bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of bovine natural killer cell cytotoxicity following activation by pro-inflammatory cytokines(181.2)
Authors: Dar Pervaiz , Patch Jared , Kenney Mary , Waters Ryan , Glabman Raisa , Kondabattulla Ganesh , Golde William 
Published: January 2023

Abstract
Bovine natural killer (NK) cells are important mediators of the innate immune response to infectious diseases of cattle. Like other mammalian species, bovine NK cells express NKp46 (CD335) and do not express CD3 or a T cell receptor. However, bovine NK cells remain poorly characterized with respect to cytokine activation, in part because the commonly used lymphoma target cell line, K562, apparently fails to induce a significant cytotoxic response by bovine NK cells. We have assessed natural cytotoxicity against a bovine-derived lymphoid cell line (BL3.1) compared to human-derived K562 cells. Lymphocytes activated in vitro with bovine cytokines (IL-2, IL-15, IL-21 and their combination) for different time periods were analyzed for killing activity using these target cells. We observed enhanced killing of BL3.1 cells, suggesting that they are more susceptible to killing by bovine NK cells than K562 cells. Killing activity was detected after 24 hrs of in vitro cytokine stimulation and maximal cytotoxicity was demonstrated following 72-96 hrs of culture with cytokines. Our data indicate that the addition of IL-21 enhances IL-2 mediated cytotoxicity, whereas IL-15 has no effect on NK cytotoxicity for these target cells. Preliminary data suggest that vaccination of cattle with an inactivated foot-and-mouth disease virus (FMDV) vaccine fails to activate NK cells isolated from peripheral blood. Future studies will investigate the ability of FMDV infection to activate bovine NK cells.
Identification of bio-active collagen type II alpha 1 protein in shark cartilage (181.3)
Authors: Merly Liza , Smith Sylvia 
Published: January 2023

Abstract
Previous studies have shown that extracts of shark cartilage (SC) induce a significant cytokine response in human leukocytes characteristic of a Th1 immune response. The nature of the bio-active component(s), however, is unknown. The aim of the present study was to identify the bio-active component(s) in SC. Cartilage extracts treated with proteases lost 80% of their cytokine-inducing property, suggesting that the active component(s) was likely a complex protein. Employing a protocol involving acid and solid phase extraction followed by ion exchange chromatography and electrophoretic separation, a partially purified bio-active preparation was obtained from commercial shark cartilage. At least two cytokine-inducing components were separated chromatographically and an anionic fraction has been identified as a small glycoprotein with at least 40% carbohydrate content. LC-MS analysis yielded five unique peptides with 100% molecular identity with collagen type II, alpha 1 protein from the lesser spotted catshark, Scyliorhinus canicula. The presence of collagen type II, alpha 1 protein in a dietary supplement has significant health implications given its role in the pathology associated with arthritis. Our findings suggest that consumers of SC, taken as prophylaxis particularly for the maintenance of joint health, should be cautious of the potential unanticipated immunomodulatory activity associated with peptides present in commercial preparations.
Role of Ikaros in hematopoiesis and tumor suppression: Selective functions of individual zinc fingers within the DNA-binding domain of Ikaros. (42.3)
Authors: Schjerven Hilde , Frietze Seth , McLaughlin Jami , Cheng Donghui , Farnham Peggy , Witte Owen , Smale Stephen 
Published: January 2023

Abstract
Ikaros, a C2H2 zinc finger transcription factor, is a critical regulator of hematopoiesis and tumor suppression in the lymphoid lineage. The C2H2 zinc finger is the most prevalent DNA-binding motif in mammals, with DNA-binding domains usually containing more tandem fingers than are needed for stable sequence-specific DNA recognition. To examine the reason for the frequent presence of multiple zinc fingers, and to investigate in greater depth the role of Ikaros in hematopoiesis and tumor suppression, we generated mice lacking finger 1 or finger 4 of the 4-finger DNA-binding domain of Ikaros. Each mutant strain exhibited a specific subset of the phenotypes observed with Ikaros null mice. Of particular relevance, fingers 1 and 4 contributed to distinct stages of B- and T-cell development and finger 4 was selectively required for tumor suppression in thymocytes and in a new model of BCR-ABL+ acute lymphoblastic leukemia. These results, combined with transcriptome profiling and DNA-binding analysis, reveal that different subsets of fingers within multi-finger transcription factors can modulate binding to different target sequences and regulate distinct target genes and biological functions. These novel mutant strains provide a powerful tool to elucidate Ikaros' role in hematopoiesis and tumor suppression. Furthermore, this study demonstrates that selective mutagenesis can facilitate efforts to elucidate the functions and mechanisms of action of this prevalent class of factors.
Helicobacter pylori infection in pigs is dominated by a Th1 and cytotoxic immune response (43.17)
Authors: Kronsteiner-Dobramysl Barbara , Bassaganya-Riera Josep , Washington Cassandra , Vento Salvador , Pedragosa Mireia , Viladomiu Monica , Carbo Adria , Hontecillas Raquel 
Published: January 2023

