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  • Review Article
  • Published:

Cytokines in the pathogenesis of rheumatoid arthritis

Nature Reviews Immunology volume 7, pages 429–442 (2007)Cite this article

Key Points

  • Cytokines regulate inflammation, autoimmunity and articular destruction in the joints of patients with rheumatoid arthritis. In particular, tumour-necrosis factor (TNF) has proved to be of particular utility as a therapeutic target.

  • T-cell activation particularly towards a T helper 1 (TH1)-cell and/or a TH17-cell phenotype is associated with the presence in the synovial tissue of interleukin-15 (IL-15), IL-1, IL-6, transforming growth factor-β (TGFβ), IL-12 and IL-23. In turn, T cells drive inflammation via IL-17 release and by cognate interactions with adjacent macrophages.

  • B cells have a critical role in synovitis, acting in part via antigen presentation and cytokine release. B-cell differentiation and expansion, in turn, is supported in the synovial tissue by IL-6, IL-10, B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL).

  • Macrophage-derived cytokines including TNF, IL-1, IL-6, IL-15 and IL-18 drive many of the pro-inflammatory pathways in synovial tissue.

  • Cytokines are responsible for osteoclast maturation and activation. There appears to be a hierarchical role for receptor activator of nuclear factor-κB ligand (RANKL) in this process together with TNF, IL-17 and IL-1.

  • Early intervention, for example with TNF-blocking agents, appears to offer higher clinical response rates and improved chances of achieving clinical remission. Clinical studies are ongoing targeting IL-6, IL-15, IL-18, IL-17, granulocyte/macrophage colony-stimulating factor (GM-CSF) and others, with the objective of further improving clinical outcomes.

Abstract

Cytokines regulate a broad range of inflammatory processes that are implicated in the pathogenesis of rheumatoid arthritis. In rheumatoid joints, it is well known that an imbalance between pro- and anti-inflammatory cytokine activities favours the induction of autoimmunity, chronic inflammation and thereby joint damage. However, it remains less clear how cytokines are organized within a hierarchical regulatory network, and therefore which cytokines may be the best targets for clinical intervention a priori. Here, we discuss the crucial effector function of cytokines in the immunological processes that are central to the pathogenesis of rheumatoid arthritis.

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Figure 1: A contextual framework for the pathogenesis of rheumatoid arthritis.
Figure 2: Pathways leading to activation of synovial T cells in rheumatoid arthritis and their key effector pathways.
Figure 3: An overview of the cytokine-mediated regulation of synovial interactions.
Figure 4: The key factors that regulate osteoclast differentiation in rheumatoid arthritis.
Figure 5: Pathways regulating chondrocyte activation and cartilage degradation in rheumatoid arthritis.

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Acknowledgements

We are grateful for financing from the Arthritis Research Campaign (UK) and The Wellcome Trust. We thank J. A. Gracie for invaluable contribution to the preparation and content of this manuscript. We are grateful for discussions with many colleagues concerning ideas contained within the content, particularly F. Y. Liew, G. Graham, P. Garside and G. Firestein. We apologize to colleagues whose work is cited via review rather than original work owing to space restraints.

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Authors and Affiliations

  1. Centre for Rheumatic Diseases, Glasgow Biomedical Research Centre, University of Glasgow, 120 University Place, Glasgow, G12 8TA, UK

    Iain B. McInnes

  2. Department of Internal Medicine 3, Friedrich-Alexander University Erlangen-Nuremberg, Krankenhausstrasse 12, Erlangen, 91054, Germany

    Georg Schett

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  1. Iain B. McInnes
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Correspondence to Iain B. McInnes.

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Glossary

Citrullinated peptide

A peptide that incorporates the amino-acid citrulline. This amino acid is generated post-translationally by peptidylarginine deiminases. Patients with rheumatoid arthritis generate characteristic autoantibodies against the part of the antigenic determinant that contains citrulline moieties.

Shared epitope

A common stretch of amino acids in the peptide-binding grooves at positions 67–74 of the HLA-DRβ-chain.

Osteoclasts

Multinucleated giant cells, of the monocyte lineage, that are responsible for bone resorption. Osteoclasts degrade bone matrix and solubilize calcium from bone. Problems with their differentiation and a decrease in their number lead to bone osteopetrosis. Conversely, an increase in their number or function induces bone osteoporosis, indicating that osteoclasts have a pivotal role in bone homeostasis.

