Several peculiar properties of ACPAs have been discovered, including fab-glycosylation in the variable region of the antibody. “We do not think these have a very strong effect on the binding to the antigens, but instead they may have important roles in the B cell activation and selection,” Dr. Grönwall said. Another peculiar property of ACPAs is that there can be IgG4 in ACPA responses, which may be a sign of chronic B cell responses, so “in ACPA-positive RA patients, there is something more to understand about the B cell responses and B cell repertories that is very interesting.”
In concluding her portion of the session, Dr. Grönwall said a key question to explore further is whether citrullination is a special modification targeted by RA autoantibodies or perhaps is simply the first to be characterized.
Dr. Grönwall stressed that ACPAs are multi-reactive to different citrullinated proteins beyond “classical” antigens, by recognition of small epitopes, and “we have a lot to learn there.” However, each B cell clone has a unique multi-reactivity pattern and different clones have different functionalities, she added. Also, because some citrulline-reactive clones bind to carbamylated and acetylated epitopes, this may explain why carbamylation and acetylation reactivity is seen in serology studies.
Dr. Grönwall said these combined findings demonstrate implications for understanding autoreactive B cell biology and also for understanding the autoreactivity profiles in different RA patients and different subsets of RA patients. “It will be interesting to continue to investigate the clinical and pathological importance of this multi-reactivity in the future.”
A deeper understanding of citrullination & rheumatoid factor activity, & how they overlap in RA, is showing new possibilities for developing diagnostics & gaining insights into pathophysiology.
Evaluating Rheumatoid Factor in RA
In the second portion of the session, Dr. Shelef outlined recent research that addresses the timing and mechanisms of RF in the development in RA. For example, understanding the risk factors for RF versus ACPAs for RA is growing. “This has been hard to tease out because RF and ACPA tend to coexist, but it’s looking like smoking is the main driver of RF, whereas for ACPAs the shared epitope may be the main driver,” she explained.
“It’s thought that MHC [major histocompatibility complex] molecules with the shared epitope, which is a sequence present in multiple different RA-associated MHC molecules, seem to bind better to citrullinated peptides, but additionally there is some evidence that those MHC molecules can bind better to peptidylarginine deiminases 4 peptides, leading to ACPAs, in more of a hapten-carrier model.”7,8
