bluuebunny/crossref_metadata_2025_split huggingface dataset:
Type 2 Diabetes Increased the Risk of Hyposmia in COVID-19 Mild Pneumonia Patients by Suppressing Nasal Immunity
Authors: Zhang Jun , Tao Ye , Xu Zhaohui , Liu Yehai 
Published: February 2023

Abstract
Type 2 diabetes mellitus (T2DM) can impair the function of nasal-associated lymphoid tissue (NALT) and result in olfactory dysfunction in patients with COVID-19. Exploring the causative alterations of T2DM within the nasal mucosa and NALT could provide insight into the pathogenic mechanisms and fill the knowledge gap between innate immunity and adaptive immunity for virus clearance. Here, a case-control study was used to compare the olfactory function (OF) among the groups of normal control (NC), COVID-19 mild pneumonia (MP), and MP patients with T2DM (MPT) after a 6–8 months’ recovery. Our clinical data suggested that MPT had a higher risk of hyposmia than MP and NC. No significant difference was found between the MP and NC. This elevated risk of hyposmia indicated that T2DM increased COVID-19 susceptibility in the nasal cavity. Furthermore, T2DM animal model (db/db mice) was used to evaluate how T2DM increased COVID-19 associated susceptibilities in the nasal mucosa and lymphoid tissues. Our animal data demonstrated upregulated microvasculature ACE2 expression and significant alterations in lymphocytes component of NALT. Specifically, db/db mice NALT had increased immune-suppressive TCRγδ+CD4-CD8- T and decreased immune-effective CD4+/CD8+TCRβ+ T cells and decreased mucosa-protective CD19+ B cells. These results indicated that T2DM increased the risk of hyposmia and COVID-19 susceptibility in the nasal cavity by suppressing the first-line defense of nasal immunity.
Functional characterization of a self-replicating and genetically tractable murine alveolar macrophage model
Authors: Thomas Sean M , Wierenga Kathryn , Pestka James , Olive Andrew J 
Published: February 2023

Abstract
Alveolar macrophages (AMs) are a critical element of the innate immune response to inhaled agents, yet functional and genetic studies of this unique macrophage population are lacking. Current strategies to obtain large quantities of AMs are cumbersome and inefficient. This is due largely to both the high cost of time and resources involved in the extraction of AMs and the inability to effectively culture AMs ex vivo for extended periods of time. While bone marrow derived macrophages (BMDMs) are modeled in numerous immortalized cell lines, AMs currently lack an acceptable model that can be used in vitro. Recently, self-replicating cells derived from the fetal mouse liver, termed “MPI” cells, have been shown to possess AM-like characteristics. Here, we show that early after isolation, these cells are SiglecFhi, Cd11chi, and Cd14low, while also expressing high levels of Pparg, Marco, Itgax, and Car4, akin to AMs. Additionally, like AMs, MPI cells effectively efferocytose dead cell debris and phagocytose silica particles. While these cells lose their “AM-likeness” over time, addition of the cytokine TGF-β dramatically delays this shift away from the AM-like phenotype. Gene expression analysis shows that in contrast to cells treated with TGF-β, untreated MPI cells cease expressing Tgfbr1, the receptor for TGF-β, concurrent with the shift away from the AM-phenotype. Further, these cells are amenable to viral transduction, and we have successfully employed CRISPR/Cas9 targeted genetic editing in MPI cells. These findings further our understanding of MPI cells as an accessible and genetically tractable model for AMs that allow for long-term and large-scale studies that are not possible with AMs isolated ex vivo.
ATG16L1 deficiency exacerbates acute small intestinal epithelial damage.
Authors: Foerster Elisabeth G , Streutker Catherine J , Philpott Dana J 
Published: February 2023

