bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification and characterization of a novel association between dietary potassium and risk of crohn’s disease and ulcerative colitis
Authors: Awasthi Amit , Malik Sakshi , Khalili Hamed 
Published: January 2023

Abstract
Crohn’s disease (CD) and Ulcerative Colitis (UC) that constitute IBD are caused by imbalance between Th1 and Th17 immune cells, and Foxp3+ T-regulatory immune cells. However, in response to environmental and gut microbial triggers, T cell immune balance is disrupted which lead to inflammation in IBD. It is suggested that smoking, diet and hygiene affect T cells functions in IBD.
It is shown that salt (sodium) can alter the balance between pathogenic Th17 and Treg cells. We identified that extracellular potassium induces the generation of Foxp3+ Tregs in human by enhancing TGF-β1-signaling. We found that extracellular potassium activates Smad 2 and 3 while suppresses Smad7 and SGK1 in human T cells. We found that extracellular potassium not only induces Foxp3 expression in human T cells but also inhibited generation of human Th1 and Th17 cells.
We further translated these findings in a prospective cohort of nearly 170,000 US women who had been followed up for over 20 years. Among a total of 194,711 women over a follow-up of 3,220,247 person-years, we documented 273 cases of CD and 335 cases of UC. Dietary intake of potassium (Ptrend = 0.005) but not sodium (Ptrend = 0.44) was inversely associated with risk of CD. Although, both dietary potassium and sodium were not significantly associated with risk of UC, there was a suggestion of an inverse association with dietary potassium (Ptrend = 0.08). The association of potassium with risk of CD and UC appeared to be modified by loci involved in the TH17 pathway that have previously been associated with susceptibility to CD, particularly SNP rs7657746 (IL21). Dietary potassium is inversely associated with risk of CD potentially by regulating immune tolerance through its effect on Tregs and Th17 pathway.
Mechanisms by which IFN-γ mitigates lipid peroxidation that leads to progressive experimental autoimmune encephalomyelitis
Authors: Robinson Rachel R , Rojano Elba Mirelle , Forsthuber Thomas 
Published: January 2023

Abstract
Multiple sclerosis (MS) is the most common demyelinating autoimmune disease of the central nervous system affecting over 2.3 million people worldwide. Although most patients are initially diagnosed with relapsing-remitting MS, the vast majority of these will eventually develop progressive MS. Importantly, the mechanisms that contribute to the progression of MS are largely unknown. IFN-γ, a well-studied pro-inflammatory cytokine, has long been implicated in the pathogenesis of MS and its preclinical model, experimental autoimmune encephalomyelitis (EAE). Although pro-inflammatory, disease-promoting effects are well documented for IFN-γ, paradoxically, protective functions have also been demonstrated for this cytokine. We are interested in protective mechanisms of IFN-γ. Previous studies in our lab revealed that mice lacking IFN-γ signaling developed severe and progressive EAE due to increased presence of myelin debris and lipid peroxidation in the CNS, the cause of which is yet to be elucidated. We hypothesize that IFN-γ helps regulate expression of scavenger receptors, antioxidant molecules, and pro-oxidant molecules in order to promote resolution of lipid peroxidation and clearance of myelin debris in the CNS during EAE. We are currently investigating key scavenger receptor, antioxidant, and pro-oxidant molecule expression in IFN-γR−/− vs. wild type mice during EAE. Our results will contribute to a better understanding of the underlying mechanisms and may lead to new treatments to prevent progression of MS.
Nutraceutical Apigenin: mechanism of action associated with its anti-inflammatory activity and regulation of dendritic cell metabolism
Authors: Moore Patrick , Ginwala Rashida , Revuri Nikil , Kranz Victoria A , Houle John D , Khan Zafar K , Jain Pooja 
Published: January 2023

