histories under adverse conditions
May, L.
Citation
May, L. (2010, April 13). Innate immune response and regulation of human life- histories under adverse conditions. Retrieved from
https://hdl.handle.net/1887/15212
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License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden Downloaded from: https://hdl.handle.net/1887/15212
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GENERAL DISCUSSION
For survival under infectious pressure humans have been dependent on robust defense mechanisms. In this thesis we hypothesized that environ- mental pressure has shaped the human immune response resulting in a ge- nome that has been set for a strong pro-in ammatory responsivenesschapter
2. In order to test innate propensity of cytokine production we designed a whole-blood assay that would be able to measure a general innate immune response irrespective of pathogen exposurechapter 3. Using this assay, we have observed that in Ghana, cytokine production was more pro-in ammatory and less anti-in ammatory with increasing age. This association was diffe- rent in an af uent society, where all cytokine responses decreased with age.
This suggests a role of adverse environmental conditions in the selective survival or the skewing of these immune responses towards a pro-in am- matory pro lechapter 4. Next, we tested whether genetic variation in pathogen receptors that induced the innate response was associated with differences in cytokine production and survival. We found an association of genetic variation in TLR4 but not in TLR2, and cytokine productionchapter 5. We expec- ted that the pathogen receptor PTX3 would also play an important role in human life-histories, since it has been reported earlier important for ferti- lity1-3. Indeed PTX3 was associated with increased female fertility in this po- pulation. We have also found genetic variants that corresponded with PTX3 productionchapter 6. However, in contrast to our expectations there were no survival differences for any of the genetic variants from the pathogen recep- tors testedchapter 5 & 6. This might indicate that there is no general bene t for the population as a whole, or rather only a disease speci c bene t, as ear- lier reported for TLR24,5, TLR46-10 and PTX311,12. An alternative would be that variation with regard to immune responsiveness would be downstream of recognition receptors. Earlier it has been found in the Netherlands that the heritability of innate IL10 production was higher than TNF13. Also in Ghana we found that IL10 was more constant upon repeated measurementchapter 3. Therefore we tested for associations with genetic variants in the IL10 gene.
We found variants that encoded for lower IL10 production and higher TNF
responsiveness i.e. a pro-in ammatory response pattern. These variants were also more present among elders compared to young, indicating a sur- vival bene t for stronger pro-in ammatory responses. Interestingly, survival bene t was different upon environmental exposure, resulting in a bene t for a pro-in ammatory response mode only for the most adverse conditi- onschapter 7.
ADVERSE ENVIRONMENTAL CONDITIONS FAVOR SELECTION FOR A PRO-INFLAMMATORY INNATE IMMUNE RESPONSE
Although adaptive responses eventually provide considerable protection against pathology, the strength of the innate response upon early infection predicts the course of infection and its nal outcome. This has been shown in mouse studies, where in the beginning of a malaria infection a strong pro-in ammatory response resulted in better elimination of the parasite14,15. In human studies it has been shown that a pro-in ammatory innate im- mune response was associated with better survival probabilities for febrile patients16. The same has been reported for meningococcal disease17. It has also been reported that an early response to malaria is characterized by an intense pro-in ammatory response, needed to attenuate parasite replica-
tion18,19. Given the pathogen-rich environment in Ghana, where especially
malaria, but also other infections and helminths are endemic, there is a high likelihood of nding their footprints in survival patterns. The most promi- nent nding is the evidence that in Ghana, with age, people become more pro-in ammatorychapter 4, and that people with a tendency to generate a hi- gher pro-in ammatory response are more likely to survivechapter 7. Therefore we conclude that a high burden of pathogens results in better survival for those with a genetic tendency to generate a high pro-in ammatory res- ponse.
IMPLICATIONS FOR LIFE-HISTORY REGULATION
When a robust in ammatory response is so crucial for human survival, we might expect that the evolved genotype and corresponding phenotype would be relatively uniform. Still variation with regard to high or low in am- mation differs substantially between humans20,chapter 3 and populations21,chapter 4. This might indicate competing adaptive pressures or a possible trade- offchapter 2. For example human tness is not solely dependent on adequate defense mechanisms but also on reproduction. Though for implantation of the fetus, a pro-in ammatory environment is needed22, it has been repor- ted that a shift towards a Th2/Treg or anti-in ammatory response mode is crucial to maintain the pregnancy23. Evidence for this line of thoughts comes from studies that often nd a link between worse pregnancy outcome and a high pro-in ammatory response, either in healthy conditions24,25, or in peo- ple with auto-immune diseases26 and diabetes27.
Interestingly, for different species it has been argued that investments in longevity trades-off with reproduction28. Evidence for this trade-off is also found within the human species29,30. We argued that the balance between pro- and anti-in ammatory responsiveness would underlie this trade-off between reproduction and maintenancechapter 2. It is very likely that, given environmental constraints, concessions have to be made to achieve a t- ness optimum that allows reproduction as well as defense. Though it is very tempting to conclude that in ammation is the sole mechanism involved in these crucial traits concerning human survival, several remarks have to be made.
