Exploring an anti-citrullinated antibody signature in ME/CFS

Prof. Mercedes Rincon

College of Medicine, University of Vermont, Burlington, Vermont, USA

Key findings

  • Anti-citrullinated autoantibodies have a pathological role in autoimmune diseases such as rheumatoid arthritis, and have previously been detected in blood samples from people with ME/CFS
  • However, in this study, serum levels of IgG1 anti-CCP and IgG4 anti-CCP were not different between people with ME/CFS, patients with multiple sclerosis and healthy control subjects.
  • Anti-citrullinated autoantibodies do not therefore appear to have a role as biomarkers for ME/CFS.


Autoantibodies occur when the immune system wrongly identifies the body’s own healthy cells as harmful, and produces antibodies against them. This can lead to the development of a so-called autoimmune disease such as multiple sclerosis or lupus. Recent findings suggest that autoantibodies may also have a role in ME/CFS, at least in some people.

Prof. Mercedes Rincon (formerly at the University of Vermont and now at the University of Colorado) is interested in the molecular mechanisms underlying autoimmune diseases, and, in some previous work, she had detected specific autoantibodies that target citrullinated proteins in the blood of people with ME/CFS.

(Prof. Rincon is pictured above right, with her colleague Prof. David Maughan, and his wife Cathleen who has had ME/CFS for the last twenty years.)

Prof. Rincon explains, “Citrullination is a protein modification that can happen sometimes in response to some infectious agents. Citrullination makes a ‘self protein’ become a ‘foreign protein’, and therefore recognised by the immune system. This leads to the generation of antibodies against those citrullinated changes.”

Such anti-citrullinated antibodies have been detected in rheumatoid arthritis – itself an autoimmune disease – where they have a pathological role and are used in diagnosis.

The characteristics of ME/CFS suggest the involvement of autoantibodies in that illness, and so Prof. Rincon’s plan was to confirm her earlier findings by looking specifically for autoantibodies targeted on citrullinated proteins (anti-CCP).

Eighty blood serum samples were obtained from the UK ME/CFS Biobank, including 40 samples from patients with ME/CFS (half with severe and half with mild disease), 20 from patients with multiple sclerosis (another known autoimmune disease), and 20 from healthy control subjects.

Levels of two autoantibodies – IgG1 anti-CCP and IgG4 anti-CCP – were measured in these samples, and compared between the patient groups.

However, there were no statistically significant differences in either autoantibody between the groups, and this was in large part due to considerable variation in levels among individuals in each group (including those with multiple sclerosis).

So, while IgG1 anti-CCP and IgG4 anti-CCP are known to be markers of other autoimmune diseases such as rheumatoid arthritis, Prof. Rincon’s results suggest that are not in ME/CFS, despite the encouraging early results.

These findings are disappointing if we were hoping for a new biomarker for ME/CFS, but they do not, on their own, rule out the role of autoimmunity in the illness, and suggest that perhaps we need to look elsewhere for the mechanisms involved.

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