Immune-mediated, non-communicable diseases, such as autoimmune diseases, allergic diseases and
asthma, are chronic disorders in which the immune system plays a pivotal role. The World Health
Organisation (WHO) has highlighted the seriousness of autoimmunity and its association with
exposure to the environment, but research on the underlying causes, mechanisms and prevention of
these disorders remain an urgent need. (1) With autoimmune diseases there is a specific,
self-reactive immune response—in the form of autoantibodies and/or T-cell responses— that can
produce a variety of clinical conditions, depending on the target of the attack. These conditions
number in the hundreds of diseases or syndromes, many of which are organ-specific (e.g.,
autoimmune thyroid disease and type- 1 diabetes), while others are systemic (e.g., systemic sclerosis,
rheumatoid arthritis, systemic lupus erythematosus). These diseases are already affecting a very
worrying 7.6–9.4% of the EU population. (2) What is more, as highlighted in the 2017 workshop on
“Autoimmune diseases – Modern Diseases” by the European Parliament’s Committee on
Environment, Public Health and Food Safety (ENVI), women are 2–10 times more likely to suffer from
autoimmune diseases than men. The severity of this situation is highlighted by the fact that
autoimmune diseases are one the leading causes of death in women under the age of 65. There is
also a clear socio-economic factor in terms of the prevalence of many autoimmune diseases, with
poorer people being at much greater risk. Research on this suggests that the less well-off are subject
to high levels of exposure at work and elsewhere. (3) The financial costs are also beginning to cause
great concern, after a US study estimated that their annual expenditure associated with autoimmune
diseases could run to a staggering $100 billion.
The WHO has also drawn attention to the fact that autoimmune diseases are multi- factorial,
meaning that both intrinsic factors, like genetics, hormones, and age, and the environment
contribute to the induction, development, and progression of autoimmune diseases. (1)
Furthermore, research has shown that the environmental contribution exceeds 50%—and is as high
as 95% for some autoimmune diseases. (4) This gives considerable weight to the idea that Judith
Sterns’ often quoted analogy 'Genetics load the gun, but the environment pulls the trigger' is
especially applicable to autoimmune diseases.
Autoimmune diseases are a perfect example of why it is time to dismiss the out-dated “one
exposure, one disease” dogma. Research on autoimmune problems focusing on single diseases and
exposures is severely hampering progress and fragmenting vital research funding. With the incidence
and prevalence of autoimmune diseases increasing, and with it the misery suffered by individuals
combined with the heavy costs to society, a wholly new approach to preventing these diseases is
desperately needed. In the EXIMIOUS project, we take a different angle, viewing autoimmune
diseases as a variety of disease phenotypes that result from different combinations of
gene–environment interactions, where some combinations of genomes and environmental
exposures lead to certain disease phenotypes, whereas other combinations might not. Furthermore,
autoimmune ‘diseases’ can be considered as just the ‘tip of the iceberg’ of a whole spectrum of
immune effects. Mapping these immune effects will allow us to detect the early effects of exposure
and to predict future disease. (5)
In the EXIMIOUS project we will introduce a completely new way of mapping exposure-induced
immune effects by combining exposomics (the systematic determination of environmental
exposures) and immunomics (the systematic mapping of the immune-system). We will then build a
multifaceted toolbox for researchers, policy makers and the general public to help them assess the
impact of the exposome (the totality of human environmental exposures) on the immune system at
the levels of individuals and large groups, which will lead to better preventive policies, reduced
healthcare costs and greater wellbeing for the people of Europe.
The central tools to achieve this aim are the immune fingerprints that will be developed during this
project, using two main methodologies: 1) in general population, birth and occupational cohorts, we
start by determining the exposome and then advance to search for immune fingerprints that reflect
exposure and 2) in the disease cohorts we start from health effects and next, we will search for
immune fingerprints reflecting both exposure and disease. These two approaches will ‘meet in the
middle’ (6), i.e., by mapping the immunome from both directions we will disentangle the immune
signature reflecting the exposome (without disease) and the immune signature reflecting
exposure-induced disease. In this way we will be able to develop a library of immune fingerprints
that can help us to better estimate the exposome at the individual level and to find early signs of
health damage caused by the exposome, and thus help to predict disease risk at the individual level.
The project is driven by a desire to improve people’s lives and reduce the incidence of disease for all
age groups, social classes and genders. As the exposome has a major role in the occurrence of
autoimmune diseases. This means the potential for disease prevention is huge, as the diseases are
invaliding (and thus reducing participation on the labour market) and generally require expensive,
lifelong medical care. In systemic sclerosis (SSc) for example, research has shown that 95% of the
disease occurrence can be explained by environmental factors, of which some are already identified,
but a majority remains unknown (5). Twenty-two percent of these patients stop working within 3
years of diagnosis. Total direct annual medical costs per SSc patient for Europe range from €3544 to
€8452, and the total annual costs—including indirect costs—can reach as much as €22,459/year. (8)
This indicates the huge potential impact of disease prevention. Understanding the role of the
exposome and having a toolbox with immune fingerprints serving as biomarkers of exposure and
predictors of the disease can thus truly revolutionise disease prevention. A toolbox of immune
fingerprints of exposure will improve our ability to assess an individual’s entire exposome, even
without being able to conduct external measurements in the person’s environment. For clinicians,
following up people with supposedly exposure-induced disease, it offers tremendous advantages for
discovering the causal environmental risk factors. For researchers and policy makers this will allow a
better understanding of the contribution of different environmental risk factors to the
immune-mediated health effects, leading to a sound prioritization of targeted preventative actions.
Next, being able to use immune fingerprints as a predictor of disease could heavily impact on disease
prevention as it can allow clinicians to screen potentially exposed individuals and make a personal
assessment of the risk of a disease occurring.
Nederlandse samenvatting:
Immunologische ziekten zoals auto-immuunziekten, allergieën en astma zijn chronische,
multifactoriële aandoeningen waarbij ons immuunsysteem een essentiële rol speelt. Onderzoek naar
auto-immuunziekten focust zich voornamelijk op een ‘one exposure one disease stigma’. Echter zijn
niet alleen deze omgevingsfactoren van belang maar ook intrinsieke factoren, zoals genetica,
hormonen en leeftijd, als de omgeving dragen bij aan auto-immuunziekten. Daarom beschouwen we
in deze studie auto-immuunziekten als een verscheidenheid van aandoeningen die resulteren uit
verschillende combinaties van gen-omgevingsinteracties. EXIMIOUS heeft als doel om de individuele
immunologische gevolgen van milieublootstelling te onderzoeken om te voorspellen welke
individuen meer kans hebben om blootstelling gerelateerde aandoeningen te ontwikkelen op basis
van hun genetische informatie.
Engelse samenvatting:
Immunological diseases like autoimmune diseases, allergies and asthma are chronic, multifactorial
disorders in which our immune system plays an essential role. Research on autoimmune diseases
mainly focuses on a ‘one exposure one disease stigma’. However, both intrinsic factors, like genetics,
hormones, and age, and the environment contribute to autoimmune diseases. Therefore, in this
study, we view autoimmune diseases as a variety of disorders that result from different combinations
of gene–environment interactions. EXIMIOUS aims to analyze the individual immunological
consequences of environmental exposures to predict which individuals are more likely to develop
exposure related disorders based on their genetic information.