Abstract

Rheumatoid arthritis (RA) is a prototype autoimmune disease, with the hallmark signs of synovial inflammation and the presence of autoantibodies. Of the different autoantibody systems present in RA, rheumatoid factors (RF) are probably the best studied. Their presence was first detected >70 years and it was in the late 1950s when it was realized that RF reacted to gamma globulins. Since the discovery of RF several other autoantibody systems have been discovered in RA, many of them directed against post-translationally modified protein antigens. The most prominent example of such autoantibodies are anti-citrullinated protein antibodies (ACPA), which are directed against a wide-array of citrullinated proteins. Now RF and ACPA determination are the two major diagnostic laboratory tests for RA and part of the EULAR and ACR criteria for RA.

In the past few years, it has become clear that the autoantibody response present in RA extends towards several other modified proteins, such as proteins modified by acetylation or carbamylation. As all these auto-antibodies recognize Post-Translationally Modified (PTM) proteins, these antibodies are collectively called Anti-Modified Protein Antibodies (AMPA). In the context of this presentation, I will focus on the auto-antibody response against citrullinated, carbamylated and acetylated proteins.

Carbamylation leads to the formation of homocitrulline. Structurally, homocitrulline greatly resembles citrulline but is one methylene group longer. Citrulline is generated when PAD enzymes modify the amino acid arginine. In contrast, the amino acid homocitrulline is generated by a chemical reaction in which cyanate reacts with the amino acid lysine. Arginine and lysine are located at different positions in the amino acid sequence of proteins, and therefore these modifications occur at different positions in proteins with different flanking amino acids. Intriguingly, although homocitrulline residues can also be recognised by auto-antibodies, these auto-antibodies often do not crossreact with citrulline. Acetylation is a process where acetyl groups are added to free amines of lysine residues by acetyl transferases. Acetylated lysine does not resemble citrulline but bears similarity to homocitrulline except at the side chain terminal amine, which is replaced by a methyl moiety.

By now it is clear that AMPA consist of different auto-antibody families that are largely distinct, but that can also display a certain degree of cross-reactivity. Therefore, the notion is emerging that, although cross-reactivity exist, different classes of AMPAs are generally seen as distinct auto-antibody families that target different antigens, but intriguingly often co-occur. As the AMPA-responses in RA are often found together, it indicates that –somehow- AMPA-reactivity has a commonality that is currently not understood.

Although, the reason why an immune response starts against PTM proteins is not known, it appears crucial to obtain understanding on the breach of tolerance towards PTM proteins as the immune response against these proteins has been intimately implicated in disease-pathogenesis. Understanding the full AMPA response, the triggers that drive AMPA production, their mutual crosstalk and the pathways by which AMPA and/or AMPA-expressing B cells possibly contribute to RA will be important for the development of curative interventions in RA. In the context of this presentation, some of these aspects will be discussed.