bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of sex on immune cells in healthy aging: elderly women have more robust natural killer (NK) lymphocytes than do elderly men
Authors: Lutz Charles T , Al-Attar Ahmad , Presnell Steven R. , Peterson Charlotte A. , Thomas D. Travis 
Published: January 2023

Abstract
Gender differences in blood leukocytes and immune responses have been reported, but there is limited knowledge of gender differences in elderly humans. We compared monocyte and lymphocyte subsets, along with soluble immune mediators in healthy men and women over the age of 70. We also measured natural killer (NK) lymphocyte cytotoxic granule exocytosis, chemokine synthesis, and cytokine synthesis in response to a variety of stimuli. We found that elderly women had significantly more circulating B cells than men, whereas men had more CD4 central memory T cells. Men also had higher monocyte levels. Women had a higher ratio of immature CD56bright NK cells to mature CD56dim NK cells, indicating a gender difference in NK cell maturation in the elderly. Moreover, compared with NK cells from men, mature NK cells from women had more vigorous cytotoxic granule responses to K562 leukemia cells and IFN-g responses to NKp46 crosslinking. Female mature NK cells were also more likely to produce MIP-1b than male mature NK cells in response to a variety of stimuli. We also measured soluble factors that affect immune cells or are produced by immune cells. Plasma adiponectin levels were higher in women, plasma levels of retinol-binding protein 4 were higher in men, but there was no significant gender difference in C-reactive protein, IL-15, or sphingosine-1-phosphate. These data support the hypothesis that gender influences immunity in general, and NK cell activity in particular, in elderly humans.
Increased antioxidant activity mitigates age-associated dysfunction of thymic stromal cells in aged mice.
Authors: Cepeda Sergio , Xiao Yangming , Venables Thomas , Griffith Ann 
Published: January 2023

Abstract
Age-associated thymic atrophy results in diminished production of new T lymphocytes and a concomitant decrease in responsiveness to new pathogens and vaccines. In addition to loss of thymic size with age, we have shown that critical stromal functions, including tissue-restricted antigen (TRA) expression, are diminished with age. We previously identified deficiency of the hydrogen peroxide quenching enzyme catalase (CAT) in thymic stromal cells as a key cause of thymic atrophy during aging, and established that thymic atrophy can be mitigated by genetic or dietary complementation of catalase antioxidant activity. Here, we find that in addition to maintaining thymic mass with age, long-term increases in catalase activity may mitigate age-associated loss of stromal function. Our preliminary studies indicate that life-long overexpression of catalase in mitochondria of transgenic mice (mCAT Tg) results in increased TRA expression, mitigated acquisition of an aged global gene expression signature, and increased maintenance of cortico-medullary organization in aged mCAT Tg mice relative to non-transgenic littermates.
The role of Indoleamine 2,3-dioxygenase (IDO) in the survival of bone marrow resident long lived Plasma cells
Authors: Maharaj Shivana M , Nair Jayakumar R , Carlson Louise M , Lee Kelvin P 
Published: January 2023

Abstract
Interactions within the bone marrow microenvironment provide critical survival signals to normal resident long lived plasma cells (LLPC). Previous work in our lab has shown that CD28 is required for LLPC survival, and we know that CD28 back signaling in to CD80/86 induces IDO production from DCs within the bone marrow microenvironment. IDO is classically known to contribute to an immunosuppressive environment (specifically with respect to T cell activity) in multiple myeloma, giving these cells the ability to survive within the bone marrow. However, to our great surprise previous results demonstrate that IDO is required for durable specific antibody responses in a normal bone marrow microenvironment. Thus we hypothesize that IDO has an additional role acting as a factor to maintain the bone marrow niche for long lived plasma cell survival, and sustained antibody production. Here we show that human myeloid derived DCs co-cultured with plasma cell lines produce IDO in vitro. In vivo models were also used, including the IDO knockout mouse model to analyze their LLPCs and the bone marrow compartment. A decrease of plasma cells in the bone marrow from wild type mice compared to IDO knock out mice was observed. These findings indicate that plasma cells can interact with dendritic cells within the bone marrow to produce IDO, and that a lack of IDO leads to a decreased number of these cells. Due to IDO deficient mice being unable to maintain long term antibody production, we propose a model wherein CD28 signaling induces IDO production, which plays a role in providing a supportive niche within the bone marrow for long lived plasma cell survival and antibody production.
Supported by: R01CA121044-08
Impaired metabolic reprograming in antigen-activated recent thymic emigrants
Authors: Cunningham Cody Alan , Fink Pamela J 
Published: January 2023

