Degeneracy and Complexity in the Immune System

在过去的十年里，越来越多的人意识到淋巴细胞识别是退化的。最近，人们进一步认识到，退化是生物系统的一种普遍属性，出现在基因网络、神经网络和其他级别的生物组织中。正如埃德尔曼和盖利指出的那样，退化几乎总是伴随着复杂性。在现代免疫学中，退化是指单个受体识别和反应不同种类的配体的能力，每个淋巴细胞克隆都有自己的退化模式(即它自己的一组刺激配体)。例如，T淋巴细胞表面的单个T细胞受体可以与多种分子结构结合，从这个意义上说，T细胞对抗原具有退化的识别能力。这样的退化系统具有很强的适应性，可以说进化本身在很大程度上依赖于一组复杂系统中的广泛退化。事实上，免疫系统中除淋巴细胞抗原受体外的大多数关键受体元件都有很大程度的退化，例如一个主要组织相容性复合体(MHC)分子可以结合非常大和多样化的一组多肽，细胞因子/趋化因子受体也因其共有的成分而具有家族关系。现在是时候重新评估和考虑退化在免疫系统中的作用了，它是免疫系统最具特征和最独特的属性之一，而不是一种特殊的和偶尔的奇怪现象。免疫系统比神经系统更能接收和处理分子信息。关于这个主题的研讨会的主旨是质疑这个不能在分子水平上依赖其受体的专一性的系统如何在操作水平上具有如此惊人的专一性。我们认为，这个话题，重点是免疫系统，但包括相关 对于圣达菲研究所来说，连接和突触可塑性等方面将是一个很好的课题，该研究所的重点是复杂性。这是进行这场讨论的最佳地点，这里已经存在一个思想家社区，他们在复杂和全球层面上都在分子识别和相互作用问题上接受过良好的培训。我们不知道以前曾举行过关于退化受体识别问题的会议或研讨会。在分子识别的研究中有许多线索将在这种背景下聚集在一起。第一个问题是这种退化的结构基础。第二，在T和B细胞识别中，免疫反应性退化的广义概念是在所有水平上吗？ 不仅与抗原有关，而且与细胞因子及其与受体的相互作用有关，以及对其识别单元相互交织的先天免疫受体(“Toll样受体”)的最新研究。另一组发现与免疫系统中的“分子拟态”有关，即感染性生物体上的抗原与人类或动物宿主中的自身抗原之间的“分子模仿”。这种模仿可能导致自身免疫，关于这一主题的文献如雨后春笋般涌现。最后，免疫发育和生理的一些最基本的方面，例如胸腺中T细胞的积极选择，本质上涉及到退化的识别事件。免疫系统中的退化识别模式提供了其健壮性和灵活性的主要来源，即适应以前从未经历过的扰动的能力。希望通过这次研讨会的作用，免疫系统通过不同策略产生输出的广泛能力能够合理化，其要素显然缺乏特异性，作为一个整体运行的系统的紧急特性可以作为数学处理的主题。

There has been an increasing realization within the past decade that lymphocyte recognition is degenerate. Even more recent is the further knowledge that degeneracy is a ubiquitous property of biological systems, appearing in gene networks, neural networks and other levels of biologic organization. As Edelman and Gaily have pointed out, degeneracy is almost invariably accompanied by complexity. Degeneracy, in contemporary immunological usage, describes the ability of a single receptor to recognize and react to a heterogeneous assortment of ligands, with each lymphocyte clone having its own pattern of degeneracy (i.e. its own set of stimulatory ligands). For example, a single T cell receptor on the surface of the T lymphocyte can bind to a large variety of molecular structures and in that sense; the T cell has a degenerate recognition for antigen. Such a degenerate system is quite adaptable and it can be argued that evolution itself depends heavily on extensive degeneracy in a set of complex systems. Actually, most of the crucial receptor elements in the immune system, aside from lymphocyte antigen receptors, are degenerate to a great extent, e.g. a single major histocompatibility complex (MHC) molecule can bind a very large and diverse set of peptides, and cytokine/chemokine receptors also have familial relationships owing to shared components. It is time to reevaluate and consider the role of degeneracy in the immune system as one of its most characteristic and distinctive attributes, rather than a peculiar and occasional oddity. The immune system, even more than the nervous system, functions to receive and process molecular information. It would be the major thrust of a workshop on this topic to question how the system, which cannot rely on the specificity of its receptors at the molecular level can behave with such marvelous specificity at the operational level. We believe that this topic, with a focus on the immune system, but including related aspects such as connectivity and synaptic plasticity, would be an excellent subject for the Santa Fe Institute, one whose focus is on complexity. This is the optimal location for this discussion, where there already exists a community of thinkers well schooled in problems of molecular recognition and interaction, at both an intricate and a global level. We are not aware that a previous conference or workshop has been held on the subject of degenerate receptor recognition. There are many threads in the study of molecular recognition that would be brought together in this context. A first question is the structural basis for the degeneracy. Second is the broad concept of degeneracy in immune reactivity at all levels?at the T and B cell recognition of antigen, but also with cytokines and their interactions with receptors, as well as recent studies of the innate immune receptors ("toll-like receptors") whose recognition units are intertwined. Another set of findings relate to "molecular mimicry" in the immune system, between the antigens on infectious organisms and self-antigens in the human or animal host. Such mimicry can lead to autoimmunity and there is a burgeoning literature on the subject. Finally, some of the most basic aspects of immune development and physiology, such as positive selection of T cells in the thymus, involve a degenerate recognition event at their essence. The pattern of degenerate recognition in the immune system provides a major source of its robustness and flexibility, its ability to adjust to perturbations, which were previously never experienced. It is hoped that through the agency of this workshop, the wide-ranging ability of the immune system to develop outputs by different strategies can be rationalized with the clear lack of specificity of its elements, and that the emergent properties of the system operating as a whole can serve as a subject for mathematical treatment.