bluuebunny/crossref_metadata_2025_split huggingface dataset:
Low affinity CD8+ T cells are a critical component in the development of experimental cerebral malaria
Authors: Jacobs Jesica R. , King Thayer P. , Lamb Tracey J. , Evavold Brian D. 
Published: January 2023

Abstract
Malaria is responsible for at least 500 million deaths annually. Of those who become infected with malaria, around 1% develop cerebral malaria, which is fatal in 15% – 20% of patients. Therefore, understanding the immune mechanisms contributing to the lethality of cerebral malaria are critical for developing appropriate therapies. Infection with Plasmodium berghei ANKA in C57BL/6 mice induces experimental cerebral malaria (ECM), which requires activated CD8 T cells. In these experiments, we used the highly sensitive two-dimensional (2D) micropipette adhesion frequency assay to define the affinity and frequency of the immunodominant glideosome associated protein 50 (GAP50)40–48 epitope. We found both high and low affinity GAP50 specific CD8 T cells are found in the spleen (d5) and brain (d6) of ANKA infected mice. However, the 2D micropipette assay was more sensitive than tetramer staining with respective measurements of 20% vs. 1.2% of CD8 T cells in the spleen and 30% vs. 13.2% of CD8 T cells in the brain of ANKA infected mice measured as specific for GAP50. Furthermore, 67% of the antigen specific CD8 T cells in the spleen and 50% in the brain had low affinity for GAP50. These data reveal that tetramer vastly underestimates the number of antigen specific cells responding during ANKA infection. Infection with the NK65 strain of P. bergei results in similar levels of parasitemia and frequency of CD8 T cells in the brain, but ECM does not develop. Unlike ANKA infection, micropipette analysis of CD8 T cells from the brains of NK65 revealed only high affinity CD8 T cells for GAP50. These data indicate that under appreciated low affinity CD8 T cells are a vital component of the pathogenic and lethal response observed in experimental cerebral malaria.
GM-CSF regulation of autophagy in monocytes enhances immune response to Cryptococcus gattii
Authors: Elsegeiny Waleed Abdel Wahab , Salas Antonio , Kullas Amy , Williamson Peter R. 
Published: January 2023

Abstract
Cryptococcal meningoencephalitis is responsible for over 15% of HIV-related deaths worldwide and is also the most common cause of non-viral meningitis in the US. The role of T-cells in cryptococcal disease is well studied however a significant portion of previously healthy non-HIV patients with cryptococcal meningoencephalitis have an intact CD4+ T-cell compartment. We observed that patients with GM-CSF autoantibodies have a decrease in autophagy within their classical monocyte compartment. This reduction in autophagy is correlated with an enhancement of IL-1β production, additionally GM-CSF synergizes with TLR2, TLR4, and TLR5 in the induction of IL-1β. The importance of GM-CSF inhibition of autophagy appears to be most dramatic when monocytes are in conditions of weak TLR stimulation, particularly TLR4 stimulation with LPS. The capsule for Cryptococcus gattii, the prominent species involved with cryptococcal meningoencephalitis in previously health adults, has been shown to have the ability to dampen or block surface recognition by the immune system, thus GM-CSF synergy may have a critical role for driving the immune response against C. gattii infection. In the murine model of myeloid-specific ATG5 deficiency, mice have enhanced survival to C. gattii infection. Additionally, this GM-CSF down-regulation of autophagy is independent of mTOR activity, and contingent on a cyclic AMP/CTLA4/DCP2 pathway.
Immune responses of channel catfish against parasite Ichthyophthirius multifiliis following theront vaccination
Authors: Xu Dehai , Zhang Qizhong , Shoemaker Craig A. , Zhang Dunhua , Moreira Gabriel S.A. 
Published: January 2023

