Rheumatoid arthritis: From autoimmunity to synovitis and joint destruction

doi:10.1016/j.jaut.2012.05.021

Journal of Autoimmunity

Volume 39, Issue 3, September 2012, Pages 222-228

https://doi.org/10.1016/j.jaut.2012.05.021 Get rights and content

Abstract

Rheumatoid arthritis is an autoimmune disease characterized by the production of two known antibodies – rheumatoid factor and anti-citrullinated peptide antibody (ACPA) – against common autoantigens that are widely expressed within and outside the joints. The interactions between genes and environment are crucial in all stages of the disease, involving namely genes from major histocompatibility complex locus, and antigens such as tobacco or microbes (e.g. Porphyromonas gingivalis). T and B cells are activated as soon as the earliest phases of the disease, rheumatoid arthritis appearing as a Th1 and Th17 disease. Inflammatory cytokines have a considerable importance in the hierarchy of the processes involved in RA. The joint destruction seen in RA is caused not only by cytokine imbalances, but also by specific effects of the Wnt system and osteoprotegerin on osteoclasts and by matrix production dysregulation responsible for cartilage damage. Both innate and adaptative immunity demonstrated their respective cornerstone position in rheumatoid arthritis, since targeted treatments has been efficiently developed against TNF-α, IL-6 receptor, IL-1β, CD20 B cells and T-cell/Dendritic cell interactions.

Highlights

► Autoimmunity in rheumatoid arthritis targets post-translational citrullination. ► Tobacco is a link between environment, genes, and autoimmunity. ► Innate immunity is highly stimulated and appears by itself a target for treatments. ► Tissue destruction is not only the result of chronic inflammation and involves specific mechanisms.

Introduction

Rheumatoid arthritis (RA) is a frequent chronic inflammatory disease. It undoubtedly belongs to autoimmune diseases with a complex network of interactions between cognate and innate immunity (Fig. 1). It results from homeostatic dysregulations that drive several major pathophysiological processes [1]. Improved knowledge of the numerous factors involved in RA led to considerable advances over the last 15 years. The introduction of targeted treatments deeply changed the face of the disease, and secondarily produced crucial information on the mechanisms underlying RA. At the present time, the prevailing hypothesis is that RA involves a deleterious synergy among several processes. Thus, RA is an autoimmune disease characterized by the production of two known antibodies – rheumatoid factor and anti-citrullinated peptide antibody (ACPA) – against common autoantigens that are widely expressed outside the joints. RA is also a chronic inflammatory and destructive disease involving many cytokines that act both in series and in parallel, meaning cascades of action and redundancy. The clinical expression of RA is both systemic (fatigue, fever, anemia, vessels and organ involvement) and local, the most devastating manifestation being joint destruction, which is ascribable in part to the inflammatory process. Experimental models have provided valuable insights into these various successive or coexisting processes.

Section snippets

Genetic factors and environmental pressure

The impact of genetic factors compared to environmental factors is reflected by the 15–30% concordance rates of RA among monozygotic twins, which is four times higher than the rate in dizygotic twins [2], [3]. The relative risk associated with each of the susceptibility polymorphisms is modest, meaning therefore, that a genetic diagnostic test for RA remains in its infancy stage [4]. However, the identification of genetic susceptibility factors can provide crucial pathophysiological insights,

Rheumatoid arthritis is an autoimmune disease

Considerable efforts made to identify autoantigens within the joint produced few tangible results. The most specific targets identified to date are deiminated peptide epitopes recognized by ACPAs. Deiminated peptides are citrullinated peptides found in many matrix proteins such as filaggrin, keratin, fibrinogen, and vimentin and found also in alpha-enolase. Thus, the development of ACPAs indicates loss of tolerance to post-translational citrullination [8]. Peptidylarginine deiminase-4 (PADI4)

From autoimmunity to synovitis

ACPAs and rheumatoid factors can develop more than 10 years before RA clinical onset [13]. This preclinical phase is longer in patients who are older at RA onset. Other preclinical abnormalities may include elevations in the serum levels of the type II TNF-α receptor (a naturally occurring TNF inhibitor), IL-15, and IL-6 [14]. Thus, autoimmunity and stimulation of innate immunity are in synergy for the development of RA.

