bluuebunny/crossref_metadata_2025_split huggingface dataset:
Peripherally-induced brain tissue resident memory CD8 T cells mediate protection against CNS infections
Authors: Urban Stina Lisa , Jensen Isaac J , Pewe Lecia L , Badovinac Vladimir P , Harty John T 
Published: January 2023

Abstract
The central nervous system (CNS) is classically viewed as an immune privileged site; however, recent advances in the field highlight the importance between the interaction of the peripheral immune system and the CNS in maintaining tissue homeostasis. Tissue resident memory (Trm) CD8 T cells have been described in almost every organ and are shown to provide a first line of defense against secondary invading pathogens. Trm CD8 T cells in the CNS have been described using multiple models of brain infections, but it is unknown whether CNS infection is required for development of brain Trm populations. Here, we show that peripheral infections and immunizations generate robust antigen (Ag)-specific CD8 memory T cells in the brain that adopt a Trm phenotype with a unique brain resident signature not prevalent in other organs. Upon peripheral antibody mediated depletion of circulating memory T cells, this brain signature was enriched without reducing proportion or number of CNS residing memory CD8 T cells. 2-photon microscopy revealed peripherally-induced Trm are highly dynamic in the CNS. CD8 T cells surveyed the tissue with multiple mechanisms including moving along the blood vessels, traveling long distances in apparently random fashion or remaining stationary. Most importantly, peripherally-induced Trm cells in the CNS showed enhanced cytokine production and provided protection against brain infections by reducing both bacterial and viral loads and morbidity and mortality associated with infections. These data increase our understanding of how peripheral immunization strategies can generate brain Trm populations and will guide potential use of T cells as therapeutic strategies against CNS infections and neurological diseases.
DAMP-mediated cardiac dysfunction: cardiomyocytes as actors and target of innate immune response
Authors: Weber Birte , Lackner Ina , Baur Meike , Gebhard Florian , Relja Borna , Marzi Ingo , Kalbitz Miriam 
Published: January 2023

Abstract

Objective
Severe trauma often led to a systemic inflammatory response, accompanied by release of danger associated molecular patterns such as the high mobility group box-1 protein (HMGB-1) and extracellular histones. The aim of this study was to clarify the influence of HMGB-1 and extracellular histones on human cardiomyocytes, in context of posttraumatic cardiac dysfunction.

Material and Methods
Cell viability, mitochondrial respiration and calcium handling of human cardiomyocytes in presence of extracellular histones or HMGB-1 were evaluated. A hemadsorption filter was tested to eliminate extracellular histones in vitro and from blood samples of multiple trauma patients (mean injury severity score &gt;16).

Results
Incubation of human cardiomyocytes with HMGB-1 or histones were associated with impaired calcium handling, mitochondrial respiration and reduction of cell viability. Furthermore, human cardiomyocytes release further cardio-depressive cytokines in the presence of extracellular histones and HMGB-1 such as IL-1b and TNF. Hemadsorption of human plasma after multiple trauma showed a significant reduction of histone levels. Furthermore, in vitro analysis of hemofiltration capacity detected a dose dependant reduction of extracellular histones.

Conclusion
Despite their positive intention as part of the immune reaction, HMGB-1 and extracellular histones are associated with detrimental effects on cardiomyocyte viability, calcium handling and mitochondrial function. Moreover, presence of DAMPs resulted in additional release of cardiodepressive cytokines. Therefore, in the context of tissue trauma cardiomyocytes are target and actor at the same time.
Immunosenescence in Type 2 Diabetic Patients with Chronic Renal Disease
Authors: Shu Kai-Hsiang , Chiu Yen-Ling 
Published: January 2023

Abstract

Background
Immunosenescence is an important challenge for an aging population. It is known that patients with end-stage renal disease suffer from immunosenescence and premature T cell aging but whether such changes occur in diabetic patients with less severe chronic renal disease is unclear.

Methods
832 patients with type 2 diabetes with different levels of renal function were recruited in this study. Immunosenescence was analyzed by staining peripheral blood with two immunophenotyping panels and analyzed by multicolor flow cytometry.

Results
Out of all the 832 participants, there were 171 patients with stage 3 CKD and 46 patients with 4/5 CKD. Compared to patients with eGFR&gt;60 ml/min, patients with more severe CKD showed progressive decreased total CD3+ T cell and CD4+ and CD8+ T cell, but not monocyte numbers. In addition, immunosenescence, as defined by various phenotypic markers, showed significant upregulation in both stage 3 and stage 4/5 patients. However, immunosenescence was not associated with proteinuria level nor worse glucose control. In age and sex adjusted regression models, stage 3 CKD patients already exhibited significant elevated percentages of CD28−, CD127− and CD57+ cells among CD8+ T cells when compared to patients with eGFR&gt;60 ml/min. In addition, stage 3 CKD patients exhibited depressed HLA-DR and CX3CR1 expression in specific monocyte subpopulations.

