Key Points
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Cytokines have essential roles in immune cell development, immunoregulation and immune effector functions.
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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.
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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.
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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.
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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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We thank B. Diamond, M. Lenardo, P. Plotz and W. Strober for reading this manuscript and providing helpful suggestions.
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DATABASES
autoimmune lymphoproliferative disease
FURTHER INFORMATION
autoimmune disease: pathogenesis
Glossary
- CROHN'S DISEASE
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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
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Denotes lymphocyte non-responsiveness to antigen, but implies an active process, not simply a passive lack of response.
- PERIPHERAL TOLERANCE
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This form of tolerance refers to the lack of responsiveness of mature lymphocytes.
- LYMPHADENOPATHY
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Enlargement of lymph nodes.
- BLAU SYNDROME
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A rare, autosomal-dominant disorder characterized by granulomatous arthritis, uveitis, skin rash and cranial neuropathy.
- CENTRAL TOLERANCE
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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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DOI: https://doi.org/10.1038/nri702
