bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sustained secretion of immunoglobulin by long-lived plasma cells from human nasal biopsies
Authors: Song Jia , Zhang Ya-na , Wang Hai , Wang Zhe-zheng , Liu Zheng 
Published: January 2023

Abstract

Background
During secondary immune responses, plasma cell survival and antibody production is mediated by extrinsic factors provided by the local environment. It is unknown whether there are long-lived plasma cells (LLPCs) in the human nasal mucosa.

Objective
To identify LLPCs and characterize functionally specific survival niche in the human nasal mucosa.

Methods
Nasal polyp (NP) biopsies were used for ex vivo air-liquid interface culture. Protein levels of immunoglobulins in tissue homogenates were detected by Bio-Plex. The expression of LLPCs related markers including NGF, TrkA, P75, IL-6, APRIL, CD138, CD20, CD4, CD8, ECP, Bcl2, Ki-67, CD3 were detected by means of quantitative RT-PCR, immunohistochemistry (IHC) and ELISA.

Results
Using an ex vivo biopsies culture, we found sustained IgG, IgA, IgE, and IgM secretion &gt;4 wk of culture. IL-6, APRIL NGF, TrkA, and P-75 were up-regulated in CRSwNP compared with controls by ELISA or IHC. We assessed TrkA+ cells, ECP+ eosinophils, and tryptase+ mast cells represent the major interstitial cell sources of NGF, while tryptase+ mast cells and CD138+ plasma cells represent the major sources for TrkA in CRSwNP by immunohistochemistry. We performed histological analysis of fresh nasal polyp tissues, and of tissue fragments harvested 10, 20, 32 days after cultured respectively and found that there’s a small portion of plasma cell in CRSwNP expressed Bcl2 pre- and post-culture. However, post-cultured plasma cells do not express Ki67.

Conclusion
This study demonstrates that the human nasal mucosa harbors a population of nonproliferating plasma cells that are instructed by the microenvironment for prolonged survival and Ab secretion.
Mouse Models for Immunology Research available from The Jackson Laboratory Repository.
Authors: Valenzuela Alicia , Fancher Karen , Rockwood Stephen , Lutz Cathleen ,   The Genetic Resource Science Team
Published: January 2023

Abstract
The mouse continues to provide researchers a means by which to address complicated immunological questions. The emergence of disruptive genetic engineering technologies have proven to be very applicable to the mouse, spawning a new generation of promising preclinical models. To facilitate access to this flourishing resource, The Jackson Laboratory (JAX) Mouse Repository offers one of the largest sets of well-characterized, genetically engineered mutant mice. Hundreds of new strains are added annually to the collection.
Our newest strains include conditionally targeted interleukins, often combined with Cre recombinase and/or reporters. The conditional Il33 knock-out/in (KO/KI) carries an EGFP reporter, a KO/KI to the Il5 gene results in Il15-specific expression of tdTomato and humanized cre, a similar KO/KI to the Il22 gene results in tdTomato/cre expression in intestinal lymphoid tissues, and a KI to Il21 results in expression of Verde green (VFP). Another new strain expresses cre and GFP within peripheral CD8+ T cells.
MMRRC program mice include a suite of strains expressing and responding to influenza virus hemagglutinin (HA) neo-self antigen for the study of immune regulation, tolerance and autoimmunity. A Pad4 KO, exhibits absent histone deimination in neutrophils and a defective response to acute infection. KOMP mice, also offered via the MMRRC portion of the JAX Mouse Repository, provide a growing number of targeted immunological mutations. Donating a strain to the Repository fulfills NIH’s requirements for sharing mice. Researchers wishing to have mice considered for inclusion in the Repository are encouraged to submit strains: www.jax.org/donate-a-mouse.
This work is supported by NIH, HHMI and private foundations.
Heterogeneity of plaque macrophages derived from CX3CR1+ monocyte precursors in atherosclerosis progression and regression at a single-cell level
Authors: Lin Jian-Da , Nishi Hitoo , Poles Jordan , Mccauley Caroline , Rahman Karishma , Hine Ashley , Vozhilla Nikollaq , Fisher Edward A. , Loke P’ng 
Published: January 2023

