bluuebunny/crossref_metadata_2025_split huggingface dataset:
The protective effects of bee venom on cisplatin-induced nephrotoxicity in mice (179.6)
Authors: Kim Hyunseong , Lee Hyojung , Lee Gihyun , Park Soojin , Shin Minkyu , Bae Hyunsu 
Published: January 2023

Abstract
Cisplatin is widely used as a potent effective anticancer drug. However it causes acute renal injury and dysfuntion, mainly nephrotoxicity. Bee venom (BV) has traditionally been used for pain reduction and known to have anti-inflammatory activities. This study designed to investigate the effects of BV on cisplatin-induced nephrotoxicity in mice. BV was administrated once a day for 5 days. After 2 days from BV injections, all groups of mice received a single injection of cisplatin. Mice were sacrificed at 72 hours after cisplatin administration for kidney histological examination and cytokine production analysis. BV treated group showed significantly reduced levels of creatinine, blood urea nitrogen (BUN) and renal tissue damage compared with control. In addition, CD4+CD25+Foxp3+ regulatory T cells (CD4+CD25+Foxp3+Tregs) were increased by BV administration. Moreover, depletion of Treg cells by anti-CD25 antibody injection abolished the renoprotective effects of BV in cisplatin induced nephrotoxicity. These results demonstrated that BV possessed remarkable renoprotective effects in cisplatin-induced nephrotoxicity through regulation of CD4+CD25+FoxP3+Tregs without interfering cisplatin anti-cancer effects.
Defective nuclear IKKα function in patients with ectodermal dysplasia with immune deficiency (180.19)
Authors: Jain Ashish , Ma Chi , Zhao Yongge , Temmerman Stephane 
Published: January 2023

Abstract
Ectodermal dysplasia with immune deficiency (EDI) is an immunological and developmental disorder caused by alterations in the gene encoding NF-κB essential modulator (NEMO; also known as IκB kinase γ subunit [IKKγ]). Missense mutations in the gene encoding NEMO are associated with reduced signal-induced nuclear translocation of NF-κB proteins, resulting in defective expression of NF-κB target genes. Here, we report 2 unrelated male patients with EDI, both of whom have normal NEMO coding sequences, but exhibit a marked reduction in expression of full-length NEMO protein. TLR4 stimulation of APCs from these patients induced normal cytoplasmic activation and nuclear translocation of NF-κB. However, cells deficient in full-length NEMO were defective in expression of NF-κB-regulated cytokines, such as IL-12, suggesting a downstream defect in chromatin accessibility for NF-κB transcription factors. TLR4-stimulated APCs from the patients were defective in IKKα-dependent H3 histone phosphorylation at the IL-12 promoter and recruitment of NF-κB heterodimers RelA and cRel to the promoter. Expression of a super-active form of IKKα restored IL-12 production in a NEMO knockdown human monocytic cell line following LPS treatment. Our findings suggest that NEMO regulates the nuclear function of IKKα and offer new insights into the mechanisms underlying diminished NF-κB signaling in patients with EDI.
Characterization of Chicken Dendritic Cell Markers (181.1)
Authors: Lillehoj Hyun , Lee Sung 
Published: January 2023

Abstract
New mouse monoclonal antibodies which detect CD80 and CD83 were developed to characterize chicken dendritic cells (DCs). The characteristics of these molecules have been studied in human, swine, ovine, feline, and canine but not in chickens. MAbs to chCD80 showed staining of chicken macrophage cell line (HD11), bursa, and spleen. MAbs against chCD80 reduced chCD80’s ability inducing T cell proliferation and IFN-γ production in blast chicken spleen cells, and NO secretion in the HD11. Two mAbs, CD83-159 and CD83-22, reacted with a HD11 and recognized a single 53 kDa protein on Western blots of lysates from LPS-stimulated spleen mononuclear cells. Immunostaining of chicken secondary lymphoid organs identified CD80+ and CD83+cells with morphologic and subtissue localization properties comparable to mammalian DCs. In vitro stimulation of spleen monocytes with concanavalin A (Con A) decreased the percentage of CD83+ cells compared with cells treated with medium alone. Interestingly, spleen cells treated with Con A in the presence of chCD83-227 mAb exhibited decreased percentage of MHCII+ cells compared with cells treated with plus an isotype-matched negative control mAb. These mAbs will be useful for future investigations of DC maturation and mechanisms of action in chickens.
Molecular characterization of antigen-specific B1 and B2 B-cells populations in Cryptococcus neoformans infection in mice (43.1)
Authors: Rohatgi Soma , Pirofski Liise-anne 
Published: January 2023

