Article

Type I Interferon in Systemic Lupus Erythematosus and Other Autoimmune Diseases

Baylor Institute for Immmunology Research, 3434 Live Oak, Dallas, Texas 75204, USA.
Immunity (Impact Factor: 19.75). 10/2006; 25(3):383-92. DOI: 10.1016/j.immuni.2006.08.010
Source: PubMed

ABSTRACT Different genetic alterations may lead to type I interferon (IFN) overproduction in human systemic lupus erythematosus (SLE). The increased bioavailability of type I IFN contributes to peripheral tolerance breakdown through the activation of immature myeloid dendritic cells (mDCs). IFN-matured mDCs activate autoreactive T cells. These cells, together with plasmacytoid DCs, help expand autoreactive B cells. IFN-matured DCs also activate cytotoxic CD8+ T cells, possibly increasing apoptotic cell availability. The capture of apoptotic cells by mDCs and of nucleic acid-containing immune complexes by plasmacytoid DCs and B cells amplifies the autoimmune reaction leading to disease manifestations. Genetic alterations in lineages other than B cells might explain other autoimmune syndromes where type I IFNs appear to be involved.

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    • "Importantly, IFN-α can impact the function of B cells through a variety of mechanisms , including TLR7 expression, survival and differentiation [29] [30] [31] [32] [33] [34]. What's more, immune cells, including B cells, display an up-regulated IFN-I-induced gene signature in SLE patients [35] [36] [37] [38] [39] [40] [41] [42]. Several recent studies have demonstrated that estrogens can promote the TLR7-and TLR9-ligand-induced production of IFN-α in pDCs [43] [44]. "
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    ABSTRACT: The activation of IFN-α signaling in B cells contributes to the pathogenesis of systemic lupus erythematosus (SLE). Many studies suggest that estrogens are closely related to the gender difference in the prevalence of SLE. However, the underlying mechanism of the interaction between estrogens and the activation of IFN-α signaling in SLE B cells remains incompletely understood. In the present study, we first found that healthy female mice showed an up-regulated type I IFN-induced gene signature in B cells compared with age-matched male mice, and in vivo study revealed that the gender difference was related to 17β-estradiol. Moreover, we found that 17β-estradiol could enhance the activation of IFN-α signaling in an ERα-dependent manner by down-regulating the expression of three microRNAs, including let-7e-5p, miR-98-5p and miR-145a-5p. These microRNAs could target the 3'UTR of the IKKε-encoding gene IKBKE directly and regulate the expression of IKKε, which can promote the activation of IFN-α signaling. In addition, compared with age-matched male mice, female mice showed a higher level of IKKε and lower levels of let-7e-5p, miR-98-5p and miR-145a-5p in B cells. Moreover, peripheral blood mononuclear cells from women showed a higher level of IKKε and lower levels of let-7e-5p, miR-98-5p and miR-145a-5p compared with those from age-matched men. These data suggest that 17β-estradiol amplifies the activation of IFN-α signaling in B cells via IKKε by down-regulating the expression of let-7e-5p, miR-98-5p and miR-145a-5p. Our findings may provide a new perspective for understanding the mechanism underlying the gender difference in the prevalence of SLE. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 04/2015; 1852(8). DOI:10.1016/j.bbadis.2015.04.019
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    • "Human PDC express Toll-like receptors (TLR), namely TLR-7 and TLR-9 that sense viral single-stranded RNA and unmethylated CpG DNA, respectively (Gilliet et al., 2008). Thus, IFN type I signature is associated with the pathogenesis of several autoimmune diseases such as systemic lupus erythematosus (SLE), psoriasis, Sjögren's syndrome and rheumatoid arthritis (Banchereau and Pascual, 2006; Farkas et al., 2001; Nestle et al., 2005; Ronnblom and Eloranta, 2013). Moreover, PDC can be activated by self-DNA coupled to antimicrobial peptides, a mechanism contributing to the pathogenesis of psoriasis (Lande et al., 2007). "
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    ABSTRACT: Objective Plasmacytoid dendritic cells (PDC) represent a rare subset of dendritic cells specialized in the production of type I IFN in response to microbial pathogens. Recent data suggested that histone deacetylase (HDAC) inhibitors possess potent immunomodulatory properties both in vitro and in vivo. In this study, we assayed the ability of the HDAC inhibitor, valproic acid (VPA), to influence the phenotype and functional properties of human PDC isolated from peripheral blood. Methods and results We showed that VPA inhibited the production of IFN-α and the proinflammatory cytokines TNF-α and IL-6 by CpG-activated PDC. VPA also affected the phenotype of PDC by reducing the expression of costimulatory molecules induced by CpG activation. Moreover, VPA reduced the capacity of CpG-stimulated PDC to promote CD4+ T cell proliferation and IFN-γ production, while enhancing the proportion of IL-10 positive T cells. Conclusion These results suggest that HDAC inhibition by VPA alters essential human PDC functions, highlighting the need for monitoring immune functions in cancer patients receiving HDAC inhibitors, but also making these drugs attractive therapies in inflammatory, and autoimmune diseases implicating PDC.
    Immunobiology 08/2014; DOI:10.1016/j.imbio.2014.03.013
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    • "Taken together, these results suggest that PTPN22*W acts as a hypomorph in myeloid cells, which could explain why it confers protection from certain diseases (eg. Crohn's disease) but cannot explain how it promotes other diseases [32], especially SLE (which is driven by excessive signaling by TLRs and type I IFN production [33]). Monocytes like other innate immune cells sense pathogens via TLRs and other pattern recognition receptors (PRRs) such as the nucleotide-binding and oligomerization domain (NOD)-like receptors (NLR) [34]. "
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    ABSTRACT: PTPN22 is a protein tyrosine phosphatase expressed by the majority of cells belonging to the innate and adaptive immune systems. Polymorphisms in PTPN22 are associated with several autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis and type 1 diabetes. This review discusses the role of PTPN22 in T and B cells, and its function in innate immune cells, such as monocytes, dendritic cells and NK cells. We focus particularly on the complexity that underlies the function of PTPN22 in the biological processes of the immune system; such complexity has led various research groups to produce rather conflicting data.
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