Conclusion
Level of immunosenescence is not significantly associated with proteinuria nor glucose control in type 2 diabetes patients. Both T cell and monocyte compartment exhibit characteristics of immunosenescence during renal function decline, starting from stage 3 CKD.
The IgM and IgG subclass distribution of anti-Galactose-alpha-1,3-galactose and anti-N-glycolylneuraminic acid antibodies in healthy adults
Authors: Kang Hee Jung 
Published: January 2023

Abstract

Background
The major xenoreactive antibodies (Abs), anti-galactose-alpha-1,3-galactose (Gal) and anti-N-glycolylneuraminic acid (Neu5Gc), exist naturally in humans and can contribute to several immunological pathogenesis in xenotransplantation. In this study, we investigated the serum titers of anti-Gal and anti-Neu5Gc Abs including the IgM, IgG, and IgG subclasses in humans to gather basic population data before launching clinical xenotransplantation.

Methods
Serum titers of anti-Gal and anti-Neu5Gc Abs were measured in 380 healthy adults using an in-house-developed enzyme-linked immunosorbent assay. The detection frequency and distribution of anti-Gal and anti-Neu5Gc IgM, IgG and IgG subclass were evaluated.

Results
The detection frequencies of Abs were as follows: for anti-Gal, IgG, 95.0%; IgM, 99.2%; IgG1, 23.2%; IgG2, 94.5%; IgG3, 12.4%; and IgG4, 3.4%, and for anti-Neu5Gc, IgG, 96.6%; IgM, 87.4%; IgG1, 1.6%; IgG2, 46.3%. The median titers of anti-Gal IgG (1,198 ng/ml, range &lt;401 – 128,758 ng/ml) and IgM (996 ng/ml, range &lt;113 – 24,698 ng/ml) were significantly higher than those of anti-Neu5Gc Abs (IgG, 194 ng/ml, range &lt;30 – 12,415 ng/ml; IgM, 328 ng/ml, range &lt;154 – 6,514 ng/ml; all P&lt;0.001). IgG2 of both anti-Gal and anti-Neu5G Abs correlated better with the IgG class than other IgG subclasses (rs = 0.762, P &lt; 0.001; rs = 0.606, P &lt; 0.001).

Conclusions
Most healthy adults possess anti-Gal and anti-Neu5Gc IgG and IgM in their sera. Overall, the titers of anti-Gal Abs are higher than those of anti-Neu5Gc Abs. IgG2 seems to be the main IgG subclass in both anti-Gal and anti-Neu5Gc natural Abs. Changes in the titers of these Abs would be a clue to understand an immunological pathogenesis in the recipients of xenotransplantation.
Obesity contributes to a dysfunctional regulatory T Cell phenotype within adipose tissue
Authors: Smith Alan J , Liu Joey , Yilmaz Ahmet , Wright Valerie , Bradley David , Hsueh Willa A 
Published: January 2023

Abstract
Adipose tissue (AT) regulatory T Cells (Tregs) play a key role in regulating inflammatory and metabolic responses. Obesity is associated with a decrease in AT Tregs as well as an increase in tissue inflammation and systemic insulin resistance in both humans and mice. We hypothesize that, in addition to the decrease in AT Treg number, there is a dysfunctional Treg phenotype caused by the increased inflammatory state within obese AT. We isolated Tregs from AT and peripheral blood(PB) from lean and obese individuals. Real-time PCR analysis was used to measure the expression of several known markers for T cell exhaustion. Protein expression of each marker was validated using FACS analysis. When compared to PB, there was a significant increase in PD-1 expression on AT Tregs. PD-1 and TIGIT were increased in Tregs isolated from obese vs. lean individuals, while CD127 expression was reduced. To determine if PD-1 expression correlates with Treg dysfunction, isolated AT and PB Tregs were added to CFSE-labeled PBMC. After 4 days culture, PB Tregs significantly inhibited proliferation but there was less suppression by AT Tregs. RNAseq analyses of PD-1 high vs. PD-1 negative AT and PB Tregs revealed a unique expression phenotype within AT Tregs. AT PD-1 high Tregs express altered metabolic and inflammatory pathways promoting loss of Tregs and increased inflammation. These data suggest that Treg exhaustion may explain the decreased Treg abundance in AT of obese individuals, which has important metabolic implications. (Partially supported by Foods for Health, a focus area of the Discovery Themes Initiative at The Ohio State University)
Characterization of DOCK8 as a novel gene associated with hemophagocytic lymphohistiocytosis
Authors: Cron Randy Q , Zhang Mingce , Cron Remy R , Absher Devin , Atkinson Prescott , Chatham Winn 
Published: January 2023