Abstract
Recent thymic emigrants (RTEs) are the youngest peripheral T cells that have completed thymic selection and egress to the lymphoid periphery. However, T cell maturation does not end in the thymus; rather, RTEs require 2 – 3 weeks in the lymphoid periphery to achieve functional maturity and enter the mature but naïve (MN) T cell pool. Following antigen encounter, RTEs are functionally distinct from MN T cells as they exhibit dampened proliferation, altered cytokine production, and increased expression of some anergy-associated genes. RTEs are a clinically important population as these cells contribute significantly to the T cell pool in neonates and adults recovering from HIV infection or chemotherapy. Here we show that, compared to MN T cells, RTEs are impaired in their ability to switch from oxidative phosphorylation to aerobic glycolysis following antigenic stimulation. This impaired metabolic reprograming contributes to the reduced proliferation and cytokine production observed in antigen-activated RTEs. This failure to undergo antigen-induced metabolic reprograming is associated with reduced expression of the transcription factor Myc. Critically, high levels of IL-2 are able to rescue the expression of Myc in RTEs resulting in proper metabolic reprograming that mimics their mature counterparts. These results suggest that an altered metabolic phenotype underlies the functional differences observed between RTEs and MN T cells and highlights a novel point for therapeutic intervention for neonates and individuals recovering from lymphoablation.
The histone lysine methyltransferase G9a maintains the transcriptional profile of mature CD8 T cells
Authors: Verbaro Daniel , Kim Byungil , Chou Chun , Shinkai Yoichi , Egawa Takeshi 
Published: January 2023

Abstract
Lineage identities of developing lymphocytes are established by both activation of lineage specific genes and repression of alternative lineage genes. The latter process depends on active gene repression by continued expression of transcriptional repressors or epigenetic silencing mediated by methylation of cytosine on DNA and lysine residues in histone tails, including Lys9 (K9) of histone H3. Here we show that the histone H3K9 methyltransferase G9a is essential for silencing of helper lineage-related genes in mature CD8+ T cells. Despite the development of normal CD4− CD8+ T cells, a proportion of G9a-deficient CD8+ T cells, when forced to divide with anti-CD3e and anti-CD28 stimulation, depressed surface CD4 in vitro. Furthermore, a substantial fraction of G9a-deficient CD8+ T cells carrying an OT-I T cell receptor derepressed surface CD4 during homeostatic proliferation following an adoptive transfer to lymphopenic host mice. These results suggest that G9a establish stable silencing of alternative lineage genes in dividing mature CD8+ T cells. We are currently conducting gene expression analysis to assess the requirement for G9a in establishment of the lineage identity of CD8+ T cells at a genome-wide level.
A pilot study to determine the prevalence of human rat lungworm (Angiostrongylus cantonensis) exposure on Hawaii Island
Authors: Jarvi Susan Irene , Quarta Stefano , Eamsobhana Praphathip , Howe Kathleen , Jacquier Steven , McHugh Robert , Kramer Kuilei , Meyers McKayla 
Published: January 2023

Abstract
The nematode Angiostrongylus cantonensis is a rat lungworm, a zoonotic pathogen that is the cause of human eosinophilic meningitis and ocular angiostrongyliasis. It is considered as a global, emerging infectious disease commonly known as rat lungworm disease (RLWD). Rats are the definitive hosts, mollusks are the obligatory intermediate hosts. Humans can become infected by ingesting intermediate hosts containing infective larvae in contaminated food or water. There are currently no diagnostic tests for RLWD available in Hawaii and prevalence of infection is unknown. To estimate prevalence of exposure to RLW parasites, working with Clinical Labs of Hawaii, LLP and Puna Community Medical Center in Pahoa, HI, we collected serum from 436 human volunteers from east Hawaii where most of the cases of RLWD in the USA originate. The presence of RLW antibodies were evaluated by indirect ELISA using crude antigen extracted from adult A. cantonensis nematodes. Of the 360 samples successfully analyzed, 76 (21%) were strongly positive, 166 (46%) weakly positive and 118 (33%) negative. Based on self-reported data, 92 (26%) believed they have or had RLWD, and 15 (4.2%) were definitively diagnosed. 77% of volunteers reported catchment systems as their main source of household water. More studies would need to be completed to evaluate the potential for water transmission of RLWD. Due to the potential for false positives using crude RLW antigen, results will be verified using dot-blots containing a 31 kDa protein which is expected to provide greater specificity.
IFN-γ produced by brain-resident cells is crucial to control cerebral infection with Toxoplasma gondii
Authors: Sa Qila , Ochiai Eri , Tiwari Ashish , Perkins Sara , Mullins Jeremi , Gehman Marie , Huckle William , Eyestone Willard H. , Saunders Thomas L. , Shelton Brent J. , Suzuki Yasuhiro 
Published: January 2023