Abstract
We examined B1 and B2 B-cell repertoires in Cryptococcus neoformans infection in mice. Flow-cytometry based antigen-specific staining for B-cell populations generated in response to pulmonary infection was performed using labeled un-encapsulated and encapsulated C. neoformans strains. FACS sorting and single-cell nested PCR was employed to characterize the IgH repertoire. An increase in total peritoneal B1a, B1b and B2 cell numbers was observed as early as day 3 post-infection. Frequencies of both acapsular and capsular antigen-specific cells were increased in the B1a subpopulation (18%, 5%) in infected compared to naïve mice (11%, 2%). The heavy chains of antigen-specific B2 and B1b cells recognizing acapsular and capsular cryptococcus belonged predominantly to the VH1 family. Interestingly, increased VH11 (22%) and VH12 (33%) usage was observed in antigen-specific B1a cells recognizing acapsular and encapsulated cryptococcus, respectively, compared to the conventional B1a population. Although all acapsular (VH11+) and capsular (VH12+) B1a cells used the same VH11.2.53 and VH12.1.78 genes, 60% and 80% rearrangements were unique, respectively. VH genes in both cases were essentially germline, however 40% of acapsular specific B1a cells had 4 or more N-nucleotide additions compared to capsular specific B1a cells (20%). These results indicate that naturally occurring phosphatidyl choline reactive B1a cells have broad specificities and can bind to encapsulated cryptococcus.
A2B adenosine receptors are essential for effective worm expulsion and enhanced Th2 type immune response to the intestinal parasite Heligmosomoides polygyrus (43.12)
Authors: Patel Nirav , Mishra Pankaj , Wu Wenhui , Hasko Gyorgy , Gause William 
Published: January 2023

Abstract
A2B adenosine receptor (A2B) signaling can modulate lymphocyte function.A2B receptors can control proinflammatory immune responses by enhancing IL-10 and down regulating IFN-γproduction.A2B receptors can activate mast cells to secrete IL-4,a Th2 cytokine that can trigger alternatively activated (M2) macrophages and expulsion of the intestinal nematode parasite, H. polygyrus (Hp).To examine whether A2B receptors contribute to the in vivo protective Th2-type immune response to helminthes, A2B-/- mice were infected with Hp.Worm burden and egg production were increased while serum IgE and IgG1 were reduced in A2B-/- mice compared to WT mice at day 14 after Hp inoculation. Worms recovered from A2B-/- mice at day 11 after secondary H. polygyrus inoculation exhibited higher protein and ATP levels,suggesting impaired host protective responses. Th2 cytokine expression and M2 macrophages markers were also inhibited in small intestines and in mesenteric lymph nodes (MLN) in A2B-/- mice at day11 after secondary Hp infection. Absence of A2B receptor signaling reduced IL-4 but not IFN-γ secreting MLN CD4+T cells after Hp inoculation. Eosinophil and M2 macrophage accumulation in the small intestine and increases in mucous producing intestinal epithelial cells were markedly inhibited in A2B-/- mice, after Hp secondary inoculation. These studies suggest that A2B receptors play an essential role in the development of the host protective Th2 type immune response during helminth infection.
Differential roles for Th1 transcription factors STAT1 and STAT4 during visceral leishmaniasis (43.22)
Authors: Snider Heidi , Gupta Gaurav , Satoskar Abhay 
Published: January 2023

Abstract
Leishmaniasis is a tropical disease caused by protozoan parasites belonging to the genus Leishmania. Leishmania donovani causes visceral disease (VL) with tropism for reticuloendothelial organs. Left untreated, L. donovani infections are fatal, often due to secondary bacterial infections and complications resulting from profound hepatosplenomegaly. Although Leishmania species are capable of parasitizing several different mammalian cell types, the definitive host cell and site of parasite replication is tissue macrophages. Proper macrophage activation and parasite clearance is contingent upon hosts mounting Th1 CD4+ T cell responses associated with the production of IL-12 and IFN-gamma. While IL-12 primarily signals upstream of the transcription factor STAT4, IFN-gamma signaling primarily leads to the activation of STAT1. Our laboratory has already shown that STAT1-/- mice are unexpectedly resistant to VL, despite its critical role in driving Th1 responses. We therefore wanted to investigate the phenotype of STAT4-/- mice. While both STAT1-/- and STAT4-/- mice were unable to mount effective Th1 cytokine responses following infection, STAT4-/- mice were highly susceptible to VL and exhibited significant tissue immunopathology compared to WT and STAT1-/- animals. These studies suggest that early STAT1 signaling is actually required for disease establishment prior to initiation of a Th1 response, while STAT4 signaling is indispensible for Th1-driven resistance.
Severe tuberculosis induces high degree of CD4 T cell differentiation (43.25)
Authors: Lyadova Irina , Nikitina Irina , Vasilyeva Irina , Ganusov Vitaly 
Published: January 2023

