Medicine and Health Sciences Commons^™

Using Pet Imaging To Track Sting-Induced Interferon Signaling, Enitome E. Bafor, Howard A. Young

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In the 19th century, Ilya Metchnikoff defined and broadened our initial understanding of phagocytosis and, in 1908, went on to show that a cellular component (i.e., DNA) stimulates immune responses (1). About a century later, Janeway conceptualized pattern recognition receptors (PRRs) and pathogen-associated molecular patterns (PAMPs) (2). Since then, we know that PAMP recognition by innate immune cells via PRRs activates the production of several cytokines, including interferons (IFNs), with the eventual recruitment of lymphocytes. Subsequent research discovered that innate immune recognition of double-stranded DNA (dsDNA) triggers autoimmune diseases (3). However, before the discovery of dsDNA sensors, an endoplasmic reticulum …

Cytokines: From Clinical Significance To Quantification, Chao Liu, Dewei Chu, Kourosh Kalantar-Zadeh, Jacob George, Howard A. Young, Guozhen Liu

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Cytokines are critical mediators that oversee and regulate immune and inflammatory responses via complex networks and serve as biomarkers for many diseases. Quantification of cytokines has significant value in both clinical medicine and biology as the levels provide insights into physiological and pathological processes and can be used to aid diagnosis and treatment. Cytokines and their clinical significance are introduced from the perspective of their pro- and anti-inflammatory effects. Factors affecting cytokines quantification in biological fluids, native levels in different body fluids, sample processing and storage conditions, sensitivity to freeze-thaw, and soluble cytokine receptors are discussed. In addition, recent advances …

Promise And Complexity Of Lupus Mouse Models, Erica Moore, Joshua A. Reynolds, Anne Davidson, Stefania Gallucci, Laurence Morel, Deepak A. Rao, Howard A. Young, Chaim Putterman

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As a follow up to a 2010 meeting deliberating on the benefits of studying mouse models of systemic lupus erythematosus (SLE), the virtual conference “Mouse models of lupus 10 years later” convened on 10 December 2020 to address a challenging decade that saw few new therapies approved, despite leaps in knowledge

Abnormalities in both innate and adaptive immunity characterize SLE, a systemic autoimmune disease with potentially severe consequences in patients. Treatment has traditionally been limited to broad-acting, side-effect-heavy immunosuppressants, which are also incompletely effective. Thus, the need for specific therapies targeting the pathogenic mechanisms of SLE remains unmet. Affirming the …

The Experts Speak: A New Feature In The Jicr, Michael Gale, Ram Savan, Adolfo Garcia-Sastre, Ludmila Prokunina-Olsso, Kuppusamy Balamurugan, Howard A. Young

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This month we launch a new feature in the JICR: The Experts Speak. This feature is designed to provide first-hand insight from topical experts in the fields of interferon, cytokines, innate immunity, and adaptive immune actions of cytokine biology in disease. We start by asking experts to comment on interferon, cytokines, and SARS-CoV-2.

Lessons Learned: New Insights On The Role Of Cytokines In Covid-19, Maja Buszko, Aleksandra Nita-Lazar, Jung Hyun Park, Pamela L. Schwartzberg, Daniela Verthelyi, Howard A. Young, Amy S. Rosenberg

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In the midst of resurging COVID-19 cases, the second NIH/FDA virtual COVID-19 and Cytokines symposium was held on 1 December 2020, focusing on longitudinal studies of COVID-19 immunity, including long-term consequences, potential associations with autoimmunity and the multisystem inflammatory syndrome in children (MIS-C).

A central and ongoing quest in COVID-19 research is to establish why and how SARS-CoV-2 elicits heterogeneity in disease severity and immunopathology among infected individuals. Hence, much effort has been exerted to understand the cellular basis of SARS-CoV-2-induced immune responses, with the aim of identifying new biomarkers and prognostic tools and developing new therapeutic options. Cytokines emerged …

Discussion Of “Is Group Testing Ready For Prime-Time In Disease Identification?” By Haber, Malinovsky, And Albert, Statistics In Medicine, 2021, Brad J. Biggerstaff

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I congratulate the authors on an interesting, instructive, and timely paper. Certainly, including the testing for SARS-CoV-2 example in a paper on a topic—group testing—of wide interest during the current COVID-19 pandemic emphasizes the relevance of the topic in public health and diagnostic medicine generally. But the thoughtful inclusion of the remaining examples—HIV, HPV, and cancer biomarker detection—illustrates that the issues considered are important even in less urgent times. In this note of discussion I will comment on two particular aspects in the paper that I found particularly informative, and then I will comment on two other, related areas that …

