Enterovirus Infection and Progression From Islet Autoimmunity to Type 1 Diabetes

OBJECTIVE To investigate whether enterovirus infections predict progression to type 1 diabetes in genetically predisposed children repeatedly positive for islet autoantibodies. RESEARCH DESIGN AND METHODS Since 1993, the Diabetes and Autoimmunity Study in the Young (DAISY) has followed 2,365 genetically predisposed children for islet autoimmunity and type 1 diabetes. Venous blood and rectal swabs were collected every 3–6 months after seroconversion for islet autoantibodies (against GAD, insulin, or insulinoma-associated antigen-2 [IA-2]) until diagnosis of diabetes. Enteroviral RNA in serum or rectal swabs was detected using reverse transcriptase PCR with primers specific for the conserved 5′ noncoding region, detecting essentially all enterovirus serotypes. RESULTS Of 140 children who seroconverted to repeated positivity for islet autoantibodies at a median age of 4.0 years, 50 progressed to type 1 diabetes during a median follow-up of 4.2 years. The risk of progression to clinical type 1 diabetes in the sample interval following detection of enteroviral RNA in serum (three diabetes cases diagnosed among 17 intervals) was significantly increased compared with that in intervals following a negative serum enteroviral RNA test (33 cases diagnosed among 1,064 intervals; hazard ratio 7.02 [95% CI 1.95–25.3] after adjusting for number of autoantibodies). Results remained significant after adjustment for ZnT8-autoantibodies and after restriction to various subgroups. Enteroviral RNA in rectal swabs was not predictive of progression to type 1 diabetes. No evidence for viral persistence was found. CONCLUSIONS This novel observation suggests that progression from islet autoimmunity to type 1 diabetes may increase after an enterovirus infection characterized by the presence of viral RNA in blood.

[1]  H. Hyöty,et al.  Enteroviruses in the pathogenesis of type 1 diabetes , 2010, Seminars in Immunopathology.

[2]  M. Richer,et al.  Coxsackievirus infection as an environmental factor in the etiology of type 1 diabetes. , 2009, Autoimmunity reviews.

[3]  N. Morgan,et al.  The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes , 2009, Diabetologia.

[4]  M. Rewers,et al.  Newborn screening for HLA markers associated with IDDM: Diabetes Autoimmunity Study in the Young (DAISY) , 1996, Diabetologia.

[5]  M. Herrath.  Can We Learn From Viruses How to Prevent Type 1 Diabetes?: The Role of Viral Infections in the Pathogenesis of Type 1 Diabetes and the Development of Novel Combination Therapies , 2009 .

[6]  S. Virtanen,et al.  The Environmental Determinants of Diabetes in the Young (TEDDY) Study , 2008, Annals of the New York Academy of Sciences.

[7]  G. Eisenbarth,et al.  A Common Nonsynonymous Single Nucleotide Polymorphism in the SLC30A8 Gene Determines ZnT8 Autoantibody Specificity in Type 1 Diabetes , 2008, Diabetes.

[8]  A. Foulis.  Pancreatic pathology in type 1 diabetes in human. , 2008, Novartis Foundation symposium.

[9]  K. Kaukinen,et al.  Detection of enteroviruses in the intestine of type 1 diabetic patients , 2007, Clinical and experimental immunology.

[10]  Marian Rewers,et al.  The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes , 2007, Proceedings of the National Academy of Sciences.

[11]  U. Boggi,et al.  Coxsackie B4 virus infection of β cells and natural killer cell insulitis in recent-onset type 1 diabetic patients , 2007, Proceedings of the National Academy of Sciences.

[12]  O. Díaz‐Horta,et al.  Occurrence of enterovirus RNA in serum of children with newly diagnosed type 1 diabetes and islet cell autoantibody-positive subjects in a population with a low incidence of type 1 diabetes , 2007, Autoimmunity.

[13]  M. Rewers,et al.  Normal but increasing hemoglobin A1c levels predict progression from islet autoimmunity to overt type 1 diabetes: Diabetes Autoimmunity Study in the Young (DAISY) , 2006, Pediatric diabetes.

[14]  G. Palacios,et al.  High Prevalence of Human Enterovirus A Infections in Natural Circulation of Human Enteroviruses , 2006, Journal of Clinical Microbiology.

[15]  M. Atkinson,et al.  Diabetes Acceleration or Prevention by a Coxsackievirus B4 Infection: Critical Requirements for both Interleukin-4 and Gamma Interferon , 2005, Journal of Virology.

[16]  B. Anderson,et al.  Care of children and adolescents with type 1 diabetes: a statement of the American Diabetes Association. , 2005, Diabetes care.

[17]  S. Tracy,et al.  Coxsackievirus B3 infection and type 1 diabetes development in NOD mice: insulitis determines susceptibility of pancreatic islets to virus infection. , 2004, Virology.

[18]  M. Rewers,et al.  Prediction of autoantibody positivity and progression to type 1 diabetes: Diabetes Autoimmunity Study in the Young (DAISY). , 2004, The Journal of clinical endocrinology and metabolism.

[19]  M. Rewers,et al.  Clinical characteristics of children diagnosed with type 1 diabetes through intensive screening and follow-up. , 2004, Diabetes care.

