DMUX-IgAN

IgA responses, as the most ambivalent facets of immunity, are also strongly involved into immunopathology. At both systemic and mucosal sites, IgA responses mix inflammation with implication in tolerance. Their mutual dependence with the microbiota illustrates a crucial [gut – immunity axis] which, when deregulated, may end as a [gut – kidney axis] and lead to IgA nephropathy (IgAN), the most frequent chronic kidney disease. Our understanding of what differs in IgA molecules involved in immunity vs tolerance vs IgAN remains controversial. Many variables impact IgA properties: from synthesis in bone marrow vs gut associated lymphoid tissue (GALT), polymerization, glycosylation, affinity for a given antigen, V-region properties, IgA1/IgA2 balance, specific functions of the IgA BCR and/or of the B-cell subset of origin. Our aim is to demultiplex these variables, by exploring and manipulating the heterogeneity of IgA responses, based on both studies of human samples (from donors and IgAN patients), and mouse models adapted to in vivo mechanistic studies of IgA properties and nephritogenicity. We will explore (1) the diversity of IgA-producing cells (2) the complexity of the corresponding secreted IgA in terms of repertoire, glycosylation and polymerization (3) the cytokine and metabolic environment of IgA+ cells, (4) the IgA-microbiota network and (5) the dysregulated IgA production in IgAN. Human B subsets will be studied by cell cytometry, functional studies and RNAseq, in parallel to mouse models engineered to produce human IgA1 and develop IgAN, in which in vivo studies will manipulate the microbiota, the diet and the cytokine environment of GALT B-cells. While biotherapies based on IgA monoclonal Abs are explored, in-depth understanding of the protective vs nephritogenic effects of IgA is mandatory. Alternative therapies for modulating IgA production by targeting diet or microbiota parameters would also be of crucial pertinence for patients affected with IgAN.