Abstract
Effector Th1 cells represent a key component of anti-TB defense. Until now it has been unclear whether active TB promotes or alters the differentiation of functionally active effector CD4 T cells. Our previous observations in mice have revealed that Mtb infection leads to the formation of highly differentiated Th1-biased effectors expressing CD27low phenotype. Here, we addressed the generation of CD27low effectors during pulmonary TB in humans. We have analyzed the percents of CD27low cells within Mtb-specific CD4 T lymphocytes (cells producing IFN-γ after stimulation with Mtb sonicate) located in the focus of lung Mtb infection or circulating in peripheral blood. In the lungs, CD27low subset formed a vast majority (&gt;70%) of Mtb-specific CD4 T cells. In blood, the percents of CD27low cells varied from low (12%) to very high (92%). The major correlates for the accumulation of CD27low cells in the blood were lung tissue destruction and clinical TB severity (r&gt;0.5; p&lt;0.0001). Following the therapy, the content of CD27low cells declined in parallel with lung tissue repair. Compared to patients, the content of CD27low cells in healthy donors and Mtb-exposed individuals was significantly lower (p&lt;0.001). Overall, there was no deficiency in the generation of CD4 effector cells during TB. Instead, active TB promoted the accumulation of highly differentiated CD27low effectors, which may serve as a valuable marker for TB severity and lung tissue destruction.
Tuberculosis-specific CD4+ and CD8+ T cells maintained in older latently infected individuals (43.27)
Authors: Canaday David , Tavera Gloria , Banks Richard , Aung Htin 
Published: January 2023

Abstract
One risk factor for reactivation of latent M. tuberculosis (MTB) is old age. Although there are significant data in elderly and nursing home patients on clinical matters such as use of two-step PPD testing, there are a severe paucity of data on changes in MTB-specific immune responses that occur with aging. We have studied MTB-specific immune responses using 13-color intracytoplasmic flow cytometry analysis of CD4+ and CD8+ memory T cell subsets simultaneously examining their expression of IFN-gamma, IL-2, MIP1-alpha, and perforin after stimulation with the MTB-antigen PPD. Data from 13 latently MTB-infected PPD+ older subjects (mean age 77 range 61-89) showed that MTB-specific responses from CD4+ and CD8+ T cells were maintained compared to 8 younger PPD+ subjects (mean age 31 range 23-40). Surprisingly, frequencies of MTB-specific IL-2 secreting effector and central memory CD4+ T cell were higher in older subjects (mean 1.1%) than in younger persons (mean 0.22%, p&lt;0.05). In older subjects, many of these MTB-specific CD4+ T cells only secreted IL-2 after stimulation while there was no defect in their ability to produce the full range of cytokines studied when stimulated with mitogen. Overall, as there was no defect in MTB-specific T cells in older persons, these data support a need to further broaden the T cell studies as well to expand to other areas such as potential deficits in macrophage function.
Regulation of T-cell dependent IgG response to soluble protein antigens in the presence and absence of intact bacteria (43.9)
Authors: Saumyaa Saumyaa , Arjunaraja Swadhinya , Torres Raul , Snapper Clifford 
Published: January 2023

Abstract
During bacterial infections the immune system encounters Ags associated with the intact bacterium simultaneously with those that are released in soluble form, although the immunologic consequences of this on IgG responses to the latter are unknown. We previously demonstrated that intact inactivated Streptococcus pneumoniae (strain R36A) inhibits IgG responses to co-immunized soluble Ags. We investigated the mechanism of this inhibition using intact R36A and soluble chicken ovalbumin (OVA). Using the i.v. route, no inhibition was observed if R36A was given 24h before or after immunization with OVA, indicating an early and transient inhibitory effect. This inhibition could be partially overcome by co-immunization with a strong adjuvant. Using transgenic OVA-specific CD4+ T cells, we observed that R36A had no significant effect on OVA-induced T-cell activation (24h) or generation of regulatory T cells (d7), and only a modest effect on proliferation (48-96h). However, R36A mediated a significant reduction in PD1+GL7+ OVA-specific T cells (germinal center T follicular helper cells) suggesting an inhibitory effect on the GC reaction. Of note, co-immunization of OVA with either intact inactivated Streptococcus agalactiae or Neisseria meningitidis resulted in a significant enhancement of the OVA-specific IgG response. These results strongly suggest that Streptococcus pneumoniae may uniquely express a component capable of inhibiting humoral immune responses to soluble antigens.
Understanding the effects of IL-18 and IL-1β in a complex pro-inflammatory milieu. (44.11)
Authors: Ferguson John , Sleeman Matt , Briend Emmanuel , Finch Donna 
Published: January 2023

