António Coutinho

Purposeless diversity and degeneracy of molecular “recognition” are the solution to the unknown: each individual immune system is a fractal of evolution

The adaptive immune system of vertebrates deals with the general problem of the co-evolution of species with greatly divergent life cycles, thus displaying enormous differences in the relative potential for genetic variation. Microorganisms duplicate in minutes, while vertebrates take months or years, as imposed by the extended developmental times that are required for reaching their typical size and structural complexity. Given the uselessness of accumulating germ-line information for complementary molecules with unique specificity towards each of the ever-changing microbial structures, any viable “solution” had to “anticipate the future” and “cover” all possibilities, that is, it had to provide for the “completeness” of immune repertoires endowed with some degree of “specificity”. Being anticipatory, therefore, immune “specificity” is necessarily based on “degeneracy” (lack of bi-univocity between ligands and immune molecules) and cooperative (specificity to a given ligand owes to this shared characteristic of a population of diverse molecules, each interacting with a variety of other ligands as well). In other words, identification (specificity) of molecular patterns (i.e., a whole microbe) owes little to the uniqueness of individual complementarities between molecular motifs on each microbe (antigen) and combining sites of immune molecules; rather, it is a distributed property of very large sets of motifs (epitopes) and complementary paratopes, constructed upon individual interactions that are very degenerate. The larger these sets are, the more precise is pattern identification. Current estimates indicate a number of “epitopes” above 1017 for a number of distinct “paratopes” in the order of 1012 (in humans). Sheer numbers of potential molecular “shapes”, however, exclude germ-line solutions, such that the astonishing evolutionary novelty consisted in transferring “variation and selection” to the somatic time of every individual, transforming each vertebrate immune system into a fractal of biological evolution. This involved a few convergent “strategies” at the molecular, cellular and systemic levels: (1) keep in germ-line molecular mechanisms that “invent” novel DNA sequences of Variable-region molecules (VRMs), and are essentially irreversible in each cell where they operate; (2) evolve a “post-mitotic resting state” for the cells expressing such VRMs, but endow them with further capacity of amplification (dynamics); (3) impose on such cells (lymphocytes) a program for “cell death by default” that can only be rescued by the cellular “utilization” of VRMs; (4) include a developmental program for the continuous production of new lymphocytes (and VRMs) from uncommitted precursors throughout life (metadynamics). In summary, these strategies result in unique possibilities: (1) a life-long source of an open-ended diversity of VRMs in “potential repertoires”; (2) the selection into the “available repertoires” of cells with VRMs that “make sense” in that individual at that point in time; (3) the selection for amplification in the “actual repertoires” of those VRMs that neutralize (are complementary) to novel molecular shapes appearing in the organism; (4) the continued “adjustment” of all repertoires to the individual’s molecular composition and history of eventual environmental contacts (memory). To be effective in antimicrobial defense, the evolutionarily novel VRM system (adaptive immunity) had to be deployed together with pre-existing “ridding mechanisms” (innate immunity), simultaneously creating the problem of “self-nonself discrimination” and of immunity versus tolerance. The respective solution owes to at least two “strategies” derived form the memory of the molecular composition of either the species or of the individual: on the one hand, to the coupling of lymphocyte activation/amplification to ancient cellular receptors for invariant microbial products that are absent from the species genome (the “biological correlates” of infection), which could thus be kept in germ-line and insure discrimination of “evolutionary self vs nonself”; on the other hand, given that self composition is always available to the developing immune system, to use the wealth of VRM diversity to ensure the “positive selection” of self-reactive lymphocytes and couple such cellular repertoires to “regulatory” functions, capable of suppressing anti-self responses, thus providing a “dominant” form of self-tolerance for discriminating “individual self vs nonself”. In turn, this process required the evolution of particular structures (e.g., thymus) where lymphocyte development and selection take place simultaneously, in the presence of ectopically expressed self antigens that are found elsewhere in the body, but are locally available through the operation of an evolutionarily novel gene-regulatory mechanism. While the evolutionary pressures tinkering the adaptive immune system may be related to the unique protection it affords upon secondary contacts with eminently transmissible microbes, it is clear that an open-ended source of molecular diversity, if coupled to the extraordinary dynamics of VRM amplification, also provides a mechanism for general molecular homeostasis. We have designated this aspect of the adaptive immune system’s operation as “immunosomatics” and argued that it may well have been where it all started.