bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression of GM-CSF in T cells is increased in multiple sclerosis and is suppressed by IFN-β therapy (BA11P.136)
Authors: Rasouli Javad , Ciric Bogoljub , Imitola Jaime , Gonnella Patricia , Hwang Daniel , Mahajan Kedar , Mari Elisabeth , Safavi Farinaz , Leist Thomas , Zhang Guang-Xian , Rostami A 
Published: January 2023

Abstract
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Studies in animal models of MS have shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) produced by T cells is necessary for development of autoimmune CNS inflammation. This suggests that GM-CSF may have a pathogenic role in MS as well. The objective of this study was to characterize GM-CSF production by T cells of MS patients, and to determine the effect of interferon-beta (IFN-β) therapy on its production. GM-CSF production by peripheral blood (PB) T cells and the effects of IFN-β were characterized in samples of untreated and IFN-β-treated MS patients vs. healthy subjects. GM-CSF production by T cells in MS brain lesions was analyzed by immunofluorescence. Untreated MS patients had significantly greater numbers of GM-CSF+ CD4+ and CD8+ T cells in PB compared to healthy controls and IFN-β-treated MS patients. IFN-β strongly suppressed GM-CSF production by T cells in vitro. A number of CD4+ and CD8+ T cells in MS brain lesions expressed GM-CSF. Elevated GM-CSF production by PB T cells in MS is indicative of aberrant hyperactivity of the immune system. Given its essential role in animal models, abundant GM-CSF production at the sites of CNS inflammation suggests that GM-CSF contributes to MS pathogenesis. Our findings also reveal a potential mechanism of IFN-β therapy, namely suppression of GM-CSF production.
Age-related thymic involution perturbs negative selection leading to autoreactive T Cells that induce chronic inflammation (inflammaging) (BA11P.141)
Authors: Coder Brandon , Wang Hongjun , Ruan Linhui , Su Dong-ming 
Published: January 2023

Abstract
The presence of chronic low-level pro-inflammatory factors in elderly individuals (termed inflammaging) is a significant risk factor for morbidity and mortality. Recently, inflammaging has been partially attributed to the persistent activation of immune cells thought to arise from latent viral infection, but the contribution of activated autoreactive T cells towards the development of inflammaging remains unclear. To determine how age-related thymic involution leads to the persistent release and activation of autoreactive T cells capable of inducing inflammaging, we used a FoxN1 conditional knock-out (FoxN1-cKO) mouse model that mimics natural thymic involution while maintaining a young periphery. We found that thymic involution leads to T cell activation shortly after thymic egress, which is accompanied by cellular infiltration into non-lymphoid tissues and elevated IL-6 and TNFα levels. Autoreactive T cell clones were detected in the periphery of FoxN1-cKO mice. A failure of negative selection, facilitated by decreased expression of Aire rather than impaired regulatory T cell (Treg) generation, led to autoreactive T cell generation. Furthermore, the young environment can reverse age-related Treg accumulation but not inflammatory infiltration. Together, these findings identify thymic involution and the persistent activation of autoreactive T cells as a source of chronic age-related inflammation (inflammaging).
Autoreactive T cell trafficking into pancreatic islets during type 1 diabetes is more permissive as infiltration increases and requires CD11c+ APCs. (CAM4P.153)
Authors: Lindsay Robin , Gebert Matthew , Wigton Eric , Bradley Brenda , Haskins Kathryn , Jacobelli Jordan , Friedman Rachel 
Published: January 2023

Abstract
Type 1 diabetes (T1D) is a largely T cell mediated autoimmune disease that destroys the β-cells of the pancreatic islets. While initiation of disease requires T cell activation in the pancreatic lymph node, T cells must enter the islets to destroy β-cells. To investigate mechanisms required for T cell entry into the islets we established an intra-vital 2-photon pancreas imaging technique in the non-obese diabetic mouse. We determined that extravasation into the pancreatic islets is an extended process compared to lymph node entry, averaging 47 minutes from T cell arrest to completion of extravasation in islets with advanced T cell infiltration. Entry was more restricted at earlier stages of infiltration, with a duration of extravasation longer than our observation period of 2 hours. T cell entry into the islets was dependent on CD11c+ antigen presenting cells (APCs) in the islets. T cells transferred prior to CD11c+ APC depletion were able to enter the islets; while CD11c+ APC depletion prevented further entry. However, antigen was not required for entry of either activated or naïve T cells, suggesting a role for CD11c+ APCs other than antigen presentation. These studies demonstrate that T cell entry requires the presence of CD11c+ APCs within the islets, and as islet infiltration increases T cell extravasation becomes less restricted. Overall, CD11c+ APCs may be a therapeutic target for treatment of T1D by preventing T cell entry into remaining or transplanted islets.
Absence in T1/ST2 receptor results in a more severe experimental nephropathy (CCR5P.208)
Authors: Reis Vanessa , Osugui Lika , Andrade David , Martins Beatriz , Keller Alexandre 
Published: January 2023