Abstract

Background
Hemophagocytic lymphohistiocytosis (HLH) is life threatening, presenting with fever, pancytopenia, coagulopathy, & multi-organ dysfunction (MOD). Familial HLH (fHLH) results from homozygous defects in perforin mediated cytolytic pathway genes used by NK & CD8 T cells. Up to 40% of secondary HLH (sHLH) patients have heterozygous defects in fHLH genes resulting in decreased cytolytic function, prolonged interaction with antigen presenting cells, & subsequent increased pro-inflammatory cytokines resulting in MOD. As NK cell dysfunction is common in HLH, we screened for novel gene associations.

Methods
By whole genome sequencing, 4 sHLH patients had mutations in DOCK8 (guanine exchange factor) critical to NK cell function. DOCK8 mutations, or wild-type (WT) sequence, were introduced into NK92 cell lines by foamy virus (FV), or by disrupting endogenous NK92 DOCK8 genes (CRISPR). WT & mutant DOCK8 NK92 cells incubated with K562 cells were compared for cytolysis, degranulation (CD107a), & cytokines [interferon-γ (IFNγ), tumor necrosis factor (TNF)].

Results
2 HLH patients had rare heterozygous DOCK8 mutations; 2 had the same DOCK8 polymorphism (D63N). 1 novel mutation was missense (A261V); 1 was a splice acceptor variant (c.54-1G&gt;T, 0.03%). The A261V mutant decreased NK lytic activity by CRISPR or FV (50% vs. WT, p=0.007), & decreased CD107a by &gt;50% (p=0.0129). The A261V DOCK8 NK cells increased expression of IFNγ & TNF by &gt;200% (p=0.0192 & p=0.0027). The D63N NK cells had similar results. The DOCK8 splicing mutant disrupted splicing by exon trapping.

Conclusion
Heterozygous DOCK8 mutations contribute to HLH by dominant-negative or hypomorphic effects yielding decreased cytolysis & increased inflammatory cytokines.
Cell-specific transcriptional signature of human immune cells in GESTALT
Authors: Kaila Mary , Shapiro Benj , Dunn Christopher , Singh Amit , Bektas Arsun , Kim Jaekwan , Piao Yulan , Wood William , Nguyen Cuong , Wallace Tonya , Mckelvey Julia , Zukley Linda , Battle Alexis , De Supriyo , Weng Nan-Ping , Sen Ranjan 
Published: January 2023

Abstract
The Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing (GESTALT) study is designed to understand the basis of immune dysfunction that accompanies human aging. Twelve immune cell subsets were purified from hundred healthy donors of age range 20 – 90 and used for transcriptomic, proteomic and epigenomic analyses. Additionally, the chronic inflammatory components of aging were assessed by analysis of serum cytokines. The results were first used to identify cell-specific signatures of each omic study and determine their inter-relationships. These observations define lineage identity of human immune cells and change that occur with differentiation of adaptive immune cells to memory cells.
A triple “no” to the enrichment of immune genes at X files
Authors: Meester Irene , Manilla-Muñoz Edgar , Solís-Soto Juan Manuel , Paniagua-Frausto Gustavo A. , Carrión-Alvarez Diego , Rodríguez-Rangel Ximena , Ruiz-Rodríguez C. Orelli 
Published: January 2023

Abstract

Objective
As sex bias in immune function has been contributed partly to a preponderance of immune system-related genes (ISRG) on the X-chromosome, we performed a comparative study to verify this viewpoint.

Methods
The comparative study consisted of three complementary strategies:

Results
The X chromosome had less ISRG than the median of the autosomal chromosomes. Among X-linked genes, ISRG ranked 4th after genes dedicated to the reproductive and nervous systems or to development, proliferation and apoptosis (not ranking genes dedicated to basal metabolism nor genes of unknown function). On the Y chromosome, ISRG ranked 2nd, and at the pseudoautosomal region 1st. Various epigenetic controllers, X-linked MSL3 and Y-linked KDM5D and UTY, were preferentially expressed in leukocytes and deserve further attention with respect to a possible role in sex biased expression or its neutralisation.

