Elsevier

Autoimmunity Reviews

Volume 17, Issue 9, September 2018, Pages 845-853
Autoimmunity Reviews

Review
ACPA mediates the interplay between innate and adaptive immunity in rheumatoid arthritis

https://doi.org/10.1016/j.autrev.2018.02.014Get rights and content

Abstract

The production of anti-citrullinated peptide antibodies (ACPAs) requires the participation of both innate immunity and adaptive immunity. On the one hand, activated innate immunity is able to produce citrullinated auto-antigens that fuel autoimmunity and provide an inflammatory environment that facilitates the breach of self-tolerance, proliferation of self-reactive T/B cells and the production of ACPAs. On the other hand, after their production by plasma B cells, ACPAs are also able to interact with innate immunity to exacerbate the manifestation and chronicity of rheumatoid arthritis (RA). This article discusses the roles of citrullinated peptides and ACPA played in innate immunity and autoimmunity. In addition, we emphasise the relationships between environmental factors and innate immunity, as well as the pathogenic function of ACPAs per se. In doing so, we hope to provide fundamental knowledge of RA pathogenesis and reveal potential therapeutic targets in RA treatment.

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)

  • O. Shamriz et al.

    Microbiota at the crossroads of autoimmunity

    Autoimmun Rev

    (2016)
  • M. Levy et al.

    Microbiota-modulated metabolites shape the intestinal microenvironment by regulating NLRP6 inflammasome signaling

    Cell

    (2015)
  • C. Huttenhower et al.

    Inflammatory bowel disease as a model for translating the microbiome

    Immunity

    (2014)
  • C. Hogeboom

    Peptide motif analysis predicts alphaviruses as triggers for rheumatoid arthritis

    Mol Immunol

    (2015)
  • F. Barbut et al.

    Fecal microbiota transplantation: review

    Ann Pharm Fr

    (2015)
  • P. Szodoray et al.

    Anti-citrullinated protein/peptide autoantibodies in association with genetic and environmental factors as indicators of disease outcome in rheumatoid arthritis

    Autoimmun Rev

    (2010)
  • X. Yu et al.

    Targeting FcgammaRs to treat antibody-dependent autoimmunity

    Autoimmun Rev

    (2016)
  • H. Uysal et al.

    Antibodies to citrullinated proteins: molecular interactions and arthritogenicity

    Immunol Rev

    (2010)
  • A. Willemze et al.

    The influence of ACPA status and characteristics on the course of RA

    Nat Rev Rheumatol

    (2012)
  • G.A. Schellekens et al.

    Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies

    J Clin Invest

    (1998)
  • L. Schmidt

    Rheumatoid arthritis

    Sykepl Fag

    (2009)
  • A. Kastbom et al.

    Anti-CCP antibody test predicts the disease course during 3 years in early rheumatoid arthritis (the Swedish TIRA project)

    Ann Rheum Dis

    (2004)
  • D. Aletaha et al.

    2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative

    Arthritis Rheum

    (2010)
  • F.F. Schwentker et al.

    The antibody response of rabbits to injections of emulsions and extracts of homologous brain

    J Exp Med

    (1934)
  • A. Zoutendyk et al.

    Auto-antibodies in the pathogenesis of disease; a preliminary study of auto-sensitization of red cells in various diseases

    S Afr Med J

    (1951)
  • E. Curis et al.

    Almost all about citrulline in mammals

    Amino Acids

    (2005)
  • D.A. Fox

    Citrullination: a specific target for the autoimmune response in rheumatoid arthritis

    J Immunol

    (2015)
  • F. Pratesi et al.

    Fingerprinting of anti-citrullinated protein antibodies (ACPA): specificity, isotypes and subclasses

    Lupus

    (2015)
  • E. Darrah et al.

    Peptidylarginine deiminase 2, 3 and 4 have distinct specificities against cellular substrates: novel insights into autoantigen selection in rheumatoid arthritis

    Ann Rheum Dis

    (2012)
  • C. Assohou-Luty et al.

    The human peptidylarginine deiminases type 2 and type 4 have distinct substrate specificities

    Biochim Biophys Acta

    (1844)
  • M.E. Stensland et al.

    Primary sequence, together with other factors, influence peptide deimination by peptidylarginine deiminase-4

    Biol Chem

    (2009)
  • R. Baccala et al.

    Sensors of the innate immune system: their mode of action

    Nat Rev Rheumatol

    (2009)
  • P. Matzinger

    Tolerance, danger, and the extended family

    Annu Rev Immunol

    (1994)
  • Q. Huang et al.

    Increased macrophage activation mediated through toll-like receptors in rheumatoid arthritis

    Arthritis Rheum

    (2007)
  • T.R. Radstake et al.

    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

    (2004)
  • Q. Huang et al.

    Heat shock protein 96 is elevated in rheumatoid arthritis and activates macrophages primarily via TLR2 signaling

    J Immunol

    (2009)
  • E. Venereau et al.

    DAMPs from cell death to new life

    Front Immunol

    (2015)
  • C. Tanikawa et al.

    Corrigendum: regulation of histone modification and chromatin structure by the p53-PADI4 pathway

    Nat Commun

    (2012)
  • M. Radic et al.

    Nucleosomes are exposed at the cell surface in apoptosis

    J Immunol

    (2004)
  • B.A. Cocca et al.

    Blebs and apoptotic bodies are B cell autoantigens

    J Immunol

    (2002)
  • I. Jorgensen et al.

    Programmed cell death as a defence against infection

    Nat Rev Immunol

    (2017)
  • M.H.C. Biermann et al.

    Oxidative burst-dependent NETosis is implicated in the resolution of necrosis-associated sterile inflammation

    Front Immunol

    (2016)
  • V. Brinkmann et al.

    Neutrophil extracellular traps kill bacteria

    Science

    (2004)
  • V. Papayannopoulos et al.

    Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps

    J Cell Biol

    (2010)
  • V. Brinkmann et al.

    Neutrophil extracellular traps: is immunity the second function of chromatin?

    J Cell Biol

    (2012)
  • J. Lee et al.

    Nicotine drives neutrophil extracellular traps formation and accelerates collagen-induced arthritis

    Rheumatology (Oxford)

    (2017)
  • R. Khandpur et al.

    NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis

    Sci Transl Med

    (2013)
  • N. Dwivedi et al.

    Deimination of linker histones links neutrophil extracellular trap release with autoantibodies in systemic autoimmunity

    FASEB J

    (2014)
  • I. Neeli et al.

    Histone deimination as a response to inflammatory stimuli in neutrophils

    J Immunol

    (2008)
  • J. Spengler et al.

    Release of active peptidyl arginine deiminases by neutrophils can explain production of extracellular citrullinated autoantigens in rheumatoid arthritis synovial fluid

    Arthritis Rheum

    (2015)
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    1

    Xiwen Dong, Zhaohui Zheng and Yue Zhai contributed equally to this work.

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