Natural Killer Cell Transcript 4 Promotes The Development Of Sjӧgren's Syndrome Via Activation Of Rap1 On B Cells, Peng Qu, Todd Wuest, Yongfen Min, Ilias Alevizos, Howard A. Young, P. Charles Lin

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Autoimmune disorders are the third most common diseases in the United States, and affect the daily lives of millions of people. In this study, we analyzed patient samples, utilized a transgenic mouse model and human B cells to reveal Natural Killer Cell Transcript 4 (NK4) as a novel regulator that promotes the development of autoimmune disorders. NK4 was significantly elevated in samples from patients with Sjӧgren's Syndrome (SS). SS patients show elevated NK4 levels. There is a strong and positive correlation between the increased levels of NK4 and the duration of SS. Interestingly, transgenic expression of NK4 in a mouse …

Ifnγ Is A Key Link Between Obesity And Th1-Mediated Autoimmune Diseases, Heekyong R. Bae, Myung-Sook Choi, Suntae Kim, Howard A. Young, M E. Gershwin, Seon Min Jeon, Eun Young Kwon

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Obesity, a characteristic of metabolic syndrome, is also associated with chronic inflammation and the development of autoimmune diseases. However, the relationship between obesity and autoimmune diseases remains to be investigated in depth. Here, we compared hepatic gene expression profiles among high-fat diet (HFD) mice using the primary biliary cholangitis (PBC) mouse model based on the chronic expression of interferon gamma (IFNγ) (ARE-Del-/- mice). The top differentially expressed genes affected by upstream transcriptional regulators IFNγ, LPS, and TNFα displayed an overlap in HFD and ARE-Del-/- mice, indicating that obesity-induced liver inflammation may be dependent on signaling via IFNγ. The top pathways …

The Dynamic Changes In Cytokine Responses In Covid-19: A Snapshot Of The Current State Of Knowledge, Maja Buszko, Jung Hyun Park, Daniela Verthelyi, Ranjan Sen, Howard A. Young, Amy S. Rosenberg

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The role of cytokines in COVID-19” online symposium was presented on 18 June 2020 by the NIH/FDA Immunology and Cytokine Interest Groups and was purposed to discuss our rapidly changing understanding of COVID-19-related cytokine responses in different stages of infection, including the etiologies, downstream consequences and possible mitigation strategies.

The symposium was opened by Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases at the US National Institutes of Health (NIAID, NIH), and Janet Woodcock, Director of the Center of Drug Evaluation and Research, Food and Drug Administration (CDER, FDA) and currently leading the therapeutics component of …

Perforin-Deficient Car T Cells Recapitulate Late-Onset Inflammatory Toxicities Observed In Patients, Kazusa Ishii, Marie Pouzolles, Christopher D. Chien, Rebecca A. Erwin-Cohen, M. Eric Kohler, Haiying Qin, Haiyan Lei, Skyler Kuhn, Amanda K. Ombrello, Alina Dulau-Florea, Michael A. Eckhaus, Haneen Shalabi, Bonnie Yates, Daniel A. Lichtenstein, Valérie S. Zimmermann, Taisuke Kondo, Jack F. Shern, Howard A. Young, Naomi Taylor, Nirali N. Shah, Terry J. Fry

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Late-onset inflammatory toxicities resembling hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) occur after chimeric antigen receptor T cell (CAR T cell) infusion and represent a therapeutic challenge. Given the established link between perforin deficiency and primary HLH, we investigated the role of perforin in anti-CD19 CAR T cell efficacy and HLH-like toxicities in a syngeneic murine model. Perforin contributed to both CD8+ and CD4+ CAR T cell cytotoxicity but was not required for in vitro or in vivo leukemia clearance. Upon CAR-mediated in vitro activation, perforin-deficient CAR T cells produced higher amounts of proinflammatory cytokines compared with WT CAR …

Dynamics Of Genomic And Immune Responses During Primary Immunotherapy Resistance In Mismatch Repair–Deficient Tumors, Nobuyuki Takahashi, Vinodh N. Rajapakse, Lorinc Pongor, Suresh Kumar, Camille Tlemsani, Rebecca Erwin-Cohen, Howard A. Young, Stephen Hewitt, Jun S. Wei, Javed Khan, Alejandro V. Villarino, Jane B. Trepel, Anish Thomas

