Mapping Exposure-Induced Immune Effects: Connecting the Exposome and the Immunome

The EXIMIOUS cohorts

In the EXIMIOUS project, we aim to identify immune fingerprints as signs of environmental exposure (biomarker). Ideally, these early signs can be picked up before health is harmed, to help prevent diseases in individuals in the general population and/or in workers with a specific type of exposure. We will extensively collect clinical and socio-economic data as well as information on the environmental exposure (exposome) and the health status of the immune system (immunome), of participants from several cohorts—covering the entire lifespan, including prenatal life.

We will follow two approaches, one starting from the exposome and the other starting from the disease. These approaches will ‘meet in the middle’.


FIRST APPROACH: STARTING FROM THE EXPOSOME

We will begin with cohorts that cover the entire lifespan: general and birth cohorts (LifeLines, DOC*X and DOC*X Generation, ENVIRONAGE) and occupational cohorts (park workers, paint factory workers, miners, metallurgy workers, waste handlers and administrative workers).


SECOND APPROACH: STARTING FROM THE DISEASE

In this approach, we start from cohorts of people that have potentially exposure-related, immune-mediated diseases, like systemic sclerosis (SSc), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), sarcoidosis and hypersensitivity pneumonitis (HP).

By using these two approaches, we will disentangle the immune fingerprint reflecting the exposome (without disease) and the immune fingerprint reflecting exposure-induced disease. The identified immune fingerprints can help us to better estimate the exposome at the individual level and to find early signs of health damage caused by the exposome, thus helping to predict disease risk for individual people.

In the general population and birth cohorts and in the occupational cohorts – all without an identified immune related disease – we will identify current and past exposures. In the disease cohorts we will identify current and past exposures in people who have potentially exposure-related immune-mediated diseases.

The ‘general population and birth cohorts’ includes A) The LifeLines Cohort, a three-generation study in the Netherlands. The aim is to understand healthy ageing; B) The ENVIRonAGE birth cohort includes mother-child pairs in Belgium. This longitudinal study investigates the influence of environmental exposures during pregnancy and early life on the health of children; C) The DOC*X cohort and DOC*X Generation are Danish databases that encompasses the entire Danish population from 1964 – 2013 PLUS children (with follow-up to 38 years of age) of all DOC*X members with their birth and health outcomes.

UH – The Netherlands

The LifeLines Cohort Study is a large, three-generation study in the Netherlands. Participants are followed-up during at least 10 years. During this time span, participants complete questionnaires and other measurements at multiple occasions. The aim of the LifeLines Cohort study is to understand healthy ageing. The ultimate goal is to better prevent, predict, diagnose and treat diseases.

For the EXIMIOUS project, we will identify cases with immune-related outcomes in the databank and biobank from LifeLines, such as Rheumatoid Arthritis, Systemic Lupus Erythematosus and Type-I-diabetes. These patients will be matched with a control group (similar age and gender; no disease). We aim to determine whether exposure predicts the disease risk of autoimmune diseases.

More information about this cohort: https://www.lifelines.nl/

UH – Belgium

The ENVIRonAGE cohort includes 1688 mother-child pairs in Belgium. The study started in 2012 and is still running for 322 children (4-6 years old) and their mothers. This longitudinal study investigates the influence of environmental exposures during pregnancy and early life on the health of children.

EXIMIOUS will include children and their mothers. We will collect and reuse data from this cohort from the prenatal period, at age 4-6 and at age 8-10. This cohort is of great value to our project as it provides information on both the exposome and the immunome in the prenatal period and at a young age.  The research question we aim to answer is whether the prenatal and postnatal exposome (environmental exposures) is related to specific immunomic profiles at a young age.

More information about this cohort: https://www.uhasselt.be/ENVIRONAGE-birth-cohort-study-design

NRCWE, REGION H, AAU – Denmark

DOC*X is a Danish database that encompasses the entire Danish population from 1964 – 2013. It contains information about the working environment in Denmark in this time period. Job Exposure Matrixes (JEMs) are applied to determine the levels of exposure for each occupational group (e.g., noise, UV-radiation, dust, workload, stress, chemicals).

