bluuebunny/crossref_metadata_2025_split huggingface dataset:
Type III interferon networks in systemic lupus erythematosus
Authors: Barnas Jennifer L , Albrecht Jennifer , Meednu Nida , Nandedkar-Kulkarni Neha D , O’Connell Mary , Looney R John , Anolik Jennifer H 
Published: January 2023

Abstract

Background
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of nucleic acid autoantibodies and immune complex deposition resulting in organ damage. A type I interferon (IFN) gene signature historically attributed to IFN-α is found in cells from SLE patients and associated with disease activity. Type III IFN (IFN-λ) is relatively understudied, but is expressed in SLE renal tubule epithelial cells (RTEC) and found in patient serum. The objective of this study was to determine if IFN-λ1 allows cross-talk between human RTEC and B cells, which may be relevant for lupus nephritis pathogenesis.

Methods
SLE peripheral blood B cell phenotyping was completed by flow cytometry (n=26). RNA was isolated for RT-PCR from primary human RTEC and B cells stimulated with Toll-like receptor (TLR) agonists. CD19+ cells were stimulated with or without IFN-λ1. IFN-λ1 protein was measured by ELISA in supernatant and serum.

Results
SLE IFN-λ1 serum levels positively correlate (p=0.006) with peripheral blood IgD- CD27- CD24- CD21- B cells, a subset which expresses CD11c and T-bet and was expanded in SLE. Healthy B cells treated with IFN-λ1 express IFIT1, ISG15 and IRF7 mRNA. IFN-λ1 promoted plasma cell differentiation in B cells activated with TLR7 agonists. IFN-λ1 mRNA and protein secretion increase in RTEC with TLR3 stimulation.

Conclusions
RTEC, which constitute the bulk of the kidney, produce IFN-λ1 upon TLR3 stimulation. B lymphocytes express an IFN signature in response to IFN-λ1. IFN-λ1 promotes plasma cells in TLR7-activated B cells. These findings suggest the potential for type III IFN networks between RTEC and B cells in the renal microenvironment which may contribute to SLE and lupus nephritis pathogenesis.
Identification of T cell epitopes in sarcoidosis
Authors: Greaves Sarah A , Falta Michael , Santos Radleigh , Pinilla Clemencia , Grunewald Johan , Fontenot Andrew 
Published: January 2023

Abstract
Sarcoidosis is an inflammatory granulomatous disease that primarily affects the lung. It has a worldwide distribution and affects individuals of all ages. Despite the prevalence of the disease, the cause of sarcoidosis remains unknown. Evidence suggests that CD4+ T cells in the bronchoalveolar lavage (BAL) of sarcoidosis patients are instrumental in disease progression. Löfgren’s syndrome (LS) is an acute form of sarcoidosis with a specific set of inflammatory symptoms. In patients with LS, disease susceptibility has been associated with expression of HLA-DR3 and an expansion of BAL CD4+ T cells expressing T cell receptor (TCR) α-chain variable region (TRAV) 12-1 and TCR β-chain variable region (TRBV) 2. These oligoclonal T cell populations accumulate within the lung and disappear with disease resolution. We hypothesize that in these HLA-DR3+ LS patients, TRAV12-1/TRBV2 CD4+ T cell clones accumulate and expand in the lung in response to unknown etiologic antigens. We have identified a set of expanded and related TRAV12-1/TRBV2 αβTCRs derived from the BAL CD4+ T cells of DR3+ LS patients. We screened T cell hybridomas expressing these disease-relevant TCRs with decapeptide positional scanning libraries and identified stimulatory mimotopes for this set of TCRs. We identified several naturally occurring peptides derived from relevant fungal and bacterial species that stimulate the LS TCRs. Validation of these peptides as pathogenic T cell epitopes in LS is currently underway. Peptides that stimulate LS-associated TCRs have not been discovered until now, making this a major novel achievement in the field. Identification of an etiologic antigen in LS will narrow our search of the stimuli driving sarcoidosis in the US.
Platelet extracellular vesicles drive inflammasome-IL1β-dependent lung injury in Sickle Cell Disease
Authors: Sundd Prithu , Vats Ravi , Brzoska Tomasz , Bennewitz Margaret , Jimenez Maritza , Pradhan-Sundd Tirthadipa , Gladwin Mark 
Published: January 2023