Abstract
Polymorphisms of the autophagy-related gene ATG16L1 are known to contribute to the genetic risk for developing Crohn’s Disease (CD), an inflammatory bowel disease that can affect the entire gastrointestinal tract. Previous studies have shown a role for autophagy in the intestinal epithelium both in Paneth cell function and in protection from intestinal damage, but no spontaneous disease at baseline. Here, we challenged mice specifically deleted for Atg16l1 in intestinal epithelial cells (Atg16l1ΔIEC) with the anti-CD3 mediated model of acute small intestinal injury. Rapid T cell activation by anti-CD3 injection results in small intestinal damage within 24 hours of injection, this typically self-resolves in wild-type mice 5 days post treatment. We found that autophagy sufficiency was protective in anti-CD3 induced injury. Atg16l1ΔIEC mice had higher mortality and worsened pathology in comparison to their wild-type littermates. We found indications of increased intestinal barrier permeability and crypt cell apoptosis in Atg16l1ΔIEC mice. In addition, expression of interferon gamma (IFNγ) and tumour necrosis factor (TNF) was significantly increased in Atg16l1ΔIEC mice, cytokines that have been implicated in driving intestinal injury in autophagy-deficient mice. Antibody-mediated blockade of either TNF or IFNγ rescued survival of Atg16l1ΔIEC mice. Interestingly, anti-IFNγ abolished both the crypt cell apoptosis and Paneth cell death at 24 hours, whereas anti-TNF did not decrease the crypt cell apoptosis or Paneth cell death, suggesting IFNγ is the primary contributor to pathology in this model. Overall, this work implicates intestinal epithelial autophagy in the protective response to acute intestinal injury.
Blocking IL1, IL33 and IL36 signaling by an anti-IL1RAP antibody is an efficient anti-inflammatory treatment that improves heart function in a model of autoimmune myocarditis
Authors: Rattik Sara , Jakobsson Gabriel , Grönberg Caitriona , Birkedal Gabriel Svensson , Millrud Camilla Rydberg , Thuring Camilla , Pettersson Nina Fransén , Falk Hanna Håkansson , Schiopu Alexandru , Liberg David 
Published: February 2023

Abstract
The IL1 receptor accessory protein (IL1RAP) is a coreceptor for the IL1, IL33, and IL36 receptors. We have developed a fully humanized antibody (CAN10) that binds IL1RAP with high affinity and disrupts IL1α, IL1β, IL33, IL36α, IL36β and IL36γ signaling without inducing ADCC. CAN10 is currently undergoing preclinical development in preparation for clinical studies.
The efficacy of IL1RAP-blockade as an anti-inflammatory treatment was investigated in a mouse model of acute peritonitis (i.p injection of MSU crystals). A CAN10 surrogate (mCAN10) decreased the recruitment of neutrophils and monocytes to the peritoneum as well as the production of e.g IL6 and KC. Blocking only IL1α/β had similar effects but notably, mCAN10 also induced additional anti-inflammatory responses including reductions in e.g IL5 and eotaxin. In addition, mCAN10, but not anti-IL1β, reduced skin inflammation in a mouse model of psoriasis. Taken together, these results indicate that blocking IL1RAP is a potent anti-inflammatory strategy that is qualitatively different from blocking IL1α/β alone.
IL1, IL33 and IL36 may have disease promoting roles in myocarditis, an inflammatory heart disease with no available treatment. Therefore, we investigated if IL1RAP blockade can counteract inflammation and decline in heart function in a model of autoimmune myocarditis (EAM). EAM was induced by immunizing Balb/C mice with αMHC peptide on day 0 and 7. Treatment with mCAN10 or isotype control started day 7 and heart function was analyzed by echocardiography at days 0, 28 and 42. Interestingly, anti-inflammatory treatment with mCAN10 potently counteracted the decline in heart function. These studies highlight the potential of blocking IL1RAP to treat inflammatory diseases.
Use of an Orally Delivered Oxysterol, a Lipid Membrane-Order (Lo) Disruptor, to Relieve IBD Symptoms in IL-10 Deficient Mouse Model
Authors: Lawrence Audrey Pearl , Bamezai Anil K 
Published: February 2023

Abstract
Inflammatory bowel disease (IBD) is a life-long condition that currently has no cure. Existing treatments fail in a significant proportion of IBD patients who are either nonresponsive to treatment or lose their initial responsiveness to these therapies over time. Genetic susceptibility of an individual in combination with environmental triggers can contribute to inflammation in the gastrointestinal (GI) tract and disease onset. Increasingly, microbiome composition is considered critical for chronic disease expression; IBD patients show altered microbiome composition as compared to healthy individuals. While IBD is of unknown explicit cause, disease etiology is perpetrated by the heightened response of immune cells (T, Innate Lymphoid, Natural Killer, B) and their secreted mediators interacting with the GI tract’s epithelial cells. Given the complexity of IBD and involvement of multiple cell types in triggering and fueling inflammation, we have tested the effectiveness of 7-Ketocholesterol (7-KC), an oxysterol, to treat IBD symptoms in IL-10 gene-deficient mice. 7-KC is known to disrupt membrane order in cells and inhibit cellular responses. IL-10 knockout mice gavaged with 7-KC show significant reduction in inflammatory gut pathology. Examination of the microbiome composition using metagenomic shotgun sequencing showed restoration of microbiome constitution in treated mice that was comparable to the normal non-disease wildtype mouse. These preliminary findings shed light on the potential for 7-KC in treating IBD symptoms. Mechanism of 7-KC action, either its effects on the microbiota and/or gut immune/non-immune cell membrane for its immune suppressing effect is currently under investigation.
Deficiency in B Cell Maturation Antigen reveals sex differences in Experimental Autoimmune Encephalomyelitis
Authors: Kumar Gaurav , Ko Rose M. , Bhatt Neal , Axtell Robert C. 
Published: February 2023