Acute-phase proteins

A group of proteins, including C-reactive protein, serum amyloid A, fibrinogen and α1-acid glycoprotein, that are secreted into the blood in increased or decreased quantities by hepatocytes in response to trauma, inflammation or disease. These proteins can be inhibitors or mediators of inflammatory processes.

Cachexia

Severe weight loss, muscle wasting and debility caused by prolonged disease. It is thought to be mediated through neuroimmunoendocrine interactions.

Cyclosporin

A commonly used immunosuppressive drug that blocks calcineurin A and thereby inhibits T-cell activation. It is used to prevent the rejection of transplanted organs and to treat some inflammatory diseases.

Collagen-induced arthritis

(CIA). An animal model of rheumatoid arthritis. CIA develops in susceptible rodents and primates after immunization with cartilage-derived type II collagen.

T-bet

A member of the T-box family of transcription factors. It is a master switch in the development of T helper 1 (TH1)-cell responses, through its ability to regulate expression of the interleukin-12 receptor, inhibit signals that promote TH2-cell development and promote the production of interferon-γ.

ELISPOT

A method based on antibody capture for enumerating specific T cells (CD4+ and CD8+) that secrete a particular cytokine (often interferon-γ).

Plasmacytoid DC

A dendritic cell (DC) subset with a morphology that resembles that of a plasmablast. Plasmacytoid DCs produce large amounts of type I interferons in response to viral infection.

Adjuvant-induced arthritis

An experimental animal model of arthritis, in which disease is induced by the administration of heat-killed mycobacteria in oil.

Follicular DCs

These are specialized non-haematopoietic stromal cells that reside in the follicles and germinal centres. These cells possess long dendrites, but are not related to dendritic cells, and carry intact antigen on their surface.

Germinal centres

Highly specialized and dynamic microenvironments that give rise to secondary B-cell follicles during an immune response. They are the main site of B-cell maturation, leading to the generation of memory B cells and plasma cells that produce high-affinity antibody.

SCID mouse

Severe combined immunodeficiency mouse. Mice of this phenotype lack functional T and B cells owing to a spontaneous mutation in the Prkdc gene (protein kinase, DNA activated, catalytic polypeptide) located on chromosome 16. These mice are often used for reconstitution of T-cell subsets to study their functions in vivo.

Affinity maturation

A process whereby the mutation of antibody variable (V)-region genes followed by selection for higher-affinity variants in the germinal centre leads to an increase in average antibody affinity for an antigen as an immune response progresses. The selection is thought to be a competitive process in which B cells compete with free antibody to capture decreasing amounts of antigen.

Receptor editing

A molecular process that involves secondary rearrangements (mostly of the light chains) that replace existing immunoglobulin molecules and generate a new antigen receptor with altered specificity.

Mantle zone

The area of a secondary follicle that surrounds the germinal centre and contains IgD+ naive, resting B cells.

Danger signals

Agents that alert the immune system to danger, usually by interacting with Toll-like receptors and other pattern-recognition receptors, and thereby promote the generation of innate and adaptive immune responses. Danger signals can be associated with microbial invaders (exogenous danger signals) or produced by damaged cells (endogenous danger signals).

IL-1 receptor antagonist

(IL-1RA). A secreted protein that binds to the interleukin-1 receptor (IL-1R), thereby blocking IL-1R downstream signalling. IL-1RA inhibits the pro-inflammatory properties of IL-1α and IL-1β.

K/BxN transgenic mouse

A mouse strain formed by crossing NOD/Lt mice with C57BL/6 KRN T-cell-receptor-transgenic mice in which T cells recognize a peptide from the autoantigen glucose-6-phosphate isomerase (GPI). These mice develop an arthritis that is mediated, and transferable, by circulating antibody against GPI.

Pannus

A sheet of inflammatory granulation tissue, composed of immune cells, blood vessels and fibrous cells, that spreads from the synovial membrane and ultimately invades the joint in rheumatoid arthritis.

Osteoblasts

Cells of mesenchymal origin that are responsible for the formation of bone.

Diapedesis

The migration of leukocytes across the endothelium, which occurs by leukocytes squeezing through the junctions between adjacent endothelial cells.

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McInnes, I., Schett, G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol 7, 429–442 (2007). https://doi.org/10.1038/nri2094

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