Abstract
Intraerythrocytic polymerization of hemoglobin S promotes hemolysis and vaso-occlusive events in the microvasculature of sickle cell disease (SCD) patients. Although platelet-neutrophil aggregates-dependent vaso-occlusion is known to occur in the lung and contribute to lung injury, the etiological mechanisms that trigger acute chest syndrome are largely unknown. Here, we use intravital imaging of the lung in transgenic humanized SCD mice and in vitro imaging of SCD patient blood flowing through a microfluidic system to identify the innate-immune mechanism that promotes platelet-neutrophil aggregate-dependent lung vaso-occlusion and injury in SCD. Platelet-inflammasome activation led to generation of IL-1β and caspase-1 carrying platelet extracellular vesicles (EVs) that bind to neutrophils and promote platelet-neutrophil aggregation in lung arterioles of SCD mice in vivo and SCD human blood in microfluidics in vitro. The inflammasome activation, platelet EV generation and platelet-neutrophil aggregation were enhanced by the presence of lipopolysaccharide at a nanogram dose in SCD but not control human blood. Inhibition of the inflammasome effector caspase-1 or IL-1β pathway attenuated platelet EV generation, prevented platelet-neutrophil aggregation, and restored microvascular blood flow in lung arterioles of SCD mice in vivo and SCD human blood in microfluidics in vitro. These results are the first to identify that platelet-inflammasome dependent shedding of IL-1β and caspase-1 carrying platelet EVs promote lung vaso-occlusion in SCD. The current findings also highlight the therapeutic potential of targeting the platelet-inflammasome dependent innate immune pathway to prevent acute chest syndrome in SCD.
Autoinflammatory Eye Disease Due to NLRP3 Inflammasome-Associated Mutations and Excessive IL-1β Responses may be Driven by Ocular Exposure to Commensals
Authors: Siak Jay , St. Leger Anthony J , Mattapallil Mary , Magone M. Teresa , Zein Wadih , Alehashemi Sara , Raychaudhuri Kumarkrishna , Meng Guangxun , Fuss Ivan , Strober Warren , Goldbach-Mansky Raphaela , Caspi Rachel R 
Published: January 2023

Abstract
In previous studies we have shown that the healthy murine ocular surface is colonized by a commensal, Corynebacterium mastitidis, that elicits IL-17 from γδ T cells and promotes local host defense. Based on that, we hypothesized that ocular inflammation in patients with NLRP3-associated mutations, including those with Cryopyrin Associated Periodic Syndrome (CAPS), may be triggered by an overactive response to their own eye surface commensals. We found that, unlike wild type mice, mice with a CAPS mutant NLRP3 gene and increased IL-1β and IL-17 responses, develop conjunctival neutrophilia and ocular inflammation following ocular exposure to C. mast. Single cell transcriptomics confirmed that conjunctival γδ T cells were the major source of IL-17 and identified increased amounts of ccr2 and s100a8 mRNA, accounting for the neutrophil infiltration. In parallel studies of patients with inflammasome-associated mutations (NLRP3 or CARD8 mutations) we found that patient PBMCs cultured with C. mast produced increased amounts of IL-17A compared to healthy controls (C. mast. status of subjects: unknown). Patient immune cells (conjunctival and PBMC) showed upregulation of RORC, BATF and STAT3 as well as interferon-related genes (IRF1, STAT1). However, unlike in mice, IL-17-related genes appeared to be more upregulated in αβ than in γδ T cells, suggesting that in patients this response may be mediated by other cells, and/or that other commensals than in mice may be the stimulus. Thus, commensals can elicit an exaggerated immune response in humans and mice with NLRP3-related autoinflammatory disease. If indeed the conjunctivitis in CAPS patients reflects a response to their own commensals, adjunct antimicrobial therapy may be considered.
Altered CD4+ T cell Transcriptional and Epigenetic Programming Define Changes in Sarcoidosis Disease Phenotypes
Authors: Tu Ting-Hui Clair , Knapp Jennifer , Harmacek Laura , Magallon Roman , Vestal Brian , Leach Sonia , Danhorn Thomas , Li Lily , Gillespie May , MacPhail Kristyn , Riley Christina , Barkes Briana , Elliott Jill , Arger Nicholas , Sommer Anne , Powers Linda , Werner Brenda , Fingerlin Tasha , Maier Lisa , Koth Laura , Hamzeh Nabeel , O’Connor Brian 
Published: January 2023