Abstract
Ichthyophthirius multifiliis (Ich) is a severe fish parasite and results in heavy losses of freshwater fish. The fish surviving natural infections or vaccinated with live theronts develop strong immune responses. Little is known about how immune genes are induced or how they interact and lead to specific immunity against I. multifiliis in channel catfish Ictalurus punctatus. This study evaluated the differential expression of immune-related genes, including immunoglobulin, immune cell receptor, cytokine, complement factor and toll-like receptors in head kidney from channel catfish at different time points after vaccination with live theronts of I. multifiliis. The vaccinated fish showed significantly higher anti-Ich antibody than those of control fish. The vast majority of immunized fish (95%) survived the parasite challenge. Expression of IgM and IgD heavy chain genes exhibited a rapid increase from 4 hours (h4) to 2 days (d2) post vaccination. Expression of immune cell receptor genes (CD4, CD8-α, MHC I, MHC II β, TcR-α, and TcR-β) showed up-regulation from h4 to d6 post vaccination, indicating that different immune cells were actively involved in cellular immune response. Cytokine gene expression (IL-1βa, IL-1βb, IFN-□ and TNF-α) increased rapidly at h4 post immunization and were at an up-regulated level until d2 compared to the bovine serum albumin control. Expression of complement factor and toll-like receptor genes exhibited a rapid increase from h4 to d2 post immunization. Results of this study demonstrated differential expression of genes involved in the specific or non-specific immune response post immunization and that the vaccination against Ich resulted in protection against I. multifiliis infection.
Fasciola hepatica Glutathione S-tranferase suppresses inflammatory cytokines and chemokines in vivo against lethal doses of lipopolysaccharide on C57Bl/6 mice.
Authors: Aguayo Vasti M. , Espino Ana 
Published: January 2023

Abstract
The world-wide helminth parasite, Fasciola hepatica, is an excellent immunomodulator. It survives in the host by preventing immune responses against itself by using excretory-secretory products (ESPs). One of the ESPs well-known for its anti-oxidant properties is Glutathione S-transferase (GST). Although it has been studied as a vaccine, the function GST plays in immunomodulation has scarcely been studied. Previously, we reported how the use of GST prior to TLR ligands significantly decreased TLR activation in vitro and boosted the survival rate of mice injected intraperitoneally with GST before a lethal dose of LPS by 80%. In this study, we investigate whether these C57BL/6 mice that survived after a lethal dose of LPS experienced a reduction in inflammatory cytokines and/or chemokines. For this, C57BL/6 6–8 week-old mice were allotted into two groups of 12 animals each. The control group (n=12) was injected intraperitoneally with 0.1M endotoxin free PBS and allowed to rest 1 hr, while the experimental group (n=12) was injected intraperitoneally with 15 ug of GST and allowed to rest 1 hour. Afterwards, both groups were injected with a lethal dose (1 mg) of E.coli LPS (serotype 0111:B4; Sigma) and monitored during a 48 hour period. Sera from mice in the experimental group were compared to the control group by using a Cytokine 20-Plex Mouse Panel kit (Invitrogen) for a wide array of cytokines and chemokines. Our results demonstrate that injecting 15ug of GST intraperitoneally 1 hour before a lethal dose of LPS gives the surviving 80% of C57BL/6 mice significantly reduced amounts of pro-inflammatory cytokines and chemokines, such as IL-1β (p = 0.0004), IL-12p70 (p = 0.0001) and MIP-1α (p = 0.0024), after 48 hrs.
Immune-microbiome axis regulates liver inflammation.
Authors: Castillo Patricia , Kumar Pawan , Hand Timothy , Kolls Jay K. 
Published: January 2023

Abstract
Autoimmune hepatitis (AIH) is a liver disease characterized by circulating autoantibodies, persistent liver inflammation, and subsequent hepatocyte damage. Both Th17 cells and the intestinal microbiome have been implicated in AIH. Patients have elevated serum IL-17, an altered microbiota, and increased bacterial translocation. In a murine AIH model, concanavalin A (con A) hepatitis, Il17ra−/− mice are protected, and gentamicin has been reported to ameliorate disease. We sought to better understand the relationship between Th17 cells and the microbiome in hepatitis.
To study this, we generated intestinal epithelial-specific IL-17RA deficient mice (Il17rafl/fl × villin cre+ mice). Absence of enteric IL-17R signaling induced commensal dysbiosis, expansion of intestinal Th17 cells, and increased bacterial translocation to the liver at the naïve state. These mice were more susceptible to con A hepatitis, exhibiting increased lethality, serum ALT, and serum and liver IFNγ as compared to controls. This elevated liver IFNγ was susceptible to BET protein inhibition ex vivo, suggesting the Ifng locus is open and susceptible to epigenetic regulation. Cohousing studies eliminated ALT differences between knockouts and controls, suggesting a role of the microbiome.
We hypothesize that disrupted enteric IL-17 signaling at the naïve state promotes intestinal dysbiosis and increased bacterial translocation to the liver. This causes epigenetic changes in the liver Ifng locus, poising cells to secrete more IFNγ upon simulation and worsen disease. Understanding the mechanism underlying exacerbated disease in Il17rafl/fl × villin cre+ mice will elucidate the role of enteric Th17 cells and the microbiome in AIH and other liver pathologies.
Microbiota metabolites SCFA promote intestinal epithelial repair and wound healing through promoting epithelial cell production of milk fat globule-EGF factor 8
Authors: Bilotta Anthony James , Ma Chunyan , Huang Xiangsheng , Yang Wenjing , Chen Liang , Yao Suxia , Cong Yingzi 
Published: January 2023