[20]  J. Ilonen,et al.  Isolation of enterovirus strains from children with preclinical Type 1 diabetes , 2004, Diabetic medicine : a journal of the British Diabetic Association.

[21]  N. Sarvetnick,et al.  Coxsackieviral-mediated diabetes: induction requires antigen-presenting cells and is accompanied by phagocytosis of beta cells. , 2004, Clinical immunology.

[22]  Å. Lernmark,et al.  A novel radioligand binding assay to determine diagnostic accuracy of isoform-specific glutamic acid decarboxylase antibodies in childhood IDDM , 1994, Diabetologia.

[23]  K. Klingel,et al.  Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells , 2004, Diabetologia.

[24]  M. Craig,et al.  Reduced frequency of HLA DRB1*03-DQB1*02 in children with type 1 diabetes associated with enterovirus RNA. , 2003, The Journal of infectious diseases.

[25]  A. Hämäläinen,et al.  Enterovirus infections as a risk factor for type I diabetes: virus analyses in a dietary intervention trial , 2003, Clinical and experimental immunology.

[26]  A. Bruu,et al.  Enteroviruses: Polioviruses, Coxsackieviruses, Echoviruses and Newer Enteroviruses , 2003 .

[27]  J. Ilonen,et al.  Enterovirus infections are associated with the induction of β‐cell autoimmunity in a prospective birth cohort study , 2003, Journal of medical virology.

[28]  M. Rewers,et al.  Prospective study of enteroviral infections and development of beta-cell autoimmunity. Diabetes autoimmunity study in the young (DAISY). , 2003, Diabetes research and clinical practice.

[29]  H. Jun,et al.  A new look at viruses in type 1 diabetes. , 2003, Diabetes/metabolism research and reviews.

[30]  A. Ziegler,et al.  No evidence for an association of coxsackie virus infections during pregnancy and early childhood with development of islet autoantibodies in offspring of mothers or fathers with type 1 diabetes. , 2001, Journal of autoimmunity.

[31]  K. Wucherpfennig,et al.  Mechanisms for the induction of autoimmunity by infectious agents. , 2001, The Journal of clinical investigation.

[32]  M. Atkinson,et al.  Type 1 diabetes: new perspectives on disease pathogenesis and treatment , 2001, The Lancet.

[33]  N. Sarvetnick,et al.  Requirements for viral-mediated autoimmune diabetes: beta-cell damage and immune infiltration. , 2001, Journal of autoimmunity.

[34]  J. Ilonen,et al.  Enterovirus infection as a risk factor for beta-cell autoimmunity in a prospectively observed birth cohort: the Finnish Diabetes Prediction and Prevention Study. , 2000, Diabetes.

[35]  M. Knip,et al.  Enterovirus RNA in serum is a risk factor for beta‐cell autoimmunity and clinical type 1 diabetes: A prospective study , 2000, Journal of medical virology.

[36]  M. Atkinson,et al.  Acceleration of type 1 diabetes by a coxsackievirus infection requires a preexisting critical mass of autoreactive T-cells in pancreatic islets. , 2000, Diabetes.

[37]  M. Rewers,et al.  Early expression of antiinsulin autoantibodies of humans and the NOD mouse: evidence for early determination of subsequent diabetes. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[38]  T. Hyypiä,et al.  Diagnosis of enterovirus and rhinovirus infections by RT‐PCR and time‐resolved fluorometry with lanthanide chelate labeled probes , 1999, Journal of medical virology.

[39]  G. Clements,et al.  Enterovirus variants in the serum of children at the onset of Type 1 diabetes mellitus , 1999, Diabetic medicine : a journal of the British Diabetic Association.

[40]  M. Rewers,et al.  Antiislet autoantibodies usually develop sequentially rather than simultaneously. , 1996, The Journal of clinical endocrinology and metabolism.

[41]  L. Kinnunen,et al.  Genetic and phylogenetic clustering of enteroviruses. , 1996, The Journal of general virology.

[42]  Roberto Gianani,et al.  ICA512 Autoantibody Radioassay , 1995, Diabetes.

[43]  M. Knip,et al.  A prospective study of the role of coxsackie B and other enterovirus infections in the pathogenesis of IDDM. Childhood Diabetes in Finland (DiMe) Study Group. , 1995 .

[44]  M. Knip,et al.  A Prospective Study of the Role of Coxsackie B and Other Enterovirus Infections in the Pathogenesis of IDDM , 1995, Diabetes.

[45]  J. Cello,et al.  Diagnosis of enteroviral meningitis with IgG‐EIA using heat‐treated virions and synthetic peptides as antigens , 1993, Journal of medical virology.

[46]  M. Roivainen,et al.  Peptide antisera targeted to a conserved sequence in poliovirus capsid VP1 cross-react widely with members of the genus Enterovirus , 1993, Journal of clinical microbiology.

[47]  M. Roivainen,et al.  Antigenic regions of poliovirus type 3/Sabin capsid proteins recognized by human sera in the peptide scanning technique. , 1991, Virology.

[48]  D. R. Gamble.  Relation of antecedent illness to development of diabetes in children. , 1980, British medical journal.