Interferon regulatory factors: critical mediators of human lupus

Jensen, Mark A.; Niewold, Timothy B.

doi:10.1016/j.trsl.2014.10.002

Cited by 33 publications

(24 citation statements)

References 145 publications

(123 reference statements)

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“…Detection of cytosolic DNA also promotes the type I IFNs production via activation of the ISD pathway, now known as the cGAS-STING-TBK1-IRF3 pathway [36, 37]. In this pathway cyclic GMP-AMP synthase (cGAS) senses DNA in a sequence-independent manner and signals via the adaptor stimulator of interferon genes (STING) to activate the interferon regulatory factor 3 (IRF3) [44, 45], a member of the IRF-family of transcription factors that participate at the interface of innate and adaptive immune responses [46, 47]. Activation of IRF3 promotes transcription of Ifnb gene [48, 49].…”

Section: Pyhin-family Proteins In Sensing Cytosolic Dna and Regulamentioning

confidence: 99%

Absent in Melanoma 2 proteins in SLE

Choubey

Panchanathan

2017

Clinical Immunology

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Type I interferons (IFN-α/β)-inducible PYRIN and HIN domain-containing protein family includes Absent in Melanoma 2 (murine Aim2 and human AIM2), murine p202, and human PYRIN-only protein 3 (POP3). The generation of Aim2-deficient mice indicated that the Aim2 protein is essential for inflammasome activation, resulting in the secretion of interleukin-1β (IL-1β) and IL-18 and cell death by pyroptosis. Further, Aim2-deficiency also increased constitutive expression of the IFN-β and expression of the p202 protein. Notably, an increased expression of p202 protein in female mice associated with the development of systemic lupus erythematosus (SLE). SLE in patients is characterized by a constitutive increase in serum levels of IFN-α and an increase in the expression IFN-stimulated genes. Recent studies indicate that p202 and POP3 proteins inhibit activation of the Aim2/AIM2 inflammasome and promote IFN-β expression. Therefore, we discuss the role of Aim2/AIM2 proteins in the suppression of type I IFNs production and lupus susceptibility.

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Section: Pyhin-family Proteins In Sensing Cytosolic Dna and Regulamentioning

confidence: 99%

Absent in Melanoma 2 proteins in SLE

Choubey

Panchanathan

2017

Clinical Immunology

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“…Additionally they play prominent role in cytokine secretion, cellular apoptosis, immune cell development, tumor suppression, and cell activation and differentiation [38, 39]. Interestingly, genetic variations in three of the nine IRFs (IRF5, IRF7, and IRF8) have been linked to SLE susceptibility, supporting a key role for this family of proteins in SLE pathogenesis.…”

Section: Polygenic Influences On Type I Ifnmentioning

confidence: 99%

“…The same risk variant has been associated with autoantibody formation in SLE patients and in healthy individuals, and most of the risk of SLE related to IRF5 genotype is found within the autoantibody positive, high IFN group of patients [42, 43]. IRF7 is another IRF family member which also interacts with the MyD88 adaptor protein downstream of TLR signaling, and is phosphorylated and activated following TLR engagement [38]. Genetic variants in the IRF7 locus have been associated with SLE in various studies [37, 44, 45].…”

Section: Polygenic Influences On Type I Ifnmentioning

confidence: 99%

Immunogenetics of systemic lupus erythematosus: A comprehensive review

Ghodke‐Puranik

Niewold

2015

Journal of Autoimmunity

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192

126

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Summary Our understanding of the genetic basis of systemic lupus erythematosus has progressed rapidly in recent years. While many genetic polymorphisms have been associated with disease susceptibility, the next major step involves integrating these genetic polymorphisms into the molecular mechanisms and cellular immunology of the human disease. In this review, we summarize some recent work in this area, including the genetics of the type I IFN response in SLE, including polygenic and monogenic factors, as well as epigenetic influences. Contributions of both HLA and non-HLA polymorphisms to the complex genetics of SLE are reviewed. We also review recent reports of specific gene deficits leading to monogenic SLE-like syndromes. The molecular functions of common SLE-risk variants are reviewed in depth, including regulatory variations in promoter and enhancer elements and coding-change polymorphisms, and studies which are beginning to define the molecular and cellular functions of these polymorphisms in the immune system. We discuss epigenetic influences on lupus, with an emphasis on micro-RNA expression and binding, as well as epigenetic modifications that regulate the expression levels of various genes involved in SLE pathogenesis and the ways epigenetic marks modify SLE susceptibility genes. The work summarized in this review provides a fascinating window into the biology and molecular mechanisms of human SLE. Understanding the functional mechanisms of causal genetic variants underlying the human disease greatly facilitates our ability to translate genetic associations toward personalized care, and may identify new therapeutic targets relevant to human SLE disease mechanisms.

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“…SLE patients may have an impaired clearance of apoptotic cells, and the antinuclear autoantibodies that characterize SLE can bind with this dead cellular debris, forming nucleic acid-containing immune complexes. Antiviral TLRs can be activated by these self DNA/RNA-containing immune complexes, resulting activation of interferon regulatory factors and the production of type I IFN and other cytokines (98). …”

Section: Recent Developments In Sle Therapymentioning

confidence: 99%

Drugs in early clinical development for Systemic Lupus Erythematosus

Postal

Sinicato

Appenzeller

et al. 2016

Expert Opinion on Investigational Drugs

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Introduction While immunosuppressive therapy has positively impacted the prognosis of systemic lupus erythematosus (SLE), many patients still do not respond to traditional therapy. Thus, active SLE disease remains a significant problem. Furthermore, conventional immunosuppressive treatments for SLE are associated a high risk of side effects. These issues call for improvement in our current therapeutic armamentarium. Areas covered In this review, the authors highlight the recent developments in therapies for SLE, and present an overview of drugs which are in early clinical development for SLE. There are many new therapeutic approaches being developed, including those focused on B-cell targets, T-cell downregulation, co-stimulatory blockade, anti-cytokine agents, and kinase inhibition, and Toll-like receptor inhibition. They also discuss peptide therapy as a potential method to re-establish immune tolerance, and some of the challenges ahead in developing and testing novel agents for SLE. Expert opinion Many novel agents are currently in development for SLE, but this encouraging news is tempered by several disappointments in clinical trials and provides a timely moment to reflect on the future of therapeutic development in SLE. It seems likely that biological heterogeneity between patients is a major contributor to difficulty in drug design in SLE.

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Interferon regulatory factors: critical mediators of human lupus

Cited by 33 publications

References 145 publications

Absent in Melanoma 2 proteins in SLE

Absent in Melanoma 2 proteins in SLE

Immunogenetics of systemic lupus erythematosus: A comprehensive review

Drugs in early clinical development for Systemic Lupus Erythematosus

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