Functionality of autoreactive B cells and autoantibodies in rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic autoimmune disease leading to synovitis and joint destruction.

The autoimmunity is characterized by autoantibodies to citrullinated proteins (ACPA) and B cells are central in the pathogenesis. Yet, we still have limited knowledge about what drives the autoreactive B cells and how ACPA IgG contribute to disease.

In this program, we will use several translational approaches to understand the B-cell repertoires, distortion in B-cell tolerance, and functionality of autoantibodies.

We have previously demonstrated that autoreactive B-cells in RA have several unique features, including Fab-glycosylation.

Recently we have also discovered that patient-derived ACPA are multi-reactive, not only to a range of citrullinated targets, but also to other post-translational modifications (i.e. carbamylation, acetylation).

This anti-modified protein autoantibody (AMPA) multi-reactivity is explained by binding to peptide consensus motifs with each B cell clone having a unique fingerprint.

We will now focus on understanding the biology of AMPA in relation to disease, and we will use an interdisciplinary B-cell pipeline, including patient immunomonitoring, RNAseq single-cell technology for studies of autoreactive B cells, and isolation of patient-derived monoclonal autoantibodies for mechanistic studies.

The goal is to increase our knowledge of fundamental processes in rheumatic disease and contribute to advances for better and more personalized treatment.