bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dependence of spontaneous autoimmunity to neuroretina on Th1 and Th17 effector cytokines
Authors: Horai Reiko , Bing So Jin , Silver Phyllis B , Jittayasothorn Yingyos , Caspi Rachel R 
Published: January 2023

Abstract
Autoimmune uveitis is a group of sight-threatening diseases caused by retina-specific autoreactive T cells. Upon activation, these retina-specific T cells differentiate into effector cells that can cross the blood-retinal barrier to cause uveitis. IFN-γ-secreting Th1 cells and IL-17A-secreting Th17 cells are thought to be pathogenic populations in tissue-specific autoimmune diseases, including uveitis. However, the contribution of either subset to disease pathogenesis is still controversial. In this study, we analyzed the role of Th1 and Th17 subsets in the R161H mice, which express a transgenic T cell receptor specific for the retinal protein IRBP and develop spontaneous uveitis with high penetrance. To understand how these effectors and their respective signature cytokines contribute to pathogenesis, we crossed R161H mice with IL-17A−/− and/or IFN-γ−/− (GKO) mice. R161H-GKO mice developed significantly attenuated disease with delayed onset, whereas disease in R161H-IL-17A−/− mice was essentially undiminished, suggesting IFN-γ, but not IL-17A, is critical for pathogenesis. Although the number of ocular infiltrating cells in R161H-GKO mice was decreased, the proportions of Th17 cells and granulocytes were increased, in line with an enhanced Th17 response in the absence of IFN-γ. Surprisingly, R161H mice made deficient in both IL-17A and IFN-γ developed more severe disease than R161H-GKO mice, although its onset was also delayed. These results suggest that ‘classic’ Th1 and Th17 cells are not the only pathogenic effectors in uveitis, and that inflammatory cytokine(s) other than IFN-γor IL-17A can also drive disease. Further mechanistic studies may uncover novel effector pathways in pathogenesis of ocular autoimmunity.
Peripheral Tolerance Regulates RBC-specific CD4+ T Cells in a Novel Mouse
Authors: Wong Sut Ling Andrea , Richards Amanda L , Zimring James C , Hudson Krystalyn 
Published: January 2023

Abstract
T cell tolerance mechanisms towards tissue-restricted antigens are well described and include deletion, anergy, or regulatory cells; however tolerance mechanisms against RBC-restricted antigens are poorly understood. Herein, we utilized the HOD mouse to investigate T cell tolerance to RBC-specific antigens. The HOD mouse expresses a fusion protein consisting of hen egg lysosyme (HEL), ovalbumin (OVA), and human blood group, Duffy driven by an RBC-specific promoter. The HOD mouse was crossed to TCR transgenic OTII mouse to generate HOD mice with autoreactive CD4+ T cells (OTII+HOD+). Young OTII+HOD+ mice do not have detectable autoantibodies, suggesting immune tolerance. Analysis of thymii 8 week-old mice revealed similar numbers of OTII CD4+ SP thymocytes between OTII+HOD+ and OTII+HOD−, suggesting that central tolerance plays little role in RBC specific CD4+ T cells. However, in the periphery, several tolerance mechanisms were identified in OTII+HOD+ mice. Autoreactive splenic CD4+ T cells in OTII+HOD+ mice underwent deletion, expressed higher levels of inhibitory markers PD-1, LAG3, CD5, and had higher numbers of CD25+Foxp3+ regulatory T cells, when compared to OTII+HOD−. Furthermore, CD4+ T cells from OTII+HOD+ had significantly reduced proliferation in response to cognate antigen, suggesting anergy or functional inactivation. Analysis of antigen presenting cells in OTII+HOD+ revealed higher frequencies of myeloid DC, known to express high levels of MHC II and propensity to activate CD4+ T cells. Finally, a break in tolerance was observed in 30% of OTII+HOD+ at 6 months, as indicated by anti-HOD antibodies. Future studies will focus on identifying defective tolerance mechanism that contributed to autoantibody genesis.
Gut intraepithelial myelin reactive CD4+T cells suppress central nervous system autoimmunity via LAG3
Authors: Kadowaki Atsushi , Miyake Sachiko , Saga Ryoko , Chiba Asako , Yamamura Takashi 
Published: January 2023

Abstract

Objective
Multiple sclerosis (MS) is an autoimmune disease that targets the myelin of the central nervous system (CNS). Increasing incidence of MS in Japan let us question which components of the immune system are altered by environmental factors. Gut mucosa is by far the largest immune organ that interacts with the external environment. Since T cells are pivotal in controlling CNS inflammation, we investigated the existence of myelin reactive T cells that might be induced in the gut and their influence on CNS autoimmunity.