Abstract
Flavonoids have a range of biological activities, including anti-inflammatory, anti-carcinogenic, and neuroprotective effects. Apigenin, one such flavonoid abundant in certain plants, has been employed for centuries in the treatment of Parkinson’s, neuralgia, asthma and other diseases owing to the positive health effects attributed to this group of compounds. Due to Apigenin’s relative abundance and low intrinsic toxicity amongst flavonoids, it can be considered as a potential natural treatment for inflammatory disorders of the central nervous system (CNS), such as multiple sclerosis. However, there is distinct lack of information regarding the molecular mechanism of action of Apigenin leading to its modulatory effects on dendritic cells (DC), a key cell type responsible for maintaining immune balance especially in specialized locations such as the CNS. Here, we investigate the effect of Apigenin on RelB, a NF-kB family protein, which is vital to DC maturation and function. Apigenin reduced cytoplasmic RelB levels in LPS-treated DCs isolated from normal peripheral blood of a healthy donor. Gene and protein expression of downstream targets of RelB activation, IL-12, IL-23, IL-6, IL-1β and TNF-α was also reduced upon Apigenin treatment. Further, RelB is also known to engineer a metabolic switch in immune cells upon inflammation to meet the increased energy requirements. We observed a decrease in glucose uptake and lactate production (glycolysis), and an increase in mitochondrial activity when LPS-induced DCs were treated with Apigenin. These results provide key information about the molecular events controlled by Apigenin in its regulation of DC activity marking its potential as a therapy for neuroinflammatory disease.
CD6 as a potential target for treating multiple sclerosis
Authors: Li Yan , Singer Nora , Whitbred Joy , Bowen Michael , Fox David A , Lin Feng 
Published: January 2023

Abstract
CD6 was established as a marker of T cells more than three decades ago, and recent studies have identified CD6 as a risk gene for multiple sclerosis (MS), a disease in which autoreactive T cells are integrally involved. Nevertheless, the precise role of CD6 in regulating T cell responses is controversial and its significance in the pathogenesis of various diseases remains elusive, partly due to the lack of animals engineered to alter expression of the CD6 gene. In this report, we found that CD6 KO mice showed decreased pathogenic T cell responses, reduced spinal cord T-cell infiltration and attenuated disease severity in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. CD6-deficient T cells exhibited augmented activation, but also significantly reduced survival and proliferation after activation, leading to overall decreased Th1 and Th17 polarization. Activated CD6-deficient T cells also showed impaired infiltration through brain microvascular endothelial cell monolayers. Furthermore, by developing CD6 humanized mice, we identified a mouse anti-human CD6 monoclonal antibody that is highly effective in treating established EAE without depleting T cells. These results suggest that 1) CD6 is a negative regulator of T cell activation, 2) at the same time, CD6 is a positive regulator of activated T cell survival/proliferation and infiltration; and 3) CD6 is a potential new target for treating MS and potentially other T cell-driven autoimmune conditions.
Engineered myelin basic protein (MBP)-specific human T regulatory cells ameliorate myelin oligodendrocyte glycoprotein (MOG) peptide-induced Experimental Autoimmune Encephalomyelitis in vivo
Authors: Kim Yong Chan , Zhang Ai-Hong , Yoon Jeongheon , Wucherpfennig Kai W , Scott David W 
Published: January 2023

Abstract
Application of expanded polyclonal T regulatory cells (Tregs) offers great promise for the treatment of undesirable immune responses. To increase efficacy and reduce possible non-specific side effects, we elected to create antigen-specific Tregs, based on chimeric antigen receptor (CAR) therapy in leukemia. Therefore, we have engineered a myelin basic protein-specific TCR in a retroviral vector and transduced it to human naïve CD4+ T cells and Tregs. The TCR V genes came from an MBP-specific T-cell clone derived from an MS patient [1–3](Ob2F3). We observed that transduced Tregs were activated in vitro in response to MBP peptide on DR15 APC and upregulated Foxp3, LAP and Helios expression. As expected, these engineered MBP-specific Tregs suppressed proliferation and cytokine production by MBP-specific T effector cells in the presence of MBP peptide. Mechanistic studies demonstrated that suppression may involve transfer of soluble mediators but is enhanced by cell contact. Furthermore, transfer of human MBP-specific Tregs into MOG-immunized mice was able to ameliorate EAE in HLA DR15-transgenic mice. MBP-specific Tregs migrated into CNS in greater numbers than irrelevant FVIII-specific Tregs in day 2 after infusion, and H&E staining indicated that infusion of MBP-specific Tregs prevented perivascular inflammatory infiltration in CNS. Thus, we propose that engineered MBP-specific Tregs may be able to control pathologic inflammation in MS in vivo.
Nutraceutical Apigenin regulates DC function in a RelB-dependent manner during neuroinflammation
Authors: Ginwala Rashida , McTish Emily , Moore Patrick , Revuri Nikil , Raman Chander , Singh Narendra Prasad , Nagarkatti Mitzi , Nagarkatti Prakash , Kranz Victoria A , Houle John D , Jain Pooja , Khan Zafar K 
Published: January 2023