Abstract
Atherosclerosis is a leading cause of death worldwide in industrialized countries. We have previously shown that disease progression and regression are strongly associated with the M1/M2 activation status of macrophages derived from inflammatory monocytes in the plaques with large differences in transcriptional profiles. However, the features of monocyte to macrophage transitions during either plaque progression or regression are poorly understood. Here, we use a combination of single-cell RNA sequencing and tamoxifen-inducible fate mapping approaches to profile 3157 and 2198 arterial cells derived from CX3CR1+ precursor in atherosclerotic mice during plaque progression and regression. There was surprising heterogeneity among the cell populations, despite derivation from a common precursor. We compared the distinct cell clusters with the IMMGEN database to define each population and then used pseudo-time analysis to model the differentiation process from monocyte precursors to activated macrophages under progression and regression conditions. Notably, distinct cell clusters with a type 1 interferon (IFN) signature was observed during progression, which was significantly rare in regression. Whereas a unique cluster in regression was marked by increased expression of various heat shock proteins (HSP). Overall, this study highlights previously unidentified genes and programs in macrophages associated with atherosclerosis progression and regression, uncovering the unexpected plasticity of CX3CR1+ monocyte derived cells.
Clonally expanded alpha-chain T-cell receptor (TCR) transcripts are present in aneurysmal lesions of patients with Abdominal Aortic Aneurysm (AAA).
Authors: Lu Song , White John V. , Judy Raquel Ines , Merritt Lisa , Lin Wan Lu , Solomides Charalambos C. , Zhang Xiaoying , Nwaneshiudu Ifeyinwa , Monos Dimitrios S. , Gaughan John P. , Oleszak Emilia L. , Platsoucas Chris D. 
Published: January 2023

Abstract
AAA is a life-threatening vascular disease and one of the ten leading causes of death of 55–74 years old men and women. Although autoimmunity may be responsible for the initiation and/or progression of the disease, limited information is available about the pathogenesis of AAA. Mononuclear infiltrates comprised mostly of T and B cells and monocytes are present in AAA lesions. We have reported (J. Immunol. 192:4897, 2014) that clonally expanded beta-chain TCR transcripts are present in AAA lesions, providing evidence suggesting that AAA is a specific antigen-driven T-cell disease. In addition to the beta-chain TCR, there are several reasons to study the clonality and the repertoire of the alpha-chain TCR in AAA. Alpha-chain TCR transcripts from AAA lesions from these patients were amplified by the non-palindromic adaptor-PCR (NPA-PCR)/Vα-specific PCR and/or the Vα-specific PCR and the amplified transcripts were cloned and sequenced. Sequence analysis revealed substantial proportions of identical alpha-chain TCR transcripts in 4 of 5 AAA patients, demonstrating that clonally expanded T cells are present in these AAA lesions. These results are statistically significant. These T-cell clones very likely have undergone proliferation and clonal expansion in vivo in response to specific, although, as yet unidentified, antigen(s) (self or non-self) recognized by the T-cell clones. Three of 5 patients with AAA were typed by DNA-based HLA-typing and all expressed DRB1 alleles positive for the DRbGln70 amino acid residue, reported to be associated with AAA. Clonally expanded T cells in AAA lesions were found in all these 3 patients. These findings provide additional evidence suggesting that AAA is a specific antigen-driven T-cell disease.
A Role for DPP4 Expression via Oxidized LDL/TLR4/TRIF/CD36 Pathways in Human Obesity and Atherosclerosis
Authors: Zhong Jixin , Rao Xiaoquan , Duan Lihua , Xia Chang , Varghese Juliet , Mihai Georgeta , Rajagopalan Sanjay 
Published: January 2023

Abstract

Objective
Dipeptidyl peptidase IV (DPP4) is well-known for its regulatory role in incretin biology. Although prior studies have suggested a role for DPP4 in atherosclerosis, the regulation of DPP4 in diabetes and atherosclerosis has not been investigated. In this study, we investigated the relationship of DPP4 with human aortic atherosclerosis and the role of obesity.

Methods and Results
We tested the expression of membrane bound DPP4 on circulating monocytes and plasma DPP4 activity (cleaved) in patients with atherosclerosis and their relationship with measures of metabolic health. In atherosclerosis, both cleaved and membrane bound DPP4 were increased. DPP4 expression on monocytes was positively correlated with atherosclerotic plaque volume assessed by high-resolution MRI with expression positively correlating with non-HDL cholesterol level (P=0.0242) but not fasting blood glucose or insulin. Oxidized low-density lipoprotein (oxLDL) up-regulated DPP4 expression on macrophages with a preferential increase in CD36+ cells. OxLDL mediated increase in DPP4 was abolished by siRNA-mediated Toll-like receptor 4 (TLR4) knock-down and considerably diminished by CD36 deficiency. Loss of TRIF but not MyD88 attenuated DPP4 increase with oxLDL.