Methods
Gut-T cells from MOG(35–55) specific T cell receptor transgenic (2D2) mice were analyzed by FACS. Sorted gut-T cells were adoptively transferred to experimental autoimmune encephalomyelitis (EAE) induced by immunization with MOG(35–55). Blocking antibodies were used for functional analysis. Gut microbiota was modulated by oral antibiotics treatment. Diets including poor or rich aryl hydrocarbon receptor ligands (AHRL) were fed to mice.

Results
Here we demonstrate that the gut epithelium of 2D2 mice is inhabited by intraepithelial T-lymphocytes (IEL) that can inhibit EAE upon transfer. The regulatory IEL had the phenotype of CD4+‘induced’IEL (CD2+CD5+), exhibited TH17-like profile and had ability to infiltrate the inflamed CNS tissue. The IEL constitutively expressed Ctla4 and Tgfb1, and markedly upregulated Lag3 in the CNS, thereby inhibiting the inflammation. We also demonstrated that the IEL are induced by gut microbiota and AHRL.

Conclusions
Gut environment favors the generation of myelin reactive T cells that have unique regulatory function. Dysbiosis or poor AHRL in diet may reduce the induction of such regulatory cells, thus promoting the development of MS.
Autoimmune demyelinating disease results from the combined effects of T cell affinity and increased bond lifetime for self antigen.
Authors: Blanchfield Jennifer Lori , Liu Baoyu , Evavold Brian D 
Published: January 2023

Abstract
A fundamental question for autoimmunity is how T cells become activated to attack self in the periphery. Antigen recognition by T cells is often characterized by affinity, defined as the strength and therefore likelihood of interaction between TCR and peptide:MHC (pMHC), with the assumption that higher affinity T cells will be more pathogenic. However, our analyses of polyclonal and monoclonal CD4+ T cells reveal a wide range of affinities for myelin oligodendrocyte glycoprotein (MOG) responsive T cells in EAE. We argue a finer degree of detail than affinity as the sole predictor of function because high and low affinity T cells promote paralytic disease. Affinity for antigen becomes a key factor in the kinetics of T cell activation, but is just one parameter. T cells also generate dynamic forces during this process and force adds a level of mechanical regulation to the TCR-pMHC bond by shortening or enhancing bond lifetimes. This is important because the lifetime contributes to functional potency of the response. For the first time, we report the bond lifetime of MOG specific T cells under applied force and demonstrate that upon activation, the T cells biophysically change, exhibiting similar lifetimes regardless of high or low affinity designation. This is novel because high, not low, affinity TCRs are predicted to exhibit long lifetimes. Comparatively, activated myelin specific T cells generate bond lifetimes similar to cells with foreign antigen specificity. In all, our data support a kinetic proofreading model of T cell activation linking antigen discrimination, actin remodeling and availability of intracellular chemical messengers where with time, high and low affinity T cells are essentially equipotent contributors to autoimmunity.
Type I interferon protects CD4 T cells from NK cell killing in a cGVHD model of SLE
Authors: Klarquist Jared , Hennies Cassandra M , Janssen Edith M 
Published: January 2023

Abstract
Myriad studies have linked type I interferon (IFN) to the pathogenesis of autoimmune diseases, including systemic lupus erythematosus (SLE). While increased levels of type I IFN are found in patients with SLE, and IFN blockade ameliorates disease in most mouse models of lupus, its precise roles in driving SLE pathogenesis remain largely unknown. Here, we dissected the role of type I IFN in disease development using the bm12 cGVHD model of SLE, where IAb (C57BL/6) mice develop SLE-like disease upon transfer of IAbm12 (bm12) CD4 T cells. Our data show increased serum levels of type I IFN over time, concomitant with the development of T follicular helper cells, germinal center (GC) B cells, plasmablasts, and anti-nuclear antibodies (ANA). However, these disease parameters are significantly reduced in IFN-α receptor-deficient (Ifnar−/−) recipient mice, indicating an important role for type I IFN sensing by non-T cells. Surprisingly, transfer of highly purified Ifnar−/− bm12 CD4 T cells into WT C57BL/6 hosts resulted in poor expansion of the transferred T cells, and limited development of GC B cells, plasmablasts, and ANA. Importantly, NK cell depletion restored the expansion of Ifnar−/− CD4 T cells and downstream sequelae. These findings suggest that one novel mechanism by which type I IFN contributes to autoimmune disease is by regulating the susceptibility of pathogenic CD4 T cells to NK cell killing, thus providing further rationale for the development of anti-IFNAR therapeutics for the treatment of SLE.
Experimental induction of autoantibodies to IgG by pigeon IgY
Authors: Aranda Ivan Sammir , Ortega Enrique , Martinez Erasmo 
Published: January 2023

