bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunological characteristics and clinical significance of urinary CD11c+ macrophages in lupus nephritis
Authors: Kim Jihye , Hong Seokchan , Lee Chang-Keun 
Published: January 2023

Abstract
Kidney-infiltrating immune cells may be involved in the pathogenesis of lupus nephritis (LN). We aimed to analyse the immunological characteristics and clinicopathologic relevance of urinary CD11c+ macrophages in patients with LN. Compared with patients with no LN or non-proliferative LN, those with proliferative LN had significantly higher urinary levels of CD11c+ macrophages, which were strongly correlated with their anti-dsDNA antibody titer. Urinary CD11c+ macrophages expressed pro-inflammatory cytokines, such as interleukin (IL)-6 and IL-1β, and resembled infiltrated monocytes rather than tissue-resident macrophages in terms of surface marker expression. They showed high expression of the chemokine receptor CXCR3, whose cognate chemokine IP-10 was expressed by urinary tubular epithelial cells (TECs). When treated with sera from systemic lupus erythematosus patients, peripheral monocytes acquired the morphological and functional properties of urinary CD11c+ macrophages, which was blocked by DNase treatment. Finally, SLE sera treated monocytes induced fibronectin expression, apoptosis, and cell detachment in HK-2 cells via IL-6 production. Importantly, the number of urinary CD11c+ macrophages was significantly associated with chronicity indices, including tubular atrophy and interstitial fibrosis, and renal response in LN patients. CD11c+ macrophages may be involved in the pathogenesis of tubulointerstitial damage in LN.
High dimensional single cell characterization of autoreactive CD8 T-cells reveals heterogeneous phenotypes that play a role in disease progression in Type 1 Diabetes
Authors: Nguyen Hai T , Dufort Mathew T. , Speake Cate , Greenbaum Carla , Linsley Peter S , James Eddie A 
Published: January 2023

Abstract
Type 1 Diabetes (T1D) is caused by beta cell destruction, eventually resulting in loss of glycemic control. Following onset, subjects with T1D exhibit diverse amounts of residual c-peptide, indicating varying levels of beta cell function. Persistence of c-peptide is correlated with reduced risk of complications and its preservation has been used as an endpoint in clinical trials. However, the immunologic factors that differentiate subjects who retain measurable c-peptide from those who do not are not well characterized. We investigated the number and phenotype of beta cell specific CD8+ T-cells in peripheral blood samples from a cohort of T1D subjects, stratified into slow progressors (c-peptide &gt; 0.1ng/ml) and rapid progressors (undetectable c-peptide), including longitudinal samples. Using tetramers corresponding to HLA-A2 epitopes, we enumerated epitope specific T-cells and sorted single cells for RNA-Seq. Differential gene expression between slow and rapid progressors indicated differences in effector, exhaustion, and regulatory pathways which were consistent with a recently published high dimensional CyTOF data set. Assembly of autoantigen specific TCRs revealed differences in clonal expansion for specific cell clusters. Pseudotime trajectory analysis of the scRNAseq data revealed that CD8+ T cells expressing the same TCR resided in different phenotypic end states. Furthermore, flow cytometric analyses demonstrated differential expression of lineage-specific cell surface markers, which correlated well with the transcriptional profiles within each cluster. Cumulatively, we discovered specific aspects of T cell function and repertoire that differ between slow- and rapid-progressing T1D subjects.
Role of ICOS expressing CXCR5+PD-1+ T helper cells in pemphigus vulgaris
Authors: Kim A Reum , Han Dawoon , Choi Ji Young , Seok Joon , Kim Song-Ee , Seo Seong-Hoon , Park Su-Hyung , Kim Soo-Chan , Shin Eui-Cheol , Kim Jong Hoon 
Published: January 2023

