Department of Biochemistry, Microbiology and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
Scand J Immunol. 2021 Aug;94(2):e13033. doi: 10.1111/sji.13033. Epub 2021 Apr 19.
Burnet envisaged the early presence of self-antigens in development, or 'the history' of an animal, ablates the animal's ability to immunologically respond against them. Lederberg added the idea that the continuous presence of self-antigens is required to maintain tolerance throughout life. We refer to Lederberg's proposal as 'The Historical Postulate'. The mechanism of central tolerance, as now understood, is consistent with The Historical Postulate. Some observations, reflecting peripheral tolerance, appear inconsistent with this postulate. For example, some foreign peripheral tissues, grafted onto an animal before the immune system develops, can be rejected as the immune system matures. The original two-signal model of lymphocyte activation was proposed in part because it accounted for peripheral tolerance in a manner consistent with The Historical Postulate. We proposed that lymphocyte activation required antigen-mediated lymphocyte cooperation, whereas antigen would inactivate lymphocytes when insufficient in number to achieve activation. We argue here that the exceptions to The Historical Postulate can be explained by the two-signal model of lymphocyte activation: they reflect the existence of greater numbers of lymphocytes specific for these antigens than for natural peripheral antigens, and so are outside the physiological limits important in selecting through evolution this mechanism of peripheral tolerance. We argue that a consideration of whether The Historical Postulate is valid is important, even if only valid within certain understandable limits. The currently popular DAMP model of CD4 T cell activation is, strictly speaking and in a manner we discuss, in violation of this postulate.
伯内特设想在发育过程中或动物的“历史”早期存在自身抗原，从而消除了动物对其产生免疫反应的能力。莱德伯格补充了一个观点，即持续存在自身抗原是维持终生耐受所必需的。我们将莱德伯格的这一观点称为“历史假设”。目前所理解的中枢耐受机制与历史假设是一致的。一些反映外周耐受的观察结果似乎与这一假设不一致。例如，一些外来的外周组织，在免疫系统发育之前移植到动物体内，随着免疫系统的成熟，可能会被排斥。淋巴细胞激活的原始双信号模型部分是因为它以与历史假设一致的方式解释了外周耐受。我们提出淋巴细胞激活需要抗原介导的淋巴细胞协同作用，而当抗原数量不足以达到激活时，抗原会使淋巴细胞失活。我们在这里认为，历史假设的例外可以用淋巴细胞激活的双信号模型来解释：它们反映了针对这些抗原的淋巴细胞数量比针对天然外周抗原的淋巴细胞数量更多，因此超出了通过进化选择这种外周耐受机制的生理限制。我们认为，即使只在某些可以理解的限制范围内有效，考虑历史假设是否有效也是很重要的。目前流行的 CD4 T 细胞激活的 DAM 模型，严格来说，正如我们所讨论的，违反了这一假设。