Abstract
H. pylori is the leading cause for peptic ulcer disease and gastric adenocarcinoma. While iTreg are required for long-term colonization without disease, Th1 and Th17 responses are associated with lower bacterial load at the expense of gastric pathology. We have developed computational models of H. pylori infection predicting a dominant Th1-response that results in lesion development in the gastric mucosa. In this study, pigs were infected with H. pylori strain SS1 or J99. Changes in PBMC populations were monitored over 2 months. Bacterial loads were assessed at 9 and 57 days post-infection. Both strains elicit a Th1 response with increased percentage of CD4+Tbet+ cells and elevated Tbet and IFN-γ mRNA in PBMC. A subset of CD8β+ cells expressing Tbet increased due to infection. These cells expressed low levels of CD8β, a property of cytotoxic T cells previously exposed to their cognate peptide. A significant increase of NK cells was observed in infected pigs pointing towards a predominant cytotoxic immune response. Strain J99 evoked a more dramatic acute response associated with bacterial clearance, while strain SS1 showed long-term colonization capacity. Ex vivo functional assays indicate strain-specific, weak and suppressed memory immune responses suggesting that specific virulence factors contribute to suppression of immune responses and chronic persistence. Data from this study will be used in the modeling process to refine computational models of H. pylori infection.
Th17 cells are associated with pathology in human schistosomiasis (43.24)
Authors: Larkin Bridget , Mbow Moustapha , Meurs Lynn , Wammes Linda , de Jong Sanne , Labuda Lucja , Smits Hermelijn , Dieye Tanaka , Polman Katja , Mboup Souleyman , Stadecker Miguel , Yazdanbakhsh Maria 
Published: January 2023

Abstract
Infection with parasitic helminths of the genus Schistosoma results in a wide range of immunopathology. Studies in murine schistosomiasis suggest that Th17 cells play a major role in the development of severe pathology; conversely, regulatory T (Treg) cells represent a mechanism to curtail excessive inflammation. We assessed by flow cytometry the profile of peripheral blood (PB) CD4 T cells in a cohort of children with urinary schistosomiasis from the village of Pakh, Department of Richard Toll, Senegal. S. hematobium-infected children with bladder pathology had a significantly higher percentage of PB IL-17+ cells with higher RORγt+/ Foxp3+ and IL-17+/ IL-10+ cell ratios than infected children without pathology. To investigate the relationship between PB values and target organs, we also examined the PB T cell response in murine S. mansoni infection (S. hematobium is non-permissive in mice) and, similar to humans, found a significantly higher percentage of CD4+ IL-17+ cells in high-pathology CBA mice than in low-pathology BL/6 mice. Moreover, a significant increase in IL-17+ cells in spleen and liver granulomas together with lower Foxp3+ cells in the spleen of CBA mice denoted a good correlation between PB and target organs. Our findings for the first time demonstrate an association between pathology and PB Th17 cells in human schistosomiasis and suggest human PB T cell subsets to faithfully reflect those mediating lesions in organs affected by the disease.
Local and systemic lymphoproliferative responses to Escherichia coli O157:H7 proteins occur after colonization and are predictive of decreased fecal shedding. (43.29)
Authors: Lahmers Kevin , Hayles Andrea , Boland Kathryn , Sheng Haiqing , Hovde Carolyn 
Published: January 2023

