George S. Eisenbarth will remain in our memories as a brilliant scientist and great collaborator. His quest to discover the cause and prevention of type 1 (autoimmune) diabetes started from building predictive models based on immunogenetic markers. Despite his tremendous contributions to our understanding of the natural history of pre-type 1 diabetes and potential mechanisms, George left us with several big questions to answer before his quest is completed.
EisenbarthGS. Lilly Lecture 1986. Genes, generator of diversity, glycoconjugates, and autoimmune beta-cell insufficiency in type I diabetes. Diabetes, 1987; 36:355–364.
3.
Diabetes Epidemiology Research International Group: Secular trends in incidence of childhood IDDM in 10 countries. Diabetes Epidemiology Research International Group. Diabetes, 1990; 39:858–864.
4.
RewersM, BugawanTL, NorrisJM, BlairA, BeatyB, HoffmanM, McDuffieRSJr, HammanRF, KlingensmithG, EisenbarthGS, ErlichHA. Newborn screening for HLA markers associated with IDDM: Diabetes Autoimmunity Study in the Young (DAISY)Diabetologia, 1996; 39:807–812.
5.
NorrisJM, BeatyB, KlingensmithG, YuL, HoffmanM, ChaseHP, ErlichHA, HammanRF, EisenbarthGS, RewersM. Lack of association between early exposure to cow's milk protein, beta-cell autoimmunity. Diabetes Autoimmunity Study in the Young (DAISY)JAMA, 1996; 276:609–614.
6.
SteckAK, BarrigaKJ, EmeryLM, Fiallo-ScharerRV, GottliebPA, RewersMJ. Secondary attack rate of type 1 diabetes in Colorado families. Diabetes Care, 2005; 28:296–300.
7.
RewersM, EisenbarthGE, NorrisJM, ErlichH, BeatyB, KlingensmithG, ElliottRB. Population and familial risk of beta-cell autoimmunity in the first two years of life: Diabetes Autoimmunity Study in the Young [abstract]Diabetologia, 1996; 39,Suppl 1:15.
8.
BarkerJM, BarrigaKJ, YuL, MiaoD, ErlichHA, NorrisJM, EisenbarthGS, RewersM. Prediction of autoantibody positivity and progression to type 1 diabetes: Diabetes Autoimmunity Study in the Young (DAISY)J Clin Endocrinol Metab, 2004; 89:3896–3902.
9.
StanleyHM, NorrisJM, BarrigaK, HoffmanM, YuL, MiaoD, ErlichHA, EisenbarthGS, RewersM. Is presence of islet autoantibodies at birth associated with development of persistent islet autoimmunity? The Diabetes Autoimmunity Study in the Young (DAISY)Diabetes Care, 2004; 27:497–502.
10.
SteckAK, JohnsonK, BarrigaKJ, MiaoD, YuL, HuttonJC, EisenbarthGS, RewersMJ. Age of islet autoantibody appearance and mean levels of insulin, but not GAD or IA-2 autoantibodies, predict age of diagnosis of type 1 diabetes: Diabetes Autoimmunity Study in the Young. Diabetes Care, 2011; 34:1397–1399.
RewersA, BabuS, WangTB, BugawanTL, BarrigaK, EisenbarthGS, ErlichHA. Ethnic differences in the associations between the HLA-DRB1*04 subtypes and type 1 diabetes. Ann N Y Acad Sci, 2003; 1005:301–309.
13.
BaschalEE, AlyTA, BabuSR, FernandoMS, YuL, MiaoD, BarrigaKJ, NorrisJM, NobleJA, ErlichHA, RewersM, EisenbarthGS. HLA-DPB1*0402 protects against type 1A diabetes autoimmunity in the highest risk DR3-DQB1*0201/DR4-DQB1*0302 DAISY population. Diabetes, 2007; 56:2405–2409.
14.
RoblesDT, EisenbarthGS, WangT, ErlichHA, BugawanTL, BabuSR, BarrigaK, NorrisJM, HoffmanM, KlingensmithG, YuL, RewersM. Millennium award recipient contribution. Identification of children with early onset and high incidence of anti-islet autoantibodies. Clin.Immunol, 2002; 102:217–224.
