Human parvovirus B19 infection in children with new onset Type 1 diabetes mellitus.
Human parvovirus B19 infection in children with new onset Type 1 diabetes mellitus.
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新发 1 型糖尿病儿童的人类细小病毒 B19 感染。
DOI：
10.1111/j.1464-5491.2005.01708.x
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Naides,SJ
中科院分区：
文献类型：
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作者：
O'Brayan,TA;Beck,MJ;Demers,LM;Naides,SJ
长期以来，病毒一直被怀疑是 1 型糖尿病 (DM) 的病原体。虽然涉及多种病毒，但有强有力的流行病学、血清学和分子学证据表明 1 型糖尿病与人类肠道病毒感染有关[1]。然而，与肠道病毒相关的糖尿病的确切机制和病例比例仍不确定[1]。已经提出了一种多阶段模型，其中初始触发事件后的连续暴露最终导致胰腺β细胞破坏[2]。在该模型中，肠道病毒感染在自身免疫途径的启动和随后的增强中发挥作用，然而，不排除其他病毒的参与[2]。出于多种原因，我们认为人类细小病毒 B19 (B19) 可能是 1 型 DM 发病机制中的候选病毒。其在儿童中的发病率最高、常见的亚临床表现以及爆发间隔不规则的地方性流行，与与 1 型 DM 的发展相关的环境病毒因子的预期特性相一致。已知该病毒可促进 T 细胞介导的淋巴增殖反应，该反应依赖于 HLA II 类抗原将其呈递给 CD4 细胞 [3]，并且理论上可产生 T 细胞介导的自身免疫。有人提出，一些存在潜在免疫功能障碍的患者可能更容易受到 B19 诱导的自身免疫调节作用的影响 [4]。此外，Kasuga 及其同事报告了一名年轻人在感染性红斑（B19 感染的常见表现）后出现新发 1 型糖尿病。 B19 IgM 和糖尿病自身抗原 IA-2 抗体的血清水平显着升高。作者注意到 B19 和 IA-2 胞外域之间的氨基酸序列同源性，表明分子模拟的潜力 [5]。此外，在动物模型中，细小病毒 Kilham 大鼠病毒被证明可诱导遗传易感大鼠患自身免疫性糖尿病 [6]。然而迄今为止，B19 在 1 型 DM 发展中的潜在作用尚未阐明。我们收集了连续入住宾夕法尼亚州立大学米尔顿·S·赫尔希医学中心的 22 名新诊断的 1 型糖尿病儿童和青少年的血清。所有患者均患有糖尿病酮症酸中毒或可检测到抗 GAD 或抗 IA-2 抗体 (Abs)。每个受试者的年龄和性别均与从门诊招募的健康对照受试者相匹配。第二个对照组由来自初级保健门诊临床实验室的年龄和性别匹配的匿名剩余血清样本组成。使用病例对照设计，我们测试了 B19 DNA、IgG 和 IgM 抗体与 1 型糖尿病诊断以及抗 GAD 和抗 IA-2 抗体存在的关联。使用特定酶免疫测定方法（Biotrin，都柏林，爱尔兰）测定针对 B19 病毒衣壳蛋白 VP2 的 IgG 和 IgM 抗体。使用免疫放射测定方法（Kronus，博伊西市，爱达荷州，美国）测定抗 GAD 和抗 IA-2 抗体。使用 B19 衣壳结构蛋白 VP1 和 VP2 共同区域的寡核苷酸探针，通过聚合酶链式反应方法测试 B19 DNA。该研究得到了我们的机构审查委员会和人类受试者保护办公室的批准。 22名糖尿病受试者的年龄范围为1至17岁（平均9.5岁，中位10岁）； 50%是男性。所有具有抗 GAD 或抗 IA-2 抗体的受试者均患有糖尿病，但一名健康对照者可检测到这两种抗体的水平。该受试者有一个患有 1 型糖尿病的兄弟姐妹。在糖尿病患者或对照患者的任何样本中均未发现 B19 DNA……
Viruses have long been suspected as causative agents of Type 1 diabetes mellitus (DM). While several viruses have been implicated, there is strong epidemiologic, serologic and molecular evidence associating Type 1 DM with enterovirus infection in humans [1]. However, the exact mechanism and proportion of cases of diabetes related to enteroviruses is still uncertain [1]. A multistage model has been proposed in which sequential exposures following an initial triggering event leads eventually to pancreatic beta cell destruction [2]. In this model, enteroviral infections play a role in both the initiation and later enhancement of the autoimmune pathway, however, involvement by other viruses is not precluded [2]. We considered the human parvovirus B19 (B19) as a likely candidate in the pathogenesis of Type 1 DM for several reasons. Its peak incidence in children, common subclinical presentation, and endemic prevalence with irregular intervals of outbreaks is compatible with properties expected of an environmental viral agent linked to the development of Type 1 DM. This virus is known to promote a T-cell-mediated lymphoproliferative response that is dependent upon its presentation to CD4 cells by HLA class II antigens [3] and could theoretically generate T-cell-mediated autoimmunity. It has been suggested that some patients with an underlying immune dysfunction may be more susceptible to an autoimmune modulation effect induced by B19 [4]. In addition, Kasuga and colleagues reported a young adult who developed new onset Type 1 DM following erythema infectiosum—a common manifestation of B19 infection. Serum levels of B19 IgM and antibodies to the diabetic autoantigen IA-2 were markedly elevated. The authors note homology in amino acid sequences between B19 and the extracellular domain of IA-2, suggesting the potential for molecular mimicry [5]. Furthermore, in an animal model, the parvovirus Kilham rat virus was shown to induce autoimmune diabetes in genetically susceptible rats [6]. To date, however, a potential role for B19 in the development of Type 1 DM has not been elucidated. We collected serum from 22 children and adolescents with newly diagnosed Type 1 DM consecutively admitted to the Penn State University Milton S. Hershey Medical Center. All had diabetic ketoacidosis or detectable levels of anti-GAD or anti-IA-2 antibodies (Abs). Each subject was age-and sex-matched with healthy control subjects recruited from outpatient sites. A second comparison group consisted of age-and sex-matched anonymous surplus serum samples from a primary care outpatient clinical laboratory. Using a casecontrol design, we tested the association of B19 DNA, IgG and IgM Abs with the diagnosis of Type 1 DM and the presence of anti-GAD and anti-IA-2 Abs. IgG and IgM antibodies to B19 viral capsid protein VP2 were assayed using specific enzyme immunoassay methods (Biotrin, Dublin, Ireland). Anti-GAD and anti-IA-2 Abs were determined using immunoradiometric assay methods (Kronus, Boise City, ID, USA). B19 DNA was tested by polymerase chain reaction methods using oligonucleotide probes to the common region of B19 capsid structural proteins VP1 and VP2. The study was approved by our Institutional Review Board and Human Subjects Protection Office. The age range of the 22 diabetic subjects was from 1 to 17 years (mean 9.5 years, median 10 years); 50% were male. All subjects with anti-GAD or anti-IA-2 Abs had diabetes with the exception of one healthy control with detectable levels of both. This subject had a sibling with Type 1 DM. B19 DNA was not found in any of the samples from diabetic or control patients …