Evolution is the axiom of today's biology. The program of work described in this application is designed to discover how evolution has shaped the vertebrate immune system and to then apply these principles to improve human health. The rate of evolution of infectious diseases (of the order of hours) is vastly more rapid than the rate of evolution of human hosts, which evolve at a rate of the order of decades. The immune system is the host response that permits a biodestructive but protective defense mechanism to somatically evolve on a time scale close to that of bacteria and viruses. In order to achieve this rapid rate of evolution, the immune system has to somatically determine the distinction between self components (i.e., those which if destroyed would kill the host) and non-self components (i.e., those which if NOT destroyed would kill the host). Discovering how this is achieved is one of the major specific aims of this program of work. Other regulatory events control the number and amount of antibodies that can be produced at protective levels, and collectively these are the principal areas of investigation. This particular program of work is designed to tackle the larger integrative issues of immune regulation. A huge effort goes into working out details of mechanism, and much less effort is directed at finding the balance between the competing demands of the organism and its defense mechanisms. One reason for this neglect is the sheer magnitude of the problem. However, this can be ameliorated by the judicious use of computer simulation tools that are able to absorb the data and keep track of the many selection pressures that govern the final state of the immune response to a given infectious disease. The proposed program of work depends on the results from many different experimental test systems. A unique feature of this proposal is to make the computer programs and their conceptual framework freely available to all members of the immunological community via the Internet and the ubiquitous web browser installed on every computer.