Conclusions
The X chromosome is not enriched for ISRG. Thus, gene-related causes for sex bias in immune responses cannot be due to the X-linked ISRG number, but may be due to 1) particular sex chromosome-linked genes, 2) sex-biased regulation of the expression of ISRG in leukocytes and/or lymphoid organs. (Funding: UDEM, UIN19592)
A clinical trial comparing aliskiren with enalapril for the treatment of C3 glomerulopathy
Authors: Karpman Diana , Hallander Hilda , Kristoffersson Ann-Charlotte , Bekassy Zivile 
Published: January 2023

Abstract

Introduction
To date there is no established, effective treatment for C3 glomerulopathy, encompassing both Dense Deposit Disease and C3 glomerulonephritis. We have previously reported that renin mediates complement activation by cleaving C3 and found that the direct renin inhibitor aliskiren blocked complement activation by renin and inhibited complement activation systemically and in the kidneys in three patients with Dense Deposit Disease. Theoretically enalapril should increase renin without blocking its effect and therefore we will conduct a clinical trial to compare these two treatments.

Material and methods
We will include patients to be treated with aliskiren or enalapril (15 in each arm). Recruitment will take place in Swedish hospitals. Children 6 years or older with a glomerular filtration rate equal to or above 50 ml/min/1.73 m2 and adults equal to or above 30 ml/min/1.73 m2 will be included. Patients will be randomized for treatment with aliskiren or enalapril, as monotherapy or in combination with immune suppressive medications. After 6 months patients will switch to the other treatment and continue on the second treatment for an additional 2.5 years. Patients will be followed regularly regarding renal function, proteinuria, blood pressure, activation of the renin-angiotensin system and complement activation assays. After 1–3 years, when medically indicated or at the end of the study, a repeat renal biopsy will be performed to validate the effect of treatment on renal morphology and complement deposition.

Conclusions
The results of this study may provide more scientific evidence for, or against, the use of aliskiren in patients with C3 glomerulopathy.
Single cell multiplex mass cytometry reveals differential abundance of specific cytotoxic memory and regulatory T cell populations in human hypertension
Authors: Alexander Matthew , Dale Bethany L , Elijovich Fernando , Wogsland Cara E , Irish Jonathan M , Madhur Meena S 
Published: January 2023

Abstract
Emerging evidence from animal models demonstrates the importance of a variety of innate and adaptive immune cells in the pathogenesis of hypertension. We hypothesized that the abundance and phenotype of circulating immune cell subsets is altered in human hypertension reflecting disease pathophysiology. We thus performed high dimensional, single cell profiling of peripheral blood mononuclear cells in humans with a panel of 31 cell surface markers using mass cytometry. Unsupervised computational analysis from 11 control and 10 hypertensive individuals matched for age, gender, race, and body mass index revealed an approximately two-fold increase in a novel memory helper CD62L+CCR7−CD161lo T cell subset in hypertensive subjects. In addition, manual gating for major known immune cell populations revealed a 40% decrease in memory cytotoxic T cells and a 29% decrease in regulatory T cells in hypertensive individuals. Unsupervised analysis of the cellular subsets of these populations using Phenograph demonstrated a selective 63% decrease in PD-1+ memory cytotoxic T cells and 49% decrease in CCR10+ regulatory T cells in hypertension. In a validation cohort, circulating PD-1+ memory cytotoxic and CCR10+ regulatory T cells were significantly decreased by 30% and 50%, respectively, without a difference in the memory helper T cell subset. Taken together, these results demonstrate novel and reproducible decreases in circulating PD-1+ memory cytotoxic and CCR10+ regulatory T cell populations in human hypertension. These findings may provide new insights into hypertension pathogenesis and potential therapeutic targets.
The expression and function of complement inhibitory protein CD55 in chronic rhinosinusitis with nasal polyp
Authors: Ruan Jianwen , Wang Hai , Liu Zheng 
Published: January 2023

Abstract

Background
The factors that regulating classic complement activation in chronic rhinosinusitis with nasal polyps (CRSwNP) remain largely unknown. CD55 functions as a complement regulatory protein by inhibiting the formation of C5 convertases.

Objectives
To investigate the expression, regulation, and function of CD55 in CRSwNP.

Methods
The expression of CD55 in sinonasal mucosal samples was investigated by quantitative RT-PCR, Western blotting, and immunofluorescence. The levels of C3d and C5b-9 in nasal tissue homogenates were analyzed by ELISA. Primary human nasal epithelial cells were cultured to investigate the regulation and function of CD55.