Abstract
Pemphigus vulgaris (PV) is an autoimmune bullous disease mediated by autoantibodies against desmoglein (DSG) 3 which is the adhesive molecule in the desmosomes. DSG3-specific CD4+ helper T cells have been demonstrated to be involved in autoantibody production and pathogenesis in mouse models and human patients. However, it remains unknown if T follicular helper (Tfh) cells expressing ICOS play a role in the pathogenesis of PV although ICOS+ Tfh cells have a critical role in various autoimmune diseases. The aim of this study was to analyze the immunological characteristics and pathogenic roles of ICOS+ Tfh cells using PV mouse model and peripheral blood mononuclear cells (PBMCs) from pemphigus patients. In addition, we tried to investigate the therapeutic effect of ICOS-ICOSL blockade in PV mice. We immunized the DSG3−/− mice by grafting skin of wild-type mice, then we adoptively transferred CD4+ T and B cells from the DSG3-primed DSG3−/− mice to RAG1−/− mice. We found that ICOS+ Tfh cells were associated with B cell development in the mouse model. By using an MHC class II tetramer, we showed that DSG3-specific ICOS+ Tfh cells were increased and significantly related to the level of anti-DSG3 antibody. In PBMCs from the patients with pemphigus vulgaris, the frequency of ICOS+CXCR5+PD-1+ memory CD4+ T cells was positively correlated with DSG3 autoantibody levels. Furthermore, the administration of anti-ICOS blocking antibody to PV mice in vivo decreased the production of anti-DSG3 antibody and prevented disease activation. Therefore, ICOS+CXCR5+PD-1+ T helper cells are associated with the disease progression and can be a therapeutic target for PV.
Glucocorticoid receptor modulates myeloid-derived suppressor cell function via mitochondria respiration and metabolism in immune thrombocytopenia
Authors: Wang Shuwen , Xie Jie , Liu Yan , Peng Jun 
Published: January 2023

Abstract

Methods
We collected 27 immune thrombocytopenia (ITP) patients who had received high-dose dexamethasone treatment. The myeloid-derived suppressor cells (MDSCs) were induced in vitro and CHIP-qPCR assays were performed. Seahorse XF analyzer was used to analyze oxygen consumption rate and parameters of mitochondrial function of MDSCs. MDSCs were treated with CPT-1 inhibitor, etomoxir, to explore the effect of inhibiting fatty acid oxidation. Glucocorticoid receptor (GR) expression was blocked in murine MDSCs which were transplanted into ITP mice.

Results
The mRNA expression of GR and mtDNA-encoded genes (ATP8, COX1, CYTB, ND1, ND5), as well as the binding of GR to mtDNA in MDSCs were decreased in steroid-resistant ITP group compared to steroid-responsive ITP group and healthy controls. MDSCs in steroid-resistant patients had decreased levels of basal respiration, maximal respiration and ATP production, suggesting that the mitochondria of MDSCs in steroid-resistant group had lower activities of electron transport chains and oxidative phosphorylation. The function of MDSCs to inhibit T-cell proliferation was decreased in steroid-resistant group. Etomoxir reduced the ability of MDSCs to block T-cell proliferation in steroid-responsive group, but did not alter the suppressive function of MDSCs on T cells in steroid-resistant group. ITP mice transplanted with GR siRNA-treated MDSCs showed lower platelet counts than those with control siRNA-treated MDSCs, suggesting that the function of MDSCs to ameliorate ITP relied on GR.

Conclusions
This study demonstrated that GR-associated MDSCs impairments are involved in the pathogenesis of ITP. It might be related to the modulation of mitochondrial respiration and metabolism by GR.
Anti-idiotypic network involved in restoring ADAMTS13 activity in immune-mediated thrombotic thrombocytopenic purpura (iTTP)
Authors: Heeb Silvan Rolf , Schaller Monica , Hovinga Johanna Anna Kremer 
Published: January 2023

Abstract
The culprit of iTTP, a fatal autoimmune disease is a severe deficiency of the von Willebrand factor-cleaving protease ADAMTS13, caused by autoantibodies inhibiting its enzymatic activity. The pathophysiology upholding remission in certain patients but leading to relapse in others is unknown. We hypothesize that one mechanism keeping pathogenic autoantibodies in check is a network of anti-idiotypic antibodies, which we aimed to identify and characterize.
From splenic mononuclear cells of two frequently relapsing iTTP patients (A and C), the anti-idiotypic IgG1 Fab κ/λ repertoire was amplified by phage display technology on previously generated selecting monoclonal anti-ADAMTS13 Fabs (Schaller et al., Blood 2014). Purified Fabs were pooled (pools A (n=4) and C (n=4)) and each pool was tested for its ability to neutralize anti-ADAMTS13 antibodies thereby restoring ADAMTS13 activity in plasma of 22 iTTP patients using the FRETS-vWF73 assay.
Single anti-idiotypic clones revealed a highly diverse IGHV gene usage within and between the two iTTP patients, but four IGHV genes were shared among them. Partial neutralization of functional ADAMTS13 inhibitors of &gt;2BU/ml in 3/11 (27%) and 5/11 (45%) patients and full neutralization in 2/11 (18%) and 3/11 (27%) patients with lower inhibitor titer (1–2BU/ml) were shown for pools A and C, respectively.
To summarize, we have identified functional anti-ADAMTS13 anti-idiotypes in the splenic IgG repertoire of two patients underlining the role of an anti-idiotypic response involved in remission of iTTP. The contribution of single anti-idiotypic Fabs to the neutralization potential and plasma mixing studies investigating acute and remission phase antibody repertoires are underway.
Increased expression of EZH2 is mediated by higher glycolysis and mTORC1 activation in lupus CD4+ T cells
Authors: Sawalha Amr , Zheng Xiaoqing , Tsou Pei-Suen 
Published: January 2023