Abstract
Escherichia coli O157:H7 (O157) is a zoonotic, human, enteric pathogen with potential for life-threatening complications. Cattle asymptomatically carry the bacteria in the gastrointestinal tract with colonization occurring at the rectoanal junction mucosa. Fecal material with high numbers of O157 contaminates the environment, food and water. Among the preharvest intervention attempts to reduce bovine carriage of O157, vaccination is promising. To date, immune responses to O157 have been evaluated solely by immunoglobulin response and not T cell responses. This study evaluated the bovine antigen specific lymphoproliferative responses to three recombinant O157 virulence proteins: intimin, TIR, and EspB, which elicit immunoglobulin responses among naturally exposed and experimentally challenged cattle. Lymphoproliferative responses were detected in the peripheral blood both in cattle that were challenged twice intraruminally and in naturally exposed cattle. There were also local lymphoproliferative responses in the mesorectal lymph nodes after challenge and in naturally exposed cattle. Mesorectal cell proliferation to all three proteins was ten-fold greater than proliferation in peripheral blood cells. The strength of the proliferative response prior to challenge correlates with shorter duration of shedding and decreased total shedding of O157. The presence of consistent, strong lymphoproliferative responses may be required for bovine vaccine efficacy.
Identification of novel epitopes from Mycobacterium tuberculosis (43.32)
Authors: Lindestam Arlehamn Cecilia , Swann Justine , Henderson Ryan , Greenbaum Jason , Sidney John , McKinney Denise , Park Daniel , Taplitz Randy , Grey Howard , Peters Bjoern , Sette Alessandro 
Published: January 2023

Abstract
Mycobacterium tuberculosis (MTB) is the one of the worldwide leading cause of death from infectious disease. The MTB genome encodes just under 4,000 different ORFs, yet epitopes recognized by human CD4+ T cells, the key cellular effector of MTB immunity, have been described for less than 2%. Our present study addresses the discovery and validation of MTB CD4+ T cell epitopes presented by HLA Class II molecules. We have identified hundreds of MTB-specific epitopes by the combined use of epitope predictions and high-throughput ex vivo ELISPOT assays using PBMC from human donors latently infected with MTB. Specificity was demonstrated by parallel testing of non-TB infected control donors. These epitopes allow us to identify previously unknown CD4+ TB antigens. We are in the process of further validating these epitopes by examining the T cell phenotype, pattern of cytokine secretion associated with epitope responses and projected population coverage as determined by quantitative binding assays, as well as investigating T cell responses as a function of clinical outcome. This study determines the breadth of MTB responses in humans and it will establish whether there is a correlation between the antigens recognized by CD4+ T cells and serological reactivity and CD8+ T cells, antigen expression in different MTB forms and other structural and biological features associated with the antigens. In addition, these epitopes can be used as tools to understand the human immunity to TB.
Adaptive immunity in the mouse model of Clostridium difficile infection (43.4)
Authors: Johnston Pehga , Gerding Dale , Knight Katherine 
Published: January 2023

Abstract
Clostridium difficile rivals MRSA as the most common hospital-acquired infection. C. difficile infection (CDI) can manifest as mild diarrhea to life-threatening psuedomembranous colitis. CDI occurs following a course of antibiotics, and although most patients recover fully from CDI, ~20% undergo recurrent disease caused by toxins A and/or B. Several studies demonstrate a correlation between anti-toxin antibody (Ab) and a decrease in recurrence; however; the contribution of the systemic and mucosal Ab response remains unclear. Our goal was to use the recently described mouse model of CDI to characterize the protective immune response. Mice infected with C. difficile developed protective immunity against CDI and did not develop CDI upon re-challenge. Infected mice generated both systemic and mucosal Ab directed against toxin. We infected CD4-/- mice with C. difficile, expecting they would succumb to CDI. Instead, the mice developed immunity and we found IgA anti-toxin Ab in both serum and the mucosa. pIgR-/- mice also developed serum anti-toxin Ab and were protected from CDI, indicating that mucosal anti-toxin Ab is not required for protection from CDI. Our studies suggest that protective anti-toxin Ab can be induced in T-cell deficient individuals and that systemic anti-toxin immunity may be sufficient for protection from CDI. The results should aid in development of vaccines for CDI, especially for individuals with immunodeficiency.
Immunization with pneumococcal polysaccharide SSS-3 and lipopolysaccharide protects against deadly Streptococcus pneumoniae infection in mice. (43.8)
Authors: Restori Katherine , Kennett Mary , Ross A. 
Published: January 2023

