bluuebunny/crossref_metadata_2025_split huggingface dataset:
GM-CSF induces podoplanin expression during dendritic cell differentiation (111.56)
Authors: Zhang Hong , Lin Xiao , Li Sky , Pahuja Anil , Ransom John , Yang Xifeng 
Published: January 2023

Abstract
Podoplanin is a mucin-type transmembrane glycoprotein containing extensive Oglycosylation in extracellular domain and two phosphorylation sites in a short cytoplasmic tail. It is expressed in kidney glomerular epithelial cells, lymphatic endothelium and subcapsular epithelial cells in murine thymus. Recently, podoplanin was found on murine F4/80 positive peritoneal macrophages and human follicular dendritic cells (FDCs) indicating that podoplanin is involved in immune response. We have reported that podoplanin is induced during Th9 and Th17 polarization. Here, we studied podoplanin expression on different types of murine myeloid cells. We found that podoplanin was not detectable on circulating and bone marrow derived neutrophils, monocytes, basophils and esinophils, its expression level on neutrophil and monocytes was not inducible followed by fMLP or TNF-a stimulation. Podoplanin was also not detectable on spleen and lymph node resided CD11b+macrophages, CD11c+ dendritic cells (cDCs) and CD8+ plasmacytoid dendritic cells (pDCs). However, podoplanin expression level has been dramatically increased on GM-CSF driven bone marrow-derived dendritic cells. These data suggest that podoplanin can be induced during GM-CSF driven dendritic cell differentiation, indicating that podoplanin may be a transient marker during dendritic cells differentiation and maturation. The mechanism of GM-CSF induced podoplanin and it significance need to be further investigated.
Interleukin-8 promoter polymorphism rs4073 is not associated with its expression level or tuberculosis susceptibility in China. (112.17)
Authors: Li Chuanyou , Che Nanying 
Published: January 2023

Abstract
Interleukin-8 (IL-8) is an important chemokine eliciting host immune response against tuberculosis (TB). However, whether IL-8 gene polymorphism is associated with TB susceptibility and its biological function remains to be answered. Ma et al. reported that rs4073 polymorphism in IL-8 promoter region was associated with TB susceptibility in the two ethnic groups in the United States. On the contrary, Cooke et al. reported that this polymorphism was not a true factor affecting TB susceptibility in Gambia. So in this study, the association between rs4073 polymorphism and TB susceptibility was analyzed on 433 TB patients and 505 healthy controls in China. Allelic and genotypic analysis showed that rs4073 polymorphism distribution between TB patients and healthy controls was not significantly different (p&gt;0.05). The effect of IL-8 rs4073 polymorphism on IL-8 expression level was also determined. ELISA analysis showed that IL-8 expression level in the peripheral blood among different genotypic doners (A/A, A/T, T/T) was not significantly different (p&gt;0.05). These results demonstrate that rs4073 polymorphism is not associated with TB susceptibility or with IL-8 expression level in Chinese population. Genetic susceptibility to TB in different ethnic groups needs to be studied carefully.
Functional role of Thioredoxin peroxidase from Clonorchis sinensis in host immune reactions (112.3)
Authors: Wi Hae Joo , Jin Yan , Bae Young Mee 
Published: January 2023

Abstract
Clonorchis sinensis (C. sinensis), one of liver flukes, can cause chronic infection while they reside in the bile duct and leads to cholangiocarcinoma in humans. We investigated interaction between live C. sinensis worm and murine macrophage cell line, RAW264.7, using a non contact co-culture transwell plate. The results shown that the worms are able to activate RAW cells to express surface TLR4 and to promote IL-10 and TGF-β secretion. There are minor differences between direct and indirect exposure of the worms. As we hypothesized that anti-oxidant enzyme produced by C. sinensis might stimulate host immune reactions, we cloned antioxidant enzyme, Thioredoxin peroxidase (TPX, 2-Cys peroxidase), and the recombinant protein (rTPX) has been produced by using the bacterial system. Mouse macrophage cells, RAW264.7 cells, were treated with rTPX and checked the level of cell surface markers. We found that expression of TLR4 and CD40 molecules were augmented at 3 and 6 hours time points, respectively. Surface expression of TLR4 was prolonged up to 48 hrs, while CD40 was temporarily expressed. ELISA results showed that IL-4 level was slightly down-regulated by TPX treatment, however, IL-10 secretion was increased and even doubled when IL-4 and TPX were treated together. Although, more than one molecule could be involved in antigenicity of C. sinensis, we report here that the TPX from C. sinensis is a candidate that acts as “infection alarm” to awake the host innate immune cells.
C-reactive protein-mediated initial protection of mice from pneumococcal infection (112.4)
Authors: Gang Toh , Hammond David , Singh Sanjay , Ferguson Donald , Agrawal Alok 
Published: January 2023

