Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China.
Department of Pharmacology, Toxicology and Therapeutics, School of Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Cells. 2022 Jan 31;11(3):492. doi: 10.3390/cells11030492.
Human type 1 diabetes mellitus is a chronic autoimmune disease characterized by the selective loss of insulin-producing -cells in pancreatic islets of genetically susceptible individuals. In this communication, a new hypothesis is postulated which is based on the observations that streptozotocin (STZ), a chemically reactive and cytotoxic compound produced by certain gram-positive bacteria, can be preferentially taken up into islet -cells and induce cytotoxicity and autoimmunity. It is hypothesized that humans might be occasionally exposed to STZ through opportunistic infections with the STZ-producing bacteria and/or through ingestion of certain food products that contain STZ. In addition, the potential presence of the STZ-producing bacteria in the gut microbiota of some individuals might be another source of long-term STZ exposure. Because of the high chemical reactivity of STZ and its breakdown products, these chemicals can covalently modify certain cellular macromolecules (e.g., DNA and proteins), and the covalently modified cellular components would serve as new antigens, potentially capable of inducing both humoral and cellular autoimmune responses in the islets of certain individuals. In addition to STZ exposure, the eventual development of autoimmunity against STZ-exposed islet -cells also depends critically on the genetic predisposition of the susceptible individuals plus the opportunistic presence of a conducive, strong environmental trigger, which often is presented as severe febrile viral infections subsequently inducing strong aberrant reactions of the body's immune system. The proposed pathogenic hypothesis is supported by a considerable body of direct and indirect evidence from laboratory animal studies and clinical observations. Certainly, more experimental and clinical studies are needed to carefully further examine each of the key components of the proposed pathogenic hypothesis.
人类 1 型糖尿病是一种慢性自身免疫性疾病，其特征是在遗传易感个体的胰腺胰岛中选择性丧失胰岛素产生细胞。在本通讯中，提出了一个新的假设，该假设基于以下观察结果：链脲佐菌素（STZ）是一种由某些革兰氏阳性细菌产生的具有化学活性和细胞毒性的化合物，可以优先被胰岛细胞摄取，并诱导细胞毒性和自身免疫。假设人类可能会通过与产生 STZ 的细菌的机会性感染和/或通过摄入某些含有 STZ 的食物产品偶尔接触到 STZ。此外，某些个体肠道微生物群中可能存在产生 STZ 的细菌，这可能是长期暴露于 STZ 的另一个来源。由于 STZ 的高化学活性及其分解产物，这些化学物质可以共价修饰某些细胞大分子（例如 DNA 和蛋白质），并且共价修饰的细胞成分将作为新的抗原，潜在地能够在某些个体的胰岛中诱导体液和细胞自身免疫反应。除了 STZ 暴露之外，针对暴露于 STZ 的胰岛细胞的自身免疫的最终发展还取决于易感个体的遗传易感性以及有利的强烈环境触发因素的机会性存在，这种触发因素通常表现为严重的发热性病毒感染，随后诱导机体免疫系统的强烈异常反应。该假设的发病机制得到了来自实验室动物研究和临床观察的大量直接和间接证据的支持。当然，需要更多的实验和临床研究来仔细进一步检查所提出的发病机制假设的每个关键组成部分。