Conclusions
DPP4 expression on monocytes correlates with atherosclerotic plaque volume with a key role for oxidized LDL in regulating DPP4 expression via CD36/TLR4/TRIF pathways. Increased DPP4 in response to oxidized lipids may represent an integrated mechanism by which post-prandial glucose metabolism is linked to lipoprotein abnormalities potentiates atherosclerosis.
Human anti-dopamine receptor 1 monoclonal autoantibody (mAb) identifies potential mechanisms of neuronal signaling in post-infectious autoimmune-mediated neuropsychiatric disease
Authors: Menendez Chandra M. , Zuccolo Jonathan , Zuccolo Amir , Ben-Pazi Hilla , Cox Carol , Swedo Susan , Cunningham Madeleine W. 
Published: January 2023

Abstract
Neuropsychiatric and movement disorders are associated with infections and anti-neuronal autoantibodies against dopamine receptors D1R and D2R. Most characterized of these disorders is Sydenham chorea (SC), an autoimmune neurologic manifestation of streptococcal-induced rheumatic fever where autoantibodies target the basal ganglia. Pediatric autoimmune neuropsychiatric disorder associated with streptococci (PANDAS) have similar autoantibodies that react with D1R and D2R. SC-derived human mAb 24.3.1 or SC derived IgG signal D2R in transfected cells by decreasing cyclic AMP-dependent kinase (cAMP) activity, reflective of an inhibitory receptor. Anti-D2R 24.3.1 increases dopamine release from human neuronal cells. However, signaling of D1R, an activating receptor, can have different biological effects. Our PANDAS-derived anti-D1R mAb, B4C, and PANDAS sera signaled D1R by activation of cAMP in transfected cells. IgG titers against D1R were significantly elevated in SC and PANDAS sera. To further show IgG recognized the D1R receptor, peptides of the extracellular loop of D1R were constructed and a defined sequence reacted significantly with human mAb B4C and PANDAS serum IgG. Human anti-D1R mAb B4C induced cAMP activity levels comparable to dopamine in a dose-dependent manner. Combined with dopamine, mAb B4C sensitized D1R to at least 50X more responsive to dopamine. In neuropsychiatric diseases where both anti-D1R and anti-D2R autoantibodies may be in combination, anti-D1R autoantibodies could sensitize D1R making it more sensitive to excess dopamine induced by anti-D2R autoantibodies; thus, contributing to dopamine signaling abnormalities and neuropsychiatric pathogenesis.
Translational profiling of microglia in Alzheimer’s disease models
Authors: Fryer John D. , Kang Silvia S. 
Published: January 2023

Abstract
Alzheimer’s disease (AD) is a neurodegenerative disease characterized pathologically by amyloidosis, tauopathy, and activation of microglia, the resident innate immune cells of the brain. Using a translational RiboTag profiling approach, we found that cellular isolation methods (enzymatic digestion, myelin removal, and CD45/CD11b sorting) altered the microglial transcriptome due to microglia activation and potential cellular contamination from sorting. Additionally, lipopolysaccharide-induced systemic inflammation generated completely different “top hits” from microglial RiboTag vs cellular isolation RNAseq datasets, likely due to microglial activation during the isolation process. RiboTag profiling of mouse models of AD revealed many significantly altered microglial transcripts that were shared between amyloidosis and tauopathy models, forming a network containing apolipoprotein E (APOE), CCL3, and CCL4. Inflammation and neutrophil chemotaxis pathways were also significantly enriched amongst the shared transcripts. This study has broad implications for microglial transcriptomic approaches and provides insights on microglial pathways associated with different pathological aspects of AD.
Autoantibodies to myelin proteins as biomarkers to identify nervous system injuries in Gulf War Illness and other neuromuscular disorders
Authors: Brahmajothi Mulugu V. , Abou-Donia Mohamed Bahie 
Published: January 2023

