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  • Review Article
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Cytokines and autoimmunity

Nature Reviews Immunology volume 2, pages 37–45 (2002)Cite this article

Key Points

  • Cytokines have essential roles in immune cell development, immunoregulation and immune effector functions.

  • Cytokines such as interleukin (IL)-2, tumour-necrosis factor (TNF) and the interferons are well known to have immunostimulatory and pro-inflammatory actions. However, the same cytokines also have unexpected, but essential, immunosuppressive actions.

  • IL-2 has essential functions in constraining lymphocyte growth by promoting apoptosis. Regulatory T cells that express the IL-2 receptor γ-chain have also been intensively studied. Deficiency of these cells can result in autoimmunity, but the exact role of IL-2 in the physiology of these cells is unknown.

  • Despite TNF's role as the prototypic cytokine that mediates proinflammatory responses, it is now clear that its in vivo role is complex. Experimental models of disease show that immune-mediated disease, including arthritis, can occur in the absence of TNF. Models of diabetes have shown that TNF can worsen or improve disease, depending on the timing and duration of exposure to this cytokine.

  • Interferons have essential functions in host defence and promote cell-mediated immunity. Type 1 interferons, in particular, have been used to treat autoimmune diseases, including those characterized by T-helper (TH)1-mediated pathology. Type 1 interferons can inhibit secretion of IL-12 and inhibit its action. Type 2 interferon (interferon-γ) and other cytokines upregulate the expression of a class of feedback inhibitors known as suppressors of cytokine signalling (SOCS). Mice deficient in Socs1 have fatal, interferon-dependent, inflammatory disease.

Abstract

Cytokines have crucial functions in the development, differentiation and regulation of immune cells. As a result, dysregulation of cytokine production or action is thought to have a central role in the development of autoimmunity and autoimmune disease. Some cytokines, such as interleukin-2, tumour-necrosis factor and interferons — ostensibly, the 'bad guys' in terms of disease pathogenesis — are well known for the promotion of immune and inflammatory responses. However, these cytokines also have crucial immunosuppressive functions and so, paradoxically, can also be 'good guys'. The balance between the pro-inflammatory and immunosuppressive functions of these well-known cytokines and the implications for the pathogenesis of autoimmune disease is the focus of this review.

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Figure 1: Cytokines and helper T-cell differentiation.
Figure 2: Summary of the immunostimulatory and immunosuppressive effects of IL-2.
Figure 3: Summary of immunosuppressive effects of TNF, the prototypic pro-inflammatory cytokine.
Figure 4: Cytokines in autoimmunity — good guys and bad guys switch sides!

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Acknowledgements

We thank B. Diamond, M. Lenardo, P. Plotz and W. Strober for reading this manuscript and providing helpful suggestions.

Author information

Authors and Affiliations

  1. Lymphocyte Cell Biology Section, Arthritis and Rheumatism Branch and Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Building 10 Room 9N252, 10 Center Drive, MSC-1820, Bethesda, 20892, Maryland, USA

    John J. O'Shea & Peter Lipsky

  2. Departments of Medicine and Ben May Institute for Cancer Research, University of Chicago, Chicago, 60637, Illinois, USA

    Averil Ma

Authors
  1. John J. O'Shea
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Corresponding author

Correspondence to John J. O'Shea.

Related links

Related links

DATABASES

LocusLink

APAF1

caspase-9

CD28

CD80

CD86

CD95

CD152

CD178

FADD

FLIP

γc

Ifi202

IFN-α

IFN-β

IFN-γ

IL-1

IL-2

IL-2R

IL-4

IL-6

IL-7

IL-9

IL-10

IL-12

Il-12p40

IL-15

IL-21

lymphotoxin-α

NOD2

Rag

Socs1

SOCS1

STAT1

Stat3

STAT4

Stat5

T-bet

TGF-β

TNFR1

TNFR2

TRADD

OMIM

autoimmune diseases

autoimmune lymphoproliferative disease

inflammatory bowel disease

multiple sclerosis

rheumatoid arthritis

SCID

systemic lupus erythematosus

type I diabetes

ulcerative colitis

FURTHER INFORMATION

Encyclopedia of Life Sciences

autoimmune disease: pathogenesis

cytokines

cytokines as mediators of disease

immunoregulation

interferons

Glossary

CROHN'S DISEASE

One of the two predominant forms of inflammatory bowel disease that afflicts human patients. The pathophysiology is unknown, but is presumed to be autoimmune in nature.

TOLERANCE

Denotes lymphocyte non-responsiveness to antigen, but implies an active process, not simply a passive lack of response.

PERIPHERAL TOLERANCE

This form of tolerance refers to the lack of responsiveness of mature lymphocytes.

LYMPHADENOPATHY

Enlargement of lymph nodes.

BLAU SYNDROME

A rare, autosomal-dominant disorder characterized by granulomatous arthritis, uveitis, skin rash and cranial neuropathy.

CENTRAL TOLERANCE

This form of tolerance refers to the lack of self-responsiveness found as lymphoid cells develop, and is associated with the deletion of autoreactive clones. For T cells, this occurs in the thymus.

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O'Shea, J., Ma, A. & Lipsky, P. Cytokines and autoimmunity. Nat Rev Immunol 2, 37–45 (2002). https://doi.org/10.1038/nri702

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