyth et al ldquoGenome-wideassociation analysis of autoantibody positivity in type 1 diabetescasesrdquo PLoS Genetics vol 7 no 8 Article ID e1002216 2006

[80] T Bazzaz M M Amoli Z Taheri et al ldquoTNF-120572 and IFN-120574gene variation and genetic susceptibility to type 1 diabetes andits microangiopathic complicationsrdquo Journal of Diabetes andMetabolic Disorders vol 13 p 46 2014

[81] httpwwwt1dbaseorgpageRegions[82] W-CG YeungWD Rawlinson andM E Craig ldquoEnterovirus

infection and type 1 diabetes mellitus systematic review andmeta-analysis of observational molecular studiesrdquo British Med-ical Journal vol 342 no 7794 article d35 2011

[83] A D Paterson ldquoGenetic epidemiology of type 1 diabetesrdquoCurrent Diabetes Reports vol 6 no 2 pp 139ndash146 2006

[84] Y-H Qiu F-Y Deng M-J Li and S-F Lei ldquoIdentificationof novel risk genes associated with type 1 diabetes mellitususing a genome-wide gene-based association analysisrdquo Journalof Diabetes Investigation 2014

[85] C J Fox and J S Danska ldquoIndependent genetic regulation ofT-cell and antigen-presenting cell participation in autoimmuneislet inflammationrdquo Diabetes vol 47 no 3 pp 331ndash338 1998

[86] P L Kendall G Yu E JWoodward and JWThomas ldquoTertiarylymphoid structures in the pancreas promote selection of Blymphocytes in autoimmune diabetesrdquoThe Journal of Immunol-ogy vol 178 no 9 pp 5643ndash5651 2007

[87] A Willcox S J Richardson A J Bone A K Foulis and NG Morgan ldquoAnalysis of islet inflammation in human type 1diabetesrdquo Clinical and Experimental Immunology vol 155 no2 pp 173ndash181 2009

[88] T Habib A Funk M Rieck et al ldquoAltered B cell homeostasisis associated with type I diabetes and carriers of the PTPN22allelic variantrdquo The Journal of Immunology vol 188 no 1 pp487ndash496 2012

[89] W S Thompson M Pekalski H Z Simons et al ldquoMulti-parametric flow cytometric and genetic investigation of periph-eral B-cell compartment in human type 1 diabetesrdquo Clinical andExperimental Immunology vol 177 no 3 pp 571ndash585 2014

[90] M Yang K Rui S Wang and L Lu ldquoRegulatory B cells inautoimmune diseasesrdquoCellular andMolecular Immunology vol10 no 2 pp 122ndash132 2013

[91] K Schroder P J Hertzog T Ravasi and D A HumeldquoInterferon-120574 an overview of signals mechanisms and func-tionsrdquo Journal of Leukocyte Biology vol 75 no 2 pp 163ndash1892004

[92] httpwwwphgfoundationorgnews4515[93] C Guiducci M Gong Z Xu et al ldquoTLR recognition of self

nucleic acids hampers glucocorticoid activity in lupusrdquo Naturevol 465 no 7300 pp 937ndash941 2010

[94] A Rabinovitch ldquoAn update on cytokines in the pathogenesisof insulin-dependent diabetes mellitusrdquo DiabetesMetabolismReviews vol 14 no 2 pp 129ndash151 1998

[95] A K Foulis M A Farquharson and A Meager ldquoImmunore-active 120572-interferon in insulin-secreting 120573 cells in type 1 diabetesmellitusrdquoThe Lancet vol 2 no 8573 pp 1423ndash1427 1987

[96] G C Toms P Baker and B J Boucher ldquoThe production ofimmunoreactive 120572- and 120574-interferon by circulating mononu-clear cells in type 1 diabetesrdquo Diabetic Medicine vol 8 no 6pp 547ndash550 1991


[97] WChehadeh J Kerr-Conte F Pattou et al ldquoPersistent infectionof humanpancreatic islets by coxsackievirus B is associatedwithalpha interferon synthesis in 120573 cellsrdquo Journal of Virology vol 74no 21 pp 10153ndash10164 2000

[98] X Li S Leung S Qureshi J E Darnell Jr and G R StarkldquoFormation of STAT1-STAT2 heterodimers and their role inthe activation of IRF-1 gene transcription by interferon-120572rdquoTheJournal of Biological Chemistry vol 271 no 10 pp 5790ndash57941996

[99] A Takaoka Y Mitani H Suemori et al ldquoCross talk betweeninterferon-120574 and -120572120573 signaling components in caveolar mem-brane domainsrdquo Science vol 288 no 5475 pp 2357ndash2360 2000

[100] M Giroux M Schmidt and A Descoteaux ldquoIFN-120574-inducedMHC class II expression transactivation of class II transacti-vator promoter IV by IFN regulatory factor-1 is regulated byprotein kinase C-120572rdquoThe Journal of Immunology vol 171 no 8pp 4187ndash4194 2003

[101] K Lind S J Richardson P Leete N G Morgan O Korsgrenand M Flodstrom-Tullberga ldquoInduction of an antiviral stateand attenuated coxsackievirus replication in type III interferon-treated primary human pancreatic isletsrdquo Journal of Virologyvol 87 no 13 pp 7646ndash7654 2013

[102] C Y Pak R G McArthur H-M Eun and J-W YoonldquoAssociation of cytomegalovirus infection with autoimmunetype 1 diabetesrdquoThe Lancet vol 332 no 8601 pp 1ndash4 1988

[103] H S Hiemstra N C Schloot P A van Veelen et alldquoCytomegalovirus in autoimmunity T cell crossreactivity toviral antigen and autoantigen glutamic acid decarboxylaserdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 98 no 7 pp 3988ndash3991 2001

[104] M Sester U Sester B CGartnerMGirndt AMeyerhans andH Kohler ldquoDominance of virus-specific CD8 T cells in humanprimary cytomegalovirus infectionrdquo Journal of the AmericanSociety of Nephrology vol 13 no 10 pp 2577ndash2584 2002

[105] A Kasuga R Harada and T Saruta ldquoInsulin-dependent dia-betes mellitus associated with parvovirus B19 infectionrdquoAnnalsof Internal Medicine vol 125 no 8 pp 700ndash701 1996

