B1: Diet as intervention in autoimmune pre-disease

Background. The increased prevalence of autoimmune diseases has been paralleled by dramatic changes in diet. The causal relationship between diet and autoimmune disease is supported by the clinical improvement in rheumatoid arthritis by dietary restriction (Lancet. 338:899). The molecular basis of the beneficial effects of diet has so far remained rather elusive. In project- related, preliminary work that was conducted within the framework of the RTG1743, we demonstrated that diet overrides genetic lupus susceptibility: Mice on dietary restriction did not develop lupus, whereas almost all mice on Western diet died thereof. We linked this to diet-induced changes in the gut microbiota and RNA expression in immune cells. Specifically, we showed that (i) diet-induced changes in the intestinal micro-/mycobiome precede disease onset, and (ii) expression of certain disease-associated genes, i.e., Tnxb, are controlled by diet (Nat Commun. 10:4097). 

Objectives. (i) Explore whether therapeutic dietary restriction at different time points can modulate the manifestation of lupus. (ii) Investigate molecular clues underlying the effects of diet in experimental autoimmune disease.

Work program. We will expose lupus-prone NZM2410/J mice to dietary interventions, which will start (i) before disease onset, (ii) when autoantibodies are detected or (iii) at the initial manifestation of clinical disease. Endpoints include (change of) clinical disease manifestation, detailed immunologic and metabolic phenotyping, as well as defining microbial communities longitudinally. To explore the molecular pathways, we will generate CRISPR/Cas constructs (i.e., of the identified Tnxb) and evaluate the impact on lupus susceptibility in both lupus-prone and lupus-resistant mice fed different diets. Specifically, we will generate transgenic mice with the lupus-protective allele from NZM2410/J mice in different genetic backgrounds, as well as NZM2410/J mice with the "wild-type" non-lupus protective Tnxb variant. These "criss-cross" transgenics will be exposed to dietay interventions and nephritis manifestation will be monitored longitudinally.