Innate immune response and regulation of human life-histories under adverse conditions

May, L. (2010)

Doctoral Thesis

Human fitness is critically reliant on the immune system to provide protection against pathogens. We argue that a pro-inflammatory response is crucial for defense against pathogens and that it is very likely that infectious pressure has resulted in selective survival for genetic variants encoding for higher pro-inflammatory responsiveness. In industrialized populations many chronic diseases have been associated with an imbalance in pro- and anti-inflammatory responsiveness. We argue that from an evolutionary perspective, these chronic diseases in later life could be explained by genetic adaptations to survive a harsh environment. In order to study the role of the innate immune response in life-history regulation in a pathogen-rich environment, we set out a study in Northern Ghana. In a population living under adverse conditions we studied the role of the inflammatory response in survival and fertility. In Chapter 1 a general introduction was given on the research hypotheses and an overview of aims and description of the study population and methods. The general frame-work of the study was explained in depth in Chapter 2. Here we hypothesized that human life-history regulation in our evolutionary past, or under adverse conditions can largely be explained by selections that operated in the innate immune response. We proposed that fertility is associated with an anti-inflammatory response, whereas survival in a pathogen-rich environment is dependent on a strong pro-inflammatory response. We hypothesize that populations living under adverse conditions have been selected for a pro-inflammatory innate immune response. Also we argue that fitness in itself is a conflict between pro- and anti-inflammatory responsiveness where concessions have to be made to allow reproduction as well as defense. Furthermore we argue that evolutionary programming of the inflammatory response might underlie age-related diseases as observed in populations living under affluent conditions. It is arbitrary how to measure an innate immune response ex vivo, that reflects a general response mode irrespective the type of pathogen involved. In Chapter 3 a method is described to test innate tendency of immune activation. The assay is also validated. Given the fact that bacteria and other pathogens normally use several TLRs together to induce an immune response, we argue that mixed stimulation of both TLR2 and TLR4 receptors gives a broader view of an immune response than with the usual assay on a single TLR-agonist. Compared to variability of cytokine production in the Netherlands, we show that ex vivo IL10 production is comparable. Therefore we suggest that in Ghana IL10 is highly genetically regulated. TNF_, on the other hand, is more prone to variation in general, but especially in Ghana and might be more dependent on environmental modulation. In Chapter 4 we compared age-related cytokine production in adverse and affluent conditions. When measured cross-sectionally, IL10 production decreases with age in the Netherlands and in Ghana. TNF_ production decreases with age in the Netherlands, but remained equal over all age-categories in Ghana or, dependent on the stimulation, increased with age. We conclude that the decline in innate cytokine responses is an intrinsic ageing phenomenon, while pathogen exposure and/or selective survival may drive pro-inflammatory responses under adverse living conditions. As TLR2 and TLR4 are important recognition receptors for a large set of pathogens, it might be that variation in these receptors results in different induction of innate immune responses and selective survival. In Chapter 5 we report that at the end of the TLR4 gene there was variation that associated with higher ex vivo LPS-induced IL10 production. None of the variants in TLR2 or TLR4 however were associated with P. falciparum infection or survival. As the prevalence of malaria was high in this area, we conclude that it is likely that in contrast to other studies, these genetic variants do not play a role in disease state and outcome of infection. Another pathogen receptor is PTX3. It is not only involved in recognition of pathogens, but also in the formation of the extracellular matrix of the oocyte. Therefore it might be crucial for female fertility. In Chapter 6 we assess whether genetic variation in PTX3 production is associated with life-time reproductive success. We found genetic variants in PTX3 that associated with higher PTX3 production capacity ex vivo and increased fertility and vice versa. We found no evidence for selective survival of genetic variants. We conclude that PTX3 is important for human fertility, whereas no concessions were made with regard to survival. In Chapter 7 we asses the role of IL10 in survival. We report on genetic variation in the IL10 gene that associated with lower IL10 and higher TNF_ production. Carriers of these genetic variants had a higher survival chance when living under adverse conditions. However, survival chances of these variants decreased when people had access to clean drinking water. We conclude to have found evidence that adverse environmental conditions favor selection for a pro-inflammatory response pattern.

• Ageing
• Epidemiologic transition
• Evolution
• Ghana
• IL10
• Innate immune response
• Life-histories
• PTX3
• TLR2
• TLR4

• All authors: May, L.
• Supervisor: Westendorp, R.G.J.
• Co-supervisor: Kuningas, M.
• Qualification: Doctor (dr.)
• Awarding Institution: Leiden University Medical Center (LUMC), Leiden University
• Date: 2010-04-13
• Sponsorship: Netherlands Foundation for the Advancements of Tropical Research (grant number WOTRO 93-467), the Netherlands Organization for Scientifi c Research (NWO 051-14-050), the EU funded Network of Excellence LifeSpan (FP6 036894), the Netherlands Genomics Initiative/Netherlands Organisation for Scientifi c Research (NWO 050-60810) and the Stichting Dioraphte.