Is There a Link between Economic Outcomes and Genetic Evolution? Cross-Country Evidence from the Major Histocompatibility Complex

This research develops a theory and presents empirical evidence of a link between economic outcomes and genetic evolution. Important properties for successful analysis of such a link are found in the adaptive immune system and particularly in the major histocompatibility complex (MHC), a genetically encoded complex involved in the defence against infections. The theory incorporates properties of the MHC in a model of mutual dependence and exhibits a trade-off in which every agent who is better off having an immune response different from that of others is also part of the protecting belt of others in a population, in which mounting similar immune responses is optimal. The data are based on large numbers of blood samples from 63 different populations. The cross-country estimates show a robust negative association between economic and health outcomes and MHC diversity and between average offers in ultimatum and trust games and MHC diversity. The analyses suggest that societies incorporating externalities from mutual dependence are economically more successful, and that the incorporation of such externalities is evident at the gene level.Economics ;

Diversity in the immune system

This thesis addresses various sources of diversity in the vertebrate immune system. In particular, we study the differences between thediversity of lymphocytes and major istocompatibility (MHC) molecules.While any individual expresses a huge diversity of B and T ymphocytes, the diversity of MHC molecules is mainly expressed at the population level. We use various mathematical models and computer simulations to study which evolutionary selection pressures mayunderlie the diversity of lymphocytes and MHC molecules. Central is the hypothesis that the adaptive immune system stores immunological decisions in lymphocytes. Instructed lymphocytes recall their appropriate mode of response whenever they recognise their specific epitope. The vertebrate immune system thereby combines the evolutionary wisdom of the innate immune system with somatic learning by the adaptive immune system. It has been proposed that het need for self-nonself discrimination is the driving force for the diversity of the adaptive immune system. Using mathematical models it has been shown that the diversity of lymphocytes giving optimal protection against infections reflects the number of self antigens that need to be tolerized. We show, however, that avoidance of inappropriate immune responses, such as autoimmune responses against self antigens that fail to induce tolerance, calls for an even higher specificity and diversity than was concluded from these previous models. According to our calculations, lymphocytes should be as specific as possible within the constraints imposed by the size of the immune repertoire. We show that the need to avoid inappropriate immune responses can also explain the limited diversity of MHC molecules within an individual. The fact that individuals express only a limited number of different MHC molecules out of the huge MHC population diversity, is usually attributed to the need to avoid repertoire depletion during self-tolerance induction. We dispute this explanation by showing that expression of extra MHC molecules tends to increase the functional T cell repertoire and that repertoire depletion only occurs at an unrealistically high individual MHC diversity. Expression of a large individual MHC diversity, however, increases the chance of inducing inappropriate immune responses. Foreign peptides presented by MHC molecules may form complexes that -- from the T cell point of view -- look similar to comlexes of MHC molecules presenting ignored self molecules. Excessive MHC diversity therefore increases the chance that lymphocytes that have been triggered by foreign peptides cause autoimmune responses against so-far ignored self antigens. Despite the limited diversity of MHC molecules within any individual, we show that there is selection for a large diversity of MHC molecules at the population level. A large population diversity of MHC molecules allows an individual to respond to different epitopes of an antigen than the other individuals in the population, thereby giving protection against coevolving pathogens. We show that the MHC polymorphism arising under host-pathogen coevolution is significantly larger than the polymorphism arising under selection for heterozygosity only. Finally, using a combined theoretical-experimental approach, we have found evidence for competition between T lymphocytes for antigen-presenting sites on antigen-presenting cells. We conjecture that the immune system may employ the MHC diversity that is left at the individual level to allow the presentation of multiple epitopes per antigen. It may thereby allow the distributed storage of immunological decisions in lymphocytes, despite the presence of T cell competition

How Specific Should Immunological Memory Be?

Protection against infection hinges on a close interplay between the innate immune system and the adaptive immune system. Depending on the type and context of a pathogen, the innate system instructs the adaptive immune system to induce an appropriate immune response. Here, we hypothesize that the adaptive immune system stores these instructions by changing from a naive to an appropriate memory phenotype. In a secondary immune reaction, memory lymphocytes adhere to their instructed phenotype. Because cross-reactions with unrelated Ags can be detrimental, such a qualitative form of memory requires a sufficient degree of specificity of the adaptive immune system. For example, lymphocytes instructed to clear a particular pathogen may cause autoimmunity when cross-reacting with ignored self molecules. Alternatively, memory cells may induce an immune response of the wrong mode when cross-reacting with subsequent pathogens. To maximize the likelihood of responding to a wide variety of pathogens, it is also required that the immune system be sufficiently cross-reactive. By means of a probabilistic model, we show that these conflicting requirements are met optimally by a highly specific memory lymphocyte repertoire. This explains why the lymphocyte system that was built on a preserved functional innate immune system has such a high degree of specificity. Our analysis suggests that 1) memory lymphocytes should be more specific than naive lymphocytes and 2) species with small lymphocyte repertoires should be more vulnerable to both infection and autoimmune diseases

Diversity of Human αβ T Cell Receptors

(a = alpha) Arstila et al. (1) estimated an average diversity of 9 * 10^5 different b chains and 4.5 * 10^5 different a chains in the human nai¨ve T cell repertoire. To calculate the total T cell repertoire diversity, the b-chain diversity was estimated within a certain variable (V) gene family, Va12^+, comprising 2.5% of the total a-chain repertoire. Finding in this particular family an estimated total of 6 * 105 different ß chains (i.e., two-thirds of the total ß-chain repertoire), Arstila et al. suggested that the total T cell receptor (TCR) diversity comprises at least (6 * 105) * 40 = 2.4 * 10^7 different aß combinations (1). The authors acknowledge that this is only a lower bound, because the calculation assumes that the ß chains that do bind at least one Va12 chain bind only one of the 4.5 * 10^5 different a chains in the Va12^+ family. If each ß chain found within the Va12^+ family were to bind an average of n different Va12 chains instead, the total estimated TCR diversity would be n-fold higher than this lower bound