Abstract
A study on veterans with Gulf War Illness (GWI) from Madison VA Hospital demonstrated a widespread disruption of damages to the white matter using magnetic resonance brain imaging suggesting a cause of prolonged chronic musculoskeletal pain. We hypothesized that exposure to various chemicals could cause delayed neurotoxicity and that myelin is an important white matter component, which play a critical role in neural function and plasticity. Any disruption to myelin may result in reduced brain connectivity, musculoskeletal pain, and cognitive dysfunction. Since myelin is composed of various proteins, dysregulation or damage over a period will form a distinguishable biomarker in CSF and in serum/plasma. Further, continued damage could elicit an immune response. With these reasoning, we measured serum/plasma levels of myelin proteins and autoantibodies specific to myelin proteins by ELISA in Veterans with Gulf War Illness (GWI) and other patients with neuronal disorders (Multiple Sclerosis (MS), Parkinson’s disease (PD), mild Traumatic Brain Injury (TBI), Flight Crews with chronic pain and veterans with Chronic Fatigue Syndrome (CFS) and Lupus (SLE)). We quantitated several myelin proteins (MPZ, MAG, MBP MOG, MOBP, PMP2, and NF155) to determine the intensity of disruption. Autoantibody levels in MS patients were used as positive control and since all the samples (n=10) tested showed the highest level of IgG specific autoantibodies compared to other cohorts. Significantly increased levels of NF155, MOG, MOBP, and MAG were observed among all groups compared to controls (p&lt;0.001). Elevated levels of MPZ and PMP2 characterized PD and SLE (p&lt;0.01) and GWI veterans showed elevated levels of MBP compared CFS and healthy cohorts.
Anti-neuronal and anti-microbial immunity link CaMKII and autism spectrum disorder with pediatric acute-onset neuropsychiatric syndrome
Authors: Chain Jennifer L. , Cox Carol J. , Alvarez Kathy M. , Menendez Chandra M. , Reim Sean M. , Shawler Paul M. , Richmand Brian , Stoner Julie , Frye Richard E. , Swedo Susan , McBride Bonnie , Cunningham Madeleine W. 
Published: January 2023

Abstract
Autism spectrum disorders (ASD) may be associated with neuropsychiatric symptoms such as tics, obsessive-compulsive behaviors, and other symptoms characteristic of pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS). Abnormal anti-neuronal autoantibody responses against the basal ganglia are elevated in neuropsychiatric disorders such as PANDAS. Our study suggests that anti-neuronal autoantibodies in ASD may be associated with the presence of PANDAS and investigates microbial polysaccharides as potential inducers of anti-neuronal autoantibodies in children with confirmed ASD or ASD/PANDAS. Functional anti-neuronal autoantibodies which signal CaMKII and induce excess dopamine release were found in ASD/PANDAS serum. Autoantibody signaling or reactivity was inhibited by 3 common microbial antigens, by a group of neuronal antigens, or by anti-IgG beads which significantly reduced CaMKII activation in ASD/PANDAS sera. Interestingly, a CamKII mutation has recently been associated with autistic symptoms in animal models and also in ASD in humans. Children with ASD/PANDAS had significantly elevated anti-neuronal autoantibodies by ELISA, and strong IgG responses against the group A streptococcal epitope GlcNAc were observed in ASD/PANDAS. Our study links three common microbial antigens to anti-neuronal antibody responses in ASD/PANDAS and suggests that molecular mimicry between host and pathogen may play a role in development of the autoantibodies and potentially lead to neuropsychiatric symptoms in ASD/PANDAS. Thus, ASD may be complicated by anti-neuronal antibodies which can develop during infections and may contribute to the co-morbid symptoms of PANDAS in ASD.
The Benzathine Penicillin G (BPG) Reformulation Preferences Study - Tonga
Authors: Sika-Paotonu Dianne , Aho George , ‘Ulufonua Lisiate Kilipeni , ‘Ofanoa Malakai , ‘Akau’ola Siale , Vaea Kolinisiupeli , Tuipulotu Amelia Afuha’amango , Toumoua Seventeen , Lilo Filimone , Fotu Latu , Tiatia Ramona , Sung Yun K. , Zonneveld Rebecca , Poot Betty , Norris Pauline , Betty Bryan , Thornley Craig , Eddie Barbara , Wineera-Parai Ranei , Baker Michael , Carapetis Jonathan 
Published: January 2023

Abstract
Acute Rheumatic Fever (ARF) is an autoimmune condition caused by untreated Group A Streptococcal (GAS) infection of the upper respiratory tract (and possibly skin). Multiple or severe attacks of ARF can cause cardiac damage, known as Rheumatic Heart Disease (RHD) which remains a significant cause of morbidity and mortality globally and is rare in developed countries. In Australia, New Zealand (NZ) and the Pacific Region, the disease burden of ARF and RHD amongst Indigenous and Pacific communities is one of the highest in the world, usually affecting children and young adults. A GAS vaccine remains years from being available and until then, the most effective recommended preventative measure for ARF requires painful monthly intramuscular injections of Benzathine Penicillin G (BPG) for 10 years or more, known as secondary prophylaxis (SP). Adherence to SP remains a challenge in many settings and improved understanding of barriers and novel approaches to BPG delivery are urgently needed. To create a reformulation of BPG that encourages SP adherence, insight is needed into the reformulation preferences of those with ARF/RHD. This work seeks to explore the experiences and investigate children/teen on SP, family, and healthcare professional and practitioner preferences for potential BPG reformulation characteristics in Tonga. Three software applications will be adapted from pre-developed applications already piloted and pretested, and optimized for use to ensure age, cultural appropriateness and efficient data collection. This is the first time software applications have been successfully developed and utilized to collect qualitative and quantitative data on individual preferences for BPG formulations and dosing regimens in Tonga.
Cereblon tunes c-Myc protein expression and regulates the metabolic function of activated T cells
Authors: Epling-Burnette Pearlie , Hesterberg Rebecca , Akuffo Afua Adutwumwa , Beatty Matthew S. , Goodheart William E. , Fernandez Mario , Cleveland John L. 
Published: January 2023

