Type I interferons inhibition of inflammatory T helper cell responses in systemic lupus erythematosus.
T helper (Th) cells play a central role in systemic lupus erythematosus (SLE). Activated autoreactive Th cells provide the help required for autoreactive B cells to differentiate and produce pathogenic autoAbs. Both autoAb-containing immune complexes and direct effects of inflammatory Th cells promote tissue injury and organ damage. In SLE, triggering of plasmacytoid dendritic cell (pDC) Toll-like receptors by autoimmune complexes containing nucleic acid autoantigens stimulates pDC secretion of high levels of type I interferons (IFN-alpha/beta). Study of SLE patients and murine disease models implicate these type I IFNs as key disease effectors. However, the role of pDC-derived type I IFNs in regulating the inflammatory function of Th cells in SLE is unknown. Although, type I IFNs are classically considered to promote Th1-mediated inflammation, they can also act as potent inhibitors of both Th1 and Th17 inflammatory cell responses. Work of ourselves and others leads us to hypothesize that if initiated during stages of SLE when Th cell-mediated tissue inflammation is absent or minimal, such as early in the disease or during periods of remission, type I IFN neutralization will disrupt the cycle of systemic autoimmune induction and disease. However, if initiated during advanced stages of disease when there is substantial ongoing Th1 (and possibly Th17) cell-mediated inflammation, targeting type I IFNs will exacerbate the Th cell-mediated inflammatory disease and thus potentiate end-organ damage and destruction. This has important implications for the application of the numerous anti-type I IFN therapies currently under development for SLE treatment.
Mangini
Alyson J
AJ
Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts 02118, USA.
Lafyatis
Robert
R
Van Seventer
Jean Maguire
JM
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D007370:Interferon Type I / Q000276:immunology* / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D018448:Models, Immunological; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
D007370:Interferon Type I