title: Relation between T-cell responses to glutamate decarboxylase and coxsackievirus B4 in patients with insulin-dependent diabetes mellitus.
abstract: BACKGROUND
  the role of enteroviruses has been implicated in the etiology of insulin-dependent diabetes mellitus (IDDM). A possible connection between glutamate decarboxylase (GAD) autoimmunity and enterovirus infections in IDDM has been suggested to be based on a homology region between GAD and the non-structural protein 2C of coxsackievirus B4 (CVB4).
  
  
  OBJECTIVE
  the aims of the study were to measure the occurrence of cellular immunity to GAD and CVB4 in Finnish patients with newly diagnosed IDDM, and to study the relation between these two responses. T-cell responses to GAD and CVB4 were analyzed in relation to HLA DQB1 risk alleles for IDDM and antibodies to GAD and CVB4.
  
  
  METHODS
  T-cell and antibody responses to GAD65 and purified CVB4 were measured in patients with newly diagnosed IDDM and in healthy children. The purified CVB4 did not contain the non-structural protein 2C thus lacking the reported homology region with GAD.
  
  
  RESULTS
  high proliferative responses of PBMC to both GAD and CVB4 were more frequent in IDDM patients than in the control children (40 vs. 16%, 27 vs. 10%; P = 0.03 and 0.04, respectively; Fisher's exact test), when the cut-off for positivity was three multiples of the median SI in the healthy children. Median SI to GAD was higher in the patients with IDDM than in the control subjects (3.10 vs. 1.55; P = 0.03, Mann-Whitney U-test). T-cell responses to GAD and CVB4 showed a positive correlation in the patients (r = 0.62, P = 0.001), but not in the control children (r = 0.23; P = 0.38).
  
  
  CONCLUSIONS
  enhanced T-cell responsiveness to CVB4 in patients with newly diagnosed IDDM support the involvement of enteroviral infections in the development of IDDM. The observed correlation between T-cell reactivity to GAD and CVB4, lacking the crossreactive protein 2C, in patients with IDDM suggests that CBV4 reactivity is associated with GAD autoimmunity in IDDM but does not reflect immunization to GAD.
authors.affiliation: Department of Biochemistry, National Public Health Institute, and Hospital for Children and Adolescents, University of Helsinki, Finland. paula.klemetti@ktl.fi
authors.forename: P
authors.initials: P
authors.lastname: Klemetti
authors.forename: H
authors.initials: H
authors.lastname: Hyöty
authors.forename: M
authors.initials: M
authors.lastname: Roivainen
authors.forename: J
authors.initials: J
authors.lastname: Ilonen
authors.forename: K
authors.initials: K
authors.lastname: Savola
authors.forename: M
authors.initials: M
authors.lastname: Knip
authors.forename: H K
authors.initials: HK
authors.lastname: Akerblom
authors.forename: O
authors.initials: O
authors.lastname: Vaarala
mesh_terms: D000293:Adolescent; D000483:Alleles; D001327:Autoimmune Diseases / Q000175:diagnosis / Q000276:immunology; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D003384:Coxsackievirus Infections / Q000150:complications / Q000175:diagnosis / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000821:virology*; D029822:Enterovirus B, Human / Q000276:immunology*; D005968:Glutamate Decarboxylase / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000235:genetics; D059866:HLA-DQ beta-Chains; D006801:Humans; D007223:Infant; D017955:Poliovirus / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013745:Tetanus Toxoid / Q000276:immunology; D014407:Tumor Cells, Cultured
chemical_list: D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D013745:Tetanus Toxoid; D005968:Glutamate Decarboxylase