University of Nebraska Medical Center, USA
Kaihong Su obtained her doctorate degree and post-doctoral training from the University of Alabama at Birmingham (UAB). After being a faculty member at UAB for 5 years, she joined the University of Nebraska Medical Center in 2008 to continue her research. The long-term goal of her lab is to understand the molecular mechanisms for autoimmune diseases, including SLE and RA. She has published 26 papers in reputed journals and served as ad-hoc reviewers for a number of scientific journals.
Anti-citrullinated protein antibodies (ACPAs) are highly specific serological markers for rheumatoid arthritis (RA) and are also believed to contribute to RA pathogenesis. However, the cellular and molecular basis of ACPA production is not fully understood. Using a single cell PCR-based antibody cloning technology, we analyzed ifcirculating plasmablasts(CD19dimCD27highCD20-) inRA patientsproduce ACPAs.Among the 195 antibodies generated from6ACPA+RA patients, 18.5% (ranging 6.5-27.6%) specifically recognize citrullinated antigens, but not their native forms. However, none of the antibodies generated from ACPA-RA patientor healthy donors reacted with citrullinated antigens. Detailed sequence analyses showed that the IgH and IgL genes encoding these ACPAs are highly mutated. Reversion of the mutated IgH and IgL genes to theircorresponding germlinegenes completely eliminated their ACPA reactivity, suggesting that the generation of circulating ACPAs is an antigen driven process. To identify the antigen sourcesfor ACPAs, we found that about half of the ACPAsreact with outer membrane proteins from Porphyromonagingivalis(P. Ging) and/or citrullinated P. Gingenolase. Some ACPAs also react with auto-antigens released in the human neutrophil extracellular traps. These results suggest that circulating plasmablasts in RA patients are a source of ACPA production and the generation of ACPAsis driven by both exogenous bacterial antigens and citrullinated self-antigens. Our data thus identifycirculating plasmablastsas potential therapeutic targetsand provide a mechanism for previous findings that plasmablasts in the bloodpredictnonresponse to anti-CD20therapy in RA patients.
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