Abstract

Objective
EZH2 is overexpressed in lupus CD4+ T cells. Increased disease activity in lupus patients is associated with a pro-inflammatory epigenetic shift in naïve CD4+ T cells, likely mediated by EZH2. Here we aim to understand the upstream mechanisms underlying EZH2 overexpression in lupus CD4+ T cells.

Methods
Naïve CD4+ T cells were isolated from lupus patients and then stimulated with anti-CD3/anti-CD28. qPCR and Western blotting were used to measure mRNA and protein expression levels, respectively. 2-Deoxy-D-glucose (2-DG) was used to inhibit glycolysis. mTORC1 signaling was inhibited using rapamycin. Oxidative stress was induced by H2O2.

Results
Because glycolysis is increased in lupus CD4+ T cells and glycolysis regulates miR-101 and miR-26a, which target EZH2, we examined the effect of inhibiting glycolysis on EZH2 expression. 2-DG significantly inhibited EZH2 expression in lupus CD4+ T cells. In addition, 2-DG restored the expression of miR-101 and miR-26a, suggesting that suppression of EZH2 by 2-DG might be mediated by miR-101 and miR-26a. Because mTORC1 is activated in lupus CD4+ T cells in part due to increased oxidative stress, and mTORC1 activation increases glycolysis, we hypothesized that mTORC1 mediates increased EZH2 expression. Indeed, inhibiting mTORC1 increased miR-101 and miR-26a and suppressed EZH2 expression in lupus CD4+ T cells. Further, H2O2 treatment increased EZH2 expression, however, this effect appears to be independent of miR-101 and miR-26a.

Conclusion
Increased EZH2 is mediated by activation of mTORC1 and increased glycolysis in lupus CD4+ T cells. Therapeutic effects from mTORC1 inhibitors and glycolysis inhibitors in lupus might be in part mediated by suppression of EZH2.
Aryl hydrocarbon receptor inhibition and non-canonical signaling activation impact Treg function in autoimmune hepatitis
Authors: Vuerich Marta , Harshe Rasika , Abrahão-Frank Luiza , Mukherjee Samiran , Gromova Barbora , Bonder Alan , Patwardhan Vilas , Robson Simon C. , Longhi Maria Serena 
Published: January 2023

Abstract
Treg are dysfunctional in autoimmune hepatitis (AIH), a severe hepatopathy characterized by hypergammaglobulinemia, presence of serum autoantibodies and interface hepatitis on histology. AIH-derived Treg display impaired expression of CD39, an ectonucleotidase that scavenges extracellular ATP to generate immunosuppressive adenosine. CD39 can be regulated upon activation of aryl-hydrocarbon-receptor (AHR), a mediator of toxin responses that also modulates T-cell immunity. Upon binding to endogenous or exogenous ligands, AHR dimerizes with aryl-hydrocarbon-receptor-nuclear-translocator (ARNT) or other non-canonical factors like estrogen-receptor-alpha (Era) or Kruppel-like-factor-6 (KLF6) to modulate gene expression. AHR is in turn regulated by the aryl-hydrocarbon-receptor-repressor (AHRR) that inhibits the transcriptional activity of the AHR/ARNT complex. We note that, compared to healthy subjects (HS), Treg obtained from AIH patients display increased AHRR levels and heightened expression of non-canonical binding factors Era and KLF6, but comparable AHR and ARNT levels. Differently from HS, AIH Treg do not upregulate CD39 expression and activity upon exposure to the AHR ligands unconjugated bilirubin (UCB), L-Kynurenine and quercetin. Silencing of AHRR and Era via siRNA boosts CD39 in AIH Treg in the presence of UCB and quercetin. We further note that, in AIH Treg, AHR binds Era with higher affinity than ARNT. In conclusion, multiple AHR signaling alterations might impact CD39 and Treg function in AIH. Targeted blockade of AHRR and Era represents a potential therapeutic approach to restore immune homeostasis in AIH and other chronic inflammatory conditions by boosting CD39.
Genetic and infectious regulators of baseline and acute immunity across ancestrally distinct human populations
Authors: Souquette Aisha , Allen Kaity , Oshansky Christine , Tang Li , Wong Sook-san , Jeevan Trushar , Ogunjimi Benson , Schultz-Cherry Stacey , Webby Richard , Gordon Aubree , Rothman Richard , Pekosz Andrew , Thomas Paul Glyndwr 
Published: January 2023