Abstract
Sarcoidosis is an inflammatory disease, which is characterized by granulomas in the lungs, extrapulmonary inflammation, and can cause death by lung fibrosis. It is known that CD4+ T cell lung population increases in Sarcoidosis. However, the immunopathology remains unclear and no biomarker has been identified. Here we use RNA-seq to examine gene expression in CD4+ T cells of differential Sarcoidosis phenotypes and healthy donors. Our data showed that BATF, a Tfh inducer/key factor in Th17 differentiation was up-regulated while BCL6, a Th17 repressor is down-regulated in RNA-seq. IRF4 and BCL6 were identified as potential transcriptional upstream regulators using IPA. IL-4 and fibrosis related genes were differentially expressed with altered disease phenotype, indicating that type 2 immune response may participate in disease phenotype progression for development of fibrosis. In addition, we used ChIP-seq and ATAC-seq to examine genome-wide epigenetic histone signatures and global chromatin accessibility associated with Sarcoidosis phenotypes. TF binding-site analysis of ATAC-seq peaks revealed an enrichment of BATF binding motifs, highlighting the utility of integrating epigenetic and transcriptional signatures to suggest molecular drivers of Sarcoidosis. Our findings identified several potential immune related biomarkers and molecular mechanisms that may drive disease progression.
Detection of T cells Reactive to Hybrid Insulin Peptides in Subjects at Risk for Type 1 Diabetes
Authors: Baker Rocky Lee , Delong Thomas , Rewers Marian J , Gottlieb Peter , Haskins Kathryn 
Published: January 2023

Abstract
Our lab recently established that Hybrid Insulin Peptides (HIPs) are antigenic ligands for diabetogenic T cell clones in the NOD mouse model of autoimmune diabetes. Importantly, we have found that the phenotype of HIP-reactive T cells present in the peripheral blood of NOD mice is indicative of ongoing autoimmunity in the pancreas. In the human setting, we demonstrated that T cells reactive to HIPs are present in the residual islets of type 1 diabetic (T1D) organ donors and more recently, in PBMC from T1D patients. Using an IFN-g ELISPOT assay to test T cell reactivity in the peripheral blood of T1D patients or control subjects to a panel of 16 HIPs, we demonstrated that 70% of the responding patients showed reactivity to multiple HIPs. To determine whether the presence of HIP-reactive T cells might serve as a biomarker of disease activity in humans, we are following longitudinally a cohort of subjects positive for multiple islet autoantibodies (Ab+), individuals that are at high risk for developing T1D. Using IFN-g ELISPOT and CFSE dilution assays, our data indicate that HIP-reactive T cells with an inflammatory phenotype can be detected before disease onset. In one Ab+ individual that showed HIP reactivity, we used single-cell RNA sequencing to study the phenotype and TCR usage of HIP-responding T cells. We observed that T cells with a regulatory phenotype (FoxP3+, CTLA-4+, LAG3+) can be observed when a proliferative (but not inflammatory) response is detected. In this ongoing study, we are reporting for the first time that HIP-reactive T cells can be observed in the peripheral blood of subjects at risk for T1D, suggesting that the balance of inflammatory vs. regulatory signals of HIP-reactive T cells could be potential indicators of disease activity.
Myasthenia gravis: From single cell signatures to cancer diagnosis
Authors: Ingelfinger Florian , Kramer Michael , Utz Sebastian , Mundt Sarah , Krishnarajah Sinduya , Galli Edoardo , Lutz Mirjam , Jurado Nicole Puertas , Widmer Corinne , Reichen Ina Camille , Piccoli Luca , Sallusto Federica , Schneiter Didier , Opitz Isabelle , Jung Hans Heinrich , Lanzavecchia Antonio , Schreiner Bettina , Becher Burkhard 
Published: January 2023

