Dissecting Protective and Pathogenic Long-lasting Humoral Immunity

Objetivo

Long term humoral immunity essentially relies on two types of cells exported from germinal centers (GC): plasma cells (PCs), which secrete antibodies, and memory B cells (MBCs). Both subsets of cells can survive for decades in humans, being responsible for the extended protection afforded by the most successful vaccines but also therapeutic failures in the context of B-cell mediated autoimmune diseases. Which cells are selected and what drives them to become long-lived, in normal or pathological conditions, remains a central question in immunology. Studies in humans have so far been curtailed by the limited amount of material available and the lack of longitudinal access to lymphoid organs. This proposal aims to address three intertwined questions for understanding the selection mechanisms underlying protective and pathogenic long-lived humoral immunity: 1. What are the cellular and molecular mechanisms driving the contraction of the MBC response in a vaccine/infectious setting? 2. Do PCs targeting a self-antigen or a vaccine/viral antigen differ in their selection, transcriptomic profile and maintenance? 3. What drives effective/defective self-reactivity purging in vaccine and pathogenic GC-dependent antibody repertoire? To tackle these questions, we have garnered unique access to key lymphoid tissues (spleen and bone marrow) involved in the initiation and long-term maintenance of the immune response from vaccinated donors and patients with a prototypic B cell-mediated autoimmune disease (immune thrombocytopenia, ITP). We believe this set of samples puts us in an ideal position, combining innovative and integrated single cell experimental approaches, to perform an in depth functional analysis of viral- and self-antigen-specific GC, MBCs and PCs and further advance our understanding of long-lived humoral immunity.