Abstract
To study pneumonia disease progression, we developed a mouse model of pneumonia by intranasal inoculation with Streptococcus pneumoniae, serotype 3. In order to combat mortality, mice were immunized with pneumococcal polysaccharide specific for serotype 3 (SSS-3) or co-immunized with SSS-3 and a low dose of lipopolysaccharide (LPS) 5 days prior to infection. Pneumonia severity was assessed during acute and resolution phases of infection. Immunization was clinically protective as evidenced by decreased bacterial recovery from the lung and blood during acute infection and increased survival. As expected, primary antibody production specific for SSS-3 was upregulated in immunized mice. Histopathological severity scores for lungs from immunized mice were lower, due to little or no inflammation while lungs from non-immunized mice exhibited moderate inflammation. Furthermore, immunization attenuated proinflammatory cytokine gene expression in the lung at acute time points. Lung microarray analysis 48 hr after infection revealed higher expression of a large number of genes in non-immunized mice that were expressed at nearly normal levels after co-immunization, including a highly significant reduction in serum amyloid a (Saa1, Saa2) gene expression. Our results demonstrate that immunization with SSS-3 and LPS significantly decreased lung bacterial burden and systemic dissemination while promoting resolution of infection.
A Functional Single-Nucleotide Polymorphism in Interleukin-6 Promoter is associated with Susceptibility to Tuberculosis (44.13)
Authors: Chen Xinchun , Zhang Guangliang , Zhang Mingxia 
Published: January 2023

Abstract
Background. Genetic variation influences susceptibility or resistance to tuberculosis (TB). Interleukin-6 contributes to protection against TB in mice, however, its role in regulating susceptibility or resistance to TB in humans is unclear. Methods. Genotyping of polymorphisms in IL-6 and IL-6R (CD126) genes were performed in two independent cohorts, namely experimental (495 cases and 358 controls) and validation (1383 cases and 1149 controls) populations. The associations of the variants with tuberculosis were tested using two case-control association studies. In addition, the regulatory effects of SNP rs1800796 (-572C&gt;G) on IL-6 production in plasma and CD14+ monocyte cultures stimulated with a Mycobacterium tuberculosis (Mtb) product were assessed. Results. The rs1800796 polymorphism is associated with increased resistance to TB (odds ratio, 0.771; confidential interval 0.684-0.870). The rs1800796GG genotype is strongly associated with reduced risk to TB (odds ratio, 0.621; confidential interval 0.460-0.838). Interestingly, CD14+ monocytes isolated from individuals with rs1800796GG genotype produced significantly lower IL-6 in response to Mtb 19kDa lipoprotein than those with CC or CG genotype do. Conclusions. We identified a genetic polymorphism in IL-6 promoter that regulates the cytokine production and host resistance to pulmonary TB in Chinese population.
Behavior-modulating function of the Duffy Antigen Receptor for Chemokines (DARC) in mice under homeostatic conditions (44.24)
Authors: Schneider Erich , Gao Ji-Liang , Holmes Gibran , Fowler Stephen , Peiper Stephen , Murphy Philip 
Published: January 2023

Abstract
DARC binds promiscuously many inflammatory chemokines without intracellular signal transduction. It is mainly expressed on endothelial cells of postcapillary venules and on erythrocytes, where it acts as a transendothelial chemokine transporter and as a chemokine sink, respectively. Surprisingly, DARC was also shown to be expressed at high density in the cerebellum of human and mouse brain, but with as yet unknown function. We addressed this question by subjecting C57Bl/6 wildtype and DARC-deficient mice to behavior experiments including Morris water maze-, elevated plus maze-, rotarod- and actometer tests. While the water maze results are ambiguous, elevated plus maze trials show a strong aversion of DARC-/- mice to walk to the end of the open arm, which is consistent with anxiety-like behavior. Moreover, DARC-/- mice show greatly reduced locomotor activity, resulting from episodes of reduced mobility that occur more frequently than in the C57Bl/6 controls (elevated plus maze, actometer). Finally, DARC-/- mice spend a significantly reduced time on the rotarod compared to C57Bl/6 controls, probably indicating impaired cerebellar function. We conclude that DARC modulates brain function. Surprisingly, this appears to be happening under homeostatic conditions, although DARC binds mainly inflammatory chemokines. Since DARC shows no signaling, this effect may be indirectly caused by altered brain chemokine concentrations or may result from as yet unknown DARC signaling pathways.
Human platelets produce and constitute the main source of IL-18 in the circulation (44.25)
Authors: Allam Ossama , Samarani Suzanne , Marzouk Rim , Ahmad Ali 
Published: January 2023