Abstract
Disease association studies suggest that the cytokines IL1 and IL18 play a role in exacerbations of Chronic Obstructive Pulmonary Disease. A classical role of IL18 is to stimulate NK and T-Cells to produce IFNγ, a cytokine associated with viral exacerbations of COPD. IL1β, which is processed by the same mechanism as IL18, can have a similar effect on IFNγ. We sought to understand their respective role in IFNγ secretion in situations where they both could be released. Treatment of PBMCs with IL18 or IL1β (in the presence of IL12) was able to induce IFNγ release. This response was most sensitive to IL1β but IL18 was able to stimulate a greater maximal response. When LPS was used as a trigger of IFNγ release, a large amount of IL1β (11ng/mL) and a low amount of IL18 (27pg/mL) could be detected in the supernatant. Co-incubation with an IL18 neutralizing antibody, or the IL1 receptor antagonist anakinra, was able to inhibit the IFNγ response by 50% in both cases. In a second system, relevant to COPD exacerbations, the infection of bronchial epithelial cells with a human Rhinovirus induced the release of both IL18 (2.5ng/mL) and IL1β (435pg/mL). Transfer of the supernatant to PBMCs or NK cells induced IFNγ production which was largely IL1-dependent; inhibition of IL18 only had a small effect on IFNγ. This data showed that while they could induce IFNγ following an inflammatory stimulus, it is the context of their release that defines a predominant role for either IL18 or IL1β.
G protein-coupled receptor kinase 6 mediated phosphorylation of activator of G protein signaling 3: role in CXCR2 activation and regulation (44.12)
Authors: Singh Vandana , Richardson Ricardo 
Published: January 2023

Abstract
G protein-coupled receptor (GPCR) kinases (GRKs) are kinases that phosphorylate activated GPCRs as their primary targets. Recent studies suggest that GRKs may have more diverse protein/protein interactions in cells. A screen to find GRK6 binding partners revealed activator of G protein signaling 3 (AGS3) as an interacting protein. Co-immunoprecipitation studies in RBL-2H3 cells stably expressing CXCR2 (RBL-CXCR2) showed that, upon stimulation with interleukin 8 (IL-8/CXCL8), GRK6 directly interact with and phosphorylate AGS3. The GRK6/AGS3 complex is time-dependent and peaks within 2-3 minutes. Over-expression of AGS3 in RBL-CXCR2 significantly inhibited intracellular Ca2+ mobilization, phosphoinositide (PI) hydrolysis and chemotaxis. Suppression of AGS3 by shRNA, in contrast, inhibited GRK6/AGS3 association and increased CXCR2 resistance to desensitization. Altogether, these data identify AGS3 as a GRK6 substrate and indicate that phosphorylation of AGS3 by GRK6 likely play an important role in modulating CXCR2 mediated cellular responses.
MicroRNAs modulate chemokine expression in naïve CD8 T cells (44.19)
Authors: Cheng Nai-Lin , Chen Xiaochun , Nguyen Cuong , Weng Nan-ping 
Published: January 2023

Abstract
Chemokines play a pivotal role in regulating T cell function and migration in a space- and time-tight fashion. With aging, the levels of several chemokines alter in serum and have detrimental impact on the immune function. However, the mechanisms that regulate chemokine expressions and their age-associated alteration are not fully understood. MicroRNAs (miRNA) are key regulators for gene expression at the posttranscriptional level but their roles in the age-associated change of gene expression in T cells have not been examined. We sought to understand the role of miRNA in regulation of chemokine expression in CD8 T cells by profiling chemokines and miRNAs in naïve and memory CD8 T cells. Six miRNAs (miR-99a, -125b, -186, -335, -424, and -542-5p) were highly expressed in naïve CD8 T cells. In addition, we found that miR-125b, -335, and -186 have a putative binding site in the 3’ UTR of CC chemokine ligand 4 (CCL4), CCL5, and CXC chemokine ligand 5 (CXCL5), respectively. These chemokines are highly expressed in activated T cells and increased serum levels with age. Currently, we are testing these individual miRNA in the chemokine-reporter transfected Jurkat cells and in human primary CD8 T cells from young (≤ 30 yrs) and old (≥ 70yrs) donors. Our preliminary findings suggest that miRNA regulates chemokine expression in CD8 T cells and such regulation may change with age.
IL-21 promotes the pathologic immune response to Pneumovirus infection (44.2)
Authors: Spolski Rosanne , Wang Lu , Wang Chi-Keung , Bonville Cynthia , Domachowske Joseph , Kim Hyoung-Pyo , Yu Zuxi , Leonard Warren 
Published: January 2023

