ReviewACPA mediates the interplay between innate and adaptive immunity in rheumatoid arthritis
Introduction
Anti-citrullinated peptide antibodies (ACPAs) are a family of autoantibodies that specifically target proteins containing peptidylcitrulline, a deiminated form of peptidylarginine [1,2]. In 1998, Schellekens et al. first reported the existence of specific antibodies targeting synthetic citrullinated peptides in sera of rheumatoid arthritis (RA) patients [3]. With the initial peptide variants used for ELISA, ACPAs were identified in 76% of RA sera with a specificity of 96% [3]. Ever since the identification of ACPAs, these newly found autoantibodies have been studied, leading to successive discoveries of their irreplaceable diagnostic values due to the robust associations of ACPAs with the pathogenesis, radiographic progression and extra-articular complications of RA [4]. Accordingly, ACPAs tests were included in the 2010 RA classification criteria [5,6]. Beyond extraordinary clinical utility, the origin of ACPAs and their potential role in coordinating the immune and non-immune system advanced our appreciation for RA pathogenesis.
The manufacture of a pathogenic autoantibody requires the participation of environmental factors, the alteration of self-tissue, and the activation of autoimmunity. The interplay between them was first verified in 1934 by Schwentker and Rivers who immunised rabbits with autolytic rabbit brain emulsions, inducing the production of “anti-brain antibodies” and neurological manifestations such as paralysis, whereas rabbits treated with fresh brain emulsions did not exhibit autoimmunity [7]. For the first time, autoantibody production was shown to require the activation of autoimmunity targeting altered tissues generated by pathogens or chemical agents [8]. After the development of this hypothesis for almost a century, it still applies to ACPA autoimmunity but has evolved in the following aspects. First, citrullinated proteins/peptides generated by exogenous or endogenous factors are the main targets of ACPAs and the fuel for ACPA autoimmunity. Second, citrullinated proteins/peptides can be presented by antigen-presenting cells (APCs) to auto-reactive lymphocytes under certain predisposing major histocompatibility complex (MHC) genetic backgrounds, thereby igniting ACPA autoimmunity [9]. Finally, ACPAs participate in the localisation of the clinical manifestation of RA and the resulting deterioration.
Therefore, this review will discuss the role of ACPA in the interactions of innate immunity and autoimmunity in detail, with a focus on environmental factors and innate immunity in RA pathogenesis and the pathogenic function of ACPA per se.
Section snippets
The induction of citrullination: citrullinated peptides and innate immunity
Citrulline metabolism in humans includes free citrulline metabolism and citrullinated protein production (Fig. 1). Free citrulline metabolism involves nitic oxide (NO) synthase (NOS), ornithine carbamoyltransferase (OCT), and argininosuccinate synthetase (ASS) and results in urea production [10]. Protein citrullination occurs in some autoimmune diseases such as RA. Citrullinated proteins (e.g., citrullinated vimentin (CV), fibrinogen and histone), which are the main targets of ACPA, are
The production of ACPA: an adaptive process under innate influence
Citrullination catalysed by PADs incurs conformational alterations to the primary proteins, changing their inherent functions and interactions with other peptides [9]. Notably, the transformation of peptidylarginine generates new epitopes with distinct and augmented antigenicity. Therefore, the production of citrullinated peptides was initially regarded as an RA-specific phenomenon. However, identification of citrullinated proteins in the ST of patients with distinct inflammatory arthritis
The effect of ACPA: interplay of innate and adaptive immunity
Due to its relatively high sensitivity and specificity in predicting RA, ACPA was initially recognised as a superior alternative to rheumatoid factor (RF) as a marker for RA [92]. After ten years follow-up of 238 RA patients in a cohort study, researchers revealed that the presence of ACPAs was the strongest independent predictor of radiographic progression (odds ratio (OR) = 4.0) [93]. Radiographic progression was more likely to be found in patients with low to moderate levels of ACPAs
Conclusion
In this review, we summarised the findings that describe the role of ACPA in the interplay between the innate immune system and autoimmunity. First, environmental factors activate the innate immune system, leading to the production of citrullinated peptides and local inflammation, which contributes to the breach of self-tolerance. Second, externalized citrullinated proteins or its mimic molecule are presented by APCs to auto-reactive T/B lymphocytes, triggering the differentiation and
Funding
This work was supported by National Basic Research Program 973 Grants (2015CB553704).
Role of the funding source
The funding supports in the writing of this article.
Declarations of interest
None.
References (123)
- et al.
Citrullination and autoimmunity
Autoimmun Rev
(2015) - et al.
Citrullination: a posttranslational modification in health and disease
Int J Biochem Cell Biol
(2006) - et al.
