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interferon type I autoimmunities

Andrew Fensome, Catherine M Ambler, Eric Arnold, Mary Ellen Banker, Matthew F Brown, Jill Chrencik, James D Clark, Martin E Dowty, Ivan V Efremov, Andrew Flick, Brian S Gerstenberger, Ariamala Gopalsamy, Matthew M Hayward, Martin Hegen, Brett D Hollingshead, Jason Jussif, John D Knafels, David C Limburg, David Lin, Tsung H Lin, Betsy S Pierce, Eddine Saiah, Raman Sharma, Peter T Symanowicz, Jean-Baptiste Telliez, John I Trujillo, Felix F Vajdos, Fabien Vincent, Zhao-Kui Wan, Li Xing, Xiaojing Yang, Xin Yang, Liying Zhang
Cytokine signaling is an important characteristic of autoimmune diseases. Many pro-inflammatory cytokines signal through the Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) pathway. JAK1 is important for the γ-common chain cytokines, interleukin (IL)-6, and type-I interferon (IFN) family, while TYK2 in addition to type-I IFN signaling also plays a role in IL-23 and IL-12 signaling. Intervention with monoclonal antibodies (mAbs) or JAK1 inhibitors has demonstrated efficacy in Phase III psoriasis, psoriatic arthritis, inflammatory bowel disease, and rheumatoid arthritis studies, leading to multiple drug approvals...
August 16, 2018: Journal of Medicinal Chemistry
Javier A Carrero, Nicholas D Benshoff, Kimberly Nalley, Emil R Unanue
The role of interferons, either pathogenic or protective, during autoimmune diabetes remains controversial. Herein, we examine the progression of diabetes in non-obese diabetic (NOD) mice lacking the type I (IFNAR) or type II (IFNGR) interferon receptors and, for the first time, in mice deficient in both receptors (DKO). All mice were bred, maintained, and monitored in a single specific pathogen-free facility with high female and low male diabetes incidence. Our expectation was that removal of interferon signaling would reduce autoimmune destruction...
July 3, 2018: Diabetes
Paoline Laurent, Vanja Sisirak, Estibaliz Lazaro, Christophe Richez, Pierre Duffau, Patrick Blanco, Marie-Elise Truchetet, Cécile Contin-Bordes
Systemic sclerosis (SSc) is a heterogeneous autoimmune disease characterized by three interconnected hallmarks (i) vasculopathy, (ii) aberrant immune activation, and (iii) fibroblast dysfunction leading to extracellular matrix deposition and fibrosis. Blocking or reversing the fibrotic process associated with this devastating disease is still an unmet clinical need. Although various components of innate immunity, including macrophages and type I interferon, have long been implicated in SSc, the precise mechanisms that regulate the global innate immune contribution to SSc pathogenesis remain poorly understood...
2018: Frontiers in Immunology
Marcos Iglesias, Anirudh Arun, Maria Chicco, Brandon Lam, C Conover Talbot, Vera Ivanova, W P A Lee, Gerald Brandacher, Giorgio Raimondi
Destruction of insulin-producing β-cells by autoreactive T lymphocytes leads to the development of type 1 diabetes. Type-I interferons (TI-IFN) and interleukin-10 (IL-10) have been connected with the pathophysiology of this disease; however, their interplay in the modulation of diabetogenic T cells remains unknown. We have discovered that TI-IFN cause a selective inhibition of IL-10 signaling in effector and regulatory T cells, altering their responses. This correlates with diabetes development in nonobese diabetic mice, where the inhibition is also spatially localized to T cells of pancreatic and mesenteric lymph nodes...