Abstract
Focal segmental glomerulosclerosis (FSGS) is a major cause of chronic kidney disease. Several studies suggest an association between Th2 and the pathogenesis of FSGS. Immune system molecules are widely associated with Th1/Th2 balance. In light of this, we chose the shaft IL-33/ST2, Th2 immune responses and kidney damage as the object of study, both related to. We used BALB/c WT and ST2-/- animals, intravenously injected with a single dose of 10mg/kg of adriamycin. Since ST2-deficient animals exhibit more severe kidney damage when induced by adriamycin, the absence of this receptor signaling is intimately related to induced loss of renal function. Observing the changes of these animals, as increase in serum creatinine levels and elevated protein/creatinine curve, more severe tissue damage and decreased expression of nephrin protein, STAT3 and Smad2/3. In addition, there was an increase in PAI-1 and nephrin phosphorylation, Prha, pTyr. Serum levels of IL-33 are also higher in ST2-/- animals. In the cellular context, we observed an increase in the percentage of TCD4pos splenic cells in these ST2-/- animals. However, CD4pos / FOXp3pos cells are less present when compared to wild type animals and similar to control animals. We also observed that the effect found in ST2-/- animals was mitigated by the transfer of TCD4pos wildtype lymphocytes. Considering all results, we can conclude so far that cytokine IL-33 plays an important role in the development and control of FSGS.
IL-23 Controls CD4+ T cell pathogenicity and IL-17A production in divergent patterns during experimental autoimmune myocarditis (CCR5P.207)
Authors: Wu Lei , Diny Nicola , Ong SuFey , Barin Jobert , Hou Xuezhou , Talor Monica , Rose Noel , Cihakova Daniela 
Published: January 2023

Abstract
Using a model of experimental autoimmune myocarditis (EAM), we established the requirement of IL-23 for the induction of cardiac autoimmunity, as Il23a-/- mice failed to mount an efficient Th17 response after immunization and were protected from myocarditis. Furthermore, we discovered that IL-23 has divergent effects on CD4+ T cell pathogenicity and IL-17A production. First, IL-23 switches on pathogenicity in CD4+ T cells, but becomes dispensable once autoreactivity is already established: CD4+ T cells raised from WT donors were able to induce EAM in Il23a-/- recipients. Moreover, even transient IL-23 stimulation ex vivo was able to fully restore pathogenicity in otherwise nonpathogenic T cells raised from Il23a-/- donors. Second, continued IL-23 signaling is required to maintain IL-17A production. Despite of inducing same level of inflammation in Il23a-/- recipients, autoreactive CD4+ T cells downregulated IL-17A production without sustained IL-23 stimulation. These divergent effects of IL-23 on T cell pathogenicity and IL-17A production may contribute to the discrepant efficacies of αIL-23 therapy in different diseases. Finally, we demonstrated that GM-CSF mediates the IL-23-driven pathogenicity of CD4+ T cells, and neutralization of GM-CSF abrogated inflammation in EAM. Combined with our finding that GM-CSF directs disease outcome by regulating macrophage polarization during later stages of EAM, GM-CSF is decisive in both the initiation and the progression of autoimmunity.
Targeted deletion of Eed arrests thymus development (HEM7P.225)
Authors: Singarapu Nandini , Xie Huafeng , Orkin Stuart , Richie Ellen 
Published: January 2023