[106] P Vigeant H AMenard andG Boire ldquoChronicmodulation ofthe autoimmune response following parvovirus B19 infectionrdquoJournal of Rheumatology vol 21 no 6 pp 1165ndash1167 1994

[107] M C Honeyman N L Stone B A Falk G Nepom and LC Harrison ldquoEvidence for molecular mimicry between humanT cell epitopes in rotavirus and pancreatic islet autoantigensrdquoJournal of Immunology vol 184 no 4 pp 2204ndash2210 2010

[108] F Ginsberg-Fellner M E Witt S Yagihashi et al ldquoCongenitalrubella syndrome as a model for Type 1 (insulin-dependent)diabetes mellitus increased prevalence of islet cell surfaceantibodiesrdquo Diabetologia vol 27 no 1 pp 87ndash89 1984

[109] D Ou L A Mitchell D L Metzger S Gillam and A J TingleldquoCross-reactive rubella virus and glutamic acid decarboxylase(65 and 67) protein determinants recognised by T cells ofpatients with type I diabetes mellitusrdquo Diabetologia vol 43 no6 pp 750ndash762 2000

[110] M G Cavallo M G Baroni A Toto et al ldquoViral infectioninduces cytokine release by beta islet cellsrdquo Immunology vol 75no 4 pp 664ndash668 1992

[111] H Hyoty P Parkkonen M Rode O Bakke and P LeinikkildquoCommon peptide epitope in mumps virus nucleocapsid pro-tein andMHCclass II-associated invariant chainrdquo ScandinavianJournal of Immunology vol 37 no 5 pp 550ndash558 1993

[112] B Conrad R N Weissmahr J Boni R Arcari J Schupbachand B Mach ldquoA human endogenous retroviral superantigen as

candidate autoimmune gene in type I diabetesrdquoCell vol 90 no2 pp 303ndash313 1997

[113] G Tapia O Cinek T Rasmussen B Grinde L C Stene andK S Roslashnningen ldquoLongitudinal study of parechovirus infectionin infancy and risk of repeated positivity for multiple isletautoantibodies theMIDIA studyrdquoPediatric Diabetes vol 12 no1 pp 58ndash62 2011

[114] G R Vreugdenhil N C Schloot A Hoorens et al ldquoAcute onsetof type I diabetes mellitus after severe echovirus 9 infectionputative pathogenic pathwaysrdquo Clinical Infectious Diseases vol31 no 4 pp 1025ndash1031 2000

[115] J W Yoon T Onodera and A L Notkins ldquoVirus-induceddiabetes mellitus XV Beta cell damage and insulin-dependenthyperglycemia in mice infected with coxsackie virus B4rdquo TheJournal of Experimental Medicine vol 148 no 4 pp 1068ndash10801978

[116] M Lonnrot K Salminen and M Knip ldquoEnterovirus RNA inserum is a risk factor for beta-cell autoimmunity and clinicaltype 1 diabetes a prospective study Childhood Diabetes inFinland (DiMe) Study Grouprdquo Journal of Medical Virology vol61 no 2 pp 214ndash220 2000

[117] DV Serreze EWOttendorfer TM Elliss C J Gauntt andMA Atkinson ldquoAcceleration of type 1 diabetes by a coxsackievirusinfection requires a preexisting critical mass of autoreactive T-cells in pancreatic isletsrdquo Diabetes vol 49 no 5 pp 708ndash7112000

[118] M S Horwitz L M Bradley J Harbertson T Krahl J Lee andN Sarvetnick ldquoDiabetes induced by Coxsackie virus initiationby bystander damage and not molecular mimicryrdquo NatureMedicine vol 4 no 7 pp 781ndash785 1998

[119] A Willcox S J Richardson A J Bone A K Foulis and NG Morgan ldquoImmunohistochemical analysis of the relationshipbetween islet cell proliferation and the production of theenteroviral capsid protein VP1 in the islets of patients withrecent-onset type 1 diabetesrdquo Diabetologia vol 54 no 9 pp2417ndash2420 2011

[120] B M Schulte M Kramer M Ansems et al ldquoPhagocytosis ofenterovirus-infected pancreatic 120573-cells triggers innate immuneresponses in human dendritic cellsrdquo Diabetes vol 59 no 5 pp1182ndash1191 2010

[121] F Brilot V Geenen D Hober and C A Stoddart ldquoCoxsack-ievirus B4 infection of human fetal thymus cellsrdquo Journal ofVirology vol 78 no 18 pp 9854ndash9861 2004

[122] M Oikarinen S Tauriainen T Honkanen et al ldquoDetection ofenteroviruses in the intestine of type 1 diabetic patientsrdquoClinicaland Experimental Immunology vol 151 no 1 pp 71ndash75 2008

[123] I S Yap G Giddings E Pocock and J K Chantler ldquoLackof islet neogenesis plays a key role in beta-cell depletion inmice infected with a diabetogenic variant of coxsackievirus B4rdquoJournal of General Virology vol 84 no 11 pp 3051ndash3068 2003

[124] K PWardW H Galloway and I A Auchterlonie ldquoCongenitalcytomegalovirus infection and diabetesrdquo The Lancet vol 1 no8114 article 497 1979

[125] C Y Pak C Y Cha R V Rajotte R G McArthur andJ W Yoon ldquoHuman pancreatic islet cell specific 38 kilodal-ton autoantigen identified by cytomegalovirus-induced mono-clonal islet cell autoantibodyrdquo Diabetologia vol 33 no 9 pp569ndash572 1990

[126] K Numazaki H Goldman I Wong and M A WainbergldquoViral infection of human fetal islets of Langerhans Replicationof human cytomegalovirus in cultured human fetal pancreatic


isletsrdquo American Journal of Clinical Pathology vol 90 no 1 pp52ndash57 1988

[127] M J Smelt M M Faas B J de Haan et al ldquoRat pancreatic betacells and cytomegalovirus infectionrdquo Pancreas vol 39 no 1 pp47ndash56 2010

[128] J Aarnisalo R Veijola R Vainionpaa O Simell M Knip andJ Ilonen ldquoCytomegalovirus infection in early infancy risk ofinduction and progression of autoimmunity associated withtype 1 diabetesrdquo Diabetologia vol 51 no 5 pp 769ndash772 2008

