The discovery in the late 1990s that autoantibodies target citrullinated proteins changed the face of rheumatoid arthritis research. Although it is not clear whether anti-citrullinated protein antibodies (ACPA) play a pathogenic role in RA or simply reflect some other underlying process or mechanism, these ACPA have a very high specificity for RA. More current research is beginning to unravel the role of autoantibodies in the progression of RA from preclinical to clinical disease.
“We see increasing ACPA autoimmune responses in our RA patients moving from pre-disease to disease,” said Rene Toes, PhD, Professor of Experimental Rheumatology at LUMC Leiden, The Netherlands. “We also see in patients that the ACPA autoantibodies are special. These antibodies are much bigger than other autoimmune antibodies. They are bigger because they are glycosylated, they carry an extra sugar.”
More importantly, Dr. Toes said, ACPA-positive individuals who carry the glycosylated antibody seem much more likely to progress from a healthy preclinical state without symptoms to clinical RA compared to those who have the conventional ACPA that is not glycosylated.
The newly established association between glycosylated forms of ACPA and progression to RA is just one of the key areas to be explored during the basic science symposium Tipping the Balance From Preclinical Immunity to Overt RA on Sunday from 4:30 – 6:00 pm in Room B304-305, Building B, Georgia World Congress Center. There is growing evidence that mechanisms intended to augment host defenses from microbial pathogens can be recruited during a pathologic autoimmune response to produce the destructive features of RA.
The basic challenge is that many individuals go through an asymptomatic period during which they have detectable levels of circulating of ACPA and no detectable signs or symptoms of RA. The goal is to find a way to use ACPA or some other biomarker that can accurately predict progression and stratify individuals at risk as well as patients who are most appropriate for early treatment.
Alter Galit, PhD, Professor of Medicine at Harvard Medical School and a Group Leader at the Ragon Institute of MGH, MIT, and Harvard, will discuss the regulation of B-cell and antibody effector functions in host defenses. She has found that glycosylation of antibodies can have direct effects on tuning on antibody effector function.
Geog Schett, MD, Professor and Head of Rheumatology and Immunology at the University of Erlangen-Nuremberg, Germany, will offer a new model of the events responsible for the pathological autoimmunity and joint destruction that are typical of RA.
Dr. Toes will discuss what is currently known about the potential role of glycosylation of variable regions of autoantibodies and the role glycosylation may play in the progression to clinical RA.
For now, he said, autoantibody glycosylation appears to be a useful biomarker of likely progression from asymptomatic antibodies to overt RA. But the initial findings need to be replicated and the mechanisms more fully described.
“People who have even early symptoms of RA probably already have these antibodies carrying extra sugars and people who are completely without symptoms probably do not,” he said. “It is very early in the work, but this potential biomarker is performing very well and looks very promising.”