Anti-citrullinated protein antibody B cells in rheumatoid arthritis: from disease-driving suspects to therapeutic targets

Doctoral Thesis

Rheumatoid arthritis (RA) is characterized by the presence of anti-citrullinated protein antibody (ACPA) B cells. Phenotypic features of these cells, together with the clinical response to CD20+ B cell depletion, indicate that ACPA B cells are involved in disease pathogenesis. In this thesis, we demonstrate citrulline reactivity in the naïve B-cell compartment, indicating that ACPA autoreactivity is not confined to antigen-experienced B cells. Additionally, we show that Epstein-Barr virus (EBV) is not detected in ACPA B cells, suggesting that EBV does not directly drive the ACPA B-cell response. We also developed a flow cytometry protocol to measure phosphorylated kinases in antigen-specific B cells. Application of this protocol revealed increased kinase phosphorylation in ACPA B cells, supporting the notion that their chronic activation is likely antigen-mediated. Building on these insights, two antigen-specific strategies to selectively deplete ACPA B...Show moreRheumatoid arthritis (RA) is characterized by the presence of anti-citrullinated protein antibody (ACPA) B cells. Phenotypic features of these cells, together with the clinical response to CD20+ B cell depletion, indicate that ACPA B cells are involved in disease pathogenesis. In this thesis, we demonstrate citrulline reactivity in the naïve B-cell compartment, indicating that ACPA autoreactivity is not confined to antigen-experienced B cells. Additionally, we show that Epstein-Barr virus (EBV) is not detected in ACPA B cells, suggesting that EBV does not directly drive the ACPA B-cell response. We also developed a flow cytometry protocol to measure phosphorylated kinases in antigen-specific B cells. Application of this protocol revealed increased kinase phosphorylation in ACPA B cells, supporting the notion that their chronic activation is likely antigen-mediated. Building on these insights, two antigen-specific strategies to selectively deplete ACPA B cells were explored. These approaches were successfully tested in multiple cell models mimicking primary ACPA B cells, and one was validated on patient-derived ACPA B cells. Collectively, this thesis advances our understanding of the initiation and persistence of the ACPA B-cell response and introduces novel, targeted therapeutic strategies aimed at the selective depletion of ACPA B cells in RA patients.Show less

Autoimmunity

Autoreactivity

B cells

ACPA

Antigen-specific targeting