Results
The mRNA and protein levels of CD55 were reduced in eosinophilic nasal polyps compared with those in noneosinophilic nasal polyps and control tissues. CD55 was prominently expressed by nasal epithelial cells in sinonasal mucosa, which was downregulated by IL-4, IL-13, and Dermatophagoides pteronyssinus group 1. The levels of C3d and C5b-9 were upregulated in eosinophilic nasal polyps and were inversely correlated with CD55 expression levels. The conversion of C3 to C3d by primary human nasal epithelial cells was enhanced in those from eosinophilic nasal polyps in comparison to those from noneosinophilic polyps. The mRNA and protein expression of E-cadherin and ZO-1 were downregulated in eosinophilic nasal polyps and were positively correlated with CD55 expression levels.

Conclusion
The reduced expression of CD55 caused by local type 2 milieu lead to hyperactivation of complement and subsequent C5b-9 formation, which may further disrupt epithelial integrity in patients with eosinophilic CRSwNP.
Understanding Genetic and Immune Cellular-Signaling Defects in Common Variable Immunodeficiency with Granulomatous Lymphocytic Interstitial Lung Disease
Authors: Lui Victor , Baxter Ryan , Routes John Michael , Verbsky James , Hsieh Elena WY 
Published: January 2023

Abstract
Common Variable Immunodeficiency (CVID) is a heterogenous disorder characterized by hypogammaglobulinemia, failure to mount vaccine responses, recurrent sinopulmonary infections. Furthermore, a subset of CVID patients develop various autoimmune and lymphoproliferative complications, highlighting the dysregulated immune mechanisms underlying the disorder. One such autoimmune complication is granulomatous lymphocytic interstitial lung disease (GLILD) which is a major cause of mortality in CVID. The clinical heterogeneity of CVID indicate that it is a collection of disorders with monogenic and polygenic defects. Due to the genetic and phenotypic complexity of CVID, our understanding of the immunopathogenesis of CVID and the development of its complications is limited. Our goal is to elucidate relationships between genetic variants and their downstream phenotypic and signaling defects in CVID patients with GLILD. We hypothesize that specific genetic variants will result in unique immune cellular (and signaling) signatures in CVID with GLILD. To identify these cellular and molecular signatures, we integrate whole exome sequencing and mass cytometry data. We examined cellular subsets affected by perturbed T and B cell receptor signaling pathways via mass cytometry, and then correlate these signatures with specific genetic variants identified through whole exome sequencing. These results will reveal mechanisms of immune dysregulation in CVID with GLILD. In CVID patients with GLILD, we find expansion of CD57+ CD8+ T cells, which may represent a class of senescent cells. We also find enrichment of CD21-low B cells within CVID patients, regardless of GLILD status.
Cholesterol crystals use both extracellular and intracellular complement to increase NLRP3 signalling pathways in atherosclerosis
Authors: Espevik Terje , Niyonzima Nathalie , Bakke Siril Skaret , West Erin , Rahman Jubayer , Aukrust Pål , Kemper Claudia , Mollnes Tom Eirik , Halvorsen Bente 
Published: January 2023

Abstract
During atherosclerosis, cholesterol precipitates into cholesterol crystals (CC) in the vessel wall which trigger plaque inflammation. In the present, study we examined the relation between complement, NLRP3 signalling pathways and CC in patients with coronary artery disease and carotid atherosclerosis. We analysed plasma, peripheral blood mononuclear cells (PBMC) and carotid plaques from patients with different degrees of atherosclerosis applying ELISAs, multiplex, qPCR, immunohistochemistry, gene profiling and bioinformatics. Transcripts of IL-1β and NLRP3 were increased and correlated in PBMC from patients with acute coronary syndrome. Immunohistochemistry of carotid plaques showed pronounced accumulation of C1q and terminal C5b-9 complement complex (TCC) around CC-clefts. Transcripts of C5aR1, C5aR2 and C3aR1 were increased in carotid plaques compared to control arteries. Priming of carotid plaques ex vivo with C5a and TNF followed by CC incubation resulted in pronounced upregulation of NLRP3 inflammasome components. Importantly, we found that intracellular “C5 system” is a major contributor of CC induced IL-1β in human macrophages through the action of C5aR1 present on mitochondria. Mechanisms underlaying the role of intracellular C5 in this process will be described. The data suggest that CC formation is an important extracellular and intracellular complement activator which in turn results in IL-1β expression and activation of NLRP3 in atherosclerotic plaques.