[129] S-A Ivarsson B Lindberg K O Nilsson K Ahlfors andL Svanberg ldquoThe prevalence of type 1 diabetes mellitusat follow-up of Swedish infants congenitally infected withcytomegalovirusrdquo Diabetic Medicine vol 10 no 6 pp 521ndash5231993

[130] A K Foulis M McGill M A Farquharson and D A HiltonldquoA search for evidence of viral infection in pancreases of newlydiagnosed patients with IDDMrdquoDiabetologia vol 40 no 1 pp53ndash61 1997

[131] N Itoh T Hanafusa K Yamagata et al ldquoNo detectablecytomegalovirus and Epstein-Barr virus genomes in the pan-creas of recent-onset IDDM patientsrdquo Diabetologia vol 38 no6 pp 667ndash671 1995

[132] Y Munakata T Kodera T Saito and T Sasaki ldquoRheumatoidarthritis type 1 diabetes and Gravesrsquo disease after acute par-vovirus B19 infectionrdquoTheLancet vol 366 no 9487 article 7802005

[133] A vonPoblotzki CGerdesU ReischlHWolf and SModrowldquoLymphoproliferative responses after infection with humanparvovirus B19rdquo Journal of Virology vol 70 no 10 pp 7327ndash7330 1996

[134] D Zipris J-L Hillebrands R M Welsh et al ldquoInfectionsthat induce autoimmune diabetes in BBDR rats modulateCD4+CD25+ T cell populationsrdquo The Journal of Immunologyvol 170 no 7 pp 3592ndash3602 2003

[135] D Zipris E Lien J X Xie D L Greiner J P Mordes and AA Rossini ldquoTLR activation synergizes with Kilham rat virusinfection to induce diabetes in BBDR ratsrdquo The Journal ofImmunology vol 174 no 1 pp 131ndash142 2005

[136] M C Honeyman B S Coulson N L Stone et al ldquoAssociationbetween rotavirus infection and pancreatic islet autoimmunityin children at risk of developing type 1 diabetesrdquo Diabetes vol49 no 8 pp 1319ndash1324 2000

[137] K L Graham N Sanders Y Tan J Allison T W H Kay andB S Coulson ldquoRotavirus infection accelerates type 1 diabetes inmice with established insulitisrdquo Journal of Virology vol 82 no13 pp 6139ndash6149 2008

[138] J A Pane N LWebster and B S Coulson ldquoRotavirus activateslymphocytes from non-obese diabetic mice by triggering toll-like receptor 7 signaling and interferon production in plasma-cytoid dendritic cells rdquo PLoS Pathogens vol 10 no 3 Article IDe1003998 2014

[139] E A M Gale ldquoCongenital rubella citation virus or viral causeof type 1 diabetesrdquo Diabetologia vol 51 no 9 pp 1559ndash15662008

[140] B Lindberg K Ahlfors A Carlsson et al ldquoPrevious exposureto measles mumps and rubellamdashbut not vaccination duringadolescencemdashcorrelates to the prevalence of pancreatic andthyroid autoantibodiesrdquo Pediatrics vol 104 no 1 article e121999

[141] F Ramondetti S Sacco M Comelli et al ldquoType 1 diabetesandmeasles mumps and rubella chilhood infections within the

Italian Insulin dependent diabetes regitstryrdquo Diabetic Medicinevol 29 no 6 pp 761ndash766 2011

[142] P Parkkonen H Hyoty L Koskinen and P Leinikki ldquoMumpsvirus infects Beta cells in human fetal islet cell cultures upreg-ulating the expression of HLA class I moleculesrdquo Diabetologiavol 35 no 1 pp 63ndash69 1992

[143] K Helmke A Otten and W Willems ldquoIslet cell antibodies inchildren with mumps infectionrdquoThe Lancet vol 2 no 8187 pp211ndash212 1980

[144] H Hyoty M Hiltunen A Reunanen et al ldquoDecline of mumpsantibodies in type 1 (insulin-dependent) diabetic children anda plateau in the rising incidence of type 1 diabetes after intro-duction of the mumps-measles-rubella vaccine in FinlandrdquoDiabetologia vol 36 no 12 pp 1303ndash1308 1993

[145] R Lower J Lower and R Kurth ldquoThe viruses in all of us char-acteristics and biological significance of human endogenousretrovirus sequencesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 93 no 11 pp 5177ndash5184 1996

[146] E Balada M Vilardell-Tarres and J Ordi-Ros ldquoImplicationof human endogenous retroviruses in the development ofautoimmune diseasesrdquo International Reviews of Immunologyvol 29 no 4 pp 351ndash370 2010

[147] M S Oberste E Gotuzzo P Blair et al ldquoHuman febrileillness caused by encephalomyocarditis virus infection perurdquoEmerging Infectious Diseases vol 15 no 4 pp 640ndash646 2009

[148] S Nagafuchi M Teshima Y Kai et al ldquoThe significanceof tyrosine kinase 2 gene in encephalomyocarditis-D virus-induced diabetes as studied in Tyk2 gene knockout mice(P6334)rdquo Journal of Immunology vol 190 pp 182ndash119 2013(Meeting Abstract Supplement)

[149] B Niklasson K E Heller B Schoslashnecker et al ldquoDevelopmentof type 1 diabetes in wild bank voles associated with isletautoantibodies the novel Ljungan virusrdquoExperimentalDiabesityResearch vol 4 no 1 pp 35ndash44 2003

[150] M Roivainen P Ylipaasto C Savolainen J Galama T Hoviand T Otonkoski ldquoFunctional impairment and killing ofhuman beta cells by enteroviruses the capacity is shared by awide range of serotypes but the extent is a characteristic ofindividual virus strainsrdquo Diabetologia vol 45 no 5 pp 693ndash702 2002

[151] E Cabrera-Rode L Sarmiento C Tiberti et al ldquoType 1 diabetesislet associated antibodies in subjects infected by echovirus 16rdquoDiabetologia vol 46 no 10 pp 1348ndash1353 2003

[152] E Cabrera-Rode L Sarmiento G Molina et al ldquoIslet cellrelated antibodies and type 1 diabetes associated with echovirus30 epidemic a case reportrdquo Journal of Medical Virology vol 76no 3 pp 373ndash377 2005

