Evolution of immune systems: specificity and autoreactivity

Multicellularity evolved well before 600 million years ago, and all multicellular animals have evolved since then with the need to protect against pathogens. There is no reason to expect their immune systems to be any less sophisticated than ours. The vertebrate system, based on rearranging immunoglobulin-superfamily domains, appears to have evolved partly as a result of chance insertion of RAG genes by horizontal transfer. Remarkably sophisticated systems for expansion of immunological repertoire have evolved in parallel in many groups of organisms. Vaccination of invertebrates against commercially important pathogens has been empirically successful, and suggests that the definition of an adaptive and innate immune system should no longer depend on the presence of memory and specificity, since these terms are hard to define in themselves. The evolution of randomly-created immunological repertoire also carries with it the potential for generating autoreactive specificities and consequent autoimmune damage.While invertebrates may use systems analogous to ours to control autoreactive specificities, they may have evolved alternative mechanisms which operate either at the level of individuals-within-populations rather than cells-within-individuals, by linking self-reactive specificities to regulatory pathways and non-self-reactive to effector pathways.

Neonatal environment exerts a sustained influence on the development of the intestinal microbiota and metabolic phenotype

The postnatal environment, including factors such as weaning and acquisition of the gut microbiota, has been causally linked to the development of later immunological diseases such as allergy and autoimmunity, and has also been associated with a predisposition to metabolic disorders. We show that the very early-life environment influences the development of both the gut microbiota and host metabolic phenotype in a porcine model of human infants. Farmpiglets were nursed by their mothers for 1 day, before removal to highly controlled, individual isolators where they received formula milk until weaning at 21 days. The experiment was repeated, to create two batches, which differed only in minor environmental fluctuations during the first day. At day 1 after birth, metabolic profiling of serum by 1H nuclear magnetic resonance spectroscopy demonstrated significant, systemic, inter-batch variation which persisted until weaning. However, the urinary metabolic profiles demonstrated that significant inter-batch effects on 3-hydroxyisovalerate, trimethylamine-N-oxide and mannitol persisted beyond weaning to at least 35 days. Batch effects were linked to significant differences in the composition of colonic microbiota at 35 days, determined by 16 S pyrosequencing. Different weaning diets modulated both the microbiota and metabolic phenotype independently of the persistent batch effects. We demonstrate that the environment during the first day of life influences development of the microbiota and metabolic phenotype and thus should be taken into account when interrogating experimental outcomes. In addition, we suggest that intervention at this early time could provide ‘metabolic rescue’ for at-risk infants who have undergone aberrant patterns of initial intestinal colonisation.