Abstract
Human C-reactive protein (CRP) protects mice from lethal Streptococcus pneumoniae infection when injected into mice 6 h before to 2 h after the administration of pneumococci. Because CRP binds to phosphocholine, it has been proposed that the protection begins with the binding of CRP to phosphocholine residues present on pneumococcal C-polysaccharide. To test this proposal, in this study, we utilized a CRP mutant incapable of binding to phosphocholine. Based on the crystal structure of CRP-phosphocholine complexes which showed that amino acids Phe66, Thr76 and Glu81 form the phosphocholine-binding site of CRP, we constructed a CRP triple mutant F66A-T76Y-E81A. We purified the mutant CRP by affinity chromatography on a phosphoethanolamine-conjugated Sepharose column. Compared to wild-type CRP, the mutant CRP bound more avidly to phosphoethanolamine but did not bind to phosphocholine-BSA, pneumococcal C-polysaccharide and whole pneumococci. In C57BL/6 mice, the half-life of the mutant CRP was the same as that of wild-type CRP. Unlike wild-type CRP, passively administered mutant CRP did not protect mice from lethal pneumococcal infection. Mice injected with mutant CRP had higher mortality rates than mice that received wild-type CRP. Decreased survival was due to the increased bacteremia in mice treated with the mutant CRP. We conclude that the phosphocholine-binding function of CRP is required for CRP-mediated initial protection of mice from pneumococcal infection.
Identification of “Asymptomatic” HLA-A*0201-Restricted CD8+ Cytotoxic T-Lymphocyte Epitopes from the Herpes Simplex Virus Glycoprotein B (113.13)
Authors: Benmohamed Lbachir , Chentoufi Aziz , Dervillez Xavier , Dasgupta Gargi , Kabbara Khaled , Villacres Maria , Nguyen Chelsea , Wechsler Steven , Sidney John , Nesburn Anthony 
Published: January 2023

Abstract
Protective “asymptomatic” human CD8+ T-cell epitopes from herpes simplex virus type 1 and type 2 (HSV1 & HSV-2) protein antigens remain largely undefined. Here, we have identified immunodominant protective "asymptomatic" human CD8+ T cell epitopes on the HSV-1 gB that are restricted to HLA-A*0201, an haplotype that covers over 50% of the human population. The 904-amino acid HSV-1 (strain 17) gB sequence was screened for potential CD8+ T cell epitopes. Ten epitopes were identified, synthesized and tested for affinity to HLA-A*0201 molecule. Two of these peptide epitopes, gB441-449 and gB561-569, exhibited high affinity for soluble HLA-A*0201 molecules. Peptide-specific CD8+ T cell proliferation (CFSE dilution) and CD107a/b cytotoxic degranulation were demonstrated against the same two epitopes in 30 sequentially studied HLA-A*0201-positive, HSV-1 seropositive asymptomatic individuals (i.e. during control of herpetic disease), but not in symptomatic individuals (i.e. with frequent herpetic disease). A heterologous lipopeptide/rAdv5 prime/boost vaccine expressing these two asymptomatic gB CD8+ epitopes induced a strong and long lasting CD8+ T-cell protective immunity against ocular and genital herpes in a susceptible HLA-A*0201 transgenic mice. Human protective asymptomatic CD8+ T-cell epitopes on HSV-1 proteins should continue to provide new insight into immune correlates of protection and aid in the development of a safe and efficient immunotherapeutic vaccine for herpes.
Development of goose monoclonal IgY antibodies for use as a passive therapeutic. (113.6)
Authors: Haese Nicole , Bradley David 
Published: January 2023

