The immune system functions on principles derivable from a consideration of its evolutionary origins. The rate of germline evolution of pathogens is vastly more rapid than that of their vertebrate hosts. The solution of natural selection was to couple a somatically generated, large, random recognitive repertoire to the biodestructive mechanisms already existent in non-vertebrates. This required two new regulatory systems: 1) A somatic decision mechanism to sort the repertoire into anti-self (to be purged) leaving a residue anti- nonself (to be activated) to protect the host and 2) a germline-selected decision mechanism that controls the magnitude and class of the effector response. The goal is to understand these two decisions. Based on these decisions, the immune system is divisible into manageable segments each of which is describable by a theoretical construct or model. These constructs are connected to provide a comprehensive framework that permits simulation of an in vivo immune response. As the system is multivariate, the computer becomes an essential tool, not only to keep track of all of the data inputs, but to extract any cryptic conclusions amenable to experimental attack. The theoretical constructs being developed cover most of immune behavior: the Associative Recognition Theory of the Self-Nonself discrimination, the B-Protecton Theory of humoral responsiveness, the T-Protecton Theory of cell-mediated responsiveness and the Adapton Theory for the determination of the magnitude and effector class of the response. These theories are linked together by a computer program based on cellular automata principles (i.e., SIS, the Synthetic Immune System). The success of this approach will be seen in several ways. First, discordance between mechanism and behavior can be revealed. Second, the consequence of a given antigenic input should be predictable. Third, it is more likely that clinical application will be derived from manipulation of the magnitude and class of the effector response than the self-nonself discrimination. Lastly, the most precious result will be the """"""""understanding"""""""" that is uniquely derived from the availability of an integrative and predictive analytical tool
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