Nossal G J, Herold K C, Goodnow C C
Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Parkville, Victoria, Australia.
Diabetologia. 1992 Dec;35 Suppl 2:S49-59. doi: 10.1007/BF00586279.
The autoimmune process that results in Type 1 (insulin-dependent) diabetes mellitus may be viewed as a failure to develop or maintain tolerance to self-antigens expressed in the islets of Langerhans. During T-cell development in the thymus, cells that are reactive with self antigens encountered there may undergo clonal deletion or, as more recently described, clonal anergy which effectively removes these cells from the pool of mature antigen reactive T cells. For antigens not found in the thymus, tolerance to self antigens is more complex and may depend on site of antigen expression, ambient concentrations of lymphokines, and availability of antigen-presenting cells that can deliver co-stimulatory signals. Transgenic mice in which the majority of T cells express T-cell receptors against "self" antigens or in which expression of antigens is targeted to peripheral tissues have proven useful for studies of tolerance in both T- and B-cell compartments. In general, T-cell reactivity against foreign antigen expressed on Beta cells does not occur because of the failure to activate T cells reactive with the antigen, termed clonal ignorance. This may be broken with, for example, viral infection or cytokines. In one transgenic model, dendritic cells that surround the islets of Langerhans have been shown to be responsible for presentation of islet antigens to the immune system. B-cell tolerance can also involve mechanisms of clonal deletion or clonal anergy similar to that occurring with T cells. In addition, a mechanism for changing the affinity of the B-cell antigen receptor termed "receptor editing" has been described, which may play an important role in diversifying the B-cell repertoire while removing self-reactive cells. Tolerance to antigens may also be inducible. For example, monoclonal antibodies against T-cell epitopes may induce antigen-specific tolerance that is transferable to other animals, and MHC blocking peptides which can inhibit T-cell responses that are restricted by disease associated MHC molecules. In conclusion, although several possible triggers and mechanisms of autoimmune diabetes can be envisioned, none can be excluded by existing data. However, advances in understanding mechanisms of tolerance to islet and other self antigens suggest potentially useful therapeutic approaches to arresting the autoimmune response.
导致1型（胰岛素依赖型）糖尿病的自身免疫过程可被视为未能对胰岛中表达的自身抗原形成或维持耐受性。在胸腺中T细胞发育过程中，与在那里遇到的自身抗原发生反应的细胞可能会经历克隆清除，或者，如最近所描述的，经历克隆无能，这有效地将这些细胞从成熟的抗原反应性T细胞库中清除。对于在胸腺中未发现的抗原，对自身抗原的耐受性更为复杂，可能取决于抗原表达的部位、淋巴因子的周围浓度以及能够传递共刺激信号的抗原呈递细胞的可用性。已证明，大多数T细胞表达针对“自身”抗原的T细胞受体的转基因小鼠，或抗原表达靶向外周组织的转基因小鼠，对于研究T细胞和B细胞区室中的耐受性很有用。一般来说，由于未能激活与抗原发生反应的T细胞（称为克隆忽视），不会发生针对β细胞上表达的外来抗原的T细胞反应性。这可能会因例如病毒感染或细胞因子而被打破。在一个转基因模型中，已证明围绕胰岛的树突状细胞负责将胰岛抗原呈递给免疫系统。B细胞耐受性也可能涉及与T细胞类似的克隆清除或克隆无能机制。此外，还描述了一种改变B细胞抗原受体亲和力的机制，称为“受体编辑”，这可能在使B细胞库多样化的同时去除自身反应性细胞方面发挥重要作用。对抗原的耐受性也可能是可诱导的。例如针对T细胞表位的单克隆抗体可能诱导可转移至其他动物的抗原特异性耐受性，以及可抑制由疾病相关MHC分子限制的T细胞反应的MHC阻断肽。总之，尽管可以设想几种可能引发自身免疫性糖尿病的触发因素和机制，但现有数据无法排除任何一种。然而，在理解对胰岛和其他自身抗原的耐受性机制方面的进展表明，有可能采用有用的治疗方法来阻止自身免疫反应。