Abstract
The mechanisms by which gut microbiota regulate intestinal homeostasis are still largely unknown. The short chain fatty acids (SCFA), mainly acetate, propionate, and butyrate, are bacterial metabolites produced from the fermentation of dietary fibers, which have been shown to regulate intestinal homeostasis. In this study, we investigated whether SCFAs promote intestinal epithelial repair and wound healing through promoting epithelial cell production of milk fat globulin E8 (MFG-E8), a known molecule promoting wound healing and cell migration via actin reorganization. Treatment with SCFAs enhanced intestinal epithelial cell (IEC) migration significantly, and promoted wound healing in both mouse and rat IEC in vitro. We then investigated how SCFAs regulated IEC gene expression by microarray. Microarray analysis showed 401 genes differentially expressed upon stimulation with butyrate, of which 196 were upregulated and 205 were downregulated. Among upregulated genes, MFG-E8 has been shown in several systems to promote IEC proliferation and tissue repair. We confirmed MFG-E8 upregulation by qRT-PCR for mRNA and Western blot for protein. Interestingly, SCFAs also upregulated several genes pertinent to actin reorganization including RhoA, Rho GTPase, and PAK1 as well as genes known to effect proliferation such as cyclin D2 and PKCδ, which are down stream of MFG-E8 signaling. Our study thus demonstrated that SCFAs promote intestinal epithelial cell tissue repair, possibly through upregulation of MFG-E8.
Microbiota metabolites derived from tryptophan modulate macrophage inflammation and migration through AMP-activated protein kinase
Authors: Ding Yufang , Krishnan Smitha , Alaniz Robert Christopher , Lee Kyongbum , Jayaraman Arul 
Published: January 2023

Abstract
It is established that the gut microbiota plays an important role in Non-Alcoholic Fatty Liver Disease (NAFLD) and different bacterial taxa have been correlated to disease. However, the specific metabolites through which the microbiota exert their effects and the target pathways in host cells are not fully understood. We used liquid chromatography-mass spectrometry metabolomics to identify two tryptophan-derived metabolites – tryptamine (TA) and indole-3-acetate (I3A) – that require the microbiota and are depleted in high-fat diet mice compared to low fat diet mice. Both I3A and TA reduced palmitate and LPS induced production of pro-inflammatory cytokines (TNFα, IL-1β and MCP-1) in RAW 264.7 macrophages, as well as inhibited macrophage migration toward the chemokine MCP-1. We identified that both palmitate and LPS reduced levels of p-AMPK and the addition of I3A and TA reversed p-AMPK reduction. Since the p-AMPK activator AICAR reduced palmitate and LPS induced inflammatory cytokine production, we propose that I3A and TA modulate inflammation through modulating p-AMPK levels.
The delivery of luminal substances across small intestinal epithelium via goblet cell associated antigen passages is increased in the presence of dietary gliadin.
Authors: McDonald Keely G. , Knoop Kathryn A. , Kulkarni Devesha Hrishikesh , Gustafsson Jenny K. , Miller Mark J. , Newberry Rodney D. 
Published: January 2023

Abstract
Celiac disease is an enteropathy caused by CD4+ T cell responses to dietary gliadin, resulting in damage to the intestinal mucosa and malabsorption. How gliadin peptides cross the epithelium to interact with the immune system is unclear. We used an in vivo imaging approach on live mice and ex vivo assays on mouse and human intestinal explants to evaluate how gliadin traversed the intestinal epithelium. We observed that gliadin crossed the epithelial barrier of mice and humans via the recently described goblet cell associated antigen passages (GAPs), and moreover, gliadin increased the formation of GAPs. The induction of GAPs by gliadin was independent of acetylcholine signaling, the pathway inducing GAP formation in the steady state. Consistent with the increase in GAPs induced by gliadin, LP-DCs isolated from mice given luminal ovalbumin (Ova) concurrently with gliadin induced enhanced antigen specific T cell responses to Ova in ex vivo LP-DC T cell co-culture assays. In vivo Ova specific T cell responses in the MLN were enhanced in mice given Ova concurrent with gliadin. Gliadin did not increase the antigen presentation capacity of the LP-DCs when added to ex vivo cultures, indicating that increased luminal antigen delivery via GAPs mediates the enhanced antigen specific T cell responses to luminal Ova. In the absence of GC’s and GAPs gliadin did not enhance the delivery of luminal antigens to the LP-DCs and did not enhance T cell responses to luminal antigens. These studies identify that gliadin uses GAPs to cross the epithelial barrier, and that gliadin induces further GAP formation in a goblet cell intrinsic manner, thus facilitating the delivery of gliadin and other antigens to the immune system.
Moving beyond microbiome-wide associations to causal microbe identification
Authors: Surana Neil , Kasper Dennis L. 
Published: January 2023