[153] O Diaz-Horta L Sarmiento A Baj E Cabrera-Rode andA Toniolo ldquoEchovirus epidemics autoimmunity and type1 diabetesrdquo in Type 1 Diabetes - Pathogenesis Genetics andImmunotherapy D Wagner Ed pp 211ndash230 InTech 2011httpwwwintechopencombookstype-1-diabetes-pathogen-esis-genetics-and-immunotherapyechovirus-epidemics-auto-immunity-and-type-1-diabetes

[154] H Hyoty and K W Taylor ldquoThe role of viruses in humandiabetesrdquo Diabetologia vol 45 no 10 pp 1353ndash1361 2002

[155] T Otonkoski M Roivainen O Vaarala et al ldquoNeonatal Type Idiabetes associated with maternal echovirus 6 infection a casereportrdquo Diabetologia vol 43 no 10 pp 1235ndash1238 2000

[156] C H Williams S Oikarinen S Tauriainen K Salminen HHyoty and G Stanway ldquoMolecular analysis of an echovirus 3


strain isolated from an individual concurrently with appearanceof islet cell and IA-2 autoantibodiesrdquo Journal of Clinical Micro-biology vol 44 no 2 pp 441ndash448 2006

[157] M L Sussman L Strauss and H L Hodes ldquoFatal coxsackiegroup B virus infection in the newborn report of a case withnecropsy findings and brief review of the literaturerdquo AmericanJournal of Diseases of Children vol 97 no 4 pp 483ndash492 1959

[158] D R GambleM L KinsleyM G FitzGerald R Bolton andKWTaylor ldquoViral antibodies in diabetesmellitusrdquoBritishMedicalJournal vol 3 no 671 pp 627ndash630 1969

[159] L Andreoletti DHober CHober-Vandenberghe et al ldquoDetec-tion of coxsackie B virus RNA sequences in whole bloodsamples from adult patients at the onset of type I diabetesmellitusrdquo Journal of Medical Virology vol 52 no 2 pp 121ndash1271997

[160] K Sadeharju A-M Hamalainen M Knip et al ldquoEnterovirusinfections as a risk factor for type I diabetes virus analysesin a dietary intervention trialrdquo Clinical and ExperimentalImmunology vol 132 no 2 pp 271ndash277 2003

[161] S Tauriainen S Oikarinen M Oikarinen and H HyotyldquoEnteroviruses in the pathogenesis of type 1 diabetesrdquo Seminarsin Immunopathology vol 33 no 1 pp 45ndash55 2011

[162] L Sarmiento E Cabrera-Rode L Lekuleni et al ldquoOccurrenceof enterovirus RNA in serum of children with newly diagnosedtype 1 diabetes and islet cell autoantibody-positive subjectsin a population with a low incidence of type 1 diabetesrdquoAutoimmunity vol 40 no 7 pp 540ndash545 2007

[163] M Karvonen M Viik-Kajander E Moltchanova I LibmanR LaPorte and J Tuomilehto ldquoIncidence of childhood type 1diabetesworldwiderdquoDiabetes Care vol 23 no 10 pp 1516ndash15262000

[164] J W Yoon M Austin T Onodera and A L Notkins ldquoVirus-induced diabetesmellitus Isolation of a virus from the pancreasof a child with diabetic ketoacidosisrdquoThe New England Journalof Medicine vol 300 no 21 pp 1173ndash1179 1979

[165] K M Drescher K Kono S Bopegamage S D Carson andS Tracy ldquoCoxsackievirus B3 infection and type 1 diabetesdevelopment in NOD mice Insulitis determines susceptibilityof pancreatic islets to virus infectionrdquo Virology vol 329 no 2pp 381ndash394 2004

[166] T Kanno K Kim K Kono K M Drescher N M Chapmanand S Tracy ldquoGroup B coxsackievirus diabetogenic phenotypecorrelates with viral replication efficiencyrdquo Journal of Virologyvol 80 no 11 pp 5637ndash5643 2006

[167] S Tracy K M Drescher N M Chapman et al ldquoTowardtesting the hypothesis that groupB coxsackieviruses (CVB) trig-ger insulin-dependent diabetes inoculating nonobese diabeticmice with CVB markedly lowers diabetes incidencerdquo Journal ofVirology vol 76 no 23 pp 12097ndash12111 2002

[168] SOikarinen S TauriainenDHober et al ldquoVirus antibody sur-vey in different european populations indicates risk associationbetween coxsackievirus B1 and type 1 diabetesrdquo Diabetes vol63 no 2 pp 655ndash662 2014

[169] O H Laitinen H Honkanen O Pakkanen et al ldquoCoxsack-ievirus B1 is associated with induction of 120573-cells autoimmunitythat portends type 1 diabetesrdquo Diabetes vol 63 no 2 pp 446ndash455 2014

[170] S Bopegamage J Precechtelova L Marosova et al ldquoOutcomeof challenge with coxsackievirus B4 in young mice after mater-nal infection with the same virus during gestationrdquo FEMSImmunology ampMedicalMicrobiology vol 64 no 2 pp 184ndash1902012

[171] P G Larsson T Lakshmikanth E Svedin C King andM Flodstrom-Tullberg ldquoPrevious maternal infection protectsoffspring from enterovirus infection and prevents experimentaldiabetes development in micerdquo Diabetologia vol 56 no 4 pp867ndash874 2013

[172] G Frisk and H Diderholm ldquoTissue culture of isolated humanpancreatic islets infected with different strains of Coxsack-ievirus B4 assessment of virus replication and effects onislet morphology and insulin releaserdquo Experimental DiabesityResearch vol 1 no 3 pp 165ndash175 2000

[173] M Roivainen S Rasilainen P Ylipaasto et al ldquoMechanisms ofcoxsackievirus-induced damage to human pancreatic 120573-cellsrdquoThe Journal of Clinical Endocrinology and Metabolism vol 85no 1 pp 432ndash440 2000

[174] S A Bopegamage and A Petrovicova ldquoIn vitro infectionof mouse pancreatic islet cells with coxsackie virusesrdquo ActaVirologica vol 38 no 5 pp 251ndash255 1994

[175] H Yin A-K Berg J Westman C Hellerstrom and G FriskldquoComplete nucleotide sequence of a coxsackievirus B-4 straincapable of establishing persistent infection in human pancreaticislet cells effects on insulin release proinsulin synthesis andcell morphologyrdquo Journal of Medical Virology vol 68 no 4 pp544ndash557 2002