2018: Frontiers in Immunology
João J Oliveira, Sarah Karrar, Daniel B Rainbow, Christopher L Pinder, Pamela Clarke, Arcadio Rubio García, Osama Al-Assar, Keith Burling, Sian Morris, Richard Stratton, Tim J Vyse, Linda S Wicker, John A Todd, Ricardo C Ferreira
BACKGROUND: The molecular heterogeneity of autoimmune and inflammatory diseases has been one of the main obstacles to the development of safe and specific therapeutic options. Here, we evaluated the diagnostic and clinical value of a robust, inexpensive, immunoassay detecting the circulating soluble form of the monocyte-specific surface receptor sialic acid binding Ig-like lectin 1 (sSIGLEC-1). METHODS: We developed an immunoassay to measure sSIGLEC-1 in small volumes of plasma/serum from systemic lupus erythematosus (SLE) patients (n = 75) and healthy donors (n = 504)...
July 27, 2018: Arthritis Research & Therapy
Kumari Anupam, Jyotsana Kaushal, Nirmal Prabhakar, Archana Bhatnagar
Diabetes mellitus is an autoimmune chronic inflammatory disease manifested by hyperglycemia and associated with imbalance in redox status and inflammatory response. Oxidative stress has been reported to affect functions of T cell repertoire- regulatory T cells (Tregs ) and cytotoxic lymphocytes (CTLs). Tregs are involved in prevention against autoreactive T cells and controlling inflammation while CTLs are major mediators of tissue injury. Hence the present study is novel as it contemplates to understand oxidative stress in diabetes vis-à-vis T cells...
October 2018: Immunobiology
Christopher J M Piper, Meredyth G Ll Wilkinson, Claire T Deakin, Georg W Otto, Stefanie Dowle, Chantal L Duurland, Stuart Adams, Emiliano Marasco, Elizabeth C Rosser, Anna Radziszewska, Rita Carsetti, Yiannis Ioannou, Philip L Beales, Daniel Kelberman, David A Isenberg, Claudia Mauri, Kiran Nistala, Lucy R Wedderburn
Juvenile dermatomyositis (JDM) is a rare form of childhood autoimmune myositis that presents with proximal muscle weakness and skin rash. B cells are strongly implicated in the pathogenesis of the disease, but the underlying mechanisms are unknown. Therefore, the main objective of our study was to investigate mechanisms driving B cell lymphocytosis and define pathological features of B cells in JDM patients. Patients were recruited through the UK JDM Cohort and Biomarker study. Peripheral blood B cell subpopulations were immunophenotyped by flow cytometry...
2018: Frontiers in Immunology
David C Thomas
The phagocyte NADPH oxidase is a multi subunit protein complex that generates reactive oxygen species at cell membranes and within phagosomes. It is essential for host defence as evidenced by the severe immunodeficiency syndrome caused by a loss of one of the subunits. This is known as chronic granulomatous disease (CGD). However, the phagocyte NADPH oxidase also has a key role to play in regulating immunity and it is notable that chronic granulomatous disease is also characterised by autoimmune and autoinflammatory manifestations...
June 25, 2018: Free Radical Biology & Medicine
Yasuhiro Kato, JeongHoon Park, Hyota Takamatsu, Hachirou Konaka, Wataru Aoki, Syunsuke Aburaya, Mitsuyoshi Ueda, Masayuki Nishide, Shohei Koyama, Yoshitomo Hayama, Yuhei Kinehara, Toru Hirano, Yoshihito Shima, Masashi Narazaki, Atsushi Kumanogoh
OBJECTIVE: Despite the importance of type I interferon (IFN-I) in systemic lupus erythematosus (SLE) pathogenesis, the mechanisms of IFN-I production have not been fully elucidated. Recognition of nucleic acids by DNA sensors induces IFN-I and interferon-stimulated genes (ISGs), but the involvement of cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) and stimulator of interferon genes (STING) in SLE remains unclear. We studied the role of the cGAS-STING pathway in the IFN-I-producing cascade driven by SLE serum...
June 26, 2018: Annals of the Rheumatic Diseases
Junlong Zhang, Xinle Liu, Yanming Meng, Hengxu Wu, Yongkang Wu, Bin Yang, Lanlan Wang
Systemic lupus erythematosus (SLE) has heterogeneous clinical manifestations. IFIH1 (interferon induced with helicase C domain 1) as one of antiviral helicase genes mediating type I interferon production, plays an essential role in the pathogenesis of SLE. The gene variants in IFIH1 could abnormally activate antiviral defenses and increased type I interferon signaling. The present study aimed to validate associations between single nucleotide polymorphisms (SNP) in IFIH1 and the pathogenesis of SLE. In total, rs1990760, rs3747517 and rs10930046 in IFIH1 are genotyped in 400 SLE patients and 659 health controls in Chinese cohort by an improved multiplex ligation detection reaction (iMLDR) technique...