Abstract
Microbiome-wide association studies have established that numerous diseases are associated with changes in the microbiota. These studies typically generate a long list of commensals implicated as biomarkers of disease, with no clear relevance to disease pathogenesis. If the field is to move beyond correlations and begin to address causation, an effective system is needed for refining this catalog of differentially abundant microbes and allow for mechanistic studies. We demonstrate that triangulation of microbe–phenotype relationships is an effective method for reducing the noise in microbiota studies and enabling identification of causal microbes. We found that gnotobiotic mice harboring different microbial communities exhibited differential survival in a colitis model. Co-housing of these mice generated animals that had hybrid microbiotas and displayed intermediate susceptibility to colitis. Mapping of microbe–phenotype relationships in parental mouse strains and in mice with hybrid microbiotas identified the bacterial family Lachnospiraceae as a correlate for protection from disease. Using directed microbial culture techniques, we discovered Clostridium immunis, a novel bacterial species, that—when administered to colitis-prone mice—protected them against colitis-associated death. To demonstrate its generalizability, we used our approach to identify 2 bacteria that induce intestinal expression of an antimicrobial peptide. Thus, we have used microbe–phenotype triangulation to move beyond the standard correlative microbiome study and identify causal microbes for 2 distinct phenotypes. Identification of disease-modulating commensals by our approach may also be applicable to human microbiome studies.
Prevention of systemic autoimmunity by dietary modulation of the gut microbiota
Authors: Ruiz Daniel Fernando Zegarra , El-Beidaq Asmaa , Iniguez Alonso , di Ricco Martina Lubrano , Mubiro Derek , Vieira Silvio Manfredo , Ruff William Edwards , Sterpka John , Kriegel Martin Alexander 
Published: January 2023

Abstract
Diet-induced modulation of host immune-microbiota interactions could be an attractive way to ameliorate autoimmunity. Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease with no cure. We used resistant starch (RS) as a novel approach to prevent SLE. We fed RS to a spontaneous TLR7 Tg and TLR7 agonist (Imiquimod, IMQ)-inducible lupus model to modulate gut microbial communities and lupus pathogenesis.
Depletion of the gut microbiota with antibiotics reduced mortality in TLR7 Tg mice. Also, IMQ-induced lupus was ameliorated in GF compared to SPF B6 mice, supporting a role for the microbiota in the pathogenesis. In both models, RS reduced mortality, kidney involvement, hepatosplenomegaly, and type I interferons. Plasmacytoid dendritic cell (pDC) accumulation and type I interferon signaling in spleen and Peyer’s patches was also reduced. Fecal 16S rDNA sequencing and culture of internal organs revealed that Lactobacillus reuteri translocates to MLN, liver and spleen in TLR7 Tg mice, and that fecal loads and translocation were suppressed by RS. Lupus induction by IMQ in GF B6 mice was exacerbated by L. reuteri monocolonization. In addition, L. reuteri gavage in the IMQ-inducible model worsened lupus manifestations, which were prevented by RS feeding before onset of disease. RS induced short-chain fatty acids (SCFA) in ileum and blood of TLR7 Tg mice, which suppressed growth of L. reuteri in vitro.
In summary, RS exerts beneficial effects in lupus-prone hosts through suppression of pathobionts and type I interferon pathways, which are known to contribute to human SLE. This study provides novel insights into diet-host-microbiota interactions and may aid in the development of functional foods to treat autoimmune diseases.
VEN-α, an engineered mammalian milk protein, demonstrates potent proinflammatory cytokine neutralization implicated in Inflammatory Bowel Disease
Authors: Alfano Randall W. , Simon Andrew , Akoyev Vladimir , Fein Seymour 
Published: January 2023

