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Environmental modulators of the immune cell balance in health and disease

Periodic Reporting for period 3 - ENVIROIMMUNE (Environmental modulators of the immune cell balance in health and disease)

Reporting period: 2017-05-01 to 2018-10-31

The incidence of autoimmune diseases in developed societies is increasing at high rates, but the underlying cause for this phenomenon has not been elucidated yet. Since the genetic architect remains considerably stable, this increase is likely associated with changes in the environment. Autoimmunity is linked to an imbalance of pro-inflammatory Th17 cells and anti-inflammatory Foxp3+ regulatory T cells (Treg). However, little is known regarding environmental factors that influence the Th17/Treg balance. We recently discovered that a sodium-rich diet severely exacerbates experimental autoimmune encephalomyelitis (EAE) through an increased induction of pathogenic Th17 cells. Surprisingly, our preliminary data indicate that high-salt conditions also significantly impair Treg function, resembling a phenotype observed in several human autoimmune diseases. In addition, we have evidence that a high-salt diet affects the gut microbiota, implicating possible indirect effects on immune cells in vivo. Based on these findings we hypothesize that excess dietary salt represents an environmental risk factor for autoimmune diseases by modulating the Th17/Treg balance by several direct and indirect mechanisms. To address this hypothesis we will 1) examine the underlying mechanisms of high-salt induced Treg dysfunction and effects on the Treg/Th17 balance by molecular and functional analysis in vitro and compare it to known risk variants of human autoimmune diseases, and 2) define direct and indirect effects of excess dietary salt on the Th17/Treg balance and autoimmunity in vivo and explore potential novel pathways for targeted interventions. Thus, the proposed study will uncover the impact of a newly discovered environmental modulator of the immune cell balance and will ultimately pave the way for new approaches in therapy and prevention of autoimmune diseases.
We have made good progress in the project, besides some drawbacks in the recruitment process for the team.

Overview of progress related to Aim 1:
The work proposed for this time period in this aim has progressed well considering the above mentioned conditions: we have now established all techniques required for the successful implementation of the project and are currently setting up the preparation of samples for the molecular analysis in the new lab.

Overview of progress related to Aim 2:
Regarding Aim 2 we made good progress as well. We already established the in vivo models in the new lab in Belgium and ethical requirements for the set-up of the other model systems were just approved to start these experiments quickly. Regarding the indirect effects of sodium on the gut microbiota we already made good progress as well together with our collaborators and we published first results regarding this topic recently in Nature (Wilck et al. 2017, Nature).

Overall, we are on a good track on the project. Currently, already several research studies and review articles directly related to the project were recently published or are under submission for publication.
At this point of the project we have significantly contributed to key pieces of scientific evidence supporting major hypotheses of the proposed project ENVIROIMMUNE. Currently, we consider the recently accepted joint publications in the leading scientific journal Nature as the most significant achievement (Wilck et al., Nature. 2017, doi: 10.1038/nature24628). This landmark paper is the first study on how a high-sodium diet affects the gut microbiota and disease in mice and men as joint project with key collaborators, covering parts of Aim 2 of the project. Besides this and other related publications, we also were able to significantly promote public attention for the underlying biology and relation of nutrition to immune cell balance and human disease such as Multiple Sclerosis (MS), which was disseminated to the public through several events. We expect to unravel detailed biology and molecular mechanisms on direct and indirect effects of this environmental factor on the immune system and disease and hopefully more scientific breakthroughs particularly until the end of the project.