Flu strikes more often in winter than in summer. Women are more prone to autoimmune diseases than men. As part of the comprehensive Human Functional Genomics Project, scientists at Radboud university medical center, together with their colleagues at the University Medical Center Groningen (UMCG) and the Broad Institute of MIT and Harvard, are investigating the origin of differences in the immune response such as these. The first five articles from this project have been published: three in the journal Cell, one in Cell Host & Microbe and one in Cell Report.
People vary greatly in their response to pathogens as well as the reactivity of their immune system overall, affecting their propensity to autoimmune diseases such as rheumatoid arthritis, type 1 diabetes and multiple sclerosis, and inflammatory diseases such as gout and Crohn’s disease. This variation in immune response also influences susceptibility to diseases such as Parkinson’s and Alzheimer’s, as well as defense against infections. Several factors may contribute to this underlying variability. Environmental factors, such as the seasons, play a role, but age, genetics, and the microbiome are also involved. Evidence points to these factors having an influence on the production of cytokines, the most important signaling molecules in our immune system.
Explaining the differences
Until now, the influence of genes and environmental factors on the variation in cytokine production has only been examined in small studies, and with a limited number of pathogens. The Human Functional Genomics Project, led by Professors Mihai Netea and Leo Joosten of Radboud university medical center, Professor Cisca Wijmenga of the UMCG and Professor Ramnik Xavier of the Broad Institute of MIT and Harvard, Massachusetts General Hospital, and Harvard Medical School is changing that situation. To explain differences in cytokine production, they have been studying groups with hundreds of healthy volunteers and patients. This makes it the most extensive study ever conducted in this field. The first reports from this project, which were published today, focus on the effects of host and environmental factors, the genes, and the microbiome.
The influence of age and body fat
The seasons appear to have a major influence on the immune response. This may help to explain why, for example, flu epidemics usually happen in the winter. The researchers found that certain cytokines have a peak in summer and that other antibodies have a peak in winter. Mihai Netea: “To our great surprise, vitamin D appeared to play only a limited role in this process.” While it was also found that age is important, the entire immune system does not deteriorate as a person gets older and instead age affects specific components of the immune system. The reason for this differential impact is still under investigation. There is also the difference between the sexes: women suffer more often from autoimmune diseases than men. But hormone concentrations were found to play no role in this process. Leo Joosten: “Perhaps this difference is due to the cytokines produced in the fat cells. The body fat percentages are very different between men and women.”
Genetics have the biggest impact
Genetic predisposition was found to have the largest influence on our immune response: 25 to 75 per cent of the strength of our immune defense is genetically determined. Again, this concerns specific parts of the immune system. In this work, researchers found 17 previously undiscovered genes involved in the production of cytokines that regulate how pathogens are detected and that initiate the response to specific pathogens. Strikingly, these are all genes which regulate the production of cytokines by other genes. The genetic predisposition for a strong immune system is partly hereditary, but can vary depending on the pathogen. Cisca Wijmenga: “For example, someone can respond very well to a virus, but poorly to bacteria. The strength of someone’s constitution is thus genetically determined for each stimulus.” Apparently, this is because the immune system must be able to adapt to the specific pathogens in a specific area.
The role of our gut inhabitants
The bacteria that live in our bodies and constitute our microbiome also affect the production of cytokines. They cause five to ten per cent of the differences in immune response. By breaking down amino acids, our intestinal bacteria supply the building blocks for acute inflammatory reactions, fever and other immune responses. This is especially the case for the degradation products of tryptophan, an amino acid that we obtain exclusively from our food. However, in response to specific pathogens, some bacteria in the intestinal flora contribute to the production of particular cytokines. One of the senior authors on the study, Ramnik Xavier, notes: “Our studies showing that the microbiome can interact in a pathogen-specific way has potential for use in immunotherapy. For example, diet, antibiotics or transplants of gut resident microbial communities could potentially influence the production of cytokines.”
From HIV to Lyme disease
Recently, similar studies have also been started in Romania and Tanzania. Netea: “This is important because until now our study populations have included only Western Europeans. The diversity in genetic backgrounds could make a big difference.” In addition, the researchers are working on new studies on the immune systems of patients with HIV, obesity, sepsis, cardiovascular disease, type 1 diabetes, gout, Lyme disease, and Candida infections. For each of these diseases they want to investigate at least 200 subjects. For each disease, the scientists compare the results with the control group of 500 healthy volunteers. Joosten: “Ultimately, we hope to understand why one person becomes ill and the other remains healthy. Based on this knowledge, we hope to develop new treatments.”
Articles: Host and Environmental Factors Influencing Individual Human Cytokine Responses, Rob ter Horst et al., Cell, doi: 10.1016/j.cell.2016.10.018, published 3 November 2016.
Linking the Human Gut Microbiome to Inflammatory Cytokine Production Capacity, Melanie Schirmer et al., Cell, doi: 10.1016/j.cell.2016.10.020, published 3 November 2016.
A Functional Genomics Approach to Understand Variation in Cytokine Production in Humans, Yang Li et al., Cell, doi: 10.1016/j.cell.2016.10.017, published 3 November 2016.
Functional and genomic architecture of Borrelia burgdorferi-induced cytokine responses, Marije Oosting et al., Cell Host & Microbe, doi: 10.1016/j.chom.2016.10.006, published 3 November 2016.
Differential Effects of Environmental and Genetic Factors on T and B Cell Immune Traits, Raul Aguirre-Gamboa et al., Cell Reports, published 3 November 2016.