Sadeharju K, Lönnrot M, Kimpimäki T, Savola K, Erkkilä S, Kalliokoski T, Savolainen P, Koskela P, Ilonen J, Simell O, Knip M, Hyöty H
Department of Virology, University of Tampere and Tampere University Hospital, Finland.
Diabetologia. 2001 Jul;44(7):818-23. doi: 10.1007/s001250100560.
AIMS/HYPOTHESIS: We evaluated the role of enterovirus infections in the pathogenesis of Type I (insulin-dependent) diabetes mellitus by monitoring enterovirus antibody levels in prediabetic children who turned positive for diabetes-associated autoantibodies in a prospective birth cohort study.
Serial serum samples taken during prospective observation starting at birth were analysed for IgG and IgA class antibodies against enterovirus antigens including purified coxsackievirus B4, echovirus 11, poliovirus 1 and a synthetic enterovirus peptide antigen using enzyme immunoassay. Maternal samples taken at the end of the third month of pregnancy were also studied. Analyses were done from 21 childen who developed autoantibodies and from 104 autoantibody-negative control children who were matched for the time of birth, gender and HLA susceptibility alleles. For comparison, adenovirus antibodies were also analysed from all samples collected.
IgG class enterovirus antibody levels were high in maternal samples and in cord blood in both case and control children. After birth the IgG levels decreased reaching a nadir at the age of 6 months. No IgA class antibodies were detected at birth but started to emerge postnatally. Antibody levels did not differ between the autoantibody positive and the control children during the first 6 months of life. From 6 months to 24 months of age, the autoantibody positive children had higher IgG and IgA levels against coxsackievirus B4, echovirus 11 and the synthetic enterovirus peptide antigens than control children but poliovirus 1 and adenovirus antibodies were closely similar in the two groups. The difference between children with autoantibodies and control children was predominantly seen among boys and among those with the HLA-DQB1*0302/x genotype.
CONCLUSIONS/INTERPRETATION: Our data show that children who seroconverted for diabetes-associated auto-antibodies develop stronger humoral immune responses to coxsackievirus B4, echovirus 11 and a synthetic enterovirus peptide antigen than children who remained negative for autoantibodies. Poliovirus antibodies induced by uniform vaccinations did not differ between the prediabetic and control children suggesting that the regulation of antibody responses to enteroviruses is not disturbed. Accordingly, the results imply a stronger enterovirus exposure in prediabetic children supporting the role of enteroviruses in the pathogenesis of Type I diabetes.
目的/假设：在一项前瞻性出生队列研究中，我们通过监测糖尿病相关自身抗体呈阳性的糖尿病前期儿童的肠道病毒抗体水平，评估肠道病毒感染在I型（胰岛素依赖型）糖尿病发病机制中的作用。
使用酶免疫测定法，对从出生开始前瞻性观察期间采集的系列血清样本进行分析，检测针对肠道病毒抗原的IgG和IgA类抗体，这些抗原包括纯化的柯萨奇病毒B4、埃可病毒11、脊髓灰质炎病毒1和一种合成肠道病毒肽抗原。还研究了妊娠第三个月末采集的母体样本。对21名出现自身抗体的儿童和104名出生时间、性别和HLA易感等位基因相匹配的自身抗体阴性对照儿童进行了分析。为作比较，对所有采集样本中的腺病毒抗体也进行了分析。
病例组和对照组儿童的母体样本及脐带血中IgG类肠道病毒抗体水平均较高。出生后IgG水平下降，在6个月龄时降至最低点。出生时未检测到IgA类抗体，但出生后开始出现。在生命的前6个月，自身抗体阳性儿童和对照儿童的抗体水平无差异。在6个月至24个月龄期间，自身抗体阳性儿童针对柯萨奇病毒B4、埃可病毒11和合成肠道病毒肽抗原的IgG和IgA水平高于对照儿童，但两组中脊髓灰质炎病毒1和腺病毒抗体水平相近。自身抗体阳性儿童与对照儿童之间的差异主要见于男孩以及具有HLA-DQB1*0302/x基因型的儿童。
结论/解读：我们的数据表明，糖尿病相关自身抗体血清学转换的儿童，比自身抗体仍为阴性的儿童，对柯萨奇病毒B4、埃可病毒11和合成肠道病毒肽抗原产生更强的体液免疫反应。由统一疫苗接种诱导的脊髓灰质炎病毒抗体在糖尿病前期儿童和对照儿童之间无差异，这表明对肠道病毒抗体反应的调节未受干扰。因此，结果提示糖尿病前期儿童肠道病毒暴露更强，支持肠道病毒在I型糖尿病发病机制中的作用。
