The role of anti-citrullinated protein antibody in pathogenesis of RA

Abstract

Rheumatoid arthritis (RA) is a common autoimmune rheumatic disease that causes chronic synovitis, bone erosion, and joint destruction. The autoantigens in RA include a wide array of posttranslational modified proteins, such as citrullinated proteins catalyzed by peptidyl arginine deiminase4a. Pathogenic anti-citrullinated protein antibodies (ACPAs) directed against a variety of citrullinated epitopes are abundant both in plasma and synovial fluid of RA patients. ACPAs play an important role in the onset and progression of RA. Intensive and extensive studies are being conducted to unveil the mechanisms of RA pathogenesis and evaluate the efficacy of some investigative drugs. In this review, we focus on the formation and pathogenic function of ACPAs.

Keywords: Anti-citrullinated protein antibody; Citrullination; Neutrophil extracellular traps; Peptidyl arginine deiminase 4; Rheumatoid arthritis.

Fig. 1

The activation of PAD4 and the interaction in NETs, PAD4 and ACPAs. Smoking, environmental dust, microorganisms in periodontitis, macrophages, and other PAD-producing cells in the mucosa may enhance the production of PAD4. With defective immune tolerance and genetic susceptibility, PAD4 can induce the formation of abnormal citrullinated proteins or peptides, promote the interaction of citrullinated proteins and the immune system, and cause genetically susceptible individuals to produce autoantibodies. Neutrophils are activated by immune complexes and inflammatory cytokines within the synovial fluid, frequently causing enhanced NETs formation in RA. In turn, NETs serve as a source of citrullinated autoantigens, further triggering the production of ACPAs. PAD4 peptidylarginine deiminase 4; ACPAs anti-citrullinated protein antibodies; NETs neutrophil extracellular traps

Fig. 2

The development of autoimmunity and progression of RA. The prediction models suggest a cascade of autoantibodies, inflammation, and arthritis. While the specificity of autoantibodies binding to ACPA is confined and their isotype is limited in healthy individuals, epitope spreading and isotype expansion may occur in RA patients

Fig. 3

The pathogenesis of ACPAs in RA. Interaction between ACPAs and citrullinated fibrinogen forms ICs, which activate inflammatory cells and the complement system with subsequent release of C3a and C5a. The uncontrolled production of pro-inflammatory cytokines and mediators creates a local inflammatory milieu. These cytokines induce the generation of MMPs and RANKL by fibroblasts. While RANKL is closely involved in the formation and activation of osteoclasts causing excessive bone resorption, MMPs, particularly, MMP13, enhance cartilage degradation. The combined effects of these mediators eventually lead to complete joint destruction. ACPAs bind to osteoclasts, stimulating the release of IL-8 and autocrine enhancement of osteoclast maturation and activation. Further, chemokines such as CXCR1 and CXCR2 overexpressed in the sensory neurons may induce allodynia. ACPAs have the multi-faceted role of altered metabolites in adipose tissue, vascular, and liver tissue. ACPAs anti-citrullinated protein antibodies; ICs immune complexes; NETs neutrophil extracellular traps; TLR-4 Toll-like receptor 4; IL-1R interleukin 6 receptor; IL-6R interleukin 6 receptor; M-CSF macrophage colony-stimulating factor; RANK receptor activator of NK-κB; MMPs matrix metalloproteinases; IL-8 interleukin-8; CXCR1 CXC chemokine receptor1; CXCR2 CXC chemokine receptor; RA rheumatoid arthritis