15.
The Environmental Determinants of Diabetes in the Young (TEDDY) study:. study design. Pediatr Diabetes, 2007; 8:286–298.
16.
BarkerJM, TrioloTM, AlyTA, BaschalEE, BabuSR, KretowskiA, RewersMJ, EisenbarthGS. Two single nucleotide polymorphisms identify the highest-risk diabetes HLA genotype: potential for rapid screening. Diabetes, 2008; 57:3152–3155.
17.
AlyTA, IdeA, JahromiMM, BarkerJM, FernandoMS, BabuSR, YuL, MiaoD, ErlichHA, FainPR, BarrigaKJ, NorrisJM, RewersMJ, EisenbarthGS. Extreme genetic risk for type 1A diabetes. Proc Natl Acad Sci U S A, 2006; 103:14074–14079.
18.
IdeA, BabuSR, RoblesDT, WangT, ErlichHA, BugawanTL, RewersM, FainPR, EisenbarthGS. Homozygosity for premature stop codon of the MHC class I chain-related gene A (MIC-A) is associated with early activation of islet autoimmunity of DR3/4-DQ2/8 high risk DAISY relatives. J Clin Immunol, 2005; 25:303–308.
19.
IdeA, BabuSR, RoblesDT, WangT, ErlichHA, BugawanTL, RewersM, FainPR, EisenbarthGS. “Extended” A1, B8, DR3 haplotype shows remarkable linkage disequilibrium but is similar to nonextended haplotypes in terms of diabetes risk. Diabetes, 2005; 54:1879–1883.
BaschalEE, AlyTA, JasinskiJM, SteckAK, NobleJA, ErlichHA, EisenbarthGS. Defining multiple common “completely” conserved major histocompatibility complex SNP haplotypes. Clin Immunol, 2009; 132:203–214.
22.
BaschalEE, AlyTA, JasinskiJM, SteckAK, JohnsonKN, NobleJA, ErlichHA, EisenbarthGS. The frequent and conserved DR3-B8-A1 extended haplotype confers less diabetes risk than other DR3 haplotypes. Diabetes Obes.Metab, 2009; 11,Suppl 1:25–30.
23.
AlyTA, IdeA, HumphreyK, BarkerJM, SteckA, ErlichHA, YuL, MiaoD, RedondoMJ, McFannK, RobertsCM, BabuSR, NorrisJM, EisenbarthGS, RewersMJ. Genetic prediction of autoimmunity: initial oligogenic prediction of anti-islet autoimmunity amongst DR3/DR4-DQ8 relatives of patients with type 1A diabetes. J Autoimmun, 2005; 25,Suppl:40–45.
24.
AlyTA, BaschalEE, JahromiMM, FernandoMS, BabuSR, FingerlinTE, KretowskiA, ErlichHA, FainPR, RewersMJ, EisenbarthGS. Analysis of single nucleotide polymorphisms identifies major type 1A diabetes locus telomeric of the major histocompatibility complex. Diabetes, 2008; 57:770–776.
25.
BaschalEE, EisenbarthGS. Extreme genetic risk for type 1A diabetes in the post-genome era. J Autoimmun, 2008; 31:1–6.
26.
ClaytonDG. Prediction and interaction in complex disease genetics: experience in type 1 diabetes. PLoS Genet, 2009; 5:e1000540.
27.
SteckAK, LiuSY, McFannK, BarrigaKJ, BabuSR, EisenbarthGS, RewersMJ, SheJX. Association of the PTPN22/LYP gene with type 1 diabetes. Pediatr Diabetes, 2006; 7:274–278.
28.
SteckAK, ZhangW, BugawanTL, BarrigaKJ, BlairA, ErlichHA, EisenbarthGS, NorrisJM, RewersMJ. Do non-HLA genes influence development of persistent islet autoimmunity and type 1 diabetes in children with high-risk HLA-DR,DQ genotypes?Diabetes, 2009; 58:1028–1033.