Abstract
Myasthenia gravis is a rare but archetypic autoimmune disease that is characterized by the autoantibody-mediated disruption of the neuromuscular junction leading to a skeletal muscle weakness. Immunomodulatory treatment options for Myasthenia gravis patients are largely unspecific, include suppression of the entire immune compartment and are often accompanied by severe side effects.
In order to identify novel biomarkers for more targeted and effective therapeutic approaches, we combined high-dimensional mass and flow cytometry with supervised and unsupervised machine-learning algorithms. Analysis of the peripheral immune compartment of Myasthenia gravis patients and healthy controls revealed a cellular immune signature consisting of inflammatory memory T helper cells with a defined cytokine profile. The abundance of the identified leukocytes in the blood strongly correlated with the patients clinical disease activity, far better than auto-Ab titers. Moreover, we were able to locate T cells with the defined signature enriched in the inflamed thymus of Myasthenia gravis patients – the key organ for the induction and maintenance of the autoimmune disease. Lastly, using an unbiased pattern recognition approach, we identified lymphomas in a subset of Myasthenia gravis patients, further highlighting the potential of the applied analysis tools.
CpG methylation in the TGFB1 and IL-6 gene promoters serve as surrogate biomarkers for diagnosis of IBD in children
Authors: Ahmad Ali , Samarani Suzanne , Dupont Claire-Lucas , Marcel Valerie , Mack David , Seidman Ernest , Deslandres Colette , Jantchou Prevost , Amre Devendra 
Published: January 2023

Abstract
Crohn’s disease (CD) and ulcerative colitis (UC) are recurrent, chronic forms of inflammatory bowel diseases (IBD), the diagnosis of which can entail long delays. The delays can lead to disease presentation with complications and high morbidity. Therefore, better diagnostic markers for IBD are required. We investigated whether methylation marks in the TGFB1 and IL-6 gene promoters could be of diagnostic utility in IBD. To this end, we conducted a case-control study using peripheral blood DNA samples from 67 CD and 37 UC pediatric patients, and from 43 age-matched healthy controls. The patients were recruited from three pediatric gastroenterology clinics across Canada. The DNA samples were processed to identify methylation sites (CpG) across the promoter regions of the TGFB1 and IL-6 genes using the Sequenom technology. After implementing quality control measures, and initial non-parametric univariate (Man-Whitney U test) analyses, multivariate logistic regression analyses was carried out to identify models with the best fit (Akaike Information Criteria) and the greatest discriminatory capabilities (Area Under the Receiver Operating Curve). Logistic regression analysis showed that a model comprising 14 TGFB1 CpG sites had high discriminatory ability to separate CD from controls (AUC=0.94). Similarly, a logistic model comprising 9 CpG sites in the TGFB1 gene had near perfect ability to discriminate between UC and controls (AUC=0.99). A logistic model comprising three CpG sites in the TGFB1 gene had moderate ability (AUC=0.81) to discriminate between CD and UC. In conclusion, CpG methylation in the TGFB1 gene promoter has high discriminative power for identifying CD and UC, and could serve as an important diagnostic markers.
Single cell profiling illustrates down-regulation of GM42031 in macrophages and microglia as a potential mechanism of neuroinflammation in transgenic GFAP-gp120 mice
Authors: Wilson Kiesha Maria , Miranda Kathryn , Kaul Marcus , Nagarkatti Prakash S. , Nagarkatti Mitzi 
Published: January 2023

