How much of our immune response is based on your genes and how much is influenced by your environment?

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Our favourite paper this month is collaboration between Stanford University (USA) and the Karolinska Instituted (Sweden). Published in Cell in January 2015, Brodin and Jojic et al. present a twin study showing that differences in the immune system between individuals are largely due to non-heritable factors. So your environment seems to be more important than your genes!

What is a twin study?

Twin studies are used to distinguish if a phenotype (a certain trait or characteristic of a person, which can be a disease as well as height or IQ) is influenced by genetics (= it’s heritable) or by environmental factors. The phenotype of interest is measured in a group of monozygotic (identical) and dizygotic (non-identical) twins. The results are then compared between groups with the assumption that, if the phenotype is caused by genetics, monozygotic twins will have the same phenotype (as they share exactly the same genes), while only 50% of dizygotic twin pairs will share the same phenotype (as they only share around 50% of their genes). If a phenotype is caused by environmental factors monozygotic and dizygotic twin pairs will demonstrate the same rates of the phenotype based on their environment.

Many phenotypes are not solely determined by genes or the environment but by a mix of the two. Many diseases for example have a genetic cause but the environment can influence disease severity and onset. Using statistical models, in this study a structural equation model, a heritability estimate can be calculated for each phenotype based on the measurements in twin pairs. An estimate of 1 would represent a phenotype completely controlled by genes, while an estimate of 0.1 means that only 10% of the phenotype is caused by genes and the rest is environmental.

The immune system is largely non-heritable

Using this model, researchers estimated the heritability of 204 immunological phenotypes based on 78 monozygotic and 27 dizygotic twins (ranging in age from 8-82 years). This included the count of 72 immune cell subsets (that are sub-classification of the big immune cell subtypes we introduced to you here) and concentrations of 43 immune messengers in the blood. It is known that these measures differ between individuals but it is unclear if due to genetic or environmental factors. While a few cell types (like central memory T cells) and cytokines (IL-12p40 and IL-7) are highly heritable, most measures (58%) had less than 20% of their variability explained by genes.

Interestingly, T and B cell subsets are less heritable compared to other immune cells and messenger molecules. One explanation for their lower heritability is the nature of how antigen-specific receptors on T and B cells are formed. The receptors are encoded by genes, but unlike most genes, they are not transcribed into proteins in a linear fashion. These genes are recombined (certain parts of the gene are combined, while other parts are not used) and mutated to allow a large number of different receptors. This way more pathogens can be recognised. But this also means every individual carries a personal repertoire of T and B cells – so even though the gene is inherited, the way it is used differs even in monozygotic twins.

One infection can have a long-term effect on the immune system

The data suggests that the environment influences the immune system. And if you think about it, it makes sense as the immune system is interacting with the environment in form of pathogens as well as toxin all the time. Why shouldn’t these interactions, which are different for each person, form and influence the immune system? This would make immune cell subsets and messengers different in each person.

To underline this point, the researcher analysed the effect one virus had on their immune measures. Cytomegalovirus (CMV) is a form of herpes virus found in 60-70% of people in industrialised countries. Analysing monozygotic twin pairs in which one carried CMV and one did not, the researcher found that the virus can influence 58% of the 204 immune phenotypes measured. CMV isn’t an acute infection but one type of livelong infection with no symptoms in most carriers illustrating how exposure to one microbe or virus can change your immune response for a long time.

Does the immune system evolve with age?

Further investigating the role of the environment, the researcher then compared the heritability estimates for all immune phenotypes in younger (60 years). The idea being that in older individuals, the immune system has been exposed to more environmental factors, which could influence the immune response over time. And indeed the counts for several cell types show a decrease in the estimated heritability with age. One example are regulatory T cells, which go from 78% heritable younger twins to 24% in older twins.

The idea that the environment manipulates the immune system over time would also mean that immune response towards infection should be non-heritable but formed by infections the immune system has seen in the past. Supporting this idea, are studies showing that the reaction towards vaccination for mumps, measles and rubella as well as oral polio and tetanus is highly heritable in young children, while Brodin and Jojic et al. found little heritability in the response towards the seasonal flu vaccination in their older individuals (mean age of 38).

Based on this data the authors brought up the interesting theory that the immune system evolves with age, making genetic influences less important over time. One striking example from the clinic underlining their point are two serious immunodeficiency syndromes caused by mutations in genes called IRAK-4 and MyD88 and associated with often lethal bacterial infection in children. However, the conditions improve with age, which also correlates with more environmental exposure. Repeated environmental exposure may therefore shift immune cell subsets in a way that genetic disadvantages can be balanced.

This is an interesting idea, however would only ever apply to “mild” genetic disadvantages and not in the case of severe immunodeficiencies such as SCID, where a mutation in a cytokine receptor causes the loss of T and B cells making every infection potentially lethal. Also there are autoimmune diseases with a late onset such as rheumatoid arthritis, so environmental exposure cannot protect from every genetic disadvantage and may also lead an imbalance causing disease.

Want to know more about this or ask a specific question? Let us know!

Further reading:

Original publication: Brodin and Jojic at al, Cell, 2015 

Comment on the paper: Casanova and Abel, Cell, 2015

Heritable response to vaccines in children: Tan et al, Vaccine ,2001 and Newport et al, Genes and Immunity, 2004 

Immunodeficiencies that get better with age: Von Bernuth et al, Science, 2008 and Ku et al, JEM, 2007

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