29.
SteckAK, BugawanTL, ValdesAM, EmeryLM, BlairA, NorrisJM, RedondoMJ, BabuSR, ErlichHA, EisenbarthGS, RewersMJ. Association of non-HLA genes with type 1 diabetes autoimmunity. Diabetes, 2005; 54:2482–2486.
30.
NorrisJM, EisenbarthGS, BeatyB, GiclasP, YuL, KlingensmithG, RewersM. Dietary antibodies, infant diet, beta-cell autoimmunity: Diabetes Autoimmunity Study in the Young (DAISY) [abstract]Autoimmunity, 1995; 21:22-A082.
31.
NorrisJM, BarrigaK, KlingensmithG, HoffmanM, EisenbarthGS, ErlichHA, RewersM. Timing of initial cereal exposure in infancy and risk of islet autoimmunity. JAMA, 2003; 290:1713–1720.
32.
NorrisJM, YinX, LambMM, BarrigaK, SeifertJ, HoffmanM, OrtonHD, BaronAE, Clare-SalzlerM, ChaseHP, SzaboNJ, ErlichH, EisenbarthGS, RewersMJ. Omega-3 polyunsaturated fatty acid intake and islet autoimmunity in children at increased risk for type 1 diabetes. JAMA, 2007; 298:1420–1428.
33.
NorrisJM, YinX, MillerMR, Clare-SalzerM, RewersM. Erythrocyte membrane omega-3 fatty acid levels are not associated with the conversion to type 1 diabetes in children with islet autoimmunity. The Diabetes Autoimmunity Study in the Young (DAISY) [abstract]Diabetes, 2010; 59,Suppl 1:A72.
34.
SimpsonM, BradyH, EisenbarthGS, RewersM, ErlichHA, NorrisJM. No association between vitamin D levels and the risk for islet autoimmunity and type 1 diabetes: DAISY. Diabetologia, 2009; 52,Suppl 1:S118–S119.
35.
NorrisJM, BarrigaK, HoffenbergEJ, TakiI, MiaoD, HaasJE, EmeryLM, SokolRJ, ErlichHA, EisenbarthGS, RewersM. Risk of celiac disease autoimmunity and timing of gluten introduction in the diet of infants at increased risk of disease. JAMA, 2005; 293:2343–2351.
36.
PooleJA, BarrigaK, LeungDY, HoffmanM, EisenbarthGS, RewersM, NorrisJM. Timing of initial exposure to cereal grains and the risk of wheat allergy. Pediatrics, 2006; 117:2175–2182.
37.
SteneLC, BarrigaK, NorrisJM, HoffmanM, KlingensmithG, ErlichHA, EisenbarthGS, RewersM. Symptoms of common maternal infections in pregnancy and risk of islet autoimmunity in early childhood. Diabetes Care, 2003; 26:3136–3141.
38.
SteneLC, BarrigaK, NorrisJM, HoffmanM, ErlichHA, EisenbarthGS, McDuffieRSJr, RewersM. Perinatal factors and development of islet autoimmunity in early childhood: the Diabetes Autoimmunity Study in the Young. Am J Epidemiol, 2004; 160:3–10.
39.
Snell-BergeonJK, SmithJ, DongF, BaronAE, BarrigaK, NorrisJM, RewersM. Early childhood infections and the risk of islet autoimmunity: the Diabetes Autoimmunity Study in the Young (DAISY)Diabetes Care, 2012; 35:2553–2558.
40.
StrachanDP. Hay fever, hygiene, and household size. BMJ, 1989; 299:1259–1260.
41.
ChatenoudL, YouS, OkadaH, KuhnC, MichaudB, BachJF. 99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: immune therapies of type 1 diabetes: new opportunities based on the hygiene hypothesis. Clin Exp Immunol, 2010; 160:106–112.
42.