Abstract
Apigenin, a natural flavonoid, found in several plants is known to have anti-oxidant and anti-inflammatory properties indicated by its use for centuries as a medicinal approach to treat inflammatory disorders. However, there are significant gaps in knowledge regarding its effect on dendritic cell (DC) function in maintaining an immune balance in immunospecialized locations like the central nervous system (CNS). In order to establish the potential utility of Apigenin as a therapeutic agent against neuroinflammatory diseases, we tested and found that Apigenin treatment ameliorated severity of disease progression and relapse after onset of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 and SJL mouse models of multiple sclerosis. An increased retention of DCs and other myeloid cells in the periphery correlated with decreased immune cell infiltration and reduced demyelination in the CNS in treated mice. Mechanistically, Apigenin treatment reduced RelB expression in presence of LPS in human peripheral blood DCs, which is central to DC maturation, its antigen presentation capabilities and DC-mediated T cell activation. IL-12A and IL-23, downstream pro-inflammatory targets of RelB were reduced upon Apigenin treatment in these cells. Further, RelB causes a metabolic switch in immune cells upon inflammation, which was seen as a decrease in glucose uptake and lactate production (glycolysis), and an increase in mitochondrial activity when LPS-induced DCs were treated with Apigenin. These results indicate a protective role of Apigenin against DC-regulated neurodegenerative effects through a probable RelB mediated pathway thus implicating a potential therapy for neuroinflammatory disease.
Combination of cannabinoids, Δ9- tetrahydrocannabinol (THC) and cannabidiol (CBD), mitigate experimental autoimmune encephalomyelitis (EAE) by altering the gut microbiome.
Authors: Al-Ghezi Zinah Zamil , Alghetaa Hasan F , Nagarkatti Mitzi , Nagarkatti Prakash 
Published: January 2023

Abstract
Multiple Sclerosis (MS), is a common autoimmune disease that affects the central nervous system. Currently, there is no cure for MS, and most treatments involve the use of immunosuppressive drugs that can have adverse effects or increased toxicity. Cannabis, commonly known as marijuana, is a product of the Cannabis sativa, and for several centuries has been used as an alternative medicine in many cultures. Cannabis sativa produces over 421 chemical compounds, including about 80 terpenophenols named phytocannabinoids, and include both psychotropic THC and non-psychoactive CBD. In the currently study, we show that a combination therapy using THC and CBD results in amelioration of EAE, an animal model of MS, by reducing hind limb paralysis, decreasing immune cellular infiltration into the brain, and mitigating the presence of inflammatory biomarkers, including gram negative bacteria-associated lipopolysaccharide (LPS). Interestingly, the gut microbiome plays an important role in immune function and studies have shown that it is altered significantly in MS patients. Inasmuch, we performed 16S rRNA sequencing on experimental groups to investigate the gut microbiome composition after using a combination of THC and CBD compared to disease controls. Interestingly, we found that EAE mice showed increase in the mucin degrading bacterial species, Akkermansia municiphila, which was significantly reduced in disease mice treated with THC+CBD. Collectively, our data suggests that THC+CBD can ameliorate EAE by preventing accumulation of mucin-degrading bacteria that would lead to increased gut microbial dysbiosis.
Using the cooling agent icilin and synthetic analogs to attenuate autoreactive T cell function during experimental autoimmune encephalomyelitis.
Authors: Ewanchuk Benjamin , Allan Euan R. O. , Yates Robin M. 
Published: January 2023