Abstract
Over thirty percent of individuals infected with human immunodeficiency virus type 1 (HIV) worldwide suffer from HIV-associated neurocognitive disorder (HAND). GFAP-gp120 transgenic (Tg) mice serve as an excellent model system for HAND because they manifest the same neuropathological attributes observed in the brains of AIDS patients. In this study, we sought to identify novel genes associated with the GFAP-gp120 neurodegenerative mouse model. Von Frey filament and hot plate tests on 8 month old GFAP-gp120 mice resulted in a significant increase in mechanical and thermal nociception in Tg versus wild-type mice. Neuropathology was confirmed via immunohistochemistry of MAP2, Synaptophysin, Iba-1, and GFAP. The MAP2 and Synaptophysin allowed us to visualize dendritic density and synaptic loss. Infiltration of macrophages was observed with anti-Iba-1 and astrocytosis with anti-GFAP Abs. Additionally, single cell RNA sequencing (scRNASeq) of encephalitogenic mononuclear cells illustrated 10 distinct clusters of cells. These clusters included: astrocytes, neurons, oligodendrocytes, endothelial cells, microglia, and macrophages. Differential expression analysis showed decreased expression of GM42031 in Tg macrophages and microglia. This locus is currently unclassified and thought to be either a long non coding RNA (lncRNA) or a gene for a NYNRIN-like protein. Until now, this particular RNA has not been associated with the GFAP-gp120 disease model. However, there has been some association of GM42031 with macrophage regulation in Parkinson’s disease and colitis models. Together our study provides novel insights into the immunopathology of HAND that may form the basis for development of effective therapeutics.
Ureaplasma parvum induces preterm birth by triggering immune responses in the fetus and at the maternal-fetal interface
Authors: Motomura Kenichiro , Romero Roberto , Theis Kevin , Winters Andrew , Xu Yi , Garcia-Flores Valeria , Zou Chengrui , Para Robert , Ahmad Madison , Slutsky Rebecca , Gomez-Lopez Nardhy 
Published: January 2023

Abstract
Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. One of every four preterm births is due to intra-amniotic infection, most commonly associated with Ureaplasma species. However, a causal link between Ureaplasma species and adverse pregnancy outcomes, as well as the triggered host immune responses, has not been investigated. Molecular microbiological surveys first revealed that Ureaplasma parvum is the most common bacterium in women with intra-amniotic infection. Ultrasound-guided intra-amniotic injection of U. parvum in pregnant mice resulted in preterm birth and neonatal death. Specific qPCR revealed that U. parvum invaded specific fetal (lung, intestine, spleen, fetal membranes, and placenta) and maternal (decidua, uterus, and cervix) compartments. Consistently, U. parvum induced a strong inflammatory response in the amniotic cavity, fetal membranes, placenta, and fetal lung and spleen, as well as at the maternal-fetal interface. However, U. parvum neither invaded the non-reproductive maternal organs nor induced a maternal systemic inflammatory response. An ex vivo model of intra-amniotic infection showed that U. parvum elicits pro-inflammatory responses in human amnion epithelial cells. Lastly, the treatment of U. parvum-injected mice with clarithromycin, a clinically relevant macrolide, prevented preterm birth and neonatal death. Collectively, this investigation provides a causal link between U. parvum and adverse pregnancy outcomes, and yields insights into the host immune responses triggered by this genital mycoplasma. Importantly, these data support the use of clarithromycin in the treatment of Ureaplasma-associated intra-amniotic infection leading to preterm birth.
Immune checkpoint dysregulation and immune activation in HIV-exposed uninfected children
Authors: Li Wei , McHenry Megan , Oyungu Eren , Yang Jing , Xia Ying , Syed Fahim , Yu Qigui 
Published: January 2023