GravesPM, BarrigaKJ, NorrisJM, HoffmanMR, YuL, EisenbarthGS, RewersM. Lack of association between early childhood immunizations and beta-cell autoimmunity. Diabetes Care, 1999; 22:1694–1697.
43.
SteneLC, OikarinenS, HyötyH, BarrigaKJ, NorrisJM, KlingensmithGJ, HuttonJC, ErlichHA, EisenbarthGS, RewersM. Enterovirus infection and progression from islet autoimmunity to type 1 diabetes: the Diabetes and Autoimmunity Study in the Young (DAISY)Diabetes, 2010; 59:3174–3180.
44.
ZieglerAG, SchmidS, HuberD, HummelM, BonifacioE. Early infant feeding and risk of developing type 1 diabetes-associated autoantibodies. JAMA, 2003; 290:1721–1728.
45.
VirtanenSM, KenwardMG, ErkkolaM, KautiainenS, Kronberg-KippilaC, HakulinenT, AhonenS, UusitaloL, NiinistoS, VeijolaR, SimellO, IlonenJ, KnipM. Age at introduction of new foods and advanced beta cell autoimmunity in young children with HLA-conferred susceptibility to type 1 diabetes. Diabetologia, 2006; 49:1512–1521.
46.
SteneLC, BarrigaK, HoffmanM, KeanJ, KlingensmithG, NorrisJM, ErlichHA, EisenbarthGS, RewersM. Normal but increasing hemoglobin A1c levels predict progression from islet autoimmunity to overt type 1 diabetes: Diabetes Autoimmunity Study in the Young (DAISY)Pediatr Diabetes, 2006; 7:247–253.
47.
BarkerJM, GoehrigSH, BarrigaK, HoffmanM, SloverR, EisenbarthGS, NorrisJM, KlingensmithGJ, RewersM. Clinical characteristics of children diagnosed with type 1 diabetes through intensive screening and follow-up. Diabetes Care, 2004; 27:1399–1404.
48.
SteffesMW, SibleyS, JacksonM, ThomasW. Beta-cell function and the development of diabetes-related complications in the diabetes control and complications trial. Diabetes Care, 2003; 26:832–836.
49.
WenzlauJM, JuhlK, YuL, MouaO, SarkarSA, GottliebP, RewersM, EisenbarthGS, JensenJ, DavidsonHW, HuttonJC. The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc Natl Acad Sci U S A, 2007; 104:17040–17045.
KawasakiE, EisenbarthGS. High-throughput radioassays for autoantibodies to recombinant autoantigens. Front Biosci, 2000; 5:E181–E190.
55.
LiuY, WenzlauJM, YuL, PatelC, EisenbarthGS, HuttonJC, DavidsonHW. Conserved epitopes in the protein tyrosine phosphatase family of diabetes autoantigens. Ann N Y Acad Sci, 2008; 1150:245–247.
56.
ManiatisAK, YuL, MiaoD, NelsonK, EisenbarthGS. Rapid assays for detection of anti-islet autoantibodies: implications for organ donor screening. J Autoimmun, 2001; 16:71–76.
57.
MiaoD, YuL, TibertiC, CuthbertsonDD, RewersM, di MarioU, EisenbarthGS, DottaF. ICA512(IA-2) epitope specific assays distinguish transient from diabetes associated autoantibodies. J Autoimmun, 2002; 18:191–196.
58.
TibertiC, YuL, LucantoniF, PanimolleF, SpagnuoloI, LenziA, EisenbarthGS, DottaF. Detection of four diabetes specific autoantibodies in a single radioimmunoassay: an innovative high-throughput approach for autoimmune diabetes screening. Clin Exp Immunol, 2011; 166:317–324.
LiuE, BaoF, BarrigaK, MiaoD, YuL, ErlichHA, HaasJE, EisenbarthGS, RewersMJ, HoffenbergEJ. Fluctuating transglutaminase autoantibodies are related to histologic features of celiac disease. Clin Gastroenterol Hepatol, 2003; 1:356–362.
61.