Abstract

Background
IgG is a frequent target of autoantibodies in a variety of experimental and clinical settings. Interestingly, the possible antigens (Ag) that may induce such a break of tolerance have not been fully studied. Since our previous observations showed the frequent co-occurrence of antibodies (Abs) to pigeon IgY and self-reactivity to IgG in hypersensitivity pneumonitis secondary to avian exposure, we decided to evaluate experimentally the role of IgY in this kind of autoimmune reactivity.

Objective
To study whether pigeon IgY induces anti-IgG reactivity in an experimental model in which foreign and self-immunoglobulins are phylogenetically related.

Methods
IgY was purified from pigeon (Columba livia) eggs, prepared in Freund’s adjuvant and immunized to Balb/c mice. Abs production to foreign (IgY) and self-antigen (mouse IgG) were evaluated by ELISA and Western blot. Tregs (CD4+CD25+Foxp3+) were also studied by flow cytometry since the first evidences suggested a T-cell dependent Ab reactivity.

Results
IgG with anti-IgY activity occurred 2 weeks after immunization. Autoantibodies were predominantly IgG and bind Fc fractions of IgG. Immunoglobulins to self-IgG showed a gradual increase and they persisted for 3 weeks. A correlation between high levels of autoantibodies and elevated Tregs was also found.

Conclusions
Pigeon IgY induced autoantibody production, it was predominantly IgG, follows a kinetic similar to soluble immune complexes formation, and bind the Fc fraction of IgG. T-cell analyses suggested a Tregs dependent reactivity. The break of tolerance to self-IgG in mammals has not been previously studied using a phylogenetically related Ag.
Suppressive modifiers of autoimmunity: Identification and characterization of genes within the Sles1 interval
Authors: Khan Shaheen , Belobrajdic Katherine , Hwang Sun-Hee , Subramanian Srividya , Casco Jose , Wakeland Edward 
Published: January 2023

Abstract
Sle1 is a potent susceptibility locus for spontaneous systemic autoimmunity derived from the NZM2410 mouse strain. The NZW-derived suppressive modifier locus, Sles1, specifically prevents the spontaneous loss in tolerance mediated by the B6.Sle1 congenic. Fine mapping combined with phenotypic characterization of series of recombinant mouse strains have mapped Sles1 to an approximately 638 KB segment on murine chromosome 17. This revealed extensive epistatic gene interactions within the Sles1 region and suggested Btnl2 and H2 genes as the strongest candidates. We have performed targeted resequencing on B6 and B6.Sles1 mice and have identified functional polymorphisms within the Sles1 interval between the two mice strains. We further generated a series of BAC transgenic mice and have performed RNA-seq analysis and cell surface expression studies on B cells, Bone-marrow derived macrophages and Bone-marrow derived dendritic cells. We are in the process of aging BAC transgenic mice and will be phenotyping all the mice at 7 months with a goal to identify one or more genes driving the pathogenesis of autoimmunity.
Bowman birk protease inhibitor suppresses GM-CSF, Th17 cells and CNS autoimmune inflammatory demyelination
Authors: Safavi Farinaz , Li Zichen , Wang Limei , Ciric Bogoljub , Rasouli Javad , Zhang Guang-Xian , Rostami Abdolmohamad 
Published: January 2023