Abstract
Inflammatory Bowel Disease, which is comprised of Crohn’s disease (CD) and ulcerative colitis (UC), are chronic and debilitating diseases. Traditional therapies, which consist of anti-inflammatories and immunomodulators, are palliative at best and do not alter the progressive course of the disease. Advances in the understanding IBD pathology have led to new therapeutic strategies that are centered around targeted biologics to significantly alter disease progression. Although these targeted biologics demonstrate significant improvements in the quality of life for patients, systemic administration can have significant negative side effects such as risk of infection and malignancies.
Ventria Bioscience utilizes a nonanimal-based expression system known as ExpressTec to express at commercially viable levels a recombinant human milk protein that has potent anti-inflammatory activity. This protein, known as VEN-α, exhibits a protective effect when T84 monolayers are exposed to proinflammatory cytokines TNF-alpha and Interferon-gamma in the presence of VEN-α in vitro. Further, when orally delivered once daily to mice subjected to DSS treatment ad libitum, VEN-α improves clinical and histopathological outcomes that is comparable to cyclosporin.
Oral delivery of VEN-α may reduce unwanted effects associated with systemic administration and at the same time concentrate the active biologic at the site of pathology. Future studies planned will focus on further detailing efficacy in other models of IBD and understanding the pharmacokinetic profile of this orally delivered biologic. However, collectively the data to date suggests the orally delivered VEN-α has potential as a novel targeted biologic in the treatment of IBD.
Fumaric acid esters hypermethylate the miR21 locus and prevent the formation of CCR6+ CD4 T cells in multiple sclerosis.
Authors: Ntranos Achilles , Ntranos Vasilis , Bonnefil Valentina , Liu Jia , Zhu Yunjiao , Watson Corey , Katz-Sand Ilana , Casaccia Patrizia 
Published: January 2023

Abstract

Background
Dimethylfumarate (DMF) is known to be converted to monomethylfumarate (MMF) by esterases and then metabolized to fumarate and citric acid via the Krebs cycle. In cancer cells, accumulation of fumarate has been shown to inhibit DNA demethylation and that prompted us to investigate whether the immunomodulatory effects of fumaric acid esters (FAEs) in MS patients could also be related to changes of DNA methylation in CD4 T cells.

Methods
PBMCs were collected for immunophenotyping and CD4 T cell isolation from 54 Naive and 36 DMF treated RRMS patients. In addition, CD4 T cells were also isolated from 7 patients before and after DMF treatment. DNA methylation was analyzed using the Infinium Methylation EPIC BeadChip array. Methylation changes were validated in naïve and memory CD4 T cell cultures in vitro using MassArray EpiTYPER. qPCR was performed to assess the effect of DNA methylation on transcript levels in CD4 T cells.

Results
DMF treatment was associated with a significant reduction of CCR6+ CD4 T cells and a strong DNA hypermethylation signature in CD4 T cells. The highest levels of DNA methylation in DMF treated patients compared to controls were detected in a DNA region that was spanning the promoter of microRNA-21 (miR21) in both the cross-sectional and longitudinal cohorts. This region was also found to be hypermethylated in naïve CD4 T cells after treatment with MMF in vitro. Naïve CD4 T cells that were treated with MMF also exhibited reduced miR21 and CCR6 transcript levels.

Conclusions
Our results suggest that by modulating DNA methylation in CD4 T cells, FAEs reduce the expression of miR21 and prevent the production of CCR6+ CD4 T cells, which in recent studies were identified as potentially encephalitogenic in MS patients.
Host-derived CD27 suppresses graft versus host disease by limiting donor T cell expansion in a caspase dependent mechanism
Authors: ONeill Rachel , Leigh Nicholas , Du Wei , Chen George , McCarthy Philip , Cao Xuefang 
Published: January 2023

Abstract
Along with TCR signaling, costimulatory pathways are involved in T cell activation. CD27 is a TNF receptor family member expressed on T−, B−, NK and hematopoietic progenitor cells and its ligand, CD70, is known to be expressed on activated antigen-presenting cells, T−, B− and NK cells. Interaction of CD27 and CD70 in inflammatory conditions has been shown to cause immune dysregulation and immunopathology. However, the role of this pathway in an allogeneic transplantation setting is previously unknown. Host-derived CD27 inhibits GVHD as CD27−/− hosts show significantly increased GVHD. This is evidenced by reduced survival, more severe weight loss, and increased clinical GVHD score. In addition, CD27−/− hosts have higher levels of proinflammatory cytokines TNF-α, IFN-γ, IL-2, and IL-17. Moreover, accumulation of donor CD4+ and CD8+ effector T cells is increased in CD27−/− versus wild-type hosts. Mechanistic analyses suggest that CD27 expressed by host hematopoietic cells is involved in the control of alloreactive T cell apoptosis and expansion. Overall, our findings demonstrate that host CD27 serves as a unique negative regulator of allogeneic T cell response by contributing to donor T cell apoptosis and inhibiting expansion of donor effector T cells.