In EXIMIOUS, we aim to determine whether exposure to work-related factors increases the risk of autoimmune disease. For this purpose, we will also retrieve hospital diagnoses (ICD8/10) from the nationwide Danish National Patient Register, and thus build the bridge between environmental exposure and health outcomes.

For more information about this cohort: http://doc-x.dk/en/ 

DOC*X Generation includes children (with follow-up to 38 years of age) of all DOC*X members with their birth and health outcomes.

The purpose of including DOC*X Generation in EXIMIOUS is to assess whether parental exposure to work-related factors in the prenatal and postnatal period increased the risk of autoimmune disease in offspring of workers.

The ‘occupational cohorts’ include (a) A Waste worker cohort, which consists of workers form waste-sorting plants. These workers are exposed to a high diversity of microorganisms and pathogens. (b) A Park workers cohort, which consists of workers from the Urban Pest Control and Surveillance Service in Spain. These workers are exposed to a broad range of exposures from working with avian and fungal antigens. (c) A group of workers exposed to mineral dust and organic solvents. This cohort includes mining workers, exposed mainly to mineral dust (silica, coal dust); workers in painting and shoe industries, exposed mainly to organic solvents; and foundry workers from a metallurgic plant, exposed mainly to mineral dust (silica, metal particles) and organic solvents.

NRWE – Denmark

The waste workers cohort consists of workers form waste-sorting plants. These workers are exposed to a high diversity of microorganisms and pathogens. They are likely to experience associated symptoms such as diarrhea, organic dust toxic syndrome or airway inflammation.

For the EXIMIOUS project, we will measure the personal exposure level at the end of a working day. We will also collect blood samples. We aim to determine the association between occupational exposure to bioaerosols and markers of health effects related to the airways.

VHIR – Spain

This cohort consists of workers from the Urban Pest Control and Surveillance Service in Spain. These workers are exposed to a broad range of exposures from working with avian and fungal antigens. The microbial and organic dust exposures increase the risk of Hypersensitivity Pneumonitis (HP).

Our research question is the following: does a higher exposure level increase the risk of HP (or other immune diseases)?

UMFST – Romania

This cohort includes a total of workers exposed to various exposure agents:

  • mining workers, exposed mainly to mineral dust (silica, coal dust);
  • workers in painting and shoe industries, exposed mainly to organic solvents;
  • foundry workers from a metallurgic plant, exposed mainly to mineral dust (silica, metal particles) and organic solvents.

These workers are matched to a control group (office workers). All the workers are recruited in Romania.

We aim to identify how occupational exposure to mineral dust and organic solvents impacts our immune system.

The disease cohort includes patients with Hypersensitivity Pneumonitis (HP), recruited from the pulmonary fibrosis clinic in Vall d’Hebron University (VHIR), and patients with newly diagnosed sarcoidosis, recruited at the sarcoidosis clinic in the University Hospitals of Leuven (Belgium). A population-based case control study will also be established with patients with systemic sclerosis, recruited from the University Hospitals of Leuven and Louvain (Belgium). Also, case control studies will be established with patients with (i) systemic lupus erythematosus and (ii) rheumatoid arthritis, recruited from the University Hospital of Louvain.

The research questions we aim to answer are:

  • Is there a difference in exposure in patients versus controls?
  • Is there a difference in the immune fingerprint of patients and controls, and does this vary when exposure varies?

University Hospital of Leuven – prof. dr. Ellen De Langhe, and University Hospital of Louvain – prof dr. Bernard Lauwerys

Autoimmune diseases have been associated with exposure to a whole range of chemical agents (e.g. silica, solvents, vinyl chloride, mercury, dioxin, pesticides, and air pollution) as well as other factors such as UV radiation. An example of a potentially exposure-induced disease is Systemic Sclerosis.

Systemic Sclerosis is a rheumatic disease that is characterized by the excessive development of scar tissue (fibrosis) in the skin and other organs. It occurs when your body begins to overproduce collagen and this accumulates in your tissue. The exact cause of SS is unknown, but it has been associated with exposure to silica, solvents and heavy metals.

In EXIMIOUS, we will establish a population-based case control study with patients with SS. These patients will be recruited from the University Hospitals of Leuven and Louvain (Belgium). Patients can participate after giving informed consent. We will compare the patients with a healthy control group, and investigate whether exposure is different in patients versus controls. We also investigate if there is a difference in the immune fingerprint from patients versus controls.