LiuE, LiM, EmeryL, TakiI, BarrigaK, TibertiC, EisenbarthGS, RewersMJ, HoffenbergEJ. Natural history of antibodies to deamidated gliadin peptides and transglutaminase in early childhood celiac disease. J Pediatr Gastroenterol Nutr, 2007; 45:293–300.
62.
BaoF, YuL, BabuS, WangT, HoffenbergEJ, RewersM, EisenbarthGS. One third of HLA DQ2 homozygous patients with type 1 diabetes express celiac disease-associated transglutaminase autoantibodies. J Autoimmun, 1999; 13:143–148.
63.
LiM, YuL, TibertiC, BonamicoM, TakiI, MiaoD, MurrayJA, RewersMJ, HoffenbergEJ, AgardhD, MuellerP, SternM, BonifacioE, LiuE. A report on the International Transglutaminase Autoantibody Workshop for Celiac Disease. Am.J Gastroenterol, 2009; 104:154–163.
64.
LiuE, EisenbarthGS. Accepting clocks that tell time poorly: fluid-phase versus standard ELISA autoantibody assays. Clin Immunol, 2007; 125:120–126.
65.
LiuE, LiM, BaoF, MiaoD, RewersMJ, EisenbarthGS, HoffenbergEJ. Need for quantitative assessment of transglutaminase autoantibodies for celiac disease in screening-identified children. J Pediatr, 2005; 146:494–499.
66.
BarkerJM, IdeA, HostetlerC, YuL, MiaoD, FainPR, EisenbarthGS, GottliebPA. Endocrine and immunogenetic testing in individuals with type 1 diabetes and 21-hydroxylase autoantibodies: Addison's disease in a high-risk population. J Clin Endocrinol Metab, 2005; 90:128–134.
67.
ZhangL, BarkerJM, BabuS, SuM, StenersonM, ChengM, ShumA, ZamirE, BadolatoR, LawA, EisenbarthGS, AndersonMS. A robust immunoassay for anti-interferon autoantibodies that is highly specific for patients with autoimmune polyglandular syndrome type 1. Clin Immunol, 2007; 125:131–137.
68.
DeaneKD, NorrisJM, HolersVM. Preclinical rheumatoid arthritis: identification, evaluation, and future directions for investigation. Rheum Dis Clin North Am, 2010; 36:213–241.
69.
DeaneKD, O'DonnellCI, HueberW, MajkaDS, LazarAA, DerberLA, GillilandWR, EdisonJD, NorrisJM, RobinsonWH, HolersVM. The number of elevated cytokines/chemokines in pre-clinical seropositive rheumatoid arthritis predicts time to diagnosis in an age-dependent manner. Arthritis Rheum, 2010; 62:3161–3172.
70.
FerucciED, MajkaDS, ParrishLA, MoroldoMB, RyanM, PassoM, ThompsonSD, DeaneKD, RewersM, ArendWP, GlassDN, NorrisJM, HolersVM. Antibodies against cyclic citrullinated peptide are associated with HLA-DR4 in simplex and multiplex polyarticular-onset juvenile rheumatoid arthritis. Arthritis Rheum, 2005; 52:239–246.
71.
KolfenbachJR, DeaneKD, DerberLA, O'DonnellCI, GillilandWR, EdisonJD, RosenA, DarrahE, NorrisJM, HolersVM. Autoimmunity to peptidyl arginine deiminase type 4 precedes clinical onset of rheumatoid arthritis. Arthritis Rheum, 2010; 62:2633–2639.
72.
YuL, WangJ, O'DellJR, OatesJ, ArendWP, EisenbarthGS. Anti-dsDNA antibody assay: high specificity and sensitivity with a filtration radioassay in comparison to low specificity with the standard ELISA. J Rheumatol, 2007; 34:734–739.
73.
American Diabetes Association. Standards of medical care in diabetes—2007. Diabetes Care, 2007; 30,Suppl 1:S4–S41.
74.
HoffenbergEJ, MacKenzieT, BarrigaKJ, EisenbarthGS, BaoF, HaasJE, ErlichH, BugawanTT, SokolRJ, TakiI, NorrisJM, RewersM. A prospective study of the incidence of childhood celiac disease. J Pediatr, 2003; 143:308–314.
