WDFY4 deficiency in NOD mice ameliorates autoimmune diabetes and insulitis

The events that initiate autoimmune diabetes in nonobese diabetic (NOD) mice remain poorly understood. CD

RSV replication is attenuated by counteracting expression of the suppressor of cytokine signaling (SOCS) molecules

AbstractHuman RSV causes an annual epidemic of respiratory tract illness in infants and in elderly. Mechanisms by which RSV antagonizes IFN-mediated antiviral responses include inhibition of type I IFN mRNA transcription and blocking signal transduction of JAK/STAT family members. The suppressor of cytokines signaling (SOCS) gene family utilizes a feedback loop to inhibit cytokine responses and block the activation of the JAK/STAT signaling pathway. To evaluate the potential of SOCS molecules to subvert the innate immune response to RSV infection, eight SOCS family genes were examined. RSV infection up-regulated SOCS1, SOCS3, and CIS mRNA expression in HEp-2 cells. Suppression of SOCS1, SOCS3 and CIS by short interfering ribonucleic acid (siRNA) inhibited viral replication. Furthermore, inhibition of SOCS1, SOCS3, or CIS activated type I IFN signaling by inducing STAT1/2 phosphorylation. These results suggest that RSV infection escapes the innate antiviral response by inducing SOCS1, SOCS3 or CIS expression in epithelial cells

Citrullinated Inhibitor of DNA Binding 1 Is a Novel Autoantigen in Rheumatoid Arthritis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150530/1/art40886_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150530/2/art40886.pd

Inflammatory properties of inhibitor of DNA binding 1 secreted by synovial fibroblasts in rheumatoid arthritis

Abstract Background Inhibitor of DNA binding 1 (Id1) is a nuclear protein containing a basic helix-loop-helix (bHLH) domain that regulates cell growth by selective binding and prevention of gene transcription. Sources of Id1 production in rheumatoid arthritis synovial tissue (RA ST) and its range of functional effects in RA remain to be clarified. Methods We analyzed Id1 produced from synovial fibroblasts and endothelial cells (ECs) with histology and real-time polymerase chain reaction (RT-PCR). Fibroblast supernatants subjected to differential centrifugation to isolate and purify exosomes were measured for Id1 by enzyme-linked immunosorbent assay (ELISA). Western blotting of Id1-stimulated ECs was performed to determine the kinetics of intracellular protein phosphorylation. EC intracellular signaling pathways induced by Id1 were subsequently targeted with silencing RNA (siRNA) for angiogenesis inhibition. Results By PCR and histologic analysis, we found that the primary source of Id1 in STs is from activated fibroblasts that correlate with inflammatory scores in human RA ST and in joints from K/BxN serum-induced mice. Normal (NL) and RA synovial fibroblasts increase Id1 production with stimulation by transforming growth factor beta (TGF-β). Most of the Id1 released by RA synovial fibroblasts is contained within exosomes. Endothelial progenitor cells (EPCs) and human dermal microvascular ECs (HMVECs) activate the Jnk signaling pathway in response to Id1, and Jnk siRNA reverses Id1-induced HMVEC vessel formation in Matrigel plugs in vivo. Conclusions Id1 is a pleotropic molecule affecting angiogenesis, vasculogenesis, and fibrosis. Our data shows that Id1 is not only an important nuclear protein, but also can be released from fibroblasts via exosomes. The ability of extracellular Id1 to activate signaling pathways expands the role of Id1 in the orchestration of tissue inflammation.http://deepblue.lib.umich.edu/bitstream/2027.42/134552/1/13075_2016_Article_984.pd