[176] MRoivainen P Ylipaasto J Ustinov THovi andTOtonkoshildquoScreening enteroviruses for 120573-cell tropism using foetal porcine120573-cellsrdquo Journal of General Virology vol 82 no 8 pp 1909ndash19162001

[177] T M Szopa D R Gamble and K W Taylor ldquoBiochemicalchanges induced by Coxsackie B4 virus in short-term cultureof mouse pancreatic isletsrdquo Bioscience Reports vol 5 no 1 pp63ndash69 1985

[178] N Welsh B Margulis L A Borg et al ldquoDifferences in theexpression of heat-shock proteins and antioxidant enzymesbetween human and rodent pancreatic islets implicationsfor the pathogenesis of insulin-dependent diabetes mellitusrdquoMolecular Medicine vol 1 no 7 pp 806ndash820 1995

[179] G G Dahlquist J E Boman and P Juto ldquoEnteroviral RNA andIgM antibodies in early pregnancy and risk for childhood-onsetIDDM in offspringrdquo Diabetes Care vol 22 no 2 pp 364ndash3651999

[180] M Elfving J Svensson S Oikarinen et al ldquoMaternalenterovirus infection during pregnancy as a risk factor inoffspring diagnosedwith type 1 diabetes between 15 and 30 yearsof agerdquo Experimental diabetes research vol 2008 pp 271958ndash271964 2008

[181] H Viskari J Ludvigsson R Uibo et al ldquoRelationship betweenthe incidence of type 1 diabetes and maternal enterovirus anti-bodies time trends and geographical variationrdquo Diabetologiavol 48 no 7 pp 1280ndash1287 2005

[182] H R Viskari M Roivainen A Reunanen et al ldquoMaternal first-trimester enterovirus infection and future risk of type 1 diabetesin the exposed fetusrdquo Diabetes vol 51 no 8 pp 2568ndash25712002

[183] R Coutant J C Carel P Lebon L Cantero-Aguilar P Lebonand P F Bougneres ldquoDetection of enterovirus RNA sequencesin serum samples from autoantibody-positive subjects at riskfor diabetesrdquo Diabetic Medicine vol 19 no 11 pp 968ndash9692002

[184] G Frisk and H Diderholm ldquoAntibody responses to differentstrains of Coxsackie B4 virus in patients with newly diagnosedtype I diabetes mellitus or aseptic meningitisrdquo Journal ofInfection vol 34 no 3 pp 205ndash210 1997


[185] G Frisk and T Tuvemo ldquoEnterovirus infections with 120573-celltropic strains are frequent in siblings of children diagnosedwithtype 1 diabetes children and in association with elevated levelsof GAD65 antibodiesrdquo Journal of Medical Virology vol 73 no3 pp 450ndash459 2004

[186] M M Maha M A Ali S E Abdel-Rehim E A Abu-ShadyB M El-Naggar and Y Z Maha ldquoThe role of coxsackievirusesinfection in the children of insulin dependent diabetes melli-tusrdquoThe Journal of the Egyptian Public Health Association vol78 no 3-4 pp 305ndash318 2003

[187] RVarela-Calvino R Ellis G Sgarbi CMDayan andM Peak-man ldquoCharacterization of the T-cell response to coxsackievirusB4 evidence that effectormemory cells predominate in patientswith type 1 diabetesrdquoDiabetes vol 51 no 6 pp 1745ndash1753 2002

[188] L C Stene S Oikarinen H Hyoty et al ldquoEnterovirus infectionand progression from islet autoimmunity to type 1 diabetesthe Diabetes and Autoimmunity Study in the Young (DAISY)rdquoDiabetes vol 59 no 12 pp 3174ndash3180 2010

[189] S OikarinenMMartiskainen S Tauriainen et al ldquoEnterovirusRNA in blood is linked to the development of type 1 diabetesrdquoDiabetes vol 60 no 1 pp 276ndash279 2011

[190] K K Salminen T Vuorinen S Oikarinen et al ldquoIsolationof enterovirus strains from children with preclinical Type 1diabetesrdquo Diabetic Medicine vol 21 no 2 pp 156ndash164 2004

[191] G G Dahlquist J Forsberg L Hagenfeldt J Boman and PJuto ldquoIncreased prevalence of enteroviral RNA in blood spotsfrom newborn children who later developed type 1 diabetes apopulation-based case-control studyrdquoDiabetes Care vol 27 no1 pp 285ndash286 2004

[192] G B Clements D N Galbraith and K W Taylor ldquoCoxsackieB virus infection and onset of childhood diabetesrdquo The Lancetvol 346 no 8969 pp 221ndash223 1995

[193] M E Craig N J Howard M Silink and W D RawlinsonldquoReduced frequency of HLA DRB1-03 DQB1-02 in childrenwith type 1 diabetes associated with enterovirus RNArdquo Journalof Infectious Diseases vol 187 no 10 pp 1562ndash1570 2003

[194] H Kawashima T Ihara H Ioi et al ldquoEnterovirus-related type 1diabetes mellitus and antibodies to glutamic acid decarboxylasein Japanrdquo Journal of Infection vol 49 no 2 pp 147ndash151 2004

[195] C Nairn D N Galbraith K W Taylor and G B ClementsldquoEnterovirus variants in the serum of children at the onsetoftype 1 diabetes mellitusrdquo Diabetic Medicine vol 16 no 6 pp509ndash513 1999

[196] H Yin A-K Berg T Tuvemo and G Frisk ldquoEnterovirus RNAis found in peripheral blood mononuclear cells in a majorityof type 1 diabetic children at onsetrdquo Diabetes vol 51 no 6 pp1964ndash1971 2002

[197] A Toniolo G Maccari G Federico et al ldquoAre enterovirusinfections linked to the early stages of type 1 diabetesrdquo inProceedings of the American Society for Microbiology MeetingCA Abst ST-902 San Diego Calif USA 2010

[198] B M Schulte J Bakkers K H W Lanke et al ldquoDetection ofenterovirus RNA in peripheral blood mononuclear cells of type1 diabetic patients beyond the stage of acute infectionrdquo ViralImmunology vol 23 no 1 pp 99ndash104 2010

