Defining the cellular origin of pathogenic autoantibodies

B cell-derived autoantibodies are found in practically all autoimmune diseases, and in many of them they are pathogenic. While globally immunosuppressive or immune cell-depleting therapies improved clinical outcomes, they often fail to remove the pathogenic B cell subsets and to improve the most severe clinical manifestations. Development of more effective therapies requires understanding of how and from which subsets autoreactive B cells arise.

Despite significant advances in our understanding of B cell maturation and tolerance, there is still conflicting evidence on the role of germinal centers (GC) in pathogenic autoantibody production. While some studies have identified selective mutations in autoreactive B cells indicative of GC-origin, others have shown

that autoantibody formation can occur in GC-depleted environments.

In this proposed work, mouse models of human autoimmune disease and novel antibody-tagging tools will be integrated with human patient cohorts to determine the origin and GC-dependence of autoantibody-producing B cells.

To understand the diversity or possible convergence of different pathogenic routes to disease, I will use mice carrying human variants that cover most of the

spectrum of human monogenic systemic autoimmune disease. Crossing of these mice with mice expressing Cre-induced Flag-tagged antibody light-chains

allows tracking the origin of autoantibodies to specific B cell subsets. Using GC-specific inducible Cre models and ELISA-based detection, I will delineate GCcontribution

to autoantibody formation across disease stages. In parallel, I will characterise autoreactive B cell subsets in human patient cohorts based on singlecell

transcriptomics and analysis of clonal sharing. This will further identify whether autoantibody-producing cells are GC-experienced.

The knowledge acquired in this proposal will provide solid foundations for the design of more targeted therapies that can eliminate autoreactive B cells.