Type I (insulin-dependent) diabetes is a Th1- and Th2-mediated autoimmune disease
Type I (insulin-dependent) diabetes is a Th1- and Th2-mediated autoimmune disease
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DOI：
10.1128/cdli.6.3.306-310.1999
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发表时间：
1999-05-01
期刊：
影响因子：
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通讯作者：
Almawi, WY
中科院分区：
文献类型：
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作者：
Azar, ST;Tamim, H;Almawi, WY
I型(胰岛素依赖型)糖尿病是一种自身免疫性疾病，病因不明，但有明确的结局，导致自身反应性白细胞及其介体对分泌胰岛素的胰腺β细胞进行性错误的免疫破坏(3)。尽管疾病的确切原因尚不清楚，但遗传、免疫学和非遗传因素的组合导致了IDDM的发生和发展(3，52)。特定的人类白细胞抗原，特别是DR3和DR4，与IDDM发病风险增加有关(52，89)，而DR2等位基因通常被描述为IDDM的“保护性”(86)。除了人类白细胞抗原的易感因素外，病毒感染(8例)、心理因素(73例)和饮食因素(8例)等也被描述为易感因素。其他研究人员未能证明这些因素与IDDM之间存在强烈的因果联系，这突显了进一步研究和识别IDDM发病机制的必要性(77)。IDDM经常与免疫紊乱共存是公认的，是体液免疫和细胞免疫固有调节失调的结果(3，8)。这表现为存在针对特定β细胞成分和其他自身抗原的自反应抗体(23，28)，循环中的自反应T细胞(78，80)，黏附分子的高表达(37，60)，血清细胞因子抑制物(57)的水平降低，以及细胞因子及其高亲和力受体(36，82)的持续表达。高血糖是胰岛素依赖型糖尿病的一个特征，出现在疾病的后期，在β细胞的定向自身免疫破坏开始后的几个月或几年(81)。T细胞和巨噬细胞衍生的细胞因子参与胰岛素依赖型糖尿病的发病机制仍是深入研究的主题；结论主要基于对遗传性糖尿病易患非肥胖糖尿病(NOD)小鼠和生物育种(BB)大鼠的研究，这两种动物模型显示出许多人类I型糖尿病的特征(4)，并集中于细胞因子在介导β细胞破坏中的直接细胞毒性和间接免疫调节作用(58，82)。基于这些研究，得出结论，Th1细胞因子加剧，而Th2细胞因子保护，IDDM(70，72)。然而，越来越多的相反证据表明，IDDM从胰岛炎症(胰腺单个核细胞浸润)到明显的高血糖进展缓慢。
Type I (insulin-dependent) diabetes (IDDM) is an autoimmune disease with an unknown etiology but with a definite outcome, resulting in the progressive misdirected immunologic destruction of insulin-secreting pancreatic β islet cells by autoreactive leukocytes and their mediators (3). Even though the precise cause of the disease remains unclear, a combination of genetic, immunologic, and nongenetic factors contributes to the onset and progression of IDDM (3, 52). Specific HLA antigens, in particular DR3 and DR4, have been associated with increased risk for IDDM development (52, 89), while DR2 alleles generally have been described as “protective” of IDDM (86). In addition to HLA predisposing factors, viral infection (8), psychological factors (73), and dietary factors (8), among others, have been described as predisposing factors. Other investigators failed to demonstrate a strong cause-andeffect link between these factors and IDDM, which highlighted the need for further investigation and identification of causative agents and mechanisms underlying the pathogenesis of IDDM (77).The frequent coexistence of IDDM with immune disorders is well established and results from an inherent dysregulation in humoral immunity and cell-mediated immunity (3, 8). This is exemplified by the presence of autoreactive antibodies targeting select β-cell constituents and other autoantigens (23, 28), circulating autoreactive T cells (78, 80), heightened expression of adhesion molecules (37, 60), reduced levels of serum cytokine inhibitors (57), and sustained expression of cytokines and their high-affinity receptors (36, 82). The development of hyperglycemia, a hallmark of IDDM, appears at later stages of the disease, months or years after the initiation of targeted autoimmune destruction of β cells (81). The involvement of T-cell-and macrophage-derived cytokines in IDDM pathogenesis remains the subject of intense investigation; conclusions were largely based on studies with the genetically IDDM-predisposed nonobese diabetic (NOD) mice and BioBreeding (BB) rats, animal models which display many of the characteristics of human type I diabetes (4), and have focused on direct cytotoxic and indirect immunomodulatory effects of cytokines in mediating β-cell destruction (58, 82). Based on such studies, it was concluded that Th1 cytokines exacerbate, while Th2 cytokines protect from, IDDM (70, 72). However, contrary evidence is accumulating which demonstrates that the progression of IDDM from insulitis (pancreatic mononuclear cell infiltration) to frank hyperglycemia is under