Abstract
Multiple sclerosis (MS) is immune mediated demyelinating disease of the central nervous system (CNS) leading to neuronal damage. The disease is heterogeneous with respect to onset and clinical course, being more prevalent in women then in men with a ratio of 3:1. Further sex differences have been observed with males having a more severe and debilitating disease course compared to females. The complex interplay of immune cells, sex hormones or genetic differences could be contributing to these clinical phenomena, which remains to be elucidated. In experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, several reports have demonstrated no sex differences in disease onset or severity in C57BL/6 mice. Herein we report that deficiency in B Cell Maturation Antigen (BCMA) in C57BL/6 mice reveals a sex difference in EAE. BCMA plays a prominent role in B cell function, however the role BCMA plays in MS and EAE is unknown. Our initial goal of this project was to determine the impact BCMA deficiency has on EAE. In doing so we confirmed that EAE disease was not different in males and females from BCMA+/+mice. Strikingly in the BCMA−/− mice, there was a significant increase in EAE disease severity in males compared to females. The increased EAE in the BCMA−/− male mice was associated with increased demyelination and infiltration of inflammatory T cells and macrophages into CNS. Also, we observed decreased splenic transitional B cells in male BCMA−/− mice compared to females. Castration of mice significantly reduces EAE in BCMA−/− mice as compared to sham controls. Altogether, our data demonstrate that male hormones exacerbates EAE in BCMA−/− mice by augmenting inflammatory responses compared to females leading to increased neuro-inflammation.
CD40 on B cells and on dendritic cells mediates experimental autoimmune encephalomyelitis pathogenesis through distinct and complementary mechanisms
Authors: Lu Ying , Xu Max , Zhang Ray , Wagner David H , Hodes Richard 
Published: February 2023

Abstract
Costimulatory CD40 plays an essential role in autoimmune disease models including experimental autoimmune encephalomyelitis (EAE), a murine model of human multiple sclerosis (MS). However, the mechanism underlying CD40 function are not well defined in these processes. Conditional knockout of CD40 on either dendritic cells (DCs) or B cells led to profoundly reduced severity of EAE induced by recombinant human MOG (rhMOG). CD40 expression on DCs, but not on B cells, was required for priming of pathogenic T helper (Th) cells in peripheral draining lymph nodes and for appearance of these pathogenic T cells in the CNS. In marked contrast, CD40 on B cells, but not on DCs, was essential for class-switched MOG-specific antibody production. The distinct function of CD40 on B cells and DC was confirmed by the ability of transferred MOG-immune serum to restore sensitivity to EAE in mice lacking CD40 on B cells but not in mice lacking CD40 on DC. Thus, CD40 expressed on B cells and on DC provides distinct and complementary pathways essential for EAE pathogenesis, providing multiple targets for intervention in EAE, and potentially for MS and other autoimmune diseases.
Evaluating the Effects of Intestinal Bacteria’s Production of GABA Neurotransmitter on an Animal Model of Multiple Sclerosis
Authors: Kohl Hannah Marie , Hoffman Kristina , Staben Kendall , Shi Xutong , Long Tyrel , Castillo Andrea , Gibson K. Michael , Roullet Jean-Baptiste , Ochoa-Repáraz Javier 
Published: February 2023