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Mismatch repair–deficient (dMMR) cancers generate a substantial number of immunogenic neoantigens, rendering them sensitive to immunotherapy. Yet, there is considerable variability in responses, and roughly one-half of dMMR cancers are refractory to immunotherapy. Here we study a patient with dMMR lung cancer refractory to immunotherapy. The tumor exhibited typical dMMR molecular features, including exceptionally high frameshift insertions and deletions (indels). Despite the treatment inducing abundant intratumoral T-cell infiltrates, it failed to elicit tumor regression, pointing to the T cells lacking cytotoxic activity. A post-treatment tumor demonstrated compound heterozygous frameshift deletions located upstream of the kinase domain in the gene encoding …

The Gut Microbiome And Xenobiotics: Identifying Knowledge Gaps, Vicki L. Sutherland, Charlene A. Mcqueen, Donna Mendrick, Donna Gulezian, Carl Cerniglia, Steven Foley, Sam Forry, Sangeeta Khare, Xue Liang, Jose E. Manautou, Donald Tweedie, Howard A. Young, Alexander V. Alekseyenko, Frank Burns, Rod Dietert, Alan Wilson, Connie Chen

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There is an increasing awareness that the gut microbiome plays a critical role in human health and disease, but mechanistic insights are often lacking. In June 2018, the Health and Environmental Sciences Institute (HESI) held a workshop, "The Gut Microbiome: Markers of Human Health, Drug Efficacy and Xenobiotic Toxicity" (https://hesiglobal.org/event/the-gut-microbiome-workshop) to identify data gaps in determining how gut microbiome alterations may affect human health. Speakers and stakeholders from academia, government, and industry addressed multiple topics including the current science on the gut microbiome, endogenous and exogenous metabolites, biomarkers, and model systems. The workshop presentations and breakout group discussions formed the …

Multi-Omics: Differential Expression Of Ifn-Γ Results In Distinctive Mechanistic Features Linking Chronic Inflammation, Gut Dysbiosis, And Autoimmune Diseases, Heekyong R. Bae, Patrick S.C. Leung, Deborah L. Hodge, John M. Fenimore, Seon Min Jeon, Vishal Thovarai, Amiran Dzutsev, Andrew A. Welcher, Michael Boedigheimer, Michael A. Damore, Myung Sook Choi, Richard A. Fravell, Giorgio Trinchieri, M. Eric Gershwin, Howard A. Young

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Low grade, chronic inflammation is a critical risk factor for immunologic dysfunction including autoimmune diseases. However, the multiplicity of complex mechanisms and lack of relevant murine models limit our understanding of the precise role of chronic inflammation. To address these hurdles, we took advantage of multi-omics data and a unique murine model with a low but chronic expression of IFN-γ, generated by replacement of the AU-rich element (ARE) in the 3’ UTR region of IFN-γ mRNA with random nucleotides. Herein, we demonstrate that low but differential expression of IFN-γ in mice by homozygous or heterozygous ARE replacement triggers distinctive gut …

Multistate Mumps Outbreak Originating From Asymptomatic Transmission At A Nebraska Wedding — Six States, August–October 2019, Matthew Donahue, Blake Hendrickson, Derek Julian, Nicholas Hill, Julie Rother, Samir Koirala, Joshua L. Clayton, Thomas Safranek, Bryan Buss

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In August 2019, 30 attendees at a Nebraska wedding developed mumps after being exposed to one asymptomatic index patient who was fully vaccinated according to Advisory Committee on Immunization Practices (ACIP) recommendations (1), resulting in a multistate outbreak. A public health investigation and response revealed epidemiologic links that extended from the index patient through secondary, tertiary, and quaternary patients and culminated in a measles-mumpsrubella (MMR) booster vaccination campaign in the local community where approximately half of the patients resided.