Abstract
Targeting inflammatory function of autoreactive T lymphocytes defines a key facet of therapeutics for autoimmune diseases such as multiple sclerosis (MS). The super-cooling drug icilin has recently been shown to limit systemic inflammation through activation of the TRPM8 calcium channel in murine models of colitis. We thus aimed to define an anti-inflammatory mechanism for the drug candidate icilin and TRPM8 in T cell-mediated adaptive neuroinflammation.
Using experimental autoimmune encephalomyelitis (EAE), a CD4+ T cell-driven model of MS, we assayed the influence of icilin on CD4+ T cell activation, proliferation, and effector function. Significant reductions in clinical disease were observed in WT EAE mice receiving icilin treatment, coinciding with fewer infiltrating leukocytes in the central nervous system. Unexpectedly, TRPM8−/− mice treated with icilin also displayed protection from EAE, showing similar reductions in disease score and leukocyte infiltration. Both WT and TRPM8−/− mice receiving icilin treatment showed significant delays in initial disease onset, attributed in vitro to reduced T cell proliferation via icilin-mediated G1 cell cycle arrest. A library of chemically and structurally related icilin analogs was screened to identify novel drug candidates targeting autoimmune T cell function. Amongst the screened drug analogs, a small fraction potently attenuated T cell proliferation in vitro.
These results suggest that TRPM8-independent ablation of T cell function drives the anti-inflammatory properties of icilin during EAE. Further, novel drug candidates structurally related to icilin represent a promising class of molecules for limiting T cell responses in MS and other autoinflammatory diseases.
Expression of MHC I and II and antigen processing genes following INF-γ treatment in fibroblastic reticular cells and double negative cells
Authors: Marti Luciana C , Agostini Fernanda , Palomino Diana Torres , Severino Patricia 
Published: January 2023

Abstract
Lymph node (LN) is a secondary lymphoid organ with highly organized structure. Fibroblastic reticular cells (FRCs) integrate LN structure, and are characterized by podoplanin expression (PDPN, gp38) and lack of CD31. FRCs are involved in several immune response processes but the mechanism is still under investigation. Another cell population present in LN is a fibroblastic cell lacking PDPN and CD31 expression, called double negative cells (DNCs). FRCs and DNCs are described to control migratory pattern and positioning of immune cells during homeostasis or inflammatory response. We evaluate in human derived FRCs and DNCs the gene expression after IFN-γ-treatment and found up-regulated genes related to antigen processing and MHC class I and II up-regulated. MHC class I is expressed by all nucleated cells and MHC class II constitutive expression is confined to the immune system antigen-presenting cells, but can be induced in several cells types. MHC class II genes control has been described to play a role in eliminting foreign antigens, while minimizing autoreactive responses against self-antigens. MHC class II molecules can fulfill additional functions by triggering a variety of signaling pathways, they can regulate proliferation and maturation to apoptosis. In addition, we were able to demonstrate that HLA-ABC and HLA-DR were increased in the membrane of both FRCs/DNCs derived from different patients/lymph nodes after treatment with IFN-γ. FRCs seem to be more responsive to IFN-γ than DNCs. Furthermore, we have tested the ability of FRCs to internalize particles, showing a functional MHC II pathway.
Identification of the genetic determinants for the frequency of regulatory T cells using system genetics
Authors: Maazi Hadi , Hartiala Jaana , Suzuki Yuzo , Crow Amanda , Lam Jonathan , Patel Nisheel , Rigas Dimanda , Sankaranarayanan Ishwarya , Gilliland Frank D , Allayee Hooman , Akbari Omid 
Published: January 2023

