Department of Diabetes Immunology, Diabetes & Metabolism Research Institute, Beckman Research Institute at City of Hope, Los Angeles, CA, USA.
Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands.
Nat Rev Endocrinol. 2021 Mar;17(3):150-161. doi: 10.1038/s41574-020-00443-4. Epub 2020 Dec 8.
Type 1 diabetes mellitus is believed to result from destruction of the insulin-producing β-cells in pancreatic islets that is mediated by autoimmune mechanisms. The classic view is that autoreactive T cells mistakenly destroy healthy ('innocent') β-cells. We propose an alternative view in which the β-cell is the key contributor to the disease. By their nature and function, β-cells are prone to biosynthetic stress with limited measures for self-defence. β-Cell stress provokes an immune attack that has considerable negative effects on the source of a vital hormone. This view would explain why immunotherapy at best delays progression of type 1 diabetes mellitus and points to opportunities to use therapies that revitalize β-cells, in combination with immune intervention strategies, to reverse the disease. We present the case that dysfunction occurs in both the immune system and β-cells, which provokes further dysfunction, and present the evidence leading to the consensus that islet autoimmunity is an essential component in the pathogenesis of type 1 diabetes mellitus. Next, we build the case for the β-cell as the trigger of an autoimmune response, supported by analogies in cancer and antitumour immunity. Finally, we synthesize a model ('connecting the dots') in which both β-cell stress and islet autoimmunity can be harnessed as targets for intervention strategies.
1 型糖尿病被认为是由自身免疫机制介导的胰岛胰岛素产生β细胞的破坏引起的。经典观点认为，自身反应性 T 细胞错误地破坏了健康（“无辜”）的β细胞。我们提出了一种替代观点，即β细胞是导致疾病的关键因素。从本质和功能上讲，β细胞容易受到生物合成应激的影响，自我防御措施有限。β细胞应激会引发免疫攻击，对重要激素的来源产生相当大的负面影响。这种观点可以解释为什么免疫疗法充其量只能延缓 1 型糖尿病的进展，并指出有机会使用能够使β细胞恢复活力的疗法，结合免疫干预策略，来逆转疾病。我们提出了这样一种观点，即免疫系统和β细胞都出现了功能障碍，这会引发进一步的功能障碍，并提出了导致人们达成共识的证据，即胰岛自身免疫是 1 型糖尿病发病机制的一个重要组成部分。接下来，我们提出了β细胞作为自身免疫反应触发因素的观点，这一观点得到了癌症和抗肿瘤免疫的类比的支持。最后，我们综合了一个模型（“连接点”），其中β细胞应激和胰岛自身免疫都可以作为干预策略的靶点。