Abstract
In vitro studies demonstrated that microglia and astrocytes produce IFN-γ in response to various stimulations including LPS, a component of the outer membrane of Gram-negative bacteria. However, the physiological role of IFN-γ production by brain-resident cells, including glial cells, in resistance against cerebral infections remains unknown. We analyzed the role of IFN-γ production by brain-resident cells in resistance to reactivation of cerebral infection with Toxoplasma gondii, an obligate intracellular protozoan parasite, using a murine model. Our study using bone marrow chimeric mice revealed that IFN-γ production by brain-resident cells is essential for upregulating IFN-γ-mediated protective innate immune responses to restrict cerebral T. gondii growth. Studies using a transgenic strain that expresses IFN-γ only in CD11b+ cells suggested that IFN-γ production by microglia, which is the only CD11b+ cell population among brain-resident cells, is able to suppress the parasite growth. Furthermore, IFN-γ production by brain-resident cells is pivotal for upregulating cerebral expression of CXCL9 and CXCL10 chemokines and recruiting T cells into the brain to control the infection. These results indicate that IFN-γ produced by brain-resident cells is crucial for facilitating both the protective innate and T cell-mediated immune responses to control cerebral infection with T. gondii.
Characterization of immunomodulatory cytokine IL-27 in tuberculosis infection.
Authors: Gideon Hannah Priyadarshini , Flynn JoAnne L 
Published: January 2023

Abstract
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), remains the world’s most successful human bacterial pathogen. Lung granulomas are the pathologic hallmark of TB. The cellular components of the granulomas play an important role in containment and progression of Mtb infection. The balance of pro and anti-inflammatory cytokines within granulomas is associated with reduction in bacterial burden. IL-27 is an immunomodulatory cytokine that modulates T cells. The properties of IL-27 as an enhancer or silencer of inflammation are yet to be evaluated in the context tuberculosis in a non-human primate (NHP) model. We used macaques, a NHP model that recapitulates human TB, to characterize the expression and modulatory effects of IL-27, especially at an individual granuloma level. In this preliminary evaluation, we characterized the cell types producing IL-27 in response to Mtb and in granulomas and correlated IL-27 production with pro and anti-inflammatory cytokines such as IFN-g, IL-2, IL-17 and IL-10. In addition we also correlated IL-27 expression with bacterial burden in granulomas. Overall, these data provide insight into immunomodulation of cytokines in tuberculosis.
Oleo-gum-resin suppresses indomethacin-induced elevation of proinflammatory biomarker and gastric injury in rats
Authors: AlSharari Shakir , Al-Rejaie Salim 
Published: January 2023

Abstract

AIM
To investigate the mucosal protective effect and the mechanisms of action of the anti-ulcer drug oleo-gum-resin in gastric injury induced by indomethacin in rats.

METHODS
Gastric mucosal injury was induced in male Wistar rats by oral administration of indomethacin at a dose of 60 mg/kg. One hour before indomethacin treatment, animals were orally pretreated with oleo-gum-resin at doses of 125 mg/kg, 250 mg/kg or 500 mg/kg. Four hours after indomethacin administration, the animals were sacrificed and their stomachs were rapidly removed and processed for the evaluation of gastric mucosal damage and the determination of the concentrations of TNF-α, IL-1β, IL-6, NO, PGE2 and myeloperoxidase (MPO) in mucosal tissues.

