The role of anti-citrullinated protein antibodies (ACPA) in the pathogenesis of rheumatoid arthritis

Abstract

The most specific autoimmunity known for rheumatoid arthritis (RA) is reflected by generation of anti-citrullinated protein antibodies (ACPA). Presence of ACPA in established RA is associated with disease severity, while generation of ACPA at early developmental phases of RA can have a strong predictive value for progressing to the full-blown disease. Hence, development of ACPA may be of crucial importance to the pathogenesis of RA. Therefore, a lot of effort has been put recently to investigate the feature of ACPA at early developmental stages of RA (before disease onset) and functional activities of these autoantibodies. Results of these studies enlarged the knowledge about the nature of ACPA, which is essential for planning the therapeutic or preventive strategies interfering with their development and pathogenic functions. In this review we describe recent evidence for a role of ACPA in the etiopathogenesis of RA and indicate key unresolved issues regarding ACPA biology that need to be clarified in the future.

The Role of the Microbiome in Driving RA-Related Autoimmunity

“…The creation of ACPA’s is brought about by a process called citrullination, which is the post-translational modification of arginine, catalyzed by peptidylarginine deiminase (PAD) enzymes resulting in the substitution of arginine to citrulline. This process decreases the proteins ability to form hydrogen bonds due to a lack of positively charged amino acids introducing a structural change within the peptide sequence and subsequent immunogenicity ( Kurowska et al, 2017 ). PAD enzymes are highly conserved throughout evolution, in humans there are five main types of PAD genes ( Chavanas et al, 2004 ) which display both tissue and substrate specificity and are involved in a plethora of physiological functions including tissue structure, apoptosis and immune regulation ( Wegner et al, 2010 ), of note PAD2 and PAD4 are likely more important in RA development given their isolation in the synovium of RA patients ( Foulquier et al, 2007 ).…”

“…PAD enzymes are highly conserved throughout evolution, in humans there are five main types of PAD genes ( Chavanas et al, 2004 ) which display both tissue and substrate specificity and are involved in a plethora of physiological functions including tissue structure, apoptosis and immune regulation ( Wegner et al, 2010 ), of note PAD2 and PAD4 are likely more important in RA development given their isolation in the synovium of RA patients ( Foulquier et al, 2007 ). As mentioned ACPA’s may be heterogeneous in terms of their fine specificity to antigens but are highly specific for RA when compared to RF ( Kurowska et al, 2017 ).…”

Measuring ACPA in the general population or primary care: is it useful?

“…Some evidence suggest that genetic (eg, the shared epitope) and environmental risk factors (eg, tobacco smoke) act in concert to increase the formation of citrullinated proteins, to promote their presentation to the immune system, to break the tolerance towards these antigens and lead to the development of ACPA 44. Interestingly, these autoantibodies are transformed over the period of time, from their systemic appearance up to RA onset, with both qualitative and quantitative changes, extensive diversification, increased avidity, new isotypes and acquisition of specific agalactosylation and core fucosylation profiles 45. Several investigations have suggested mechanisms by which ACPA may be directly pathogenic in RA 46.…”

Efficacy and safety of NI-0101, an anti-toll-like receptor 4 monoclonal antibody, in patients with rheumatoid arthritis after inadequate response to methotrexate: a phase II study

“…Anti-citrullinated protein antibodies (ACPAs) are characteristic of RA and may be present prior to the emergence of clinical symptoms of the disease 2 3. Citrullinated proteins and ACPAs form immune complexes4 5 which belong to the damage-associated molecular pattern (DAMP) family 6. DAMPs are important regulators of innate inflammatory responses.…”