Abstract
When vaccination is not cost effective or possible, one of the primary alternatives is passive immunotherapies. Passive therapeutic antibodies have been shown to be effective in the treatment, not only of infectious agents, but also for toxins, venoms, and cancer targets. Recent research in our laboratory as well as others, has demonstrated the potential of avian-derived passive therapeutic antibodies. We have demonstrated goose-derived polyclonal antibodies, from either sera or eggs, are therapeutic for several viral diseases. The avian immunoglobulin IgY is the primary avian antibody isotype. IgY is similar to mammalian IgG, but lacks the ability to interact with mammalian Fc receptors, complement, and other factors that promote inflammation. IgY’s potential as a therapeutic agent is boosted by its higher avidity than IgG and recognizes more epitopes than mammalian antibodies. These advantages are due to the evolutionary distance between mammalian and avian species. In this work we present initial studies to develop goose mIgY, utilizing traditional mammalian monoclonal protocol that will be commercialized against viral or other targets responsive to single epitope treatment, with the product displaying the inherent advantages of avian antibodies.
An NLRP7-containing inflammasome mediates recognition of microbial lipopeptides and restrict intracellular bacterial replication in human macrophages (114.6)
Authors: Stehlik Christian , Khare Sonal , Dorfleutner Andrea , Bryan Nicole , Yun Chawon , Radian Alexander , de Almeida Lucia , Rojanasakul Yon 
Published: January 2023

Abstract
Nod-like receptors (NLRs) emerged as central cytosolic pattern recognition receptors (PRRs). However, the function of the majority of NLRs is currently unknown. We identified that NLRP7 functions as a PRR in primary human macrophages. Activation of NLRP7 by cytosolic microbial acylated lipopeptides (acLP) causes ASC-dependent inflammasome formation in a cytosolic high-molecular weight complex, Caspase-1 activation and maturation and release of interleukin (IL)-1β and IL-18. Reconstitution of an NLRP7/ASC/pro-Caspase-1 inflammasome, but not of an NLRP3/ASC/pro-Caspase-1 inflammasome is sufficient to respond to intracellular delivery of acLP. However, in macrophages both NLRP7 and TLR2 are required for the acLP-mediated release of IL-1β. While TLR2 is necessary for the transcription of pro-IL-1β and pro-IL-18, NLRP7 mediates the Caspase-1-dependent maturation and release of both cytokines. Therefore, NLRP7 and TLR2 contribute to the host defense against intracellular Gram positive bacteria, since knock-down of either NLRP7 or TLR2 promotes intracellular replication of Listeria monocytogenes and knock-down of NLRP7 also increases the intracellular replication of Staphylococcus aures. Our study therefore increases our currently limited understanding of NLR activation, inflammasome assembly and maturation of IL-1β and IL-18 in human macrophages.
Development of PLZF-expressing γδ NKT cells in Itk-/- mice (115.13)
Authors: Yin Catherine , Narayan Kavitha , Sylvia Katelyn , Immunological Genome Project The , Kang Joonsoo , Berg Leslie 
Published: January 2023

Abstract
In conventional αβ T cells, the Tec family tyrosine kinase, Itk is required for signaling downstream of the TCR. Itk also regulates αβ T cell development, lineage commitment, and effector function. A well-established feature of Itk-/- mice is their inability to generate T helper type 2 (Th2) responses that produce IL-4, IL-5, and IL-13; yet these mice have spontaneously elevated levels of serum IgE. We have previously shown the cause of this phenotype is due to the increase of the mature Vγ1.1+Vδ6.3+ (V6) subset of γδ T cells in Itk-/- mice. Wild type V6 γδ T cells display characteristics similar to αβ NKT cells including dual secretion of IL-4 and IFNγ along with expression of the transcription factor PLZF; therefore they are γδ NKT cells. Along with increased proportions of mature V6 cells in Itk-/- mice, V6 cells in Itk-/- mice have increased IL-4 secretion and elevated levels of PLZF expression. Based upon PLZF expression and the use of the IL-4 reporter (4Get) mice, our data indicate that γδ NKT cells have similar differentiation stages as αβ NKT cells, and that Itk-/- γδ NKT cells are blocked during development. Together, these data indicate that Itk signaling regulates γδ T cell lineage development and effector function, and is required to control IgE production in vivo.
Mechanisms of plasticity in the peripheral T cell receptor repertoire (115.15)
Authors: Thomas Paul , Wang George , Dash Pradyot 
Published: January 2023

Abstract
We recently reported a method for amplifying paired T cell receptor (TCR) αβ CDR3 regions from single cells in mice and have developed a similar protocol for human cells. Using this technique, we have discovered a surprising plasticity in peripheral TCR repertoire, particularly under conditions of inflammation. This plasticity includes two major mechanisms: TCR modulation and TCR revision. Modulation consists of the up or down regulation of secondary allele expression, almost exclusively from the TCRα locus. Revision results in changes to the amino acid sequence of the TCR by de novo rearrangement. Here we describe the upregulation of both processes in CD8+ T cells derived from influenza-infected lungs when compared to circulating naïve T cells. In particular, instances of modulation and dual chain expression are elevated over the course of a primary influenza T cell response, whereas in recall responses memory cells express only a single allele of each TCR chain. In repeated infections, revised TCRs are observed by using out of frame TCR sequences as an internal, lineage specific, barcode. The relative contribution of each mechanism to the activation of autoreactive T cells is assessed in genetic models.
S-Adenosylmethionine-dependent methylation modulates T cell immune response and lupus autoimmunity (116.13)
Authors: Yang Mei-Ling , Gee Alaric , Gee Renelle , Mamula Mark 
Published: January 2023

