Relation between T-cell responses to glutamate decarboxylase and coxsackievirus B4 in patients with insulin-dependent diabetes mellitus

Background: the role of enteroviruses has been implicated in the etiology o f insulin-dependent diabetes mellitus (IDDM). A possible connection between glutamate decarboxylase (GAD) autoimmunity and enterovirus infections in I DDM has been suggested to be based on a homology region between GAD and the non-structural protein 2C of coxsackievirus B4 (CVB4). Objectives: the aim s of the study were to measure the occurrence of cellular immunity to GAD a nd CVB4 in Finnish patients with newly diagnosed IDDM, and to study the rel ation between these two responses. T-cell responses to GAD and CVB4 were an alyzed in relation to HLA DQB1 risk alleles for IDDM and antibodies to GAD and CVB4. Study design: T-cell and antibody responses to GAD65 and purified CVB4 were measured in patients with newly diagnosed IDDM and in healthy ch ildren. The purified CVB4 did not contain the non-structural protein 2C thu s lacking the reported homology region with GAD. Results: high proliferativ e responses of PBMC to both GAD and CVB4 were more frequent in IDDM patient s 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 thr ee 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 t he control children (r = 0.23; P = 0.38). Conclusions: enhanced T-cell resp onsiveness to CVB4 in patients with newly diagnosed IDDM support the involv ement of enteroviral infections in the development of IDDM. The observed co rrelation between T-cell reactivity to GAD and CVB4, lacking the crossreact ive protein 2C, in patients with IDDM suggests that CBV4 reactivity is asso ciated with GAD autoimmunity in IDDM but does not reflect immunnization to GAD. (C) 1999 Elsevier Science Ltd. All rights reserved.