First of all, it is unlikely that survival of the human species would rely on a single mechanism. In this thesis we found that the achievement of tness in- volves also other mechanisms than the pro- or anti-in ammatory response.
For example PTX3 was in the Ghana population associated with increased fertility, whereas no concessions were made with regard to survivalchapter 6.
Second, the existence of a possible trade-off would be hard to prove in prac- tice; suppose that indeed anti-in ammatory responsiveness would increase fertility but decrease survival chances. Then, the highest fertiles would not even reach the reproductive period; let alone that we can measure their fertility, which can be estimated best at the age when reproduction has ter- minated. In our methodology, by asking fertility histories, at the same time we have selected the population on survival.
Third, under adverse conditions each pregnancy is a major challenge, resul- ting in high maternal mortality gures31. Therefore survival chances would directly increase by lowering the amount of offspring, irrespective of immu- ne status. Moreover, in Ghana survival of a pregnancy might have to do with a strong immune response of the mother rather than an anti-in ammatory response, needed for fertility per se.
Fourth, we have provided evidence and argued that for initial ght against infection pro-in ammatory responses are favoured. At the same time we expect that there would also be an evolutionary bene t for down-regulation to overcome sustained in ammation. Mechanisms of downregulation can be found in innate and adaptive immune responses. As a result, we expect that with regard to survival ideal immune regulation would involve fast ac-
celeration as well as proper inhibition of in ammation. It is probable that both mechanisms are favoured by selection.
In conclusion the pro-in ammatory versus anti-in ammatory dichotomy might be an oversimpli cation of the mechanism underlying life-history re- gulation.
IMPLICATIONS FOR LATE LIFE SURVIVAL
In our past, humans have been pre-occupied with eary survival and repro- duction. It is therefore very unlikely that in man’s natural environment there has been any selection whatsoever on late life survival or longevity32. Even up to several generations ago, the majority did not reach an age above 40 or 50 years. To this end, investment in health beyond this period is regarded as a waste of resources that would eventually not result in higher tness i.e.
a larger amount of offspring. It has been only recently that in a large part of the world ageing was possible due to a decline in extrinsic mortality. During this ageing process we can observe a higher incidence of age-related chro- nic diseases such as atherosclerosis, cardiovascular diseases, cancer or dia- betes. These conditions can either be explained by a lack of investment in late-life survival and therefore regarded as a process of accumulation of da- mage32. Interestingly many age-related pathologies can be associated with imbalance in pro- and anti-in ammatory immune regulation33-35. Therefore the ageing process is also argued to be rather an effect of antagonistic plei- otropy: a consequence of investment in early survival36.
In this thesis we have seen that, with regard to innate immune responsi- veness, ageing in a low pathogen environment is different than in a high pathogen environmentchapter 4. We have concluded that this could be a plei- otropic effect of selective survival for a pro-in ammatory responsiveness in an adverse environmentchapter 7. Alternatively, but not mutually exclusive, it might as well be that a life-long burden of infection would accelerate ageing of the immune response37-39 or drives it towards a pro-in ammatory direction40. It might therefore be that a higher infectious burden during life leads to a higher chance to develop chronic diseases as atherosclerosis41. There are several prospective studies that found pathogen burden to pre- dict cardiovascular events42. Likewise it has been argued that the reduction
of antigenic load has directly resulted in an increase in life-expectancy in developed societies43. As selective survival and/or provocation of immune responses contribute largely to health at late-life, we expect that environ- mental conditions largely contribute to the pace of ageing in various popu- lations.
EPIDEMIOLOGIC TRANSITIONS HAVE REDUCED THE BENEFIT FOR IN- FLAMMATION
Back to Ghana: In the recent years, improved environmental conditions have reduced mortality risks in this population44,45. Vaccination campaigns, anti- biotics, improved healthcare and socioeconomic status have made this de- cline in mortality possible. As a result a larger proportion of the population is surviving up to the reproductive period and is allowed to age, implying a reduced selective pressure on the in ammatory response. In this thesis we described that for example improved drinking water has reduced mortality rates tremendously. Interestingly in the group that had access to clean drin- king water, the bene t of the pro-in ammatory response (a lower IL10-pro- ducting genotype) reducedchapter 7. There are several interpretations of these
ndings. In line with our earlier reasoning, it might be that in older age there is less mortality from infection and survival increases, but at the same time mortality from age-related pathologies is on the increase. Alternatively, of- ten pathologies as cerebral malaria and septic shock are associated with a lack in downregulation of in ammation46-52. Therefore regulatory adaptive responses are considered to play a role in the prevention of pathologies and contribute to a large extent to survival. It has also been argued that patho- gen exposure plays a major role in the augmentation of the regulatory res- ponse53,54. In this area pathogens were previously constantly challenging im- mune responses, and nowadays in a more intermittent manner. The effect on immune regulation remains unknown. Further research however would be needed to understand the meaning of development for immune regula- tion, including the learning of the anti-in ammatory response as well as the cross-talk between innate and adaptive immune responses. From the same line of reasoning, because a large part of the population is already exposed to an improved environment, possibly with altered selection strategies, this might explain why we did not nd any evidence for survival bene t for ge- netic variants in TLR2, TLR4chapter 5 or PTX3chapter 6. In conclusion, improved
environmental conditions have changed ancient selective pressures and the relation between appropriate immune regulation and health. As the human genome has been evolved to deal with an adverse environment and has still to catch up with the new setting, development has resulted in lower adap- tation of immune regulation to environmental conditions.