75.
HoffenbergEJ, EmeryLM, BarrigaKJ, BaoF, TaylorJ, EisenbarthGS, HaasJE, SokolRJ, TakiI, NorrisJM, RewersM. Clinical features of children with screening-identified evidence of celiac disease. Pediatrics, 2004; 113:1254–1259.
76.
RewersM. Epidemiology of celiac disease: what are the prevalence, incidence, and progression of celiac disease?Gastroenterology, 2005; 128,4 Suppl 1:S47–S51.
77.
RewersM, LiuE, SimmonsJ, RedondoMJ, HoffenbergEJ. Celiac disease associated with type 1 diabetes mellitus. Endocrinol Metab Clin North Am, 2004; 33:197–214xi.
78.
SimmonsJH, KlingensmithGJ, McFannK, RewersM, TaylorJ, EmeryLM, TakiI, VanyiS, LiuE, HoffenbergEJ. Impact of celiac autoimmunity on children with type 1 diabetes. J Pediatr, 2007; 150:461–466.
79.
SimmonsJH, KlingensmithGJ, McFannK, RewersM, IdeLM, TakiI, LiuE, HoffenbergEJ. Celiac autoimmunity in children with type 1 diabetes: a two-year follow-up. J Pediatr, 2011; 158:276–281.e1.
80.
SimpsonM, MojibianM, BarrigaK, ScottFW, FasanoA, RewersM, NorrisJM. An exploration of Glo-3A antibody levels in children at increased risk for type 1 diabetes mellitus. Pediatr Diabetes, 2009; 10:563–572.
81.
TaplinCE, MojibianM, SimpsonM, TakiI, LiuE, HoffenbergEJ, NorrisJM, ScottFW, RewersM. Antibodies to the wheat storage globulin Glo-3A in children before and at diagnosis of celiac disease. J Pediatr Gastroenterol Nutr, 2011; 52:21–25.
BarkerJM, YuJ, YuL, WangJ, MiaoD, BaoF, HoffenbergE, NelsonJC, GottliebPA, RewersM, EisenbarthGS. Autoantibody “subspecificity” in type 1 diabetes: risk for organ-specific autoimmunity clusters in distinct groups. Diabetes Care, 2005; 28:850–855.
84.
ChaseHP. Diabetes: A History of a Center and a Patient. Denver, CO: The Children's Diabetes Foundation at Denver, 2011.
85.
The Environmental Determinants of Diabetes in the Young (TEDDY) Study. Ann N Y Acad Sci, 2008; 1150:1–13.
86.
HagopianWA, ErlichH, LernmarkA, RewersM, ZieglerAG, SimellO, AkolkarB, VogtRJr., BlairA, IlonenJ, KrischerJ, SheJ. The Environmental Determinants of Diabetes in the Young (TEDDY): genetic criteria and international diabetes risk screening of 421 000 infants. Pediatr Diabetes, 2011; 12:733–743.
87.
BonifacioE, YuL, WilliamsAK, EisenbarthGS, BingleyPJ, MarcovinaSM, AdlerK, ZieglerAG, MuellerPW, SchatzDA, KrischerJP, SteffesMW, AkolkarB. Harmonization of glutamic acid decarboxylase and islet antigen-2 autoantibody assays for National Institute of Diabetes and Digestive and Kidney Diseases Consortia. J Clin Endocrinol Metab, 2010; 95:3360–3367.
88.
MichelsAW, OstrovDA, ZhangL, NakayamaM, FuseM, McDanielK, RoepBO, GottliebPA, AtkinsonMA, EisenbarthGS. Structure-based selection of small molecules to alter allele-specific MHC class II antigen presentation. J Immunol, 2011; 187:5921–5930.
89.
EisenbarthGS. Banting Lecture 2009: an unfinished journey: molecular pathogenesis to prevention of type 1A diabetes. Diabetes, 2010; 59:759–774.
