The role of cytokines in the pathogenesis of cutaneous lupus erythematosus
Section snippets
Introduction to cutaneous lupus erythematosus
Lupus erythematosus (LE) encompasses a broad range of cutaneous symptoms including malar rash, discoid rash, photosensitivity and oral ulcers as well as systemic symptoms such as arthritis, renal disease, abnormal serologies and hematologic disease. Patients may have cutaneous lupus erythematosus (CLE), systemic lupus erythematosus (SLE) or both. The American College of Rheumatology defines SLE as the presence of at least four of eleven diagnostic criteria. The prevalence of SLE varies
The pathogenesis of CLE
The pathogenesis of CLE is multifactorial and incompletely understood. It involves ultraviolet (UV) light, keratinocyte apoptosis, cytokine release, B cell hyperactivity, and activation of T cells and dendritic cells. Cytokines play an important role in the pathogenesis of CLE. Cytokines induce and inhibit immune cells and each other. Their roles may be different in the various CLE subtypes.
Cytokines are grouped into two functional classes: T-helper 1 (Th1) cell-produced cytokines and T-helper
Key points
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UV light directly increases the levels of TNFα and certain types of interferon and interleukin. These cytokines are important in the pathogenesis of CLE. They mediate the immune cell dysfunction, tissue inflammation and tissue injury present in CLE.
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UV light induces keratinocyte apoptosis, which may increase the release of cytokines and autoantigens.
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Keratinocyte necrosis and the action of UV light on keratinocytes displace nucleoproteins from inside the cell to the cell surface. Antibodies bind
Key points
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Increased IFN, especially type I IFN, plays an important role in the pathogenesis of CLE.
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In CLE, plasmacytoid dendritic cells (pDCs) produce type I IFN in response to nuclear antigens, immune complexes and UV light. Type I IFN increases leukocyte recruitment to the skin via inflammatory cytokines, chemokines and adhesion molecules. Type I IFN also upregulates the production of cytotoxic proteins. In total, these actions induce and propagate cutaneous inflammation.
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Mutations in the IFN regulatory
Key points
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TNFα is increased in the serum and skin of CLE patients.
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Keratinocytes produce TNFα in response to UV light and inflammatory cytokines, particularly IL-1α, IL-18 and IFN-γ.
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In CLE, high levels of TNFα increase the production of inflammatory cytokines, chemokines and adhesion molecules, which recruit inflammatory cells into the skin.
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TNFα also activates B cells to produce antibodies and increases the expression of nuclear antigens on the keratinocyte surface.
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The −308A TNFα promoter polymorphism is
Key points
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Many inflammatory interleukins play important roles in the pathogenesis of CLE.
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Increased levels of IL-6 and IL-10 in CLE may cause B cell hyperactivity.
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Decreased IL-12 levels in LE enable increased humoral immune responses and UV-induced keratinocyte apoptosis.
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IL-17 likely contributes to the increased production of inflammatory cytokines and chemokines in CLE.
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High levels of IL-18 and the IL-18 receptor in CLE increase TNFα production, decrease IL-12 production and trigger keratinocyte death.
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New
Conclusions
Many studies point to cytokines as important factors in the pathogenesis of CLE. IFNs, TNFα and ILs all play significant roles. The actions and interactions of these cytokines in CLE are complex. The cytokine pathways are impacted by UV light, genetic and other environmental factors. They are further complicated in that they may vary with CLE subtype. Current research is continuing to expand our knowledge of these pathways and identify potential targets for the treatment of CLE.
Acknowledgements
This material is supported by the Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development and a VA Merit Review grant to VPW.
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