IL-6 selectively suppresses cDC1 specification via C/EBPβ

Cytokines produced in association with tumors can impair antitumor immune responses by reducing the abundance of type 1 conventional dendritic cells (cDC1), but the mechanism remains unclear. Here, we show that tumor-derived IL-6 generally reduces cDC development but selectively impairs cDC1 development in both murine and human systems through the induction of C/EBPβ in the common dendritic cell progenitor (CDP). C/EBPβ and NFIL3 compete for binding to sites in the Zeb2 -165 kb enhancer and support or repress Zeb2 expression, respectively. At homeostasis, pre-cDC1 specification occurs upon Nfil3 induction and consequent Zeb2 suppression. However, IL-6 strongly induces C/EBPβ expression in CDPs. Importantly, the ability of IL-6 to impair cDC development is dependent on the presence of C/EBPβ binding sites in the Zeb2 -165 kb enhancer, as this effect is lost in Δ1+2+3 mutant mice in which these binding sites are mutated. These results explain how tumor-associated IL-6 suppresses cDC1 development and suggest therapeutic approaches preventing abnormal C/EBPβ induction in CDPs may help reestablish cDC1 development to enhance antitumor immunity

T Helper 1 Cellular Immunity Toward Recoverin Is Enhanced in Patients With Active Autoimmune Retinopathy

Autoimmune retinopathy (AIR) causes rapidly progressive vision loss that is treatable but often is confused with other forms of retinal degeneration including retinitis pigmentosa (RP). Measurement of anti-retinal antibodies (ARA) by Western blot is a commonly used laboratory assay that supports the diagnosis yet does not reflect current disease activity. To search for better diagnostic indicators, this study was designed to compare immune biomarkers and responses toward the retinal protein, recoverin, between newly diagnosed AIR patients, slow progressing RP patients and healthy controls. All individuals had measurable anti-recoverin IgG and IgM antibodies by ELISA regardless of disease status or Western blot results. Many AIR patients had elevated anti-recoverin IgG1 levels and a strong cellular response toward recoverin dominated by IFNγ. RP patients and controls responded to recoverin with a lower IFNγ response that was balanced by IL-10 production. Both AIR and RP patients displayed lower levels of total peripheral blood mononuclear cells that were due to reductions of CD4+ TH cells. A comparison of messenger RNA (mRNA) for immune-related genes in whole blood of AIR patients versus RP patients or controls indicated lower expression of ATG5 and PTPN22 and higher expression of several genes involved in TH cell signaling/transcription and adhesion. These data indicate that an immune response toward recoverin is normal in humans, but that in AIR patients the balance shifts dramatically toward higher IFNγ production and cellular activation

A unique role for galectin-9 in angiogenesis and inflammatory arthritis

Abstract Background Galectin-9 (Gal-9) is a mammalian lectin secreted by endothelial cells that is highly expressed in rheumatoid arthritis synovial tissues and synovial fluid. Roles have been proposed for galectins in the regulation of inflammation and angiogenesis. Therefore, we examined the contribution of Gal-9 to angiogenesis and inflammation in arthritis. Methods To determine the role of Gal-9 in angiogenesis, we performed human dermal microvascular endothelial cell (HMVEC) chemotaxis, Matrigel tube formation, and mouse Matrigel plug angiogenesis assays. We also examined the role of signaling molecules in Gal-9-induced angiogenesis by using signaling inhibitors and small interfering RNA (siRNA). We performed monocyte (MN) migration assays in a modified Boyden chamber and assessed the arthritogenicity of Gal-9 by injecting Gal-9 into mouse knees. Results Gal-9 significantly increased HMVEC migration, which was decreased by inhibitors of extracellular signal-regulating kinases 1/2 (Erk1/2), p38, Janus kinase (Jnk), and phosphatidylinositol 3-kinase. Gal-9 HMVEC-induced tube formation was reduced by Erk1/2, p38, and Jnk inhibitors, and this was confirmed by siRNA knockdown. In mouse Matrigel plug assays, plugs containing Gal-9 induced significantly higher angiogenesis, which was attenuated by a Jnk inhibitor. Gal-9 also induced MN migration, and there was a marked increase in MN ingress when C57BL/6 mouse knees were injected with Gal-9 compared with the control, pointing to a proinflammatory role for Gal-9. Conclusions Gal-9 mediates angiogenesis, increases MN migration in vitro, and induces acute inflammatory arthritis in mice, suggesting a novel role for Gal-9 in angiogenesis, joint inflammation, and possibly other inflammatory diseases.https://deepblue.lib.umich.edu/bitstream/2027.42/142380/1/13075_2018_Article_1519.pd