University Hospital of Louvain – prof dr. Bernard Lauwerys

Autoimmune diseases have been associated with exposure to a whole range of chemical agents (e.g. silica, solvents, vinyl chloride, mercury, dioxin, pesticides, and air pollution) as well as other factors such as UV radiation. Another example of a potentially exposure-induced disease is Systemic Lupus Erythematosus.

Systemic Lupus Erythematosus, or Lupus in short, is an autoimmune disease in which the body’s immune system mistakenly attacks healthy tissue in many parts of the body (e.g. joints, skin, kidneys, lungs, …). Symptoms vary but often include fatigue, joint pain, rash and fever. It is a chronic disease for which a cure has yet to be found.

In EXIMIOUS, we will establish a case control study with patients with SLE (and controls). The patients will be recruited from the University Hospital of Louvain. Participants are included after giving informed consent.  We will assess both exposures (mostly past exposures) and immune fingerprints. We will compare the patients with the control group to determine whether there is a difference in exposure and in the immune fingerprint.

University Hospital of Louvain – prof dr. Bernard Lauwerys

Autoimmune diseases have been associated with exposure to a whole range of chemical agents (e.g. silica, solvents, vinyl chloride, mercury, dioxin, pesticides, and air pollution) as well as other factors such as UV radiation. Another example of a potentially exposure-induced disease is Rheumatoid Arthritis (RA).

Rheumatoid Arthritis is a chronic inflammatory disorder that primarily affects the joints. Most commonly, the wrists and hands are involved. It is characterized by swollen, painful and stiff joints. Environmental exposures such as chemicals and air pollutants are thought to increase the risk of RA.

For EXIMIOUS, we will establish a case control study with RA patients (and controls). The patients will be recruited from the University Hospital of Louvain. Participants are included after giving informed consent. We will compare the patients with a healthy control group to assess whether (a) there is a difference in exposure, and (b) there is a difference in immune fingerprints.

University Hospital of Leuven – prof. dr. Jonas Yserbyt

Sarcoidosis is an immune-mediated, granulomatous disease that is mainly characterized by the development of the focal aggregation of immune cells or ‘granulomas’. In sarcoidosis, granulomas can form in any organ but they are mostly seen in the lungs and lymph nodes. The disease can result in various symptoms, depending on which organs are affected.

The cause of sarcoidosis is unknown, but experts think it results from the body’s immune system responding to an unknown substance. Several lines of evidence support the idea that this disease, in genetically susceptible hosts, arises due to exposure to one or several antigens such as (a combination of) organic and mineral dust particles.

For EXIMIOUS, we will establish a population-based case control study with Sarcoidosis patients, recruited at the Sarcoidosis clinic in the University Hospital of Leuven (Belgium). They will be matched to a control group of healthy participants. Participants are included after giving informed consent. We will compare the patients with a healthy control group to assess whether (a) there is a difference in exposure, and (b) there is a difference in immune fingerprints.

Vall d’Hebron University Hospital – Dr. Xavier Muñoz

Hypersensitivity pneumonitis (HP) or extrinsic allergic alveolitis is a rare immune system disorder that affects the lungs.

It is caused by a hypersensitivity to inhaled organic agents. Examples of such agents are bacteria, fungi and molds, proteins and chemicals. Not all people exposed to such agents are similarly at risk of disease development, but the amount of exposure does increase the risk.

These agents trigger the immune system, causing inflammation in the lungs. This inflammation makes it difficult for the lungs to function properly. If the condition goes untreated or is not well controlled over time, the inflammation becomes chronic and can lead to permanent damage to the lungs. This can severely impair the lung function. Symptoms are coughing, shortness of breath, fatigue, …

For EXIMIOUS, we will establish a population-based case control study with HP patients, recruited from the pulmonary fibrosis clinic in Vall d’Hebron University (VHIR). The patients will be matched with a healthy control group. Participants are included after giving informed consent. We will compare the patients with a healthy control group, and investigate whether exposure is different in patients versus controls. We also investigate whether there is a difference in the immune fingerprint from patients versus controls.