Abstract
Polycomb group proteins regulate cell fate and differentiation by modifying histones to maintain chromatin in a compacted state that silences expression of inappropriate genes. EED is an essential core component of the Polycomb repressive complex 2 which trimethylates lysine 27 on histone H3. To determine the role of Eed in thymus organogenesis, we excised eed specifically from thymic epithelial cells (TECs) by crossing Eedfl/fl mice with a FoxN1Cre strain. We found a hypoplastic and highly cystic thymus in four week FoxN1Cre/+;Eedfl/fl mice. Cortical and medullary TECs were depleted in the mutants; however, the cortical compartment was more profoundly affected. TEC depletion was coupled with decreased thymocyte cellularity, which is not surprising given that TECs provide indispensable maturation and survival signals to thymocytes. The thymus and parathyroid glands arise respectively from ventral (Foxn1+) and dorsal (Gcm2+) endodermal progenitors in the 3rd pharyngeal pouch. We did not observe an alteration in the allocation of endodermal progenitors to a thymus versus parathyroid fate indicating that altered pouch patterning is not responsible for the TEC phenotype. At E15.5, mutant and wildtype fetal thymic lobes were comparable in size and TEC subset composition. However, by E16.5 defects in TEC differentiation and survival are apparent and this phenotype progresses rapidly with age. Current work focuses on the role of eed in maintaining TEC progenitors.
Homeostatic proliferation of thymocytes is controlled through dynamic regulation of delta like 4 (HEM7P.229)
Authors: Serwold Thomas , Vroegindeweij Eric , Kim MiJeong , Vazquez Sara 
Published: January 2023

Abstract
The thymus has a remarkable ability to sustain T cell development and T cell output from thymuses with quantitative and qualitative deficiencies in T cell progenitors, suggesting a role for homeostatic pathways in controlling T cell development. However, these homeostatic pathways are currently uncharacterized. We find that Delta-like 4 (Dll4), which is expressed on thymic epithelial cells (TECs) and is essential for driving T cell lineage commitment, is dynamically regulated in response to thymocyte deficiencies, and plays a major role in thymocyte homeostasis. We observe that TECs express elevated Dll4 levels in multiple lines of mice that have defective T cell development, as well as in mice subjected to antibody or irradiation-induced thymocyte depletion. Recovery of thymus cellularity after thymic injury is accompanied by re-establishment of normal levels of Dll4. In vitro proliferation of thymocytes increases proportionally in response to elevated levels of Dll4 expressed on stromal cells. Furthermore, Dll4 levels on stromal cells diminish in response to interactions with thymocytes themselves. These findings implicate dynamic control of Dll4 levels as a major homeostatic mechanism that regulates thymocyte proliferation.
Expression analyses revealed thymic stromal co-tansporter/Slc46A2 is in stem cell populations and is a putative tumor suppressor (HEM8P.237)
Authors: Kim Moon , Kim Ki , Yoon Min 
Published: January 2023

Abstract
By combining flow cytometry and database searches, we extended the expression profiling of TSCOT/Slc46A2/Ly110, that was shown to be expressed in the bipotent precursor and cortical thymic epithelial cells. Genome scale analysis verified that TSCOT is tissue- and cell type- specific in thymus and is also expressed in other epithelial tissues. Coexpression profiling with genes, Foxn1 and Hoxa3, revealed the role of TSCOT during the tissue formation including early thymic organogenesis. TSCOT expression was detected in all thymic epithelial (TEC), but not in the CD31+ endothelial lineage of fetal thymus. In addition, ABC transporter-dependent side population and Sca-1+ of fetal TEC population contain TSCOT-expressing cells, indicating TEC stem cells express TSCOT. TSCOT expression was identified as early as in differentiating embryonic stem cells. TSCOT expression is not under the control of Foxn1 since TSCOT is present in the thymic rudiment of nude mice. By the searches for expression variation, TSCOT is positively associated with GRHL3 and IRF6. Cytokines such as IL1b, IL22 and IL24 are the potential regulators of the TSCOT expression. Surprisingly, we found TSCOT expression in the lung was diminished in the lung cancers suggesting TSCOT may be involved in the suppression of lung tumor development. From these results, a model for TEC differentiation from the stem cells was proposed in the context of multiple epithelial organ formation.
In vitro evaluation of B cell function using activation-induced cytidine deaminase in HIV-infected patients on antiretroviral therapy (HUM6P.244)
Authors: Gonzalez Ivan , Correa Adriana , arheart Kristopher , Frasca Daniela , Blomberg Bonnie 
Published: January 2023