On The Inadequacy Of Species Distribution Models For Modelling The Spread Of Sars-Cov-2: Response To Araújo And Naimi, Joseph D. Chipperfield, Blas M. Benito, Robert B. O'Hara, Richard J. Telford, Colin J. Carlson

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The ongoing pandemic of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing significant damage to public health and economic livelihoods, and is putting significant strains on healthcare services globally. This unfolding emergency has prompted the preparation and dissemination of the article “Spread of SARS-CoV-2 Coronavirus likely to be constrained by climate” by Araújo and Naimi (2020). The authors present the results of an ensemble forecast made from a suite of species distribution models (SDMs), where they attempt to predict the suitability of the climate for the spread of SARS-CoV-2 over the coming months. They argue that climate is …

Evaluating Gene Drive Approaches For Public Benefit, Michael R. Santos

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Gene drive approaches—those which bias inheritance of a genetic element in a population of sexually reproducing organisms—have the potential to provide important public benefits. The spread of selected genetic elements in wild populations of organisms may help address certain challenges, such as transmission of vector-borne human and animal diseases and biodiversity loss due to invasive animals. Adapting various naturally occurring gene drive mechanisms to these aims is a long-standing research area, and recent advances in genetics have made engineering gene drive systems significantly more technically feasible. Gene drive approaches would act through changes in natural environments, thus robust methods to …

Adaptive In Vivo Device For Theranostics Of Inflammation: Real-Time Monitoring Of Interferon-Γ And Aspirin, Chaomin Cao, Ronghua Jin, Hui Wei, Zhongning Liu, Shengnan Ni, Guo Jun Liu, Howard A. Young, Xin Chen, Guozhen Liu

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Cytokines mediate and control immune and inflammatory responses. Complex interactions exist among cytokines, inflammation, and the innate and adaptive immune responses in maintaining homeostasis, health, and well-being. On-demand, local delivery of anti-inflammatory drugs to target tissues provides an approach for more effective drug dosing while reducing the adverse effects of systemic drug delivery. This work demonstrates a proof-of-concept theranostic approach for inflammation based on analyte-kissing induced signaling, whereby a drug (in this report, aspirin) can be released upon the detection of a target level of a proinflammatory cytokine (i.e., interferon-γ (IFN-γ)) in real time. The structure-switching aptamer-based biosensor described here …

Meeting Overview: Interferon Lambda - Disease Impact And Therapeutic Potential, Thomas R. O'Brien, Howard A. Young, Raymond P. Donnelly, Ludmila Prokunina-Olsson

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A meeting entitled, "Interferon Lambda: Disease Impact and Translational Potential," was held on the campus of the National Institutes of Health in Bethesda, Maryland, on October 25-26, 2018. To our knowledge, this was the first meeting that focused exclusively on interferon lambda (IFN-λ). The meeting's purpose was to enhance interdisciplinary communication and promote new collaborations. The gathering brought together an international group of scientists from a wide range of disciplines. Sessions included: IFN-λ Biology, Therapy and Genetic Variation; IFN-λ and Hepatitis C Virus Infection; IFN-λ in Other Infections; and IFN-λ - Hepatic Fibrosis and Cancer. The next meeting on IFN-λ …

Post–Modern Epidemiology: When Methods Meet Matter, George Davey Smith

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In the last third of the 20th century, etiological epidemiology within academia in high-income countries shifted its primary concern from attempting to tackle the apparent epidemic of noncommunicable diseases to an increasing focus on developing statistical and causal inference methodologies. This move was mutually constitutive with the failure of applied epidemiology to make major progress, with many of the advances in understanding the causes of noncommunicable diseases coming from outside the discipline, while ironically revealing the infectious origins of several major conditions. Conversely, there were many examples of epidemiologic studies promoting ineffective interventions and little evident attempt to account for …

Durvalumab In Combination With Olaparib In Patients With Relapsed Sclc: Results From A Phase Ii Study, Anish Thomas, Rasa Vilimas, Christopher Trindade, Rebecca Erwin-Cohen, Nitin Roper, Liqiang Xi, Venkatesh Krishnasamy, Elliot Levy, Andy Mammen, Samantha Nichols, Yuanbin Chen, Vamsidhar Velcheti, Faye Yin, Eva Szabo, Yves Pommier, Seth M. Steinberg, Jane B. Trepel, Mark Raffeld, Howard A. Young, Javed Khan, Stephen Hewitt, Jung Min Lee

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Purpose: Despite high tumor mutationburden, immune checkpoint blockade has limited efficacy in SCLC. We hypothesized that poly (ADP-ribose) polymerase inhibition could render SCLC more susceptible to immune checkpoint blockade. Methods: A single-arm, phase II trial (NCT02484404) enrolled patients with relapsed SCLC who received durvalumab, 1500 mg every 4 weeks, and olaparib, 300 mg twice a day. The primary outcome was objective response rate. Correlative studies included mandatory collection of pretreatment and during-treatment biopsy specimens, which were assessed to define SCLC immunephenotypes: desert (CD8-positive T-cell prevalence low), excluded (CD8-positive T cells in stroma immediately adjacent/within tumor), and inflamed (CD8-positive T cells …