Selective deimination of vimentin in calcium ionophore-induced apoptosis of mouse peritoneal macrophages
Biochem Biophys Res Commun
(1998) Innate immune sensing of pathogens and danger signals by cell surface toll-like receptors
Semin Immunol
(2007)- et al.
TLRs, future potential therapeutic targets for RA
Autoimmun Rev
(2017) - et al.
NFAT control of innate immunity
Blood
(2012) - et al.
Ca2+-dependent deimination-induced disassembly of intermediate filaments involves specific modification of the amino-terminal head domain
J Biol Chem
(1989) - et al.
Localisation of citrullinated proteins in normal appearing white matter and lesions in the central nervous system in multiple sclerosis
J Neuroimmunol
(2014) - et al.
Rheumatoid arthritis
Lancet
(2009) - et al.
The interplay between the innate immune system and the microbiota
Curr Opin Immunol
(2014)
Microbiota at the crossroads of autoimmunity
Autoimmun Rev
Microbiota-modulated metabolites shape the intestinal microenvironment by regulating NLRP6 inflammasome signaling
Cell
Inflammatory bowel disease as a model for translating the microbiome
Immunity
Peptide motif analysis predicts alphaviruses as triggers for rheumatoid arthritis
Mol Immunol
Fecal microbiota transplantation: review
Ann Pharm Fr
Anti-citrullinated protein/peptide autoantibodies in association with genetic and environmental factors as indicators of disease outcome in rheumatoid arthritis
Autoimmun Rev
Targeting FcgammaRs to treat antibody-dependent autoimmunity
Autoimmun Rev
Antibodies to citrullinated proteins: molecular interactions and arthritogenicity
Immunol Rev
The influence of ACPA status and characteristics on the course of RA
Nat Rev Rheumatol
Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies
J Clin Invest
Rheumatoid arthritis
Sykepl Fag
Anti-CCP antibody test predicts the disease course during 3 years in early rheumatoid arthritis (the Swedish TIRA project)
Ann Rheum Dis
2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative
Arthritis Rheum
The antibody response of rabbits to injections of emulsions and extracts of homologous brain
J Exp Med
Auto-antibodies in the pathogenesis of disease; a preliminary study of auto-sensitization of red cells in various diseases
S Afr Med J
Almost all about citrulline in mammals
Amino Acids
Citrullination: a specific target for the autoimmune response in rheumatoid arthritis
J Immunol
Fingerprinting of anti-citrullinated protein antibodies (ACPA): specificity, isotypes and subclasses
Lupus
Peptidylarginine deiminase 2, 3 and 4 have distinct specificities against cellular substrates: novel insights into autoantigen selection in rheumatoid arthritis
Ann Rheum Dis
The human peptidylarginine deiminases type 2 and type 4 have distinct substrate specificities
Biochim Biophys Acta
Primary sequence, together with other factors, influence peptide deimination by peptidylarginine deiminase-4
Biol Chem
Sensors of the innate immune system: their mode of action
Nat Rev Rheumatol
Tolerance, danger, and the extended family
Annu Rev Immunol
Increased macrophage activation mediated through toll-like receptors in rheumatoid arthritis
Arthritis Rheum
Expression of toll-like receptors 2 and 4 in rheumatoid synovial tissue and regulation by proinflammatory cytokines interleukin-12 and interleukin-18 via interferon-gamma
Arthritis Rheum
Heat shock protein 96 is elevated in rheumatoid arthritis and activates macrophages primarily via TLR2 signaling
J Immunol
DAMPs from cell death to new life
Front Immunol
Corrigendum: regulation of histone modification and chromatin structure by the p53-PADI4 pathway
Nat Commun
Nucleosomes are exposed at the cell surface in apoptosis
J Immunol
Blebs and apoptotic bodies are B cell autoantigens
J Immunol
Programmed cell death as a defence against infection
Nat Rev Immunol
Oxidative burst-dependent NETosis is implicated in the resolution of necrosis-associated sterile inflammation
Front Immunol
Neutrophil extracellular traps kill bacteria
Science
Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps
J Cell Biol
Neutrophil extracellular traps: is immunity the second function of chromatin?
J Cell Biol
Nicotine drives neutrophil extracellular traps formation and accelerates collagen-induced arthritis
Rheumatology (Oxford)
NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis
Sci Transl Med
Deimination of linker histones links neutrophil extracellular trap release with autoantibodies in systemic autoimmunity
FASEB J
Histone deimination as a response to inflammatory stimuli in neutrophils
J Immunol
Release of active peptidyl arginine deiminases by neutrophils can explain production of extracellular citrullinated autoantigens in rheumatoid arthritis synovial fluid
Arthritis Rheum
Cited by (0)
- 1
Xiwen Dong, Zhaohui Zheng and Yue Zhai contributed equally to this work.