Abstract
Methylation modification is a key factor to maintain T and B cell immune responses and contributes to the development of autoimmune diseases. Failure to maintain the methylation status of CpG dinucleotide triggers T cell autoreactivity and results in the pathogenesis of systemic lupus erythematosus (SLE). However, methylated proteins have been considered as auto-antigens such as arginine-methylated myelin basic protein in multiple sclerosis (MS) and symmetrical dimethyl-arginines of SmD1 and SmD3 in SLE. Importantly, transmethylation reaction cannot achieve without the methyl donor supply. Herein, we demonstrate that the disruption of the metabolism of s-adenosylmethionine (SAM) cycle, the major methyl donor source for transmethylation, can modulate T cell functions. By giving excess methyl donor, SAM, or methylation inhibitor, methylthioadenosine (MTA), T cell immune responses were suppressed includes TCR signaling defect, impaired multiple Th1/Th2 cytokine productions, decreased T cell activation and proliferation. Moreover, intraperitoneal treatment of MTA markedly ameliorates splenomegaly, lymphadenopathy, peripheral autoantibodies production, renal IgG deposition and lymphocyte infiltration into the kidney in lupus-prone MRL/lpr mice. These studies demonstrate the central role of SAM-dependent methylation associated with T cell function and MRL lupus autoimmunity.
Cannabinoid receptor-2-selective agonists improve recovery in experimental autoimmune encephalomyelitis (116.7)
Authors: Kong Weimin , Li Hongbo , Adhikary Sabina , Tuma Ronald , Ganea Doina 
Published: January 2023

Abstract
Previous studies showed that cannabinoids have anti-inflammatory effects in experimental autoimmune encephalomyelitis (EAE), but the mechanism is elusive. In the present study, we investigated the effects of Gp1a (a new CB2 selective agonist) in EAE. EAE developed in a similar way in both vehicle and Gp1a treatment group, but mice treated with Gp1a recovered faster than the vehicle group. Cellular analysis was performed in spleen, brain and spinal cord. In spleen, there was no difference in numbers of CD3+ T cells, Th1 and Th17 cells, or macrophages. In contrast, CNS mononuclear cell analysis showed fewer CD3+ T cells, Th1 and Th17 cells, macrophages and activated microglia in spinal cord but not in brainin the Gp1a treatment group. Accordingly, for the Gp1a-treated group, histology studies also showed fewer CD3+ T cells, CD11b+ macrophages/microglia and less Iba-1 expression in spinal cord but not in brain. In vivo cell proliferation as measured through BrdU incorporation in CD3+CD45hi, CD11b+CD45hi and CD11b+CD45int mononuclear cells was not affected by Gp1a treatment. We hypothesize that Gp1a inhibits cell migration to the CNS. We also analyzed gene expression in brain and spinal cord following EAE development and found lower levels of VCAM-1, CXCL-10 and MMP9 in spinal cord. We also found that Gp1a inhibits MMP9 and TNFα production in BV.2 cells (a microglia cell line). We conclude that Gp1a improves EAE recovery through inhibiting immune cell migration into CNS.
IFN-γ induced antimicrobial response against M. leprae in human macrophages (117.12)
Authors: Realegeno Susan , Teles Rosane , Kelly-Scumpia Kindra , Modlin Robert 
Published: January 2023