IMPLICATION FOR POPULATIONS THAT ARE CONFRONTING AN EPI- DEMIOLOGIC TRANSITION
In recent years, vaccination programs, antibiotics, improved hygiene and sanitation have reduced the infectious burden in many African countries55. Epidemiologic transitions have a tremendous impact on the health of a po- pulation. Though with the decrease of mortality due to infectious causes and increase in life-expectancy there has also been reported an increase of age-related conditions56-59. Interestingly the incidence of chronic diseases is now actually becoming a major health burden and is even defeating that of infectious disease in many sub-Saharan countries60. Also in immigrants, for example Americans from Sub-Saharan African origin, have been reported as being more susceptible to chronic diseases61,62, resulting in higher all-cause mortality rates in this group compared to those from European descent63. It has been proposed that a genetic predisposition for pro-in ammatory responsiveness is a very likely explanation64-67.
As with the control of infectious diseases, the mean life-expectancy of the world’s population will further increase, so will the burden of chronic disea- ses. Of special concern are populations in transition, that are rapidly impro- ving resources and living conditions. Speci cally people from low income countries are in addition to their struggle with infections also facing upco- ming epidemics of age-related diseases60. From an evolutionary perspective in this thesis we have provided evidence that the human genome has been set for early survival. Demonstrating that infectious pressure results in a selection for pro-in ammatory resistance genes may offer new opportuni- ties to anticipate and understand the health consequences of epidemiologic transitions. Therefore awareness of new epidemics related to ageing and development is needed in order to strengthen health care systems to pro- vide care for both infectious and chronic diseases.
NEXT STEPS: IMMUNE REGULATION IN ITS ORIGINAL CONTEXT
Here it has been shown that human life-history regulation under natural conditions comprises more than genetics and innate immune responses.
In this thesis we mainly focused on the role of in ammation on survival.
Although we have found, in line with our hypotheses, that a strong pro- in ammatory response is bene cial for survival, there are still many gaps in our knowledge about its behavior under natural conditions.
In our natural environment innate and adaptive immune regulation were synchronised. Innate immune responses largely contribute to recognition and ammunition to ght initial infection. On the other hand, adaptive re- sponses provide a subsequent netuning of the response and it’s further outcome, including down-regulation of the killing-mode and pathogen- speci c immunity. In orchestration, both contribute to survival of infection.
Unknown is how they cooperate; for example, how is a genetic tendency to generate a strong pro-in ammatory immune response re ected in adaptive immune regulation? What is the role of the environment in their cross-talk?
Interestingly, the hygiene hypothesis assumes that due to changes in envi- ronmental conditions particular adaptive responses no longer are conform their original pattern. To be precise, pathogen exposure, and speci cally helminths would contribute to a better Treg induced regulatory capacity of in ammation. This response is found less pronounced in those with in-
ammatory conditions as allergies. Therefore elimination of pathogens is considered as a cause of many allergies, most of those concentrated in de- veloped areas54. In addition, especially in a pathogen-rich environment re- gulatory reponses induced by helminths have been suggested as having a positive impact on malaria infection. Often cerebral malaria for example is associated with a lack of down-regulatory capacity and release of Th17 dri- ven pro-in ammatory responses53. It has been suggested that co-infection with helminth might provide protection by immune modulation, dampening severe in ammation68. Combined with our ndings, this would suggest that there might have been an evolutionary bene t for a mechanism that would involve strong in ammation as a start, capable of strong inhibition in the end. It would also suggest that with the advert of development, immune regulation might have lost its original context.
In conclusion, the immune response has been evolved to work optimally in a pathogen-rich environment. With epidemiologic transitions, the roles and orchestration of innate and adaptive immune responses are no longer in concert. Therefore the behaviour of the immune response as well as its bene ts for survival should be understood in its original context. Through this thesis we have hopefully contributed a fraction to this topic. Further research on its regulation in various environments, may provide further in- sight in the consequences for health that we introduce with the further era- dication of pathogens, vaccinations and better hygiene.
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