Abstract
Past studies show that the production of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, by gut bacteria is decreased in patients with multiple sclerosis (MS). Furthermore, the administration of GABAergic compounds ameliorates the progression of experimental autoimmune encephalomyelitis (EAE), a murine model of MS. We investigated whether modifying the microbiota of mice with GABA-producing bacteria reduced the severity of EAE. We genetically modified a Lactococcus lactis with increased copies of the genes encoding the enzyme glutamic acid decarboxylase (GAD), which synthesizes GABA, and the GABA/glutamate antiporter (GadC). This modified L. lactis strain (GAD-L. lactis) produced significantly increased GABA, measured by ELISA, compared to control L. lactis strain, with an unmodified plasmid (P-L. lactis). These strains were compared with sham treatment as probiotic treatments against EAE. EAE-induced C57BL/6 mice were divided into three groups: sham group (EAE induced, treated with autoclaved media; n = 10); EAE mice treated with P-L. lactis (n = 10); and EAE mice treated with GAD-L. lactis (n = 10). The treatments occurred five times a week via oral gavage (5 x 108 CFU/mouse). The oral administration of GAD-L. lactis significantly reduced the severity of EAE and body weight loss during disease, compared to both the P-L. lactis and sham groups. Our results indicate that oral treatment with a probiotic strain that produces enhanced GABA levels protects against the progression of CNS demyelination. Immunophenotyping studies will help us understand the mechanism of action of GAD-L. lactis and its potential as a novel approach to treat autoimmune disorders.
ST8Sia6 expression in beta cells mitigates onset of autoimmune diabetes in the murine NOD model
Authors: Choe Justin , Belmonte Paul , Rajcula Matthew , McCue Shaylene , Shapiro Michael J , Shapiro Virginia 
Published: February 2023

Abstract
Cell surface hypersialylation is used by malignant cells as a survival mechanism, leveraging interactions with inhibitory Siglec receptors to dampen immune rejection. In this study, we harnessed this mechanism to prevent autoimmune rejection of beta cells in the context of Type 1 Diabetes. Mice were engineered to express the sialyltransferase ST8Sia6 in a beta cell specific manner (βST mice) and crossed to the non-obese diabetic (NOD) mouse model of spontaneous autoimmune diabetes. Both female and male littermates on the NOD background developed diabetes by 300 days (56% and 80.8%, respectively). βST mice, however, demonstrated minimal occurrence of disease (5.3% and 16.6%). Additionally, histologic analysis of pancreas sections from non-diabetic βST and littermate mice suggested a similar degree of immune infiltration at 4 and 8 weeks of age, but the severity of infiltration was drastically reduced only in the βST mice at 20 weeks of age. IHC for various leukocyte markers suggested no difference in composition of immune infiltrates at the 8 week time point. To determine whether protection was due to central or peripheral mechanisms, euglycemic βST and littermate mice at 16 weeks of age were challenged with anti-PD-L1 monoclonal antibodies; both groups resulted in similar induction of disease, suggesting that ST8Sia6 dependent protection occurs peripherally. Physiologically, an insulin tolerance test demonstrated no difference between βST mice and littermates, suggesting no systemic effects of beta cell ST8Sia6 expression. The induced expression of ST8Sia6 has been shown to mitigate autoimmune attack in the NOD mouse and presents a novel path forward for improving the success of curative islet transplant into diabetic patients.
BT-11 (omilancor), a first-in-class, topical therapeutic for psoriasis, ameliorates disease severity and inflammation through activation of LANCL2 pathway
Authors: Tubau-Juni Nuria , Leber Andrew , Hontecillas Raquel , Chauhan Jyoti , Bassaganya-Riera Josep 
Published: February 2023

Abstract
BT-11 (omilancor) is a small molecule therapeutic that activates the LANCL2 pathway in immune and epithelial cells, resulting in regulatory effects at the intersection of immunity and metabolism. LANCL2 modulates the plasticity between Th17 and regulatory T cells (Tregs), favoring the stability and suppressive capacity of Tregs. Given the implication of the LANCL2 pathway in autoimmune disease and the demonstrated clinical efficacy and safety of BT-11 in a Phase 2 clinical trial of UC, we evaluated the therapeutic efficacy of BT-11 in psoriasis. In an imiquimod-induced mouse model of psoriasis, pharmacological activation of LANCL2 through topical BT-11 treatment ameliorates disease severity, resulting in over 60% reduction of PASI score. Indeed, BT-11 treatment decreased acanthosis and immune cell infiltration, with no signs of parakeratosis. The loss of LANCL2 in mice resulted in increased hyperkeratosis and parakeratosis. Local LANCL2 activation by BT-11 resulted in decreased TNF, IL17, IL6 and IL21-producing cells in the spleen. Additionally, LANCL2 activation regulated keratinocyte metabolism and function. Keratinocytes from BT-11-treated mice presented lower metabolic activation, reported as decreased ATP production, mitochondrial respiration and glucose metabolism. In translational studies with human PBMCs, BT-11 modulated the metabolic profile of CD4+ T cells at late state glycolysis, favoring oxidative pathways, and decreased expression of proinflammatory cytokines (IFNγ, TNFα), while upregulating IL-10. These results merit further exploration into the implication of LANCL2 signaling in human psoriasis and leverages the development of BT-11, as a first-in-class, topical therapeutic for psoriasis.
Development and characterization of new swine immune reagents to understand immune correlates for vaccines, infection, and biomedical research outcomes
Authors: Gourapura Renukaradhya J , Loving Crystal L , Kenney Scott , LaBresh Joanna , Patil Veerupaxagouda , Byrne Kristen , Walker Kristen , Dai Chaohui , Hailstock Taylor , Lunney Joan K 
Published: February 2023