RAPID: Resource of Asian Primary Immunodeficiency Diseases

Availability of a freely accessible, dynamic and integrated database for primary immunodeficiency diseases (PID) is important both for researchers as well as clinicians. To build a PID informational platform and also as a part of action to initiate a network of PID research in Asia, we have constructed a web-based compendium of molecular alterations in PID, named Resource of Asian Primary Immunodeficiency Diseases (RAPID), which is available as a worldwide web resource at http://rapid.rcai.riken.jp/. It hosts information on sequence variations and expression at the mRNA and protein levels of all genes reported to be involved in PID patients. The main objective of this database is to provide detailed information pertaining to genes and proteins involved in primary immunodeficiency diseases along with other relevant information about protein–protein interactions, mouse studies and microarray gene-expression profiles in various organs and cells of the immune system. RAPID also hosts a tool, mutation viewer, to predict deleterious and novel mutations and also to obtain mutation-based 3D structures for PID genes. Thus, information contained in this database should help physicians and other biomedical investigators to further investigate the role of these molecules in PID

Cortical gamma-oscillations modulated by auditory–motor tasks-intracranial recording in patients with epilepsy

Human activities often involve hand-motor responses following external auditory–verbal commands. It has been believed that hand movements are predominantly driven by the contralateral primary sensorimotor cortex, whereas auditory–verbal information is processed in both superior temporal gyri. It remains unknown whether cortical activation in the superior temporal gyrus during an auditory–motor task is affected by laterality of hand-motor responses. Here, event-related Γ-oscillations were intracranially recorded as quantitative measures of cortical activation; we determined how cortical structures were activated by auditory-cued movement using each hand in 15 patients with focal epilepsy. Auditory–verbal stimuli elicited augmentation of Γ-oscillations in a posterior portion of the superior temporal gyrus, whereas hand-motor responses elicited Γ-augmentation in the pre- and postcentral gyri. The magnitudes of such Γ-augmentation in the superior temporal, precentral, and postcentral gyri were significantly larger when the hand contralateral to the recorded hemisphere was required to be used for motor responses, compared with when the ipsilateral hand was. The superior temporal gyrus in each hemisphere might play a greater pivotal role when the contralateral hand needs to be used for motor responses, compared with when the ipsilateral hand does. Hum Brain Mapp, 2010. © 2010 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78227/1/20963_ftp.pd

Induction of PPM1D following DNA-damaging treatments through a conserved p53 response element coincides with a shift in the use of transcription initiation sites

PPM1D (Wip1), a type PP2C phosphatase, is expressed at low levels in most normal tissues but is overexpressed in several types of cancers. In cells containing wild-type p53, the levels of PPM1D mRNA and protein increase following exposure to genotoxic stress, but the mechanism of regulation by p53 was unknown. PPM1D also has been identified as a CREB-regulated gene due to the presence of a cyclic AMP response element (CRE) in the promoter. Transient transfection and chromatin immunoprecipitation experiments in HCT116 cells were used to characterize a conserved p53 response element located in the 5′ untranslated region (UTR) of the PPM1D gene that is required for the p53-dependent induction of transcription from the human PPM1D promoter. CREB binding to the CRE contributes to the regulation of basal expression of PPM1D and directs transcription initiation at upstream sites. Following exposure to ultraviolet (UV) or ionizing radiation, the abundance of transcripts with short 5′ UTRs increased in cells containing wild-type p53, indicating increased utilization of downstream transcription initiation sites. In cells containing wild-type p53, exposure to UV resulted in increased PPM1D protein levels even when PPM1D mRNA levels remained constant, indicating post-transcriptional regulation of PPM1D protein levels