"Science is made with facts, as a house is made with stones: but an accumulation of facts is no more a science than a heap of stones is a house".
Theoretical thinking is often neglected by scientists for its excessive abstraction and its lack of use in the everyday life. However, theoretical framework or paradigms are indispensable in experimental science. They define the experimental ways to explore a natural phenomenon and give meaning to observations and data. Unfortunately, a negative aspect of paradigms is that they act as "perception filter". They focus attention on some fact but lead to ignore others. Based on interdisciplinary approach (immunology, microbiology, evolution theory, system theory), I tried to revisiting some dominant paradigms in Immunology.
The Unspecific Side of Acquired Immunity Against Infectious Disease: Causes and Consequences.
Acquired immunity against infectious disease (AIID) has long been considered as strictly dependent on the B and T lymphocytes of the adaptive immune system. Consequently, AIID has been viewed as highly specific to the antigens expressed by pathogens. However, a growing body of data motivates revision of this central paradigm of immunology. Unrelated past infection, vaccination, and chronic infection have been found to induce cross-protection against numerous pathogens. These observations can be partially explained by the poly-specificity of antigenic T and B receptors, the Mackaness effect and trained immunity. In addition, numerous studies highlight the importance of microbiota composition on resistance to infectious disease via direct competition or modulation of the immune response. All of these data support the idea that a non-negligible part of AIID in nature can be nonspecific to the pathogens encountered and even of the antigens expressed by pathogens. As this protection may be dependent on the private T and B repertoires produced by the random rearrangement of genes, past immune history, chronic infection, and microbiota composition, it is largely unpredictable at the individual level. However, we can reasonably expect that a better understanding of the underlying mechanisms will allow us to statistically predict cross-protection at the population level. From an evolutionary perspective, selection of immune mechanisms allowing for partially nonspecific AIID would appear to be advantageous against highly polymorphic and rapidly evolving pathogens. This new emerging paradigm may have several important consequences on our understanding of individual infectious disease susceptibility and our conception of tolerance, vaccination and therapeutic strategies against infection and cancer. It also underscores the importance of viewing the microbiota and persisting infectious agents as integral parts of the immune system.
Generation of individual diversity: a too neglected fundamental property of adaptive immune system:
The fitness gains resulting from development of the adaptive immune system (AIS) during evolution are still the subject of hot debate. A large random repertoire of antigenic receptors is costly to develop and could be the source of autoimmune reactions. And yet, despite their drawbacks, AIS-like systems seem to have been independently acquired in several phyla of metazoans with very different anatomies, longevities, and lifestyles. This article is a speculative attempt to explore the selective pressures, which favored this striking convergent evolution. It is well known that the AIS enables an organism to produce a specific immune response against all natural or artificial antigenic structures. However, it is frequently neglected that this response is highly variable among individuals. In practice, each individual possesses a "private" adaptive immune repertoire. This individualization of immune defenses implies that invasion and escape immune mechanisms developed by pathogens will certainly not always be successful as the specific targets and organization of the immune response are somewhat unpredictable. In a population, where individuals display heterogeneous immune responses to infection, the probability that a pathogen is able to infect all individuals could be reduced compared to a homogeneous population. This suggests that the individual diversity of the immune repertoire is not a by-product of the AIS but of its fundamental properties and could be in part responsible for repeated selection and conservation of the AIS during metazoan evolution. The capacity of the AIS to improve the management of cooperative or parasitic symbiotic relationships at the individual level could be a secondary development due to its progressive integration into the innate immune system. This hypothesis constitutes a new scenario for AIS emergence and explains the selection of MHC restriction and MHC diversification.
Redefining the Immune System as a Social Interface for Cooperative Processes:
Viewed from a neo-Darwinian perspective, the main function of the metazoan immune system (IS) is to insure host integrity against invading microorganisms, which are only considered as selfish competitors that reduce the host's resources, inflict tissue damage, and ultimately compromise host fitness. Coevolution of the host and these competitors has been described as a perpetual arms race (known as the Red Queen hypothesis, Van Valen). This vision implicitly suggests that “The IS evolved under selective pressure imposed by infectious microorganisms” (Janeway) and that the ultimate objective of the IS is to conserve the integrity and sterility of the host. In fact, numerous observations from microbiology and ecology have challenged this paradigm and suggest that infectious organisms and the IS play a crucial, unexpected role in evolution. I propose that the innate and adaptive metazoan IS has evolved under selective pressure favoring symbiosis, a source of genetic diversity, HGT, and cooperation that globally promote better adaptation to selective pressure. In this view, the metazoan IS appears to be responsible for: (i) management of the cooperation of syngeneic cells, which may explain the numerous functions of the IS in the development and maintenance of organisms in the absence of infection; (ii) detection of selfish/cheater behavior of syngeneic or allogeneic cells; and (iii) elimination and memorization of cheaters. This invites reinterpretation of the condition for IS activation. The “danger signal” proposed by Matzinger could be redefined as “selfish/cheater signals.” The importance of selfish/cheater behavior in activation of the IS is demonstrated by the ability of the IS to tolerate our allogeneic cooperative microbiota and fight syngeneic selfish cells (tumors). The crucial importance of infections for the evolution/adaptation of life and maintenance of the fitness of consortia strongly suggests that complete neutralization of infection by immune systems cannot be favorable to host adaptation. Consequently, I propose that vertebrate IS must partially tolerate selfish/cheater/infectious organisms. Only cheaters strongly affecting the fitness of consortia must be eliminated. This could explain the fact that all organisms are, in natural conditions, always infected. These infections are not the consequence of failure of the immune system but a logical consequence of the necessity to partially tolerate infectious organisms, a source of HGT, new potential cooperative partners, etc. This is in total opposition to the classical view of the IS, considered only as a defense mechanism conferring “sanctuary status” on the organisms and obsessed with the eradication of infection and host sterility.