Pathogenic Citrulline‐Multispecific B Cell Receptor Clades in Rheumatoid Arthritis

Abstract

Our findings suggest that broad ACPA specificities in RA arise from a restricted repertoire of evolving citrulline-multispecific B cell clades with pathogenic potential.

Recognition of Amino Acid Motifs, Rather Than Specific Proteins, by Human Plasma Cell–Derived Monoclonal Antibodies to Posttranslationally Modified Proteins in Rheumatoid Arthritis

“…The presently described monoclonal ACPAs all showed consistent and clear specific reactivity with citrullinated peptides and intact proteins in several assays in which we used low concentrations of the respective antibodies. This is true also for another set of recently published monoclonal ACPAs (27), from which 2 were also used in the validation experiment of our large peptide array (see Supplementary Figure 5 [http://onlinelibrary.wiley.com/ doi/10.1002/art.40699/abstract]). Previously, studies utilizing human monoclonal ACPAs (41-43)*, including those from our own laboratory, have used single and more limited detection systems and often high concentrations of the antibodies, which may yield false-positive responses.…”

“…Instead, these observations further emphasize the importance of analyzing ACPAs at the monoclonal level, both concerning triggering events and concerning disease-causing mechanisms. The growing list of reported monoclonal ACPAs (27,(41)(42)(43)(45)(46)(47)(48) represents an important resource for such studies.…”

New Relationships for Old Autoantibodies in Rheumatoid Arthritis

“…Taking this model further, autoantibodies against citrullinated IgG could trigger the development of the entire ACPA repertoire, due to epitope spreading and the extensive cross‐reactivity and general citrulline reactivity of ACPAs . In this scenario, citrullinated IgG would be “antigen zero” of ACPA development.…”

Reply

“…In fact, the RA field has been especially active in making use of mAb derived from the immunoglobulin sequences from patient‐derived B cells and plasma cells. Thus, several recently published studies , including our own, extend the first generation of RA patient B cell–derived mAb .…”

“…Although our study delved deeply into the characteristics of plasma cell–derived ACPAs from synovial fluid, the sample studied was from a single individual, and our investigation was therefore not powered to address the matter of frequencies. We instead acknowledge that valid enumeration and phenotyping of antigen‐specific B cells between patients, time points, and anatomic sites represent an interesting area for future investigation, especially given the use of tetramers and high‐throughput approaches.…”