A Closer Look at Antibodies in RA: How Anti-Citrullinated Protein Antibodies, Anti-Modified Protein Autoantibodies & Rheumatoid Factor Activity Overlap

She said smoking is also a risk factor for ACPAs, but only if the shared epitope is present.

Dr. Shelef went on to explain several ways that RF is different in RA vs. non-RA, including binding sites, isotypes bound, RF isotypes, affinity maturation, as well as IgG-reactive T cells that are uniquely present in RA.

“There are several reasons why we care about these differences,” Dr. Shelef shared. The first is for diagnostic opportunities, if RF binds to different sites in RA but not in non-RA. As an example, she highlighted a 2020 study by Falkenburg et al. showing an engineered IgG has increased binding in RA versus Sjögren’s syndrome, and findings like this can be developed further for better diagnostics.⁹

Differences between RF in RA and non-RA can also provide pathophysiologic insights, which Dr. Shelef and her colleagues have explored by asking if IgG-RF could develop due to loss of tolerance against citrullinated IgG.¹⁰ To investigate, they evaluated all of the different linear epitopes of IgG that could be bound by IgG in RA using a peptide array.

They found that IgG binds to citrulline-containing linear IgG peptides in seropositive RA, which signals a partial epitope overlap between RF and ACPAs, she explained. “Now we are seeing an IgG that binds to citrulline containing IgG peptides, so this antibody could be considered an ACPA because it’s binding to citrulline. It could be considered RF because it’s binding to IgG. So we have this entity that is now maybe in the middle, which leaves many questions remaining. For example, could some of these ACPAs bind the citrulline-containing peptides or maybe even citrullinated IgG? Possibly, and that is something we are investigating.”

Dr. Shelef concluded that even though an understanding of RF and its intersection with ACPAs is growing, questions clearly remain, and further research is needed to define the functional roles of RF in vaccination, infection and RA.

Carina Stanton is a freelance science journalist based in Denver.

References

1. Aletaha D, Neogi T, Silman AJ, et al. Rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis.2010 Sep;69(9):1580–1588.
2. Amara K, Israelsson L, Stålesen R, et al. A refined protocol for identifying citrulline-specific monoclonal antibodies from single human B cells from rheumatoid arthritis patient material.Bio-protocol. 2019 Sep 5;9(17):e3347.
3. Steen J, Forsström B, Sahlström P, et al. Recognition of amino acid motifs, rather than specific proteins, by human plasma cell-derived monoclonal antibodies to posttranslationally modified proteins in rheumatoid arthritis. Arthritis Rheumatol. 2019 Feb 7;71(2):196–209.
4. Titcombe PJ, Wigerblad G, Sippl N, et al. Pathogenic citrulline-multispecific B cell receptor clades in rheumatoid arthritis. Arthritis Rheumatol. 2018 Dec;70(12):1933–1945.
5. SahlströmP, Hansson M, Steen J, et al. Different  hierarchies of anti–modified protein autoantibody reactivities in rheumatoid arthritis. Arthritis Rheumatol. 2020 Oct;72(10):1643–1657.
6. Sun M, Rethi B, Krishnamurthy A, et al. Anticitrullinated protein antibodies facilitate migration of synovial tissue-derived fibroblasts. Ann Rheum Dis. 2019 Dec;78(12):1621–1631.
7. Auger I, Balandraud N, Massy E, et al. Peptidylarginine deiminase autoimmunity and the development of anti-citrullinated protein antibody in rheumatoid arthritis: The hapten-carrier model. Arthritis Rheumatol. 2020 Jun;72(6):903–911.
8. Scally SW, Petersen J, Law SC, et al. A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. J Exp Med. 2013 Jun;210(12):2569–2582.
9. Falkenburg WJJ, Oskam N, Koers J, et al. Identification of clinically and pathophysiologically relevant rheumatoid factor epitopes by engineered IgG targets. Arthritis Rheumatol. 2020 Dec;72(12):2005–2016.
10. Zheng Z, Mergaert AM, Fahmy LM, et al. Disordered antigens and epitope overlap between anti–citrullinated protein antibodies and rheumatoid factor in rheumatoid arthritis. Arthritis Rheumatol. 2020 Feb;72(2):262–272.