June 21, 2018: Scientific Reports
Casper Marsman, Fanny Lafouresse, Yang Liao, Tracey M Baldwin, Lisa A Mielke, Yifang Hu, Matthias Mack, Paul J Hertzog, Carolyn A de Graaf, Wei Shi, Joanna R Groom
Plasmacytoid dendritic cells (pDCs) play a critical role in bridging the innate and adaptive immune systems. pDCs are specialized type I interferon (IFN) producers, which has implicated them as initiators of autoimmune pathogenesis. However, little is known about the downstream effectors of type I IFN signaling that amplify autoimmune responses. Here, we have used a chemokine reporter mouse to determine the CXCR3 ligand responses in DCs subsets. Following TLR7 stimulation, conventional type 1 and type 2 DCs (cDC1 and cDC2, respectively) uniformly upregulate CXCL10...
June 5, 2018: Immunology and Cell Biology
Justine Calise, Susana Marquez Renteria, Peter K Gregersen, Betty Diamond
Interferon regulatory factor 5 (IRF5) is widely recognized as a risk locus for systemic lupus erythematosus (SLE). Risk gene and IRF5 activation is triggered through toll-like receptor signaling. In myeloid cells, this leads to production of type I interferon and inflammatory cytokines, with enhanced production in cells of individuals harboring IRF5 risk alleles. Mouse models have also demonstrated the importance of IRF5 in B cell function, particularly plasma cell differentiation and isotype switching. Here, we evaluated the major SLE risk haplotype of IRF5 on the functional attributes of freshly isolated B cells from human subjects who do not have evidence of SLE or other forms of autoimmunity...
2018: Frontiers in Immunology
Tatsuma Ban, Go R Sato, Tomohiko Tamura
The transcription factor interferon regulatory factor-5 (IRF5) plays an important role in innate immune responses via the TLR-MyD88 (Toll-like receptor - myeloid differentiation primary response 88) pathway. IRF5 is also involved in the pathogenesis of the autoimmune disease systemic lupus erythematosus (SLE). Recent studies have identified new regulators, both positive and negative, which act on IRF5 activation events in the TLR-MyD88 pathway such as post-translational modifications, dimerization and nuclear translocation...
May 31, 2018: International Immunology
Antonio Puccetti, Piera Filomena Fiore, Andrea Pelosi, Elisa Tinazzi, Giuseppe Patuzzo, Giuseppe Argentino, Francesca Moretta, Claudio Lunardi, Marzia Dolcino
Behçet disease (BD) is a chronic inflammatory multisystem disease characterized by oral and genital ulcers, uveitis, and skin lesions. Disease etiopathogenesis is still unclear. We aim to elucidate some aspects of BD pathogenesis and to identify specific gene signatures in peripheral blood cells (PBCs) of patients with active disease using novel gene expression and network analysis. 179 genes were modulated in 10 PBCs of BD patients when compared to 10 healthy donors. Among differentially expressed genes the top enriched gene function was immune response, characterized by upregulation of Th17-related genes and type I interferon- (IFN-) inducible genes...
2018: Journal of Immunology Research
Rebecca L Ambrose, Yu Chih Liu, Timothy E Adams, Andrew G D Bean, Cameron R Stewart
Host recognition of intracellular viral RNA and subsequent induction of cytokine signaling are tightly regulated at the cellular level and are a target for manipulation by viruses and therapeutics alike. Here, we characterize chromosome 6 ORF 106 (C6orf106) as an evolutionarily conserved inhibitor of the innate antiviral response. C6orf106 suppresses the synthesis of interferon (IFN)-α/β and proinflammatory tumor necrosis factor (TNF) α in response to the dsRNA mimic poly(I:C) and to Sendai virus infection...