Abstract
IL-18 is a pro-inflammatory cytokine belonging to the IL-1 family. The cytokine is known to be produced from macrophages, dendritic cells, keratinocytes, adrenal cortex etc in the body. The cytokine is produced as an inactive precursor protein, which is cleaved into mature form by activated caspase 1. We show here for the first time that human platelets contain abundant amounts of this cytokine, and release it upon activation. The platelets also contain components of the inflammasome, which activate caspase 1 and process the IL-18 precursor into mature form during the platelet activation process. Different activating agents activate platelets and release IL-18 to variable extent, the maximum being observed with thrombin. Furthermore, the released cytokine further activates platelets and enhances platelets to produce more IL-18. In addition to the cytokine, the platelets also release its antagonist, IL-18 binding protein (IL-18BP), upon activation. Surprisingly, a part of the cytokine appears to be synthesized within platelets. We also show here for the first time that inflammasome assembly occurs in platelets and the platelet-released IL-18 constitutes the major source of this cytokine in the circulation, as we found little amount of this cytokine in platelet-free plasma. Our findings have important implications for chronic inflammatory diseases, metabolic syndrome and cardiovascular diseases in which increased IL-18 levels play a pathogenic role.
IL-21 reduces production of pro-inflammatory cytokines by activated CD8 T cells (44.26)
Authors: Parmigiani Anita , Lichtenheld Mathias , Pahwa Savita 
Published: January 2023

Abstract
Background: Chronic HIV infection is characterized by systemic immune activation (IA), accumulation of T cells with a skewed terminally-differentiated profile and a progressive loss of IL-21 production. Experiments described below address the hypothesis that IL-21 prevents IA in healthy individuals. Methods: Purified CD8 T cells from healthy donors were activated for 48 hrs. by antiCD3+antiCD28 in the presence of IL-21 and, respectively, its absence. Cytokine synthesis and secretion were evaluated by real time PCR and ELISA. Results: CD8 T cells TCR-stimulated in the presence of IL-21 produced less pro-inflammatory cytokines TNF alpha and IL-12p70, compared to CTL stimulated in the absence of exogenous cytokine. Moreover, IL-21 induced significantly higher amounts of the anti-inflammatory cytokine IL-10 and lower levels of IL-2. Conclusions: IL-21 could act as a favorable immunomodulatory agent in the context of chronic infections such as HIV because: i) it limits the production of pro-inflammatory mediators by CD8 T cells; and ii) it induces the anti-inflammatory cytokine IL-10.
IL-22 inhibits CCL20 expression induced by Helicobactor pylori infection (44.28)
Authors: Chen Jia-Perng , Liao Fang 
Published: January 2023

Abstract
Helicobactor pylori is a Gram-negative bacterium that infects the human gastric mucosa and causes various gastric diseases including gastritis, gastric ulcer, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer. Given that Helicobactor pylori infection induces CCL20 production in gastric mucosa and leads to gastric inflammation, and that IL-22/IL-22R axis has been shown to play a critical role in regulating homeostasis and inflammation of epithelial cells at barrier surfaces, we investigate the effect of IL-22 on CCL20 expression induced by Helicobactor pylori. We demonstrated that Helicobactor pylori infection in AGS, a gastric epithelial cell line, significantly induces CCL20 expression. Functional analysis of the CCL20 promoter revealed that activation of NF-κB is required for CCL20 expression induced by Helicobactor pylori. Of interest, we found that IL-22 is able to reduce Helicobactor pylori-induced CCL20 expression by attenuating NF-κB activation. We further demonstrated that the suppressive effect of IL-22 on CCL20 is mediated by STAT3 since IL-22 fails to inhibit CCL20 production in AGS cells with STAT3 knockdown. Our findings suggest that STAT3 suppressing NF-κB activation is an anti-inflammatory mechanism for IL-22 to reduce inflammatory chemokine gene transcription during Helicobactor pylori infection.