ACPAs are clearly pathogenic, as demonstrated by studies of animal models.

Cytokine imbalances involved in synovitis

The cytokines form a tangled and redundant network whose overall balance depends on multiple interactions. Regarding inflammation, the result at a given point in time is either progression or resolution of the inflammatory process. However, none of the cytokines has a single effect and none of the phases of the inflammatory process depends on a single cytokine. Thus, the cytokine network is both pleiotropic and redundant. The inflammation that characterizes RA is ascribed to a predominance of

Innate effector cells in rheumatoid synovitis

Synovial fluid and synovial tissue home many types of innate effector cells. Macrophages (predominantly M1 phenotype) the major effectors of synovitis, act via cytokines secretion, mainly TNF-α, IL-1β, IL-6; they produce also short half-life mediators of inflammation, metalloproteinases and are turned toward phagocytosis and enhanced antigen-presentation. Macrophage activation is driven by cytokines, cell contact (with activated T cells), toll-like receptors (TLRs) (mainly TLR 2/6, 3, 8) and

Joint destruction

RA is a potentially devastating disease because of its potential for joint destruction. Joint destruction is largely due to chronic inflammation, although to some extent it seems independent from the inflammatory process. Cartilage and bone destruction are, in part, mediated by distinct pathological pathways. For example, the abundant osteoclasts that are characteristic of rheumatoid inflammation directly damage bone, although they do not appear to affect cartilage [49]. Several studies have

Disclosure

Marie-Christophe Boissier: consultant and symposium fees from Debiopharm (Switzerland), Neovacs, Peptinov, Pfizer-France, Transgene, VaxConsulting. Research grants from Abbott-France, Amgen-France, Centocor, MSD-France, Menarini-France, Néovacs, Pfizer-France, Servier, Sherring-Plough-France, UCB-France. Luca Semerano: symposium fees from BMS France, Menarini France, Roche France, UCB France. Salima Challal, Nathalie Saidenberg: none; Géraldine Falgarone: Symposium fees: BMS-France,

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ReviewRheumatoid arthritis: From autoimmunity to synovitis and joint destruction

Abstract

Highlights

Introduction

Section snippets

Genetic factors and environmental pressure

Rheumatoid arthritis is an autoimmune disease

From autoimmunity to synovitis

Cytokine imbalances involved in synovitis

Innate effector cells in rheumatoid synovitis

Joint destruction

Disclosure

Jt Bone Spine

Semin Immunol

J Autoimmun

Am J Pathol

Blood

Jt Bone Spine

Kidney Int

Exp Cell Res

Jt Bone Spine

Immunity

Jt Bone Spine

Vaccine

J Autoimmun

J Autoimmun

J Biol Chem

Cytokine

Jt Bone Spine

J Autoimmun

J Autoimmun

J Autoimmun

Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins

Arthritis Rheum

Twin concordance rates for rheumatoid arthritis: results from a nationwide study

Br J Rheumatol

Developments in the scientific understanding of rheumatoid arthritis

Arthritis Res Ther

Immunity to citrullinated proteins in rheumatoid arthritis

Annu Rev Immunol

A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination

Arthritis Rheum

Specific interaction between genotype, smoking and autoimmunity to citrullinated alpha-enolase in the etiology of rheumatoid arthritis

Nat Genet

Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and alpha-enolase: implications for autoimmunity in rheumatoid arthritis

Arthritis Rheum

New autoantigens in rheumatoid arthritis (RA): screening 8268 protein arrays with sera from patients with RA

Ann Rheum Dis

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Proc Natl Acad Sci USA

Review
Rheumatoid arthritis: From autoimmunity to synovitis and joint destruction