Abstract
Background: B cell populations and function depend on the stage of HIV-1 infection. Good virologic control can normalize B cell populations, but data regarding the effect on B cell function is lacking. Method: We investigated B cell populations and intrinsic function among a perinatally and behaviorally infected HIV-1 patients based on virologic control and correlated both. Peripheral blood monocytes were collected from a HIV-negative (HN), behaviorally infected HIV patients with undetectable viral load of &lt;40 copies/mL (BU) and two perinatally infected groups. These groups were categorized by viral load: undetectable group (PU) of &lt;40 copies/mL and a low level viremia (PLLV) of &lt;200 copies/mL. Activation-induced cytidine deaminase mRNA quantification was used after in vitro stimulation with CpG oligodeoxynucleotides to measure intrinsic B cell function. Results: B cell populations were similar in the HN and BU groups, which differed from the PU and PLLV groups. The PU and PLLV groups demonstrated higher percentages of naïve B cells and lower percentages of IgM and switch memory B cells, demonstrating patterns of cellular aging. However, the exhausted B cell populations were not significantly different between groups. Virologic control did not affect B cell function in the infected groups when compared to the uninfected group. Conclusion: Good virologic control, defined as &lt; 200 viral copies/mL, normalizes B cell populations and more importantly intrinsic B cell function.
The role of Epstein-Barr virus in cervical cancer: exploring the immunological mechanisms for production of anti-Estein-Barr virus IgA in high risk women with dysplasia (HUM6P.250)
Authors: Fisher Rebecca , Melton Scott , Ferguson Amelia , Oddo Hope , Velasco-Gonzales Cruz , Hagensee Michael 
Published: January 2023

Abstract
Human papillomavirus (HPV) alone is a necessary but insufficient cause of cervical cancer due to the high number of infections that spontaneously resolve. We have evidence supporting Epstein-Barr Virus (EBV), a known oncovirus implicated in several cancer types, as a co-factor for cervical disease in HIV+ women. Longitudinal analysis of ELISA data from 453 serum samples, collected over a five year time period from 89 HIV+ women, indicated IgA, but not IgG, against EBV viral capsid antigen (VCA) predicted cervical dysplasia. Sera were also tested for IgG and IgA against HPV16,18 L1 protein and EBV nuclear antigen-1, but no predictive value was observed for these additional targets. Measures of HIV disease control, HIV viral load and CD4 T cell count, were also not predictive of dysplasia. Multivariate models indicated that HPV IgG status did not alter the significance of the EBV VCA IgA prediction. Cervical EBV DNA detection suggests local EBV infection; however, cervical Ab responses are generally IgG. The repetitive structure of the EBV capsid may trigger T cell independent Abs, but the longevity of IgA detection opposes this notion. We hypothesize EBV in the cervix may result in formation of lymphoid-like follicles, as seen in cervicitis, for Ab production. We are collecting dysplastic cervical tissue to establish the existence and functionality of these structures as well as assessing for molecules influencing IgA class switching, such as CXCL-13, BAFF and APRIL.
Interleukin-2/anti-interleukin-2 antibody complexes expand T regulatory cells and protect against allergen-induced airway hyperreactivity (HYP7P.256)
Authors: Neunkirchner Alina , Wojta-Stremayr Daniela , Schmetterer Klaus , Mager Lukas , Reichl Victoria , Rosloniec Edward , Naumann Ronald , Dekan Gerhard , Jahn-Schmid Beatrice , Bohle Barbara , Pickl Winfried 
Published: January 2023

Abstract
T-cells play a key role in the development and maintenance of allergic diseases and thus represent a promising target for therapeutic interventions. Evidence from SIT studies suggest that regulatory T-cells (Treg) might counterbalance the Th2-biased immune response. We here created double transgenic (tg) allergy mice expressing a human TCR specific for the major mugwort (Artemisia vulgaris) pollen allergen Art v 1 and HLA-DR1 to study the response to the aero-allergen in vivo. After allergen-specific sensitization, only double tg allergy mice, but not single tg or wt control mice showed enhanced airway-hyperreactivity (AHR) upon challenge, which was associated with airway and lung inflammation. Significantly, treatment of allergy mice with three daily i.p. injections of IL-2/anti-IL-2 mAb complexes induced a 6-fold increase of CD25+Foxp3+ Treg among CD3+CD4+T-cells in peripheral blood (17.9±6.2% versus 3.1±1.4%) compared to a 8-fold increase of CD39+ and KLRG1+ Treg subsets, respectively (17.2±7.9% versus 2.1±1.5%; 1.6±0.2% versus 0.2±0.2%). Furthermore, expansion of Treg by IL-2/anti-IL-2 mAb complexes before sensitization prevented mice from allergen-induced AHR upon challenge and significantly reduced Art v 1-specific serum IgE, when compared to sham-treated mice. Such in vivo expanded Treg might have similar effects in therapeutic settings. In summary, expansion of Treg by IL-2/anti-IL-2 mAb complexes seems to be a promising strategy to interfere with allergic diseases.
Osteopontin regulates Cxcr2 expression and neutrophil recruitment in endodontic infection (INC6P.302)
Authors: Singh Rani , Hui Tommy , Matsui Aritsune , Rittling Susan 
Published: January 2023