[199] H Champsaur E Dussaix D Samolyk M Fabre C Bachand R Assan ldquoDiabetes and Coxsackie virus B5 infectionrdquoTheLancet vol 315 no 8162 p 251 1980

[200] C di Pietro M J del Guercio G P Paolino M Barbi PFerrante and G Chiumello ldquoType 1 diabetes and Coxsackievirus infectionrdquo Helvetica Paediatrica Acta vol 34 no 6 pp557ndash561 1979

[201] P Ylipaasto K Klingel A M Lindberg et al ldquoEnterovirusinfection in human pancreatic islet cells islet tropism invivo and receptor involvement in cultured islet beta cellsrdquoDiabetologia vol 47 no 2 pp 225ndash239 2004

[202] F Dotta S Censini A G S van Halteren et al ldquoCoxsackieB4 virus infection of 120573 cells and natural killer cell insulitis inrecent-onset type 1 diabetic patientsrdquoProceedings of theNationalAcademy of Sciences of the United States of America vol 104 no12 pp 5115ndash5120 2007

[203] M Oikarinen S Tauriainen T Honkanen et al ldquoAnalysis ofpancreas tissue in a child positive for islet cell antibodiesrdquoDiabetologia vol 51 no 10 pp 1796ndash1802 2008

[204] S J Richardson A Willcox A J Bone A K Foulis and NG Morgan ldquoThe prevalence of enteroviral capsid protein vp1immunostaining in pancreatic islets in human type 1 diabetesrdquoDiabetologia vol 52 no 6 pp 1143ndash1151 2009

[205] P Ylipaasto B Kutlu S Rasilainen et al ldquoGlobal profilingof coxsackievirus- and cytokine-induced gene expression inhuman pancreatic isletsrdquo Diabetologia vol 48 no 8 pp 1510ndash1522 2005

[206] D P Strachan ldquoHay fever hygiene and household sizerdquo BritishMedical Journal vol 299 no 6710 pp 1259ndash1260 1989

[207] J F Bach ldquoThe effect of infections on susceptibility to autoim-mune and allergic diseasesrdquo The New England Journal ofMedicine vol 347 no 12 pp 911ndash920 2002

[208] H S Lee T Briese CWinkler et al ldquoNext-generation sequenc-ing for viruses in children with rapid-onset type 1 diabetesrdquoDiabetologia vol 56 no 8 pp 1705ndash1711 2013

[209] T Boettler and M Von Herrath ldquoProtection against or trig-gering of Type 1 diabetes Different roles for viral infectionsrdquoExpert Review of Clinical Immunology vol 7 no 1 pp 45ndash532011

[210] N M Chapman K Coppieters M von Herrath and S TracyldquoThe microbiology of human hygiene and its impact on type 1diabetesrdquo Islets vol 4 no 4 pp 253ndash261 2012

[211] K M Drescher and S Tracy ldquoThe CVB and etiology of type 1diabetesrdquo Current Topics in Microbiology and Immunology vol323 pp 259ndash274 2008

[212] H Al-Hello B Davydova T Smura et al ldquoPhenotypic andgenetic changes in coxsackievirus B5 following repeated passagein mouse pancreas in vivordquo Journal of Medical Virology vol 75no 4 pp 566ndash574 2005

[213] M Flodstrom A Maday D Balakrishna M M Cleary AYoshimura and N Sarvetnick ldquoTarget cell defense prevents thedevelopment of diabetes after viral infectionrdquoNature Immunol-ogy vol 3 no 4 pp 373ndash382 2002

[214] G Frisk K Jansson M Ericsson and H Diderholm ldquoDiffer-ences in inhibition of replication between Coxsackie B4 virusstrains in various cell lines by antibodies to some cell surfaceproteinsrdquo Virus Research vol 73 no 2 pp 121ndash130 2001

[215] T M Szopa P A Titchener N D Portwood and K W TaylorldquoDiabetes mellitus due to virusemdashsome recent developmentsrdquoDiabetologia vol 36 no 8 pp 687ndash695 1993

[216] E Jaeckel M Manns and M von Herrath ldquoViruses anddiabetesrdquo Annals of the New York Academy of Sciences vol 958pp 7ndash25 2002

[217] S Skarsvik J Puranen J Honkanen et al ldquoDecreased in vitrotype 1 immune response against coxsackie virus B4 in childrenwith type 1 diabetesrdquoDiabetes vol 55 no 4 pp 996ndash1003 2006

[218] K Klingel S Stephan M Sauter et al ldquoPathogenesis of murineenterovirus myocarditis virus dissemination and immune celltargetsrdquo Journal of Virology vol 70 no 12 pp 8888ndash8895 1996


[219] B O Roep H S Hiemstra N C Schloot et al ldquoMolecularmimicry in type 1 diabetes immune cross-reactivity betweenislet autoantigen and human cytomegalovirus but not Cox-sackie virusrdquo Annals of the New York Academy of Sciences vol958 pp 163ndash165 2002

[220] M A Atkinson M A Bowman L Campbell B L DarrowD L Kaufman and N K Maclaren ldquoCellular immunityto a determinant common to glutamate decarboxylase andCoxsackie virus in insulin-dependent diabetesrdquo The Journal ofClinical Investigation vol 94 no 5 pp 2125ndash2129 1994

[221] W Richter T Mertens B Schoel et al ldquoSequence homologyof the diabetes-associated autoantigen glutamate decarboxylasewith coxsackie B4-2C protein and heat shock protein 60mediates no molecular mimicry of autoantibodiesrdquo Journal ofExperimental Medicine vol 180 no 2 pp 721ndash726 1994

[222] N C Schloot S JMWillemen G Duinkerken JWDrijfhoutR R P de Vries and B O Roep ldquoMolecular mimicry intype 1 diabetes mellitus revisited T-cell clones to GAD65peptides with sequence homology to coxsackie or proinsulinpeptides do not crossreact with homologous counterpartrdquoHuman Immunology vol 62 no 4 pp 299ndash309 2001

[223] R S Fujinami M G von Herrath U Christen and JL Whitton ldquoMolecular mimicry bystander activation orviral persistence infections and autoimmune diseaserdquo ClinicalMicrobiology Reviews vol 19 no 1 pp 80ndash94 2006