July 6, 2018: Journal of Biological Chemistry
Jie An, Joshua J Woodward, Weinan Lai, Mark Minie, Xizhang Sun, Lena Tanaka, Jessica M Snyder, Tomikazu Sasaki, Keith B Elkon
OBJECTIVE: Type I interferon (IFN-I) is strongly implicated in the pathogenesis of Systemic Lupus Erythematosus (SLE) as well as rare monogenic 'interferonopathies' such as Aicardi-Goutieres Syndrome (AGS) caused by mutations in the DNA exonuclease, TREX1. The DNA-activated IFN-I pathway, cyclic GMP-AMP (cGAMP) synthase (cGAS), is linked to subsets of AGS and lupus. We identified inhibitors of DNA-cGAS interaction and tested lead candidate, X6, in a mouse model of AGS. METHODS: Trex1-/- mice were treated orally from birth with either X6 or HCQ for 8 weeks...
May 21, 2018: Arthritis & Rheumatology
Sunetra Sase, Asako Takanohashi, Adeline Vanderver, Akshata Almad
Aicardi-Goutières syndrome (AGS) is an early-onset, autoimmune and genetically heterogeneous disorder with severe neurologic injury. Molecular studies have established that autosomal recessive mutations in one of the following genes are causative: TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1 and IFIH1/MDA5. The phenotypic presentation and pathophysiology of AGS is associated with over-production of the cytokine Interferon-alpha (IFN-α) and its downstream signaling, characterized as type I interferonopathy...
May 2018: Brain Pathology
Chi-Chien Lin, Jung-Ju Wu, Yi-Gen Pan, Ya-Hsuan Chao, Fang-Chu Lin, Ying-Ray Lee, Ching-Liang Chu
BACKGROUND: Gold lotion (GL), a natural mixed product made from the peels of six citrus fruits, has recently been identified as possessing anti-oxidative, anti-inflammatory, and immunomodulatory effects. GL has been used to protect skin against UV-induced damage, but its activity against psoriasis, a chronic autoimmune skin disease caused by dysregulation between immune cells and keratinocytes, is not known. We therefore evaluated the effect of GL on imiquimod (IMQ)-induced psoriasis-like inflammation in mice...
April 24, 2018: Journal of the Science of Food and Agriculture
Marc Bienias, Normi Brück, Constanze Griep, Christine Wolf, Stefanie Kretschmer, Barbara Kind, Victoria Tüngler, Reinhard Berner, Min Ae Lee-Kirsch
To review recent scientific advances and therapeutic approaches in the expanding field of type I interferonopathies. Type I interferonopathies represent a genetically and phenotypically heterogenous group of disorders of the innate immune system caused by constitutive activation of antiviral type I interferon (IFN). Clinically, type I interferonopathies are characterized by autoinflammation and varying degrees of autoimmunity or immunodeficiency. The elucidation of the underlying genetic causes has revealed novel cell-intrinsic mechanisms that protect the organism against inappropriate immune recognition of self nucleic acids by cytosolic nucleic acid sensors...
April 20, 2018: Current Rheumatology Reports
Iris L A Bodewes, Erika Huijser, Cornelia G van Helden-Meeuwsen, Liselotte Tas, Ruth Huizinga, Virgil A S H Dalm, P Martin van Hagen, Noortje Groot, Sylvia Kamphuis, Paul L A van Daele, Marjan A Versnel
OBJECTIVE: Upregulation of type I interferons (IFN-I) is a hallmark of systemic autoimmune diseases like primary Sjögren's syndrome (pSS), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). Expression of IFN-I is induced by three different receptor families: Toll-like receptors (TLRs), RIG-like receptors (RLRs) and DNA-sensing receptors (DSRs). TANK-binding kinase (TBK1) is an important signaling hub downstream of RLRs and DSRs. TBK1 activates IRF3 and IRF7, leading to IFN-I production and subsequent induction of interferon stimulated genes (ISGs)...
July 2018: Journal of Autoimmunity
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