The aim of this project is to develop an implantable biochip system to investigate the complexity of drugs/biomarkers relationships in chronic inflammatory diseases. To reach this goal, a multidisciplinary approach is needed because the system requires: (i) The development of an innovative sensor to detect an array of drugs, including nanotechnology and system level integration to improve sensor specificity; (ii) The development of new micro-electronics technology to decrease chip size for implantation in mice as well as a convenient chip remote powering data transmission; (iii) Testing in murine models of chronic inflammation; (iv) Investigating the pharmacokinetics of biochemical enzymes-substrates to identify the best cytochrome P450 isoforms, out of more than 3,000 possibilities, to be integrated onto the biochip in order to ensure the detection of those exogenous and endogenous compounds which are relevant for the specified medical application. To best address all of these multidisciplinary demands, the project partnership includes experts in: (i) Nano-sensing, with a special focus on P450 biosensors (S.Carrara/EPFL), (ii) Chip fabrication with focus on implantable systems (Dehollain /EPFL), (iii) Biomarker variations (our group), (iv) Pharmacokinetics (Von Mandach/University of Zurich Hospital).

Class switch recombination (CSR) is an irreversible somatic recombination mechanism by which B cells switch their surface immunoglobulin class expression from IgM and IgD to other isotype with distinct effector function. This diversification is essential for a protective adaptive humoral immune response. B cell receptor (BCR) activation together with exogenous signals, including tumor necrosis factor (TNF) family members, Toll-like receptors (TLRs) ligands or cytokines trigger CSR. We have shown that extracellular adenosine critically contributes to CSR in murine mature B cells. Murine naïve B cells release ATP upon coordinate B cell receptor (BCR) and Toll Like Receptors (TLRs) stimulation. The released ATP is hydrolysed to adenosine by plasma membrane ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1) CD39 and ecto-5′-nucleotidase (5’-NT) CD73. Remarkably germinal center and isotype switched B cells display higher expression of CD73.  Moreover, CD39 and CD73 deficient B cells showed in vitro a significant impairment in their capacity to differentiate to class switch plasma cells upon BCR and TLR engagement, underlying the role of adenosine in the B cells isotype switching process. Ig CSR-deficiencies in human can be dependent from an intrinsic B cell defect, however most of them are still molecularly undefined and diagnosed as common variable immunodeficiency (CVID). Notably, CVID patients with impaired class switched antibody responses are selectively deficient in CD73 expression in B cells, suggesting that CD73 dependent adenosine generation contributes to the pathogenesis of this disease.