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Although sex disparity in immunological function and susceptibility to various inflammatory and infectious disease is recognized in adults, far less is known about the situation in young infants during immune development. We have used an outbred piglet model to explore potential early sex disparity underlying both mucosal immune development and systemic responses to novel antigen. Despite similarities in intestinal barrier function and therefore, presumably, antigen exposure, females had less CD172+ (Sirp-α) antigen presenting cells and expression of MHCIIDR at 28 days old compared to males, along with greater regulatory T-cell numbers. This suggests that, during infancy, females may have greater potential for local immune regulation than their male counterparts. However, females also presented with significantly greater systemic antibody responses to injected ovalbumin and dietary soya. Females also synthesized significantly more IgA in mesenteric lymph nodes, whereas males synthesized more in caecal mucosa, suggesting that plasma cells were retained within the MLN in females, but increased numbers of plasma cells circulated through to the mucosal tissue in males. Significant effects of inulin and Bifidobacterium lactis NCC2818 on the developing immune system were also sex-dependent. Our results may start to explain inconsistencies in outcomes of trials of functional foods in infants, as distinction between males and females is seldom made. Since later functionality of the immune system is highly dependent on appropriate development during infancy, stratifying nutritional interventions by sex may present a novel means of optimizing treatments and preventative strategies to reduce the risk of the development of immunological disorders in later life.

Epidemiological studies have demonstrated that exposure to farm environments during childhood can be linked to reductions in the incidence of immune disorders, but generating an appropriate model is difficult. 108 half-sibling piglets were born on either extensive (outdoor) or intensive (indoor) farms: at 1 day old, a subset of piglets from each litter were transferred to a high-hygiene isolator facility to create differences in rearing environment either during birth/first day or during the subsequent 56 days of life. Interactions between CD14, CD16, MHCIIDR, and capillary endothelium were assessed using four-color quantitative fluorescence immunohistology. Effects of birth and rearing environment on the antigen-presenting microenvironment of the proximal and distal jejunum (professional and stromal) were apparent at 5, 28, and 56 days after birth However, effects on CD4+CD25+Foxp3+ regulatory T-cells (Tregs) in the intestinal mucosa were apparent around weaning at 28 days but had disappeared by 56 days. These Tregs were reduced in the isolator piglets compared to their farm-reared siblings, but this effect was less marked in piglets born on the extensive farm and required administration of antibiotics. Our results suggest that there may be at least two windows of opportunity in which different farm environments were influencing immune development: one during the perinatal period (up to the first day of life), and one during later infancy. Furthermore, the differences on Tregs suggest that the effects of early life influences may be particularly critical around weaning.

Studying the pathogenesis of an infectious disease like colibacillosis requires an understanding of the responses of target hosts to the organism both as a pathogen and as a commensal. The mucosal immune system constitutes the primary line of defence against luminal micro-organisms. The immunoglobulin-superfamily-based adaptive immune system evolved in the earliest jawed vertebrates, and the adaptive and innate immune system of humans, mice, pigs and ruminants co-evolved in common ancestors for approximately 300 million years. The divergence occurred only 100 mya and, as a consequence, most of the fundamental immunological mechanisms are very similar. However, since pressure on the immune system comes from rapidly evolving pathogens, immune systems must also evolve rapidly to maintain the ability of the host to survive and reproduce. As a consequence, there are a number of areas of detail where mammalian immune systems have diverged markedly from each other, such that results obtained in one species are not always immediately transferable to another. Thus, animal models of specific diseases need to be selected carefully, and the results interpreted with caution. Selection is made simpler where specific host species like cattle and pigs can be both target species and reservoirs for human disease, as in infections with Escherichia coli.

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.