In P8, we have investigated the pharmacological basis of using dimethyl fumarate (DMF) in the treatment of pemphigoid diseases (PDs). Already in the gut, DMF is converted into monomethyl fumarate (MMF), an agonist of the G protein coupled receptor HCA2 (GPR109A). Indeed, we found evidence that HCA2 mediates the recently described protective effect of oral DMF in a mouse model of bullous pemphigoid (BP)-like epidermolysis bullosa acquisita (EBA). Thus, DMF ameliorated pemphigoid disease-like skin lesions in female Hcar2+/+ mice, but not in Hcar2-/- animals. Unexpectedly, vehicle-treated female Hcar2-/- animals were partially protected from EBA suggesting a Janus-faced function of HCA2: detrimental if activated by endogenous agonists and beneficial in response to exogenously applied drugs. In the 2nd FP, we will investigate the reason of this ambivalent function to firmly establish HCA2 as a drug target for the treatment of PDs. First, we will scrutinize the role of endogenous HCA2 activators, including butyrate, β-hydroxybutyrate, and nicotinic acid, by modifying the diet. As a potential effect of diet-related metabolites on PD pathology could have important ramifications for patient care, we will search for indirect evidence of HCA2 activation by performing metabolomic studies in mice and human patients. Second, we will define the cell type(s) that mediate effects of endogenous and pharmacological HCA2 activators. A state-of-the-art investigation of this question is possible using a novel mouse line, we have generated, in which loxP sites have been inserted into the Hcar2 locus. If there is no complete overlap in the target cells, we will aim to limit pharmacological HCA2 activation to the body compartment, in which beneficial effects prevail. Third, we will address the kinetic profiles of endogenous and pharmacological HCA2 activators that may explain their distinct actions. To approach this point, we will determine the kinetic profile of the drug’s plasma concentrations after oral administration in BP patients, who will be part of the clinical trial on DMF in BP, initiated by the CRU consortium and funded by the EU commission, and will model it in mice by infusing the compound through a subcutaneously implanted adjustable pump.