RESULTS
Linear hemorrhagic mucosal lesions were observed primarily in the glandular stomach 4 h after oral administration of indomethacin. Pretreatment with oleo-gum-resin markedly reduced the number and severity of gastric lesions in a dose dependent manner. The mucosal concentrations of TNF-α, IL-1β, IL-8, NO, and MPO, which indicates the degree of mucosal infiltration by neutrophils, increased concomitantly with the occurrence of gastric injury in the indomethacin administered rats while PGE2 levels inhibited in this group. Pretreatment with oleo-gum-resin significantly decreased the levels of these inflammatory factors in gastric tissue elicited by indomethacin and enhanced the PGE2 levels.

CONCLUSION
The mucosal protective effects afforded by oleo-gum-resin on gastric injury induced by indomethacin are mediated by inhibition of mucosal proinflammatory cytokine production and neutrophil infiltration, leading to suppression of mucosal inflammation and subsequent tissue destruction.
MAdCAM signaling through integrin α4β7 modulates surface expression of CCR5 and markers of CD4+ T cell activation.
Authors: Perrone Ian , Cicala Claudia , Nawaz Fatima , Ray Jocelyn , Olowojesiku Ronke , Waliszewski Mia , Jelicic Katija , Wei Danlan , Van Ryk Donald , Ansari Aftab Ahmed , Fauci Anthony S , Arthos James 
Published: January 2023

Abstract
Integrin α4β7 mediates homing of lymphocytes, including CD4+ T cells, to gut-associated lymphoid tissue (GALT) through an interaction with Mucosal Addressin Cell Adhesion Molecule (MAdCAM), expressed on gut endothelial venules. MAdCAM facilitates rolling adhesion of CD4+ T lymphocytes along the gut endothelium prior to extravasation. Previous work also indicates that MAdCAM interactions with α4β7 provide a co-stimulatory signal to T cells. α4β7+/CD4+ T cells are a preferred target of HIV during the acute phase of infection. We hypothesized that signaling through α4β7 via MAdCAM renders cells susceptible to HIV infection and replication. In this study we characterized the response of α4β7+/CD4+ T cells to costimulation via MAdCAM in order to better understand whether the induced phenotype would support an enhanced degree of viral replication. We found that CD4+ T cells upregulated CCR5, an HIV coreceptor, in response to MAdCAM costimulation. We also observed the rapid induction of CD69, a known marker of activation. This induction was restricted to α4β7+ cells, including both the CD45RO+ α4β7+ memory subset and CD45ROneg/α4β7+ naive cell subset. We also observed decreased surface expression of two MAdCAM ligands; integrin β7+ was down-regulated within four hours post MAdCAM costimulation and L-selectin was shed with similar kinetics. This shedding occurred primarily in the CD45ROneg subset. Overall these results indicate that MAdCAM-mediated costimulation through α4β7 activates CD4+ T cells in a unique manner that is likely conducive to viral replication. Of note we found that CCR5, the principal HIV coreceptor, was upregulated. Interestingly, the surface expression of two MAdCAM ligands, L-selectin and α4β7, were both reduced.
Regulator of G Protein Signaling 10 is a novel regulator of intestinal inflammation
Authors: Houser Madelyn C , Tansey Malú G 
Published: January 2023

Abstract
Sustained intestinal inflammation has been implicated in the development and progression of numerous diseases, including neurodegenerative disorders such as Parkinson’s disease (PD). Identifying mechanisms that regulate intestinal immune responses can provide insight into the pathogenesis of these disorders and present new therapeutic targets.
Regulator of G protein Signaling 10 (RGS10) is a GTPase-activating protein that alters proinflammatory activity in microglia, macrophages, and T cells and also regulates immune cell chemotaxis. Furthermore, RGS10 is protective in animal models of PD pathology and potentially deficient in human PD patients. These findings and the known involvement of the intestine in PD prompted an investigation of the function of RGS10 in the gut, a system in which it had not previously been examined.
This study determined that RGS10 is expressed in intestinal epithelial cells and at higher levels in intestinal immune cells where it acts as an anti-inflammatory regulator. RGS10-null mice exhibit greater baseline intestinal inflammation, compromised tight junction integrity, and altered microbiota composition with greater abundances of pathobionts compared to WT mice. These changes are physiologically relevant, as RGS10-deficient animals exhibit more severe pathology in response to intestinal injury and inflammation than do their WT counterparts. Levels of α-synuclein – the protein that aggregates in brains and colons of PD patients – are also higher in the intestine of RGS10-null mice, likely as a result of chronic inflammation. This study identifies RGS10 as a novel regulator of mucosal immune function and suggests that reduced levels of this protein may contribute to pathology in human disease.
Innate immune protein lipocalin-2 and iron mitigate EGCG-mediated inhibition of myeloperoxidase
Authors: Yeoh Beng San , Olvera Rodrigo Aguilera , Singh Vishal , Xiao Xia , Kennett Mary J. , Joe Bina , Lambert Joshua D. , Vijay-Kumar Matam 
Published: January 2023