[224] M S Horwitz A Ilic C Fine E Rodriguez and N SarvetnickldquoPresented antigen from damaged pancreatic 120573 cells activatesautoreactive T cells in virus-mediated autoimmune diabetesrdquoJournal of Clinical Investigation vol 109 no 1 pp 79ndash87 2002

[225] G R Vreugdenhil P G Wijnands M G Netea J W Mvan der Meer W J G Melchers and J M D GalamaldquoEnterovirus-induced production of pro-inflammatory and T-helper cytokines by human leukocytesrdquo Cytokine vol 12 no 12pp 1793ndash1796 2000

[226] G R Vreugdenhil P G Wijnands M G Netea et al ldquoCox-sackie B virus induces TNF-120572 production in human pancreaticductal cellsrdquo in Enterovirus and Type 1 Diabetes Mellitus Puta-tive Pathogenic Pathways G R Vreugdenhil Ed dissertationthesis Print Panters Iskamp Enschede The Netherlands 2001

[227] M S Horwitz A Ilic C Fine B Balasa and N SarvetnickldquoCoxsackieviral-mediated diabetes induction requires antigen-presenting cells and is accompanied by phagocytosis of betacellsrdquo Clinical Immunology vol 110 no 2 pp 134ndash144 2004

[228] M S Horwitz C Fine A Ilic and N Sarvetnick ldquoRequire-ments for viral-mediated autoimmune diabetes 120573-cell damageand immune infiltrationrdquo Journal of Autoimmunity vol 16 no3 pp 211ndash217 2001

[229] D Hober W Chehadeh J Weill et al ldquoCirculating and cell-bound antibodies increase coxsackievirus B4-induced produc-tion of IFN-120572 by peripheral blood mononuclear cells frompatients with type 1 diabetesrdquo Journal of General Virology vol83 no 9 pp 2169ndash2176 2002

[230] W Chehadeh A Bouzidi G Alm P Wattre and D HoberldquoHuman antibodies isolated from plasma by affinity chro-matography increase the coxsackievirus B4-induced synthesisof interferon-120572 by human peripheral blood mononuclear cellsin vitrordquo Journal of General Virology vol 82 no 8 pp 1899ndash1907 2001

[231] D Hober W Chehadeh A Bouzidi and P Wattre ldquoAntibody-dependent enhancement of Coxsackievirus B4 infectivity ofhuman peripheral blood mononuclear cells results in increased

interferon-120572 synthesisrdquo Journal of Infectious Diseases vol 184no 9 pp 1098ndash1108 2001

[232] P Sauter P-E Lobert B Lucas et al ldquoRole of the capsidprotein VP4 in the plasma-dependent enhancement of theCoxsackievirus B4E2-infection of human peripheral bloodcellsrdquo Virus Research vol 125 no 2 pp 183ndash190 2007

[233] P Sauter W Chehadeh P-E Lobert et al ldquoA part of the VP4capsid protein exhibited by coxsackievirus B4 E2 is the targetof antibodies contained in plasma from patients with type 1diabetesrdquo Journal of Medical Virology vol 80 no 5 pp 866ndash878 2008

[234] J G RosmalenW van Ewijk and P J Leenen ldquoT-cell educationin autoimmune diabetes teachers and studentsrdquo Trends inImmunology vol 23 no 1 pp 40ndash46 2002

[235] F Brilot H Jaidane V Geenen and D Hober ldquoCoxsackievirusB4 infection of murine foetal thymus organ culturesrdquo Journal ofMedical Virology vol 80 no 4 pp 659ndash666 2008

[236] H Jaıdane J Gharbi P-E Lobert et al ldquoProlonged viral RNAdetection in blood and lymphoid tissues fromCoxsackievirus B4E2 orally-inoculated Swiss micerdquo Microbiology and Immunol-ogy vol 50 no 12 pp 971ndash974 2006

[237] H Jaıdane P Sauter F Sane A Goffard J Gharbi and DHober ldquoEnteroviruses and type 1 diabetes towards a betterunderstanding of the relationshiprdquo Reviews inMedical Virologyvol 20 no 5 pp 265ndash280 2010

[238] O Vaarala ldquoLeaking gut in type 1 diabetesrdquo Current Opinion inGastroenterolgy vol 24 no 6 pp 701ndash706 2008

[239] X Xu J DrsquoHoker G Stange et al ldquo120573 cells can be generated fromendogenous progenitors in injured adult mouse pancreasrdquo Cellvol 132 no 2 pp 197ndash207 2008

[240] S Bonner-Weir ldquo120573-cell turnover its assessment and implica-tionsrdquo Diabetes vol 50 no 1 pp S20ndashS24 2001

[241] M Almgren T Schlinzig D Gomez-Cabrero et al ldquoCesareandelivery and hematopoietic stem cell epigenetics in the new-born infant implications for future healthrdquo The AmericanJournal of Obstetric and Gynecology vol 211 no 5 pp 502e1ndash502e8 2014

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Himsworth reported the existence of two types of diabetesin 1935 ldquoinsulin sensitiverdquo (type I) and ldquoinsulin insensitiverdquo(type II) His work [6] was an important landmark in theunderstanding of diabetes and treatment strategies

2 Types of Diabetes Mellitus

Diabetes mellitus (DM) is classified as a group of metabolicdiseases with a typical clinical state of hyperglycemia (highblood glucose levels) which is an outcome of defectiveinsulin secretion insulin action or both [7] Hyperglycemiais correlated with typical acute diabetic symptoms thatinclude excessive urine production (polyuria) and high urinesugar levels (glycosuria) the consequences of which arethirst increased fluid intake (polydipsia) increased eating(polyphagia) weakness fatigue blurred vision unexplainedweight loss and lethargy Chronic hyperglycemia is furtherrelated to prolonged damage dysfunction and failure ofdifferent organs Secondary complications due to fluctuationsin blood glucose arise from vascular degeneration whichresults in damage of eyes kidneys nerves blood vesselsand heart causing dysfunction and failure of the organs oreventual gangrene with a probable loss of toes feet andlegs These complications decrease the quality of life and caneventually lead to premature death Table 1 shows the recentclassification of diabetes according to the American DiabetesAssociation and World Health Organization which includesfour clinical categories of diabetes [7ndash9] In this review wefocus on type 1 diabetes because it is the most commonendocrine disorder in children with a worldwide increase inincidence