Abstract
IL-21 is a type I cytokine whose targets include both lymphoid and myeloid populations and whose role in host responses to pulmonary pathogens has not been evaluated. Pneumonia virus of mice (PVM) is a natural rodent pathogen that initiates a respiratory infection in mice that resembles severe human respiratory syncytial virus (RSV) disease. We demonstrate that IL-21 is expressed by CD4+ T cells in the lung following infection of animals with PVM. Examination of PVM-infected Il21r-/- mice revealed much less lung infiltration by neutrophils than was seen in WT mice, and consistent with this, Il21r-/- mice also had reduced levels of the chemokine CXCL1 in both bronchoalveolar lavage fluid and lung parenchyma. Both CD8+ and CD4+ T cells as well as γδ T cells were also reduced in PVM-infected Il21r-/- mice, even though CD8+ T cell cytokine responses were not diminished. Th17 cytokines were expressed at the same levels as in WT mice, but IL-6 production in response to PVM was diminished in Il21r-/- mice. Although virus recovery was similar in WT and Il21r-/- mice, the absence of IL-21 signaling conferred a survival advantage to Il21r-/- mice, indicating that IL-21 can contribute to a detrimental inflammatory state in the lung. Overall, our findings suggest that therapeutic manipulation of IL-21 signaling, such as IL-21 receptor blockade, may represent an immunomodulatory strategy for averting the negative sequelae of this and potentially other respiratory virus infections.
CCL18 does not require CCR6 for functional activity in mice (44.3)
Authors: Atamas Sergei , Luzina Irina 
Published: January 2023

Abstract
CCL18 is an orphan chemokine present in primates but not in mice. Human CCL18 is fully functional in mice in vivo: it is chemotactic to mouse T lymphocytes similar to its effect on human T cells, suggesting that although mice have lost CCL18 after evolutionary separation from primates, its receptor remains preserved and functional. Attempts to identify CCL18 receptor have been unsuccessful, but a recent study (Am J Respir Crit Care Med 2011, 183:A5574) suggested that CCR6, the receptor for CCL20, is also used by CCL18. To explore this possibility, we administered a replication-deficient recombinant adenoviral construct encoding human CCL18 (AdV-CCL18) to mouse lungs in wild type (WT) and CCR6-deficient (-/-) animals. Non-manipulated as well as AdV-NULL-infected control WT mice had 2-4% of lymphocytes in their bronchoalveolar lavage (BAL), whereas AdV-CCL18-infected WT mice had 20-25 % of BAL lymphocytes. Flowcytometric analyses showed that less than 5% of CD3+ BAL cells in CCL18-expressing WT mice were also CCR6+. Histological changes caused by CCL18 delivery were similar in WT and CCR6 -/- mice, with characteristic perivascular and peribronchial infiltration of T cells which was not observed in AdV-NULL-treated mice. Thus, it appears that human CCL18 utilizes a receptor different than CCR6 in mice. A possibility exists that mice and humans utilize different CCL18 receptors, but it is unlikely considering the remarkable similarity of CCL18 effects on human and mouse cells.
TGF-β dramatically reduces the numbers of short-lived effector CD8 T cells during primary and secondary influenza virus infections. (44.4)
Authors: Hu Yinghong , Wu Tao , Bouchard Keith , Cauley Linda 
Published: January 2023

Abstract
Highly differentiated CTLs make large quantities of proinflammatory cytokines and contribute to high mortality rates during influenza virus infections. Some pathogens trigger robust responses by short lived effector CD8 T cells (SLECs) which express KLRG1 but not CD127. Other less differentiated CD8 T cells which lack KLRG1 and quickly regain CD127 expression are better equipped to avoid deletion which led to the designation memory precursor cells (MPECs). Recent studies have shown that influenza virus-specific CTLs do not adhere to this pattern, since very small numbers of virus-specific CTLs acquired the KLRG1+CD127- phenotype during the peak of the effector response. We show that exposure to TGF-β during antigen stimulation greatly increases the size of the CTL response and changes the balance between the numbers of MPECs and SLECs during primary and secondary influenza virus infections. We reveal a dichotomy in the response to TGF-β which develops as the virus-specific CTLs become more differentiated. Our data suggest that TGF-β protects the lungs from immune damage through widespread depletion of SLECs, while simultaneously helping less pathogenic virus-specific CTLs colonize the mucosa where they can enhance to response to repeated viral infection.