Ion Gresser 1928-2019, Jan Vilcek, Howard A. Young

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Ion Gresser, a virologist who transformed understanding of the roles of interferons, may be best remembered for showing that in mice, interferon-α (IFN-α) can produce acute and chronic disease. At the time Gresser began these studies, interferon was considered to be a selective antiviral substance, harmless to uninfected cells and organisms, and there was no indication that cytokines would play a role in pathogenesis. That belief was shattered with the 1975 Nature publication with the simple title “Lethality of interferon preparations for newborn mice.” Gresser subsequently demonstrated that antibodies to IFN-α can protect young mice from death caused by infection …

Ifn-Γ: A Cytokine At The Right Time, Is In The Right Place, J. Daniel Burke, Howard A. Young

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Interferon gamma has long been studied as a critical mediator of tumor immunity. In recent years, the complexity of cellular interactions that take place in the tumor microenvironment has become better appreciated in the context of immunotherapy. While checkpoint inhibitors have dramatically improved remission rates in cancer treatment, IFN-Γ and related effectors continue to be identified as strong predictors of treatment success. In this review, we provide an overview of the multiple immunosuppressive barriers that IFN-Γ has to overcome to eliminate tumors, and potential avenues for modulating the immune response in favor of tumor rejection.

Report On The 2018 Cancer, Autoimmunity, And Immunology Conference, Colleen S. Curran, Connie L. Sommers, Howard A. Young, Katarzyna Bourcier, Marie Mancini, Elad Sharon

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With the increased use of cancer immunotherapy, a number of immune-related adverse events (irAEs) are being identified. These irAEs can be compared with known autoimmune disorders in similar tissues, with important similarities and differences. Understanding the etiology of irAEs may bring to light concepts applicable to immune responses in cancer, autoimmunity, and infectious disease. This immunobiology is especially relevant to cancer patients with preexisting allogeneic transplants or autoimmune disease who are undergoing cancer immunotherapy. To address these facets of cancer immunotherapy, academic leaders from these various disciplines discussed current irAE basic and clinical research, irAE diagnosis and management, and the …

Critical Role Of Post-Transcriptional Regulation For Ifn-Γ In Tumor-Infiltrating T Cells, Fiamma Salerno, Aurelie Guislain, Julian J. Freen-Van Heeren, Benoit P. Nicolet, Howard A. Young, Monika C. Wolkers

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Protective T cell responses against tumors require the production of Interferon gamma (IFN-γ). However, tumor-infiltrating T cells (TILs) gradually lose their capacity to produce IFN-γ and therefore fail to clear malignant cells. Dissecting the underlying mechanisms that block cytokine production is thus key for improving T cell products. Here we show that although TILs express substantial levels of Ifng mRNA, post-transcriptional mechanisms impede the production of IFN-γ protein due to loss of mRNA stability. CD28 triggering, but not PD1 blocking antibodies, effectively restores the stability of Ifng mRNA. Intriguingly, TILs devoid of AU-rich elements within the 3ʹuntranslated region maintain stabilized …

Partners In Crime: Fledgling Tumors Hijack Inflammation, Balamurugan Kuppusamy, Howard A. Young

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While inflammation is a normal physiological response after tissue injury, the chemicals/mediators that are released by the damaged tissue can be toxic to the cells. This underlying inflammation increases the likelihood of cellular DNA damage and aberrant cell growth (Kiraly and others 2015). In this scenario, inflammation functions as a ‘‘behind-curtain factor’’ for many disorders. Cancer has long been known to be closely tethered to inflammation. Widespread evidence shows that inflammatory diseases such as colitis, pancreatitis, and hepatitis make their respective organs highly susceptible to eventual cancer development (Shalapour and Karin 2015). However, other studies have shown that in due …

Thymic Expression Of Il-4 And Il-15 After Systemic Inflammatory Or Infectious Th1 Disease Processes Induce The Acquisition Of"Innate" Characteristics During Cd8 + T Cell Development, Natalia S. Baez, Fabio Cerbán, Constanza Savid-Frontera, Deborah L. Hodge, Jimena Tosello, Eva Acosta-Rodriguez, Laura Almada, Adriana Gruppi, Maria Estefania Viano, Howard A. Young, Maria Cecilia Rodriguez-Galan