Abstract
Immunomodulatory drugs, such as lenalidomide, pomalidomide, and CC122 are glutarimide derivatives that alter T cell effector functions, reverse tolerance, and increase cytokine production. We hypothesized that cereblon (CRBN), the molecular target of these drugs, is a negative regulator of T cell function. Therefore, germline Crbn knockout mice were used to investigate its role in T cell regulation. Similar to human T cells treated with immunomodulatory drugs, stimulated Crbn−/− T cells exhibit increased proliferation and cytokine production and maintain this phenotype in the absence of CD28 co-stimulation. Using Gene Set Enrichment Analysis (GSEA) to identify transcriptional drivers of differentially expressed genes, we found that Myc and its family member Max may drive the observed activated phenotype in Crbn−/− T cell. Crbn−/− T cells have Myc-related phenotypic changes, such as increased cell size, CD98 expression, glucose uptake, glutamine and arginine uptake, increased intracellular polyamine biosynthesis, and oxygen consumption. Similar increases in Myc-related processes were observed in activated human T cells treated with immunomodulatory drugs. While c-myc mRNA is similar, Crbn−/− T cells and drug-treated human T cells have prolonged c-Myc protein expression. CRBN, a substrate receptor for the DDB1/Cul4A/Rbx1 E3 ubiquitin ligase complex, has only one known endogenous substrate which is glutamine synthetase (GS). GS interacts with CRBN through acetylated lysine residues yielding a protein that is succeptable to polyubiquitinlyation. Collectively, this suggests that CRBN tunes c-Myc-regulated pathways in activated T cells and that this process is blocked by immunomodulatory drugs.
Programmed cell death ligand 1 (PD-L1) regulates tumor initiating cell (TIC) generation by controlling the stemness gene Oct4 through mTORC1
Authors: Gupta Harshita B. , Deng June , Clark Curtis A. , Drerup Justin Michael , Wu Bogang , Sareddy Gangadhara , Hurez Vincent , Vadlamudi Ratna , Li Rong , Curiel Tyler J. 
Published: January 2023

Abstract
TIC mediate tumor formation, drug resistance and relapse. We reported that PD-L1 promotes tumor mTORC1, and TIC number and functions. Knocking down PD-L1 reduced expression of stemness genes Oct4 and Nanog and the mTORC1 signaling component Raptor in B16 melanoma and ID8agg ovarian cancer (OC) cells. To understand how PD-L1 controls stemness, we treated control and PD-L1 KO (KO) B16 cells with rapamycin (mTORC1 inhibitor), PI3K inhibitor wortmannin, Notch inhibitor Compound E, and c-Myc inhibitor JQ1. Only rapamycin affected control and KO CD133+CD44+CD24+ TIC differentially (50% reduced TIC in control versus 0% in KO, p=0.0075). We over-expressed Oct4 in B16 but failed to get clones, so over-expressed it in ID8agg PD-L1lo cells (KI) and found that TICs (CD44+CD24+) had improved proliferation and 2-fold more TIC than PD-L1lo cells (p=0.015, p=0.018). We sorted ID8agg, PD-L1lo and KI TIC and cultured them in stem cell medium. KI TICs formed four-fold bigger spheres than PD-L1lo TIC (p&lt;0.0001), consistent with improved self-renewal. The KI spheres were also 1.5-fold larger than those of ID8agg (p=0.032). ID8agg, PD-L1lo and KI cells were then treated with rapamycin. KI TIC were resistant to rapamycin treatment (3 fold reduction in control, 2.9 fold in PD-L1lo versus none in KI), suggesting that PD-L1 drives stemness through mTORC1 driven Oct4 expression. Thus, PD-L1 regulates stemness genes through mTORC1.