Abstract
Studies have identified genetic, viral, and immunological associations with the quality of anti-influenza immunity and/or influenza disease severity, however, there has not been an integrative analysis of these factors, both at baseline and during acute infection. Using samples from healthy or flu infected human cohorts across 5 countries, we found that herpesviruses (HVs) have unique and interactive effects on cytokine levels specific to anatomic location during flu infection. Similar cytokine associations were also observed in healthy controls. Additionally, HV infection is also associated with decreased flu severity and virus shedding, and increased antibody titers. Associations between cytokine levels and flu severity were consistent in cohorts of similar ancestral and environmental backgrounds, however unique correlates were observed in populations from distinct backgrounds. Further, we identified ~100 variants in immune related genes either enriched in or absent from a given ancestral population, a portion of which are eQTLs at baseline, supporting the potential of host genetics to impact immune variation. Ongoing work focuses on assessing which SNPs are eQTLs in response to bacterial and viral TLR agonists. Ancestry informative marker PCA values and eQTLs will be included in the statistical models to account for the collective effects of infectious, biological, and genetic factors. These results will provide insight into which factors predominantly affect a given immune measure and how this contributes to immune competence and variation across distinct populations. Understanding these interactions will have implications for other infectious diseases, autoimmunity, clinical study design, and immunotherapy.
Synergic effect of combined intervention with clindamycin and PPARγ agonist in an HLA-II mouse model of Group A Streptococcal Necrotizing Fasciitis
Authors: Nookala Suba , Mukundan Santhosh , Combs Colin , Satpati Abhijit , Kotb Malak 
Published: January 2023

Abstract
Group A Streptococcus (GAS, Streptococcus pyogenes) is an important human pathogen that can cause a broad spectrum of diseases ranging from self-limiting pharyngitis and impetigo to deeper, life-threatening invasive infections such as streptococcal toxic shock syndrome and necrotizing fasciitis (NF). An overarching pro-inflammatory cytokine storm and a rapidly progressive tissue destruction lead to significant morbidity and lethal outcomes of GAS NF. Transcriptome profiling of uninfected and GAS infected skin from HLA-II transgenic mouse models of GAS NF revealed strong activation of inflammatory signaling and inhibition of peroxisome proliferator-activated receptor (PPAR) signaling pathways. Specifically, PPARgamma (PPARγ), a lipid ligand-activated transcription factor driving adipogenic and anti-inflammatory effects, was a significantly inhibited upstream regulator and this inhibition was reflected in downregulation of PPARγ-dependent genes. So far, there are no reports on the role of PPARγ in GAS infections. Here, we explored the potential use of the PPARγ selective synthetic agonist, pioglitazone (PZ), in combination with clindamycin (CLN), as a combined therapeutic approach in vivo in an HLA-II mouse model of GAS NF. Although the mechanism of synergy is not understood, our data demonstrate that combined CLN PZ intervention offers significant advantages over treatment with CLN alone, and uncover a new role for PPARγ in attenuating skin lesions, GAS burden, IL-6 and IFN-γ levels, and weight loss during GAS NF. To our knowledge, this is the first report to demonstrate the benefits of a combined host- and pathogen-directed treatment approach to ameliorate severity and inflammation during GAS NF.
HIV-1 infection is associated with increased prevalence of immature neutrophils and alterations in total neutrophil phenotype and metabolic profile
Authors: Connelly Ashley N , Pal Harish , Davis Marcus , Ong Krystle , Kuznetsova Valeriya , Fay Christian , Overton E. Turner , Hel Zdenek 
Published: January 2023