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Innate CD8 + T cells express a memory-like phenotype and demonstrate a strong cytotoxic capacity that is critical during the early phase of the host response to certain bacterial and viral infections. These cells arise in the thymus and depend on IL-4 and IL-15 for their development. Even though innate CD8 + T cells exist in the thymus of WT mice in low numbers, they are highly enriched in KO mice that lack certain kinases, leading to an increase in IL-4 production by thymic NKT cells. Our work describes that in C57BL/6 WT mice undergoing a Th1 biased infectious disease, …

Translational Repression Of Pre-Formed Cytokine-Encoding Mrna Prevents Chronic Activation Of Memory T Cells, Fiamma Salerno, Sander Engels, Maartje Van Den Biggelaar, Floris P.J. Van Alphen, Aurelie Guislain, Wanqi Zhao, Deborah L. Hodge, Sarah E. Bell, Jan Paul Medema, Marieke Von Lindern, Martin Turner, Howard A. Young, Monika C. Wolkers

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Memory T cells are critical for the immune response to recurring infections. Their instantaneous reactivity to pathogens is empowered by the persistent expression of cytokine-encoding mRNAs. How the translation of proteins from pre-formed cytokine-encoding mRNAs is prevented in the absence of infection has remained unclear. Here we found that protein production in memory T cells was blocked via a 3′ untranslated region (3′ UTR)-mediated process. Germline deletion of AU-rich elements (AREs) in the Ifng-3′ UTR led to chronic cytokine production in memory T cells. This aberrant protein production did not result from increased expression and/or half-life of the mRNA. Instead, …

Interferon-Gamma Impairs Maintenance And Alters Hematopoietic Support Of Bone Marrow Mesenchymal Stromal Cells, Marieke Goedhart, Anne S. Cornelissen, Carlijn Kuijk, Sulima Geerman, Marion Kleijer, Jaap D. Van Buul, Stephan Huveneers, Marc H.G.P. Raaijmakers, Howard A. Young, Monika C. Wolkers, Carlijn Voermans, Martijn A. Nolte

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Bone marrow (BM) mesenchymal stromal cells (MSCs) provide microenvironmental support to hematopoietic stem and progenitor cells (HSPCs). Culture-expanded MSCs are interesting candidates for cellular therapies due to their immunosuppressive and regenerative potential which can be further enhanced by pretreatment with interferon-gamma (IFN-γ). However, it remains unknown whether IFN-γ can also influence hematopoietic support by BM-MSCs. In this study, we elucidate the impact of IFN-γ on the hematopoietic support of BM-MSCs. We found that IFN-γ increases expression of interleukin (IL)-6 and stem cell factor by human BM-MSCs. IFN-γ-treated BM-MSCs drive HSPCs toward myeloid commitment in vitro, but impair subsequent differentiation of …

Tipsheet: Student Mental Health And Resources, Unl Office Of The Executive Vice Chancellor

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Stress, depression, anxiety, alcohol abuse, eating disorders, and other mental health challenges affect at least 1 in 5 college students*. Faculty can be an important source of support for UNL students. Here are some strategies for supporting student mental health:

1. Communicate the importance of mental health. Mental health is just as important as physical health. When someone breaks a leg they go to the hospital. Mental illness is the same thing. If someone is feeling depressed they should seek treatment. Normalize mental health by talking about getting support if you notice your students struggling with stress, depression, anxiety, etc. …

The Interplay Of Type I And Type Ii Interferons In Murine Autoimmune Cholangitis As A Basis For Sex-Biased Autoimmunity, Heekyong R. Bae, Deborah L. Hodge, Guo Xiang Yang, Patrick S.C. Leung, Sathi Babu Chodisetti, Julio C. Valencia, Michael Sanford, John M. Fenimore, Ziaur S.M. Rahman, Koichi Tsuneyama, Gary L. Norman, M E. Gershwin, Howard A. Young

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We have reported on a murine model of autoimmune cholangitis, generated by altering the AU-rich element (ARE) by deletion of the interferon gamma (IFN-γ) 3' untranslated region (coined ARE-Del−/−), that has striking similarities to human primary biliary cholangitis (PBC) with female predominance. Previously, we suggested that the sex bias of autoimmune cholangitis was secondary to intense and sustained type I and II IFN signaling. Based on this thesis, and to define the mechanisms that lead to portal inflammation, we specifically addressed the hypothesis that type I IFNs are the driver of this disease. To accomplish these goals, we crossed ARE-Del−/− …