Abstract
Green tea (Camellia sinensis, Theaceae) contains a plethora of antioxidant polyphenols that may promote health. Amongst these polyphenols, the (−)-epigallocatechin-3-gallate (EGCG) is extensively studied for its potential therapeutic properties in models of inflammatory bowel disease (IBD), although its molecular mechanism is not completely understood. Here, we demonstrate that EGCG can inhibit the activity of myeloperoxidase (MPO; a pro-oxidant neutrophil enzyme associated with IBD flares) in a dose-dependent manner in vitro. By using spectral analysis, we show that EGCG prevents the MPO-catalyzed reaction by reverting the reactive peroxidase heme back to its native inactive ferric state. Oral administration of EGCG to dextran sodium sulfate (DSS)-induced colitic mice significantly reduced the colonic MPO activity and alleviated pro-inflammatory mediators associated with gut inflammation, confirming that our findings extend to in vivo conditions as well. In light of previous reports that EGCG can complex with innate immune protein lipocalin-2 and iron, we next tested whether these factors can affect the bioactivity of EGCG. Intriguingly, the presence of lipocalin-2 or iron significantly mitigate the ability of EGCG to inhibit MPO in vitro. Further, the efficacy of EGCG against DSS-induced gut inflammation is diminished when orally co-administered with iron. These findings indicate that EGCG-mediated inhibition of MPO could be one of the mechanisms by which EGCG exerts its mucoprotective effects. However, counter-regulatory factors such as host lipocalin-2 and dietary iron could explain why EGCG does not ameliorate gut inflammation in some IBD patients.
Toll-Like Receptor abundance in colonic epithelium is selectively altered in HIV disease and partially normalizes with effective Antiretroviral Therapy
Authors: McCausland Marie R , Levine Alan D 
Published: January 2023

Abstract

Background
Since the intestinal mucosa and microbiome are disrupted in HIV disease, we studied the abundance of innate immune sensors, Toll-Like Receptors (TLR), in the epithelia of patients with Viremia, prior to antiretroviral therapy (ART) initiation, Immune Success (IS- &gt;500 CD4 T cells/ul after 2 years of ART; suppressed viremia), and Immune Failure (IF- &lt;350 CD4 T cells/ul after 2 years of ART; suppressed viremia). Viremia and IF show increased systemic immune activation; therefore, modulation of intestinal TLR abundance may offer a mechanism behind persistent inflammation in HIV.

Method
Immunofluorescence for TLR3, TLR4, and TLR9 on sections cut from paraffin embedded colonic biopsies of uninfected, viremic, IS, and IF was imaged with a DeltaVision microscope and quantified with Metamorph software.

Results
Viremic patients have significantly higher viral TLR9 and TLR3, and significantly lower bacterial TLR4, on the surface epithelium when compared to levels seen on uninfected control. Viremic patients have significantly higher TLR9, similar TLR3, and significantly lower TLR4 expression, in the crypts when compared to uninfected control. TLR9 abundance remains elevated in IF, while normalization occurs in IS. TLR3 abundance on surface epithelium and crypt is even more elevated in IF and IS, suggesting an effect of ART. TLR4 abundance on surface epithelium normalizes in IF and IS; in the crypt, in IS TLR4 decreases further.

Conclusion
Epithelial TLR abundance is selectively altered in HIV disease; effective ART partially normalizes some TLRs, and enhances TLR3. Mucosal TLR desensitization or hyper-vigilance, possibly caused by disrupted cytokine levels in the HIV+ colon, may contribute to systemic inflammation.