Abstract
Children who are HIV-exposed uninfected (CHEU) are a growing population worldwide. CHEU suffer greater morbidity and mortality from infectious diseases, likely due to their impaired cell-mediated immunity (CMI) and hyper-inflammatory responses. As CMI and inflammatory responses are regulated by immune checkpoints (ICPs) that play a key role in maintaining immune homeostasis, we determined whether CHEU had altered expression of the ICP axes. We used multiplex immunoassays to quantify plasma levels of 16 soluble ICPs (sBTLA, sCD27, sCD28, sCD40, sCD80, sCTLA-4, sGITR, sGITRL, sHVEM, sICOS, sLAG-3, sLIGHT, sPD-1, sPD-L1, sTIM-3, and sTLR-2) from 46 CHEU and 37 children who are HIV-unexposed uninfected (CHUU) from AMPATH in western Kenya. We demonstrated that all ICPS except GITR were detected in all samples. Compared to CHUU, CHEU had significantly higher levels of 2 sICPs: soluble CD40 (sCD40) and soluble TIM-3 (sTIM-3). As CD40 plays an essential role in antigen-presenting cell functions, while TIM-3 is a key member of immunosuppressive ICPs that inactivate T cell activity, the dysregulated sCD40 and sTIM-3 could play a role in the impaired CMI in CHEU and can be explored as biomarkers for adverse health outcomes in CHEU. A previous study showed that the percentage of activated CD8 T cells (CD8+CD38high) was increased in Canadian CHEU. Therefore, we also studied the activation of T cells in PBMCs from Kenya and found that CHEU had higher percentages of activated CD4 (CD4+CD38+HLA-DR+) and CD8 (CD8+CD38+HLA-DR+) T cells in the peripheral blood compared to CHUU. Our study demonstrated that the ICP axes were dysregulated in CHEU, and we provided additional support to the notion that the immune system in CHEU is altered.
Expression of Pattern Recognition Receptor mRNA in Pediatric Patients with Otitis Media with Effusion
Authors: Yeo Seung Geun , Park Dong Choon 
Published: January 2023

Abstract

Importance
Otitis media with effusion (OME) in children often requires surgical treatment. Pattern recognition receptors (PRRs), which are involved in innate immunity in the middle ear, are believed to play an important role in relapse and chronicity of OME.

Objective
To investigated the expression of PPRs in children with OME.

Participants
Total 126 patients under 10 years of age who were diagnosed with OME and underwent unilateral or bilateral ventilation tube insertion (VTI).

Main outcomes and measures
Expression levels were compared in children with and without bacteria in the middle ear cavity, with and without concomitant diseases, by characteristics of middle ear fluid, and in children who were and were not otitis prone.

Results
Mean [SD] expression level of PRR mRNAs did not differ significantly in children with and without bacteria in the middle ear, with and without concomitant diseases, or by characteristics of middle ear fluid. However, mean [SD] expression level of TLR2 (0.037 [0.079] vs 0.093 [0.124]; MD, 0.056; 95% CI, 0.018 to 0.094), TLR4 (0.015 [0.054] vs 0.036 [0.047]; MD, 0.021; 95% CI, 0.003 to 0.039), TLR6 (0.038 [0.072] vs 0.107 [0.170]; MD, 0.069; 95% CI, 0.020 to 0.118), TLR9 (0.229 [0.256] vs 0.611 [0.840]; MD, 0.382; 95% CI, 0.146 to 0.618), NOD-1 (0.004 [0.002] vs 0.008 [0.014]; MD, 0.004; 95% CI, 0.001 to 0.008), and RIG-I (0.034 [0.086] vs 0.092 [0.191]; MD, 0.058; 95% CI, 0.002 to 0.114) mRNAs were lower in the otitis prone group than in the non-otitis prone group.

Conclusions and relevance
These findings suggest that PRRs are involved in the pathophysiology of OME. OME is frequent and chronic in children with low levels of TLR, NLR, and RIG-I mRNAs.