Type 1 diabetes usually develops before the age of 30 withpeaks at 2 4ndash6 and 10ndash14 years of age Type 1 diabetes patientsdepend on external insulin (usually injected subcutaneously)for survival Approximately 5ndash10 of diabetics with type1 diabetes (T1D) show gradual destruction of the insulinproducing 120573-cells in the pancreas This destruction leads toabsolute insulin deficiencyThe disease usually appears when80ndash90 of the 120573-cells are destroyed [10 11]

Autoimmune-mediated destruction of 120573-cells has beenassociated with T1D because 85ndash90 of the cases showone or more autoantibodies [12] Some of the autoanti-gens described by different authors include enzyme glu-tamic acid decarboxylase (GAD65) [13] insulin (IAA) [14]insulinoma associated antigens (identified as tyrosine phos-phatases IA-2 and IA2120573) [15 16] islet cell antigens (ICA-69) [17] enzyme carboxypeptidase-H [18] GM-gangliosides[19] 38 kD autoantigen [20] sex determining region-Y boxprotein (SOX13) [21] and zinc transporter 8 protein (ZnT8A)also known as the solute carrier family 30 member 8(SLC30A8) [22] The presence of two or more antibodieshas been suggested as predictive markers for T1D [23 24]In the present times commercial kits are available and somelaboratories have developed in-house methods for detectionof some of these antibodies The predictive value of thesemarkers would be of importance for intervention measuresHowever it is difficult to identify the right time to measurethese antibodies Another unclear aspect is whether these

antibodies are produced after the cell destruction or ifantibodies induce the cellular destruction

Treatment of T1D usually consists of insulin admin-istration via injections or pumps Insulin therapy resultsin improvements yet T1D is considered to be a chronicdisease for which there is no prevention or cure The diseaseprogresses in the majority of diabetic patients and the result-ing dysglycemia leads to microangiopathic or neuropathiccomplications

3 Type 1 Diabetes Major HistocompatibilityComplex Related Genetic Factors

Type 1 diabetes is amultifactorial disorder requiring a geneticpredisposition and a trigger for the destructive process asobserved in other autoimmune diseases [25 26] T1D has astrong genetic component Relatives of diabetic patients havea high risk of developing the disease siblings have a greaterrisk than offspring and there is a high concordance rateamong identical twins [27 28] This genetic predisposition(or lack thereof) is determined by the balance betweensusceptibility and resistance alleles Among various factorsthe major histocompatibility complex (MHC) glycoproteinsare very important in the recognition of the tissues by theimmune system

Genetic wide association studies (GWAS) help to identifyand measure the DNA variations in the human genomeand identify disease risk factors in a given populationThis is done by measuring single nucleotide polymorphism(SNP) changes occurring frequently as single base pairchanges in the DNA sequences [29 30] These variationsare identified by genotyping using the next-generationsequencing and chip based microarray [31] Epigenome wideassociation studies (EWAS) using this modern technologyhave shown that besides the HLA-A HLA-B and HLA-DP1205731 other strong markers include HLA-DR1205731 HLA-DQ1205721 and HLA-DQ1205731 The HLA-DR1205731lowast0301 haplotypescarrying HLA-DR1205733lowast0202 alleles showed a higher riskthan HLA-DR1205731lowast0301 haplotypes carrying DR1205733lowast0101 inDR1205731lowast0301lowast0301 homozygotes with twoDR1205733lowast0101 alleles[31ndash35]

The human leukocyte antigen (HLA) region of the 6p21chromosome encodes glycoprotein of the MHC which hasa function in presenting antigenic peptides to T-cells MHCis a cluster of genes that are situated on the short armof chromosome 6 and vary in length depending on theirhaplotypes The MHC locus first discovered by Snell andHiggins [36] comprises 121 functional genes which includeall of the MHC class I and MHC class II genes MHCI molecules constitutively expressed in most cells presentantigens for binding to CD8+ T-cells and display peptidesfrom proteins synthesized within the cell On the otherhand MHC II molecules constitutively expressed in antigen-presenting cells (APCs) such asmacrophages dendritic cellsand B-cells are important to the human immune responsebecause they present peptide antigens to T-helper (CD4+)cells revealing peptides from engulfed proteins present inthymic stromal cells or antigen-presenting cells [37ndash39]


















4 Epigenetics




loci MHC class I



DP1205731DQ1205721DQ1205731DR1205731DR1205733 TNF-120572








MHC II





DR

DR-alpha



DR1205732DR1205733DR1205734














2 which is counted
































































vitro)


























Virus Mechanisms





Molecular mimicry

Antibody-dependent



Neogenesis




Coxsackieviruses


enhancement (ADE)








































11 Conclusion










Acknowledgments


References




































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

































4 Epigenetics




loci MHC class I



DP1205731DQ1205721DQ1205731DR1205731DR1205733 TNF-120572








MHC II





DR

DR-alpha



DR1205732DR1205733DR1205734














2 which is counted
































































vitro)


























Virus Mechanisms





Molecular mimicry

Antibody-dependent



Neogenesis




Coxsackieviruses


enhancement (ADE)








































11 Conclusion










Acknowledgments


References




































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















loci MHC class I



DP1205731DQ1205721DQ1205731DR1205731DR1205733 TNF-120572








MHC II





DR

DR-alpha



DR1205732DR1205733DR1205734














2 which is counted
































































vitro)


























Virus Mechanisms





Molecular mimicry

Antibody-dependent



Neogenesis




Coxsackieviruses


enhancement (ADE)








































11 Conclusion










Acknowledgments


References




































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















2 which is counted
































































vitro)


























Virus Mechanisms





Molecular mimicry

Antibody-dependent



Neogenesis




Coxsackieviruses


enhancement (ADE)








































11 Conclusion










Acknowledgments


References




































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




































































vitro)


























Virus Mechanisms





Molecular mimicry

Antibody-dependent



Neogenesis




Coxsackieviruses


enhancement (ADE)








































11 Conclusion










Acknowledgments


References




































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




























Virus Mechanisms





Molecular mimicry

Antibody-dependent



Neogenesis




Coxsackieviruses


enhancement (ADE)








































11 Conclusion










Acknowledgments


References




































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















































11 Conclusion










Acknowledgments


References




































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






















Acknowledgments


References




































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























































































































































































































































of






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