Abstract
Serine proteases play numerous roles in immune system and their inhibition modulates immune and autoimmune responses. Bowman Birk inhibitor (BBI), a soybean-derived serine protease inhibitor potently suppresses experimental autoimmune encephalitis (EAE) after oral administration. In this study, we show that BBI inhibits development of Th17 cells and reduces Th17 cell encephalitogenicity by suppressing their GM-CSF production and decreasing their numbers in the CNS of EAE mice. We also demonstrate that BBI induces IFN-γ production in Th17 cell culture, and that lack of IFN-γ or IFN-γR abrogates Th17 suppressive effect of BBI. In addition, BBI requires IL-27R, Stat-1, T-bet, and IL-10 to inhibit Th17 development. Taken together, our data demonstrate that BBI suppresses pathogenic Th17 cells through IFN- γ dependent pathway and ameliorates EAE. This suggests a novel immunomodulatory effect for serine protease inhibitors in immunity. In addition, BBI has potential to be safe oral therapy for autoimmune diseases, such as multiple sclerosis.
Oligonol Induces the Expression of the Anti-aging Molecule, SIRT1, via the AMPK-Autophagy Pathway
Authors: Park Seul-Ki , Seung Rak-Kyun , Kim Ji-Ae , Shin Ok Sarah 
Published: January 2023

Abstract
Oligonol, mainly found in lychee fruit, is an antioxidant polyphenolic compound which has been shown to have anti-inflammatory and anti-cancer properties. The detailed mechanisms by which oligonol may act as an anti-aging molecule have not been determined. In this study, we evaluated the ability of oligonol to modulate sirtuin (SIRT) expression in human lung epithelial (A549) cells. Oligonol was added to A549 cells and reactive oxygen species (ROS) production, mitochondrial superoxide formation, and p21 protein levels were measured. Signaling pathways activated upon oligonol treatment were also determined by western blotting. Furthermore, the anti-aging effect of oligonol was evaluated ex vivo in mouse splenocytes and in vivo in Caenorhabditis elegans. Oligonol specifically induced the expression of SIRT1, whose activity is linked to gene expression, metabolic control, and healthy aging. In response to influenza virus infection of A549 cells, oligonol treatment significantly up-regulated SIRT1 Oligonol specifically induced the expression of SIRT1, whose activity is linked to gene expression, metabolic control, expression and down-regulated viral hemagglutinin expression. Oligonol treatment also resulted in the activation of autophagy pathways and the phosphorylation of AMP-activated protein kinase (AMPK). Furthermore, oligonol-treated spleen lymphocytes from old mice showed increased cell proliferation, and mRNA levels of sirt1 in the lungs of old mice were significantly lower than those in the lungs of young mice. Additionally, in vivo lethality assay revealed that oligonol extended the lifespan of C. elegans infected with lethal Vibrio cholerae.
Comparative evaluation of inflammatory responses in mice exposed to gold nanoparticles of biological and chemical origins
Authors: Sharma Nilesh , Sadrinia Cyrus , Sahi Shivendra 
Published: January 2023

Abstract
Gold nanoparticles have found an ever-increasing application in diagnostics and therapeutics in recent times. In vivo and in vitro toxicity studies reveal often contradictory results. It has been shown that the toxicity, if caused, depends on the shape, size and crystal characteristics of the nanomaterial. In this background, nanoparticles–unconventionally synthesized from plant cell culture (ccAuNPs)–were compared to chemically-synthesized nanoparticles (csAuNPS) after administering repeated doses of (IP) 200 μL of each (40nm size) to c57bl/6 mice for 5 and 30 days. Control was maintained with an equal dose of PBS. Differential patterns of cytokine activities were observed between the two categories and two periods of exposure. Levels of Leptin, IL-1b, IL-10 and GCSF were significantly (p&lt;0.05) elevated for both ccAuNPS and csAuNPS groups with respect to control in case of short exposure. Under long exposure, both nanomaterials induced significantly (p&lt;0.05) lower activities of TNF-α and IL-6 than control, but for ccAuNPs, the levels of IL-1b, IGF-1 and GCSF were significantly lower than in csAuNPS and control both. There were no significant changes in body weight or liver function enzymes, ALT and AST, with respect to control for both groups of nanomaterials.
Cell division cycle 42 (Cdc42) regulates functions of plasmacytoid dendritic cells
Authors: Stutte Susanne , Schulz Anna M. , Kugler Ina , Imhof Axel , Brakebusch Cord , Brocker Thomas 
Published: January 2023