Abstract
The USDA-NIFA Swine Immune Toolkit Initiative has a goal to generate priority immune reagents, based on inputs from veterinary immunology researchers worldwide, and pipeline them for marketing. Our efforts are aimed at expression of soluble proteins and production of panels of monoclonal antibodies (mAbs) using collaborations with commercial partners for protein expression and mAb production. Generation of new panels of mAbs reactive with porcine IL-5 and IL-21 have been initiated. Panels of mAbs to IL-6, IL-13, IL-17A, IL-28B, CXCL10, and BAFF are being screened for their reactivity in multiple immune assays. Reactivity tests of labeled anti-IL-6, -IL-17A, -IL-13 and -CXCL10 mAbs for intracellular staining of porcine myeloid and T cells using flow cytometry-based assays are in progress. Sensitive sandwich ELISA assays are now available for IL-17A, IL-13 and CXCL10; other targets are being screened for best mAb pairs for such assays. Planning for the generation of SLA-I & -II tetramers to identify swine CD4 and CD8 T cells specific for influenza virus peptides has been initiated. For each target, our goal is to provide the veterinary community with new commercial reagents and standardized techniques using these reagents for their research efforts. Tools and reagents generated by this project will undoubtedly advance swine immune, disease, vaccine, and biomedical research efforts.
Avian-specific immune reagents and immunoassays to analyze poultry immune response
Authors: Lillehoj Hyun S , Kim Woohyun , Lu Mingmin , Panebra Alfredo , Lee Yungsub , Hong Yeongho , Panebra Alfredo 
Published: February 2023

Abstract
NIFA-funded grant to identify chicken immune molecules, particularly cytokines and chemokines and to characterize their function resulted in new sets of avian-specific immune tools useful in the studies host immune responses after infections and vaccinations. Total 65 new monoclonal antibodies (mAbs) have been validated for their specificity against avian molecules using several assays including ELISA, immunohistochemistry, Western blot, flow cytometry, qPCR, and cell proliferation. All the target molecules that we selected have shown to have critical functions in host defense against pathogens and include 13 cytokines (interleukin-4, 7, 10, 12, 13, 17F, 21, 22, 23, 26, 34, IFN-α, IFN-κ, TNF-α, CSF-1, and TGF-β) and 3 chemokines (CXCLi2, CCL4 and 5). Functional similarity and dissimilarity were discovered between immune molecules of avians and mammals. These immune reagents will be useful for studies in host-pathogen immunobiology of infections and vaccinations in poultry.
(This research was supported by USDA NIFA award number: 2017-67015-26793)
Development of antigen sandwich ELISA to detect interferon-alpha (IFN-α) using monoclonal antibodies in chicken
Authors: Lee Youngsub , Kim Woo hyun , Lillehoj Hyun S 
Published: February 2023

Abstract
Interferon alpha (IFN-α) belongs to the type I interferon family which mediates an early innate immune response to viral infections. In the present study, we developed a sandwich ELISA using specific mouse monoclonal antibodies (mAbs) to measure IFN-α production in chickens. Recombinant chicken IFN-α (chIFN-α) expressed in yeast was used to immunize the mice. Five mAbs which specifically recognize chIFN-α antigen were selected and characterized. For sandwich ELISA development, mAbs were labeled with biotin, followed by a pairing assay to identify the best capture and detection antibodies. Two sets of mouse anti-chIFN-α mAb pairs were identified as optimum pairs of antibodies for detection of chIFN-α. The sandwich ELISA effectively detected native chicken IFN-α in chicken macrophage cells stimulated by polyinosinic:polycytidylic acid and its minimum detectable level was about 25 pg/mL. The anti-viral activity of chIFN-α against vesicular stomatitis virus (VSV) was evaluated in chicken embryonic fibroblast and the mouse anti-chIFN-α mAbs which neutralize the activity of chicken IFN-α against VSV were identified. The newly developed antigen capture sandwich ELISA for the detection of chIFN-α will be a useful tool to monitor IFN-α production in chickens during viral infections.