Abstract
Despite successful viral control, HIV-1-infected individuals have a higher risk of developing life-threatening comorbidities including liver and cardiovascular diseases which are associated with inflammation and immune dysregulation. However, the specific mediators driving these pathologies are not yet understood. Neutrophils are increasingly recognized as a heterogeneous population with critical roles in immune regulation and disease pathogenesis. Methods of neutrophil characterization developed in our laboratory have facilitated the identification of novel neutrophil subpopulations including two subsets of low-density neutrophils (LDNs). LDNs are known to be expanded in inflammatory conditions including cancers and chronic infections. The LDN subpopulations identified in our laboratory represent different maturation states as indicated by their distinct nuclear morphologies and phenotypic differences [mature (mLDNs) CD16+CD64Low and immature (imLNDs) CD16−CD64+]. Our findings indicate that imLDNs have a reduced capacity for reactive oxygen species production and phagocytosis. We present data demonstrating that HIV-1/AIDS is associated with a higher frequency of imLDNs and significant alterations in total neutrophil phenotype (decreased CD16 and increased CXCR4 and CD10), function, and metabolism including increased expression of genes related to oxidative phosphorylation and mTOR signaling. Observed changes in neutrophil populations correlate with key clinical parameters including CD4+ T cell count, level of liver fibrosis, and arterial stiffness suggesting an important role for these cells and specific subsets in the pathogenesis of HIV-1/AIDS and potentially other inflammatory diseases.
Complement-driven inflammasome activation on circulating blood monocytes in immune reconstitution inflammatory syndrome in TB-HIV coinfected patients
Authors: Lage Silvia Lucena , Wong Chun-Shu , HSU Denise C , Sturdevant Daniel , Manion Maura , Naqvi Nuha S , Lisco Andrea , Laidlaw Elizabeth , Mejia Yolanda , Amaral Eduardo Pinheiro , Sereti Irini 
Published: January 2023

Abstract
Inflammasome and complement pathways have been independently implicated in the pathogenesis of Tuberculosis (TB) immune reconstitution inflammatory syndrome (IRIS), a clinical complication affecting individuals initiating antiretroviral therapy (ART). Here we sought to investigate whether dysregulated complement contributes to inflammasome activation during TB-IRIS. Caspase-1+ specks are cytosolic inflammasome aggregates responsible for IL-1β and IL-18 release. We detected higher numbers of monocytes with spontaneous caspase-1+ specks in IRIS patients (n=9, baseline median CD4 count= 46 cells/mL and VL= 606,754 copies/mL) in comparison with TB infected, non-IRIS controls (n=7, baseline median CD4 count= 47 cells/mL and VL= 85,831 copies/mL) at IRIS time-point (p&lt;0.05). Patients experiencing IRIS also showed elevated C1q and C3 deposition on monocytes, followed by increased levels of the membrane attack complex (MAC) molecule, C9 (p&lt;0.01). Levels of membrane-bound C9 (r= 0.69, p&lt;0.05), and the cell-associated MAC inhibitor, CD59 (r = 0.6 p &lt;0.05), correlated with IL-18 plasma levels and were associated with caspase-1 activation on patients-derived monocytes (r= 0.85, p&lt;0.001 and r= 0.97, p&lt;0.001, respectively to C9 and CD59), supporting a role for sublytic MAC-driven membrane pore formation in inflammasome activation on patient cells. Because the expression level of CD59 strongly correlated with caspase-1 activation within the CD14high monocyte subsets, our data suggest that those cells were able to prevent full MAC deposition, therefore undergoing sublytic MAC-driven inflammasome activation. This data may help identify new targets for prevention or treatment of TB-IRIS inflammatory syndrome.
The chemokine CCL17 is associated with protection against HIV-1 acquisition
Authors: Powell Timothy R , Duarte Rodrigo , Hotopf Matthew , Hatch Stephani , de Mulder Miguel , Marín-Hernández Daniela Marin , Breen Gerome , Lewis Cathryn , Nixon Douglas F. 
Published: January 2023

Abstract
Millions are exposed to the human immunodeficiency virus type 1 (HIV-1) every year, but not all exposed individuals become infected. This suggests a key role for host genetics in resilience or susceptibility to HIV-1 infection, but a comprehensive study of the genetic mechanisms contributing to HIV-1 acquisition risk is lacking. Here, we performed LD score regression analysis using summary statistics from the largest genome-wide association study of HIV-1 acquisition, consisting of 6,334 infected patients and 7,247 population controls. We found that HIV-1 acquisition is polygenic and highly heritable (28%). Genetic correlations performed alongside UK Biobank data revealed associations between HIV-1 acquisition and smoking, prospective memory and socioeconomic traits. Gene-level enrichment analysis identified EF-hand calcium binding domain 14 (EFCAB14) as a novel risk gene for HIV-1 acquisition. We also observed that risk variants for HIV-1 acquisition were significantly enriched for genes expressed in T-cells, but also those expressed in striatal and hippocampal neurons, which could explain the behavioral parameters genetically correlated with acquisition. Finally, we modeled how inter-individual variation in risk for HIV-1 acquisition influences the pre-exposed immune profile, by testing how individualized polygenic risk scores influence blood levels of 34 inflammatory markers in 406 HIV-1-negative individuals. We showed that higher genetic risk for HIV-1 acquisition was associated with lower levels of CCL17. Our findings corroborate a complex model for HIV-1 acquisition, whereby susceptibility is moderated by specific behavioral, cellular and immunological parameters.