Abstract
Cell division cycle 42 (Cdc42) is a member of the Rho guanosine triphosphatase family and has pivotal functions in actin organization, cell migration and proliferation. We recently demonstrated that conventional dendritic cells with a Cdc42 deficiency show a significant reduction in lysosomal MHC class II–processing proteins, such as cathepsins, as they are lost by enhanced secretion.
Similarly, we found that Cdc42-deficient plasmacytoid dendritic cells (pDCs) are phenotypically more mature as they up-regulate MHCII and the co-stimulatory molecule CD86. Furthermore, their homing capacity is strongly impaired in steady state causing strongly reduced pDC cell numbers in peripheral organs. In addition, after inflammatory stimulation pDC infiltration is impaired when Cdc42 is absent. We analyzed Cdc42 deficient pDCs in more detail to understand the molecular contribution of Cdc42 in pDC functions and their migratory behavior.
Dietary Poly Unsaturated Fatty Acid (PUFA) regulation of Organ and Tissue Microenvironments in an Iso-Caloric Pair-Fed Mouse Model
Authors: Talmadge James E , Khadge Saraswoti , Thiele Geoffrey M , Klassen Lynnell W , Sharp John Graham , Duryee Michael J , McGuire Timothy R , Dafferner Alicia , Britton Holly , Beck Jordan , Black Paul , DiRussio Concetto 
Published: January 2023

Abstract
The majority of omega-3 (ω3) and ω3 PUFA diet studies have not differentiated dietary PUFA content from obesity. Our studies used pair-fed iso-caloric diets containing 35.5% of calories from fat with an ω6:ω3 ratio in ω6 and ω3 diets of 42:1 and 1:1 respectively with DeCarli diets and fish oil substituting for 70% of olive oil. The ω3 diet contained eicosapentaenoic (EPA) and docosahexaenoic (DHA) acid at a 3:1 ratio, while the ω6 diet contained linoleic acid and a low level of linolenic acid. Female BALB/c mice were monitored for weight gain, diet consumption and sacrificed (12 wks) to examine mammary gland, spleen, bone and hepatic histopathology, leukocyte phenotypes and organ and tissue lipidomics. In association with pair feeding there were no differences in diet consumed and weight gain. The ω6 cohort had decreased numbers of progenitor cells and an increase in splenic subcapsular extramedullary hematopoiesis and hepatocyte lipidosis, hypertrophy and multinucleation and increased hepatic vascularity with thicker intima. The ω-6 cohort also had mammary fat pads (MFPs) with increased adipocytes in the tubular epithelium, stromal cellularity and epithelial tissue density. These changes and subclinical inflammation were accompanied by organ specific lipodemic changes, including increases in arachidonic acid (AA) in the plasma, spleen and liver, but not MFPs, of the ω-6 mice, and an increase in EPA and DHA in the plasma, spleen, MFPs and liver of the ω-3 mice. Further, B and T cells and macrophages had an increase in the % of phospho NFκβ+ cells and the liver and MFPs had an increase in the ω3 PUFA, docosapentaenoic acid. In summary, the dietary ω6:ω3 ratio, independent of obesity, regulates mammary gland, spleen and hepatic inflammation.
NAFLD induces neuroinflammation and accelerates Alzheimer’s disease
Authors: Bynoe Margaret S 
Published: January 2023

Abstract
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease afflicting about one third of the world’s population and 30% of the US population. It is induced by consumption of high lipid diets and is characterized by liver inflammation and subsequent liver pathology leading to steatosis and steatohepatitis. We fed mice with high fat/lipid diet (HFD) or a standard diet (SD) and monitored them for signs of systemic or central nervous system inflammation. We found that NAFLD induced acute liver inflammation and accelerates signs of Alzheimer’s disease (AD) in an AD-Transgenic model. Moreover, chronic NAFLD induced advanced signs of AD in WT mice. In the chronic disease stage, we observed neuronal apoptosis and decreased brain expression of low-density lipoprotein receptor-related protein-1 that is involved in beta-amyloid clearance, in both WT and APP-Tg mice. HFD fed mice harbored numerous activated and proliferating microglial cells in their brain. Removal of mice from HFD during acute disease reversed liver pathology and neuroinflammation and decreased beta-amyloid plaque load. Concomitant with microglial cell activation, we observed profound changes in microbiota, resulting in a more pathogenic microglial phenotype. Interestingly, removal of mice from HFD completely abrogated microglial cell activation and proliferation and changes in gut. Based on these findings, we conclude that inflammation induced by HFD induces profound pathogenic changes in the gut concomitant with pathogenic changes in the CNS leading to neurodegeneration.