Abstract
The role of IFN-γ in inducing an antimicrobial response in macrophages was investigated in leprosy, a disease caused by intracellular bacterium M. leprae. Tuberculoid leprosy (T-lep) is characterized by few skin lesions with low bacterial numbers, whereas lepromatous leprosy (L-lep) is characterized by disseminated skin lesions and increased bacilli numbers. The host immune response in T-lep is characterized by Th1 cytokines and expression of the vitamin D dependent antimicrobial pathway, in contrast to L-lep, which is predominately Th2. We have linked expression of the Th1 cytokine IFN-γ and antimicrobial response in leprosy by induction of vitamin D dependent antimicrobial response genes CAMP and DEFB4. IFN-γ is present in T-lep patients, where the disease is self-limited, however, the role of IFN-γ in antimicrobial activity is unclear. IFN-γ mediates antimicrobial activity against M. tuberculosis, a related pathogen, in the presence of vitamin D sufficient serum, but not in the presence of vitamin D deficient serum. Our preliminary data shows that M. leprae infected macrophages pretreated with IFN-γ prior to infection in combination with post-infection IFN-γ treatment in vitamin D sufficient serum reduced bacterial viability by approximately 80% compared to media control. Our studies suggest that IFN-γ can trigger a vitamin D dependent antimicrobial response in human macrophages as well as antimicrobial activity against M. leprae.
Efferocytosis induces macrophages to produce IL-4 and activate invariant NKT cells to suppress inflammation (117.17)
Authors: Zeng Melody , Pham Duy , Brutkiewicz Randy , Kaplan Mark , Dinauer Mary 
Published: January 2023

Abstract
Efferocytosis of apoptotic neutrophils by macrophages is fundamental to the resolution of inflammation. In this study we demonstrate using a mouse sterile peritonitis model, a circuit requiring the activation of NKT cells by efferocytosing macrophages to resolve inflammation. Following ingestion of apoptotic neutrophils, macrophages produced IL-4 and IL-13, which in an autocrine manner, resulted in cells with an M2 phenotype. Efferocytosing macrophages displayed increased cell surface expression of CD1d and activated invariant NKT (iNKT) cells that produced IL-4 during the later phase of inflammation. Peritoneal inflammation was exaggerated in mice lacking IL-4 or NKT cells, suggesting both are required to suppress inflammation. Furthermore, sterile peritoneal inflammation was also enhanced and prolonged in NADPH oxidase-deficient mice with X-linked chronic granulomatous disease (X-CGD). We found that X-CGD exudate macrophages expressed reduced surface CD1d and were impaired in activating iNKT cells, which contributed to the persistent inflammation in these mice. Therefore, efferocytosis-induced IL-4 production and activation of iNKT cells by macrophages are immunomodulatory events in an innate immune circuit required to resolve sterile inflammation.
TLR agonist treatment elicits an increase in DNA repair machinery (117.19)
Authors: Harberts Erin , Fishelevich Rita , Gaspari Anthony 
Published: January 2023

Abstract
The toll-like receptor (TLR) pathway is stimulated by pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs). Activation of this pathway leads to an inflammatory and immunomodulating response appropriate for the stimulus by which it was activated. Recently a body of literature has emerged indicating that TLR stimulation may not only result in an inflammatory response, but may also lead to an up-regulation of DNA repair genes and an increase in functional DNA repair after injury. These conclusions are drawn from studies conducted in the mouse animal model, however the human DNA repair response to TLR activation has yet to be investigated. Using an in vitro cell culture system, we find that human DNA repair genes are similarly up-regulated. Previously, only TLR 7 and TLR 9 agonists have been shown in mice to stimulate increased DNA repair; in this study we expand the panel of TLR agonists investigated and show that the induction of this phenomenon may not be unique to the previously studied TLR agonists. This functional increase in repair after injury may lead to a wide range of outcomes for the cells involved and warrants further study into the ever broadening role of TLR signaling in controlling cell fate.
Intradermal route of infection with Francisella tularensis subspp novicida elicits differential induction of a wide array of cytokines and chemokines (117.7)
Authors: Biffa Demelash , Buntzman Adam , Barrigan Lydia , Frelinger Jeffrey 
Published: January 2023

Abstract
Francisella tularensis is highly virulent and infectious bacterial pathogen and a category A select agent. Many aspects of immunity to the infection are not well understood. This study is part of ongoing work to understand the immune response following cutaneous exposure. The aim of the study was to determine cytokines/chemokines induced in response to intradermal infection with F. tularensis subspp novicida. Further aim was to determine the correlation between induction of cytokines/chemokines with bacterial load. C57BL/6J mice were intradermally infected with F. novicida U112 WT and DotU. DotU mutants do not grow inside macrophages and are greatly attenuated. The results investigated wide array of induced anti-and pro-inflammatory cytokines/chemokines in spleen. Higher levels of INF-γ and P-10 were expressed at 24hrs post-infection in spleen of mice infected with WT compared to DotU or mock control. The recovered number of viable bacteria from the spleen peaked at 24hrs and correlated with increased induction of INF-γ. Studies are underway to elucidate the role of cytokines/chemokines in shaping adaptive immunity.