Degeneracy and Complexity in the Immune System

Torrey Pines Inst For Molecular Studies, San Diego CA

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Abstract

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.