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: 21.56). 10/2006; 25(3):383-92. DOI: 10.1016/j.immuni.2006.08.010
Source: PubMed


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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    • "Further, dysregulation of innate and adaptive immune responses is central to the development of pathogenic autoantibodies in the development of autoimmune diseases such as SLE (Pisetsky, 2008; Mu~ noz et al., 2010; Tsokos, 2011). Additionally, increased serum levels of type I interferon (IFN-a) and increased expression of the IFN-inducible genes (the " IFN-signature " ) in most SLE patients and certain mouse models are associated with the severity of the disease (Baechler et al., 2004; Banchereau and Pascual, 2006; Lu et al., 2007). BPA, an environmental estrogen and an endocrine disruptor, is widely used in the manufacture of polycarbonate plastics and epoxy resins found in food containers (Rao and Richardson, 1999; Melnick et al., 2002; vom Saal et al., 2007; Cooper et al., 2008). "
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    ABSTRACT: Environmental factors contribute to the development of autoimmune diseases, including systemic lupus erythematosus (SLE), which exhibits a strong female bias (female-to-male ratio 9:1). However, the molecular mechanisms remain largely unknown. Because a feedforward loop between the female sex hormone estrogen (E2) and type I interferon (IFN-α/β)-signaling induces the expression of certain p200-family proteins (such as murine p202 and human IFI16) that regulate innate immune responses and modify lupus susceptibility, we investigated whether treatment of myeloid cells with bisphenol A (BPA), an environmental estrogen, could regulate the p200-family proteins and activate innate immune responses. We found that treatment of murine bone marrow-derived cells (BMCs) and human peripheral blood mononuclear cells with BPA induced the expression of ERα and IFN-β, activated the IFN-signaling, and stimulated the expression of the p202 and IFI16 proteins. Further, the treatment increased levels of the NLRP3 inflammasome and stimulated its activity. Accordingly, BPA-treatment of BMCs from non lupus-prone C57BL/6 and the lupus-prone (NZB x NZW)F1 mice activated the type I IFN-signaling, induced the expression of p202, and activated an inflammasome activity. Our study demonstrates that BPA-induced signaling in the murine and human myeloid cells stimulates the type I IFN-signaling that results in an induction of the p202 and IFI16 innate immune sensors for the cytosolic DNA and activates an inflammasome activity. These observations provide novel molecular insights into the role of environmental BPA exposures in potentiating the development of certain autoimmune diseases such as SLE. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Full-text · Article · Aug 2015 · Molecular and Cellular Endocrinology
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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.
    Full-text · Article · Apr 2015 · Biochimica et Biophysica Acta
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    • "A caveat with these studies is that not all members of the IFN-I family were compared. Thirdly, IFN-Is can cause numerous adverse side-effects and induce autoimmunity (e.g., lupus, thyroiditis, diabetes, dermatitis, Sjogren’s syndrome, and arthritis) especially in patients with a history of autoimmune manifestations (114). The autoimmune outcomes in these settings are thought to be a combination of tolerogenic immune function failures and IFN-I mediated maturation of DCs that present autoantigens to activate autoreactive T cells and B cells that make autoantibodies (115). "
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    ABSTRACT: It has been well-established that type I interferons (IFN-Is) have pleiotropic effects and play an early central role in the control of many acute viral infections. However, their pleiotropic effects are not always beneficial to the host and in fact several reports suggest that the induction of IFN-Is exacerbate disease outcomes against some bacterial and chronic viral infections. In this brief review, we probe into this mystery and try to develop answers based on past and recent studies evaluating the roles of IFN-Is in infection and immunity as this is vital for developing effective IFN-Is based therapeutics and vaccines. We also discuss the biological roles of an emerging IFN-I, namely IFN-ε, and discuss its potential use as a mucosal therapeutic and/or vaccine adjuvant. Overall, we anticipate the discussions generated in this review will provide new insights for better exploiting the biological functions of IFN-Is in developing efficacious therapeutics and vaccines in the future.
    Full-text · Article · Aug 2014 · Frontiers in Immunology
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