Campbell I L, Harrison L C
Burnet Clinical Research Unit, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Mol Biol Med. 1990 Aug;7(4):299-309.
Evidence from epidemiological and histopathologic studies in humans with autoimmune type 1 (insulin-dependent) diabetes suggests that beta-cell destruction within the islets of Langerhans progresses through a number of stages. In this review we draw on recent experimental evidence in an attempt to define the molecular pathology of these stages. Stage 1 is postulated to be initiated by modification of the beta cell by virus, chemical or other factors, leading to the production of interferon-alpha, hyperexpression of major histocompatibility complex (MHC) class I molecules and induction of MHC class II molecules. Experiments in transgenic mice suggest that overexpression of MHC molecules is in itself detrimental to beta-cell function. Shedding of antigen(s) from dying beta cells in combination with hyperexpression of MHC molecules may be a powerful immunogenic stimulus. Stage 2 commences with infiltration of the islets by immuno-inflammatory cells (termed insulitis). It is proposed that production of cytokines from the infiltrating cells induces "phenotypic switching" in beta cells, with further upregulation of MHC molecules and the induction of intracellular adhesion molecule-1 expression and interleukin-6 production. Together, these properties are seen as a prerequisite for the presentation of autoantigen by beta cells to adherent T lymphocytes and autoimmune activation. The final stage encompasses autoimmune-mediated destruction of the beta cells by the targeted delivery of cytotoxic cytokines and other mediators.
对患有自身免疫性1型（胰岛素依赖型）糖尿病的人类进行的流行病学和组织病理学研究证据表明，朗格汉斯胰岛内的β细胞破坏会经历多个阶段。在本综述中，我们借鉴了最近的实验证据，试图确定这些阶段的分子病理学。假设阶段1由病毒、化学物质或其他因素对β细胞的修饰引发，导致α干扰素的产生、主要组织相容性复合体（MHC）I类分子的过度表达以及MHC II类分子的诱导。转基因小鼠实验表明，MHC分子的过度表达本身对β细胞功能有害。垂死β细胞释放的抗原与MHC分子的过度表达相结合，可能是一种强大的免疫原性刺激。阶段2始于免疫炎症细胞（称为胰岛炎）浸润胰岛。有人提出，浸润细胞产生的细胞因子会诱导β细胞发生“表型转换”，进一步上调MHC分子，并诱导细胞间黏附分子-1的表达和白细胞介素-6的产生。这些特性共同被视为β细胞将自身抗原呈递给黏附性T淋巴细胞并引发自身免疫激活的先决条件。最后阶段包括通过细胞毒性细胞因子和其他介质的靶向递送，由自身免疫介导的β细胞破坏。
