Uncovering molecular mechanisms leading to the onset of rheumatoid arthritis

Principal Investigator

Scientific interest within the context of the graduate college:

Rheumatoid arthritis (RA) represent a chronic and prevalent autoimmune disease characterized by inflammation and progredient joint destruction. Both anti-citrullinated protein antibodies (ACPA) and autoreactive ACPA-producing B cells play a key role in disease pathogenesis. However, the exact mechanisms leading to disease onset remain poorly understood. Notably, ACPA are not only present in RA patients, but can be also detected in a certain fraction of healthy individuals where they are indicating an increased risk of developing RA in the future. The proposed study thus aims to investigate the role of autoreactive ACPA-producing B cells in ACPA-positive healthy individuals and to understand the molecular mechanisms that eventually lead to the onset of inflammatory disease. By focusing on autoreactive B cells, we aim to uncover novel molecular insights into the pathogenesis of RA and identify potential therapeutic targets to prevent disease progression.

Project description:

We have collected a cohort of ACPA-positive healthy individuals as well as of ACPA-positive RA patents. The project aims to perform a molecular phenotyping of B cells in these patients where we seek to understand the behavior, characteristics and differences of autoreactive cells in ACPA-positive healthy individuals and RA patients. We plan to apply cutting-edge technology including bar-coded tetramers, mass cytometry and single-cell sequencing to characterize autoreactive ACPA-producing B cells. The overall aim is to understand the mechanisms that lead to onset of disease.

Aim 1: Examine the phenotypic and functional characteristics of autoreactive B cells in ACPA-positive individuals and RA patients using mass cytometry. We will use mass cytometry to perform a deep phenotyping of PBMCs of ACPA-positive individuals and RA patients where we will focus on activation markers and signaling pathway activity in response to ex vivo stimulation.

Aim 2: Examine the phenotypic and functional characteristics of autoreactive B cells in ACPA-positive individuals and RA patients using scRNAseq. Using scRNAseq and bar-coded tetramers, we will focus on the molecular phenotype of ACPA-producing autoreactive B cells in ACPA-positive individuals and RA patients.

Aim 3: Clinical Correlation. Access to clinical datasets will allow assessment of the correlation between B cell characteristics and clinical outcomes in ACPA-positive individuals.

Application details

References