Abstract
Regulatory T (Treg) cells are indispensable components of immune regulation contributing to the maintenance of respiratory tolerance and preventing autoimmunity and exaggerated immune responses. The frequency and absolute number of Treg cells in lymphoid and non-lymphoid tissues are tightly regulated through incompletely understood mechanisms. In this study, we sought to understand the pulmonary immune regulation through identification of the genetic determinants of the frequency and absolute number of CD4+FOXP3+T cells in mice using a genome-wide association study (GWAS) approach. We quantified the frequency and absolute number of CD4+FOXP3+T cells in the lungs and spleen of 102 inbred strains from the hybrid mouse diversity panel under steady state conditions and after exposure to house dust mite (HDM).
Among strains of mice examined, the absolute number of pulmonary CD4+FOXP3+ T cells varied by 312-fold at the steady state and 210-fold after HDM exposure. A GWAS analysis results revealed several loci that contribute to the regulation of CD4+FOXP3+ T cells in the lungs and spleen of mice, including a locus on chromosome 5 harboring the homeodomain-only protein (Hopx) gene. Characterization of Hopx−/− mice validated the GWAS findings by demonstrating that the frequency and number of CD4+FOXP3+ T cells are higher in the lungs of Hopx−/− compared to WT mice at the steady state and after HDM exposure. We found that in contrast to the lungs, the number of CD4+FOXP3+ T cells is lower in the spleen of Hopx−/− compared to WT mice at the steady state. Our findings suggest that Hopx is a novel genetic determinant of the frequency and number of CD4+FOXP3+ T cells in mice with opposing directional effects in mucosal and secondary lymphoid organs.
Amelioration of pulmonary inflammation through T cell activation in murine asthma model
Authors: Alvarez Carlos A , Jones Mark B. , Cobb Brian A 
Published: January 2023

Abstract
Asthma is an increasingly common chronic inflammatory airway disorder with phenotypic heterogeneity driven by age, gender, atopy, lung function, lifestyle, body mass indexes, and the underlying cellular and molecular pathways. In asthma, T helper (Th) cells drive inflammatory cascades via cytokine/inflammatory mediators and recruit leukocytes into the airway. While treatments are available, such as inhaled corticosteroids, individuals with severe asthma are often steroid resistant and have a poor quality of life. It is therefore important to develop our understanding of the underlying T cell driven mechanisms leading to pulmonary inflammation such that novel therapies may be developed. Previous work from our lab has demonstrated the importance of commensal microbiota in the development and maintenance of peripheral homeostasis. Exposure to bacterial polysaccharides, such as PSA from Bacteroides fragilis, inhibits Th1 and Th2 activity in murine models by activation of CD4+ FoxP3− CD45Rblo CD62Llo CD44hi T effector memory (Rblo Tem) cells in an IL-10 dependent fashion. Here, we show that activated Rblo Tem cells can reverse established pulmonary inflammatory disease in a murine house dust mite (HDM) model. Adoptive transfer of these cells nearly eliminates lung pathology and severely limits tissue infiltration by leukocytes. These results provide a rationale for the use of autologous cell transfer as a means to prevent and reverse ongoing inflammatory lung disease.
Characterizing childhood resistance to deadly immune dysfunction in severe infections
Authors: Joachim Rose Bernadette , Suber Freeman , Kobzik Lester 
Published: January 2023

Abstract
Epidemiological data show that pre-pubertal children possess a relative resistance to death from severe infections—particularly those characterized by “cytokine storm” and profound immune dysfunction (e.g. the 1918 pandemic flu, measles, bacteremia). To assess the role that pubertal status may have on an animal’s ability to appropriately regulate inflammation, we employed an endotoxemia model of sterile sepsis in mice. Following acute endotoxin injection (i.p., 23 μg/g), pre-pubertal mice (PND 25) exhibited significantly better survival than post-pubertal mice (PND 35) over a 72-hour period (78 vs. 29%, p&lt;0.0001, n&gt;50). Serum endotoxin concentrations were similar in both age groups at 2 and 20hr time points, suggesting that the difference in mortality was not due to differential endotoxin absorption. Surprisingly, improved survival among pre-pubertal animals did not correlate with a decreased inflammatory response. At 2hr pre-pubertal mice had higher absolute white blood cell counts, elevated numbers of Ly6G+CD11B+ granulocytic cells in the peritoneal cavity, and increased levels of several pro-inflammatory cytokines, compared to post-pubertal animals. In contrast, by 20hr pre-pubertal mice showed significantly decreased expression of pro-inflammatory cytokines, and increased expression of the anti-inflammatory cytokine IL-10 (1100 ± 290 vs. 750 ± 225 pg/ml, p&lt;0.001). Blockade of puberty with leuprolide substantially improved survival compared to age-matched post-pubertal mice (75 vs. 32%, p&lt;0.0001, n&gt;30), and treatment of pre-pubertal mice with estradiol increased subsequent mortality, suggesting a causal role for sex hormone(s) in the increased susceptibility of post-pubertal mice.