Abstract
The integrin binding protein osteopontin (OPN) protects against bone destruction in a mouse model of endodontic infection. Here we have tested the hypothesis that this effect of OPN is mediated by effects on migration of innate immune cells to the site of infection. We used the subcutaneous chamber and air pouch as models of endodontic infection in mice. In vitro analysis of CXCR2 expression was determined by FACS and migration was assessed using transwell assay. Using both the chamber and a modified air-pouch infection model, we showed that neutrophil accumulation at the site of infection is significantly reduced in OPN KO mice, but there are very few macrophages and monocytes, and there is little effect of OPN on their accumulation. OPN does not affect neutrophil survival. Reduced neutrophil accumulation is accompanied by lower levels of myeloperoxidase activity and an increase in bacterial load in the absence of osteopontin. In vitro, OPN increases the ability of these cells to migrate in transwell assays when added in either to the upper or the lower chambers. Furthermore, OPN increases expression of CXCR2 on bone marrow neutrophils, in an alphav-integrin dependent manner. Biotinylation assays show that OPN suppresses the internalization of CXCR2. Together, these results support a model whereby OPN binding to the alphav integrin regulates CXCR2 internalization on neutrophils, increasing the ability of these cells to migrate in response to CXCR2 ligands.
Glycolysis regulates macrophage differentiation into IL-10 producing phenotype (INM6P.342)
Authors: Suzuki Hiroaki , Hisamatsu Tadakazu , Naganuma Makoto , Ebinuma Hirotoshi , Nakamoto Nobuhiro , Mori Kiyoto , Kitazume Mina , Shimamura Katsuyoshi , Chiba Sayako , Kanai Takanori 
Published: January 2023

Abstract
There are a lot of reports indicating that cellular metabolic state or some metabolites regulate the phenotype of immune cells. In case of macrophages (Mφ), it is believed that regulatory and inflammatory Mφ shifts ATP production to each oxidative phosphorylation and glycolysis, respectively. However, it is not clear how metabolic pathway affects Mφ in the acquisition of their specific phenotypes. In this report, we tried to reveal how glycolysis affects Mφ during the acquisition of IL-10 producing phenotype. We used in vitro differentiated human monocyte derived Mφ cultured in the presence of M-CSF or M-CSF plus IFNγ as IL-10 producing-Mφ (M-Mφ) or inflammatory Mφ (Mγ-Mφ), respectively. M-Mφ showed regulatory Mφ-like phenotypes and produced more IL-10 when it was stimulated with LPS compared to Mγ-Mφ. Interestingly, M-Mφ differentiated with glycolysis inhibitors (2-deoxy-D-glucose or DCA) produced significantly lower amount of IL-10 and lager amount of IL-6 compared to M-Mφ differentiated without glycolysis inhibitors. Glycolysis inhibited M-Mφ reduced the expression of regulatory Mφ marker genes (MRC1 and CCL22) and exhibited distinct pattern of cell surface antigens (CD163, CD206, CD209 and HLA-DR) compared to M-Mφ. DNA microarray analysis revealed that inhibition of glycolysis affects gene expression profiles during Mφ differentiation. Our finding suggests that glycolysis plays key roles in the course of differentiation of Mφ into IL-10 producing phenotype.
Identifying biomarkers from an in vitro carrageenan model of inflammation in swine (INM8P.359)
Authors: Myers Michael , Deaver Christine , Peters Sharla , Swaim Heidi , Yancy Haile 
Published: January 2023

Abstract
Carrageenan-induced inflammation, though extensively used as a model of local inflammation, has not been fully characterized on the genomic and proteomic level. The goal of this study was to develop an in vitro carrageenan model of local inflammation for use in studies of novel non-steroidal anti-inflammatory drug efficacy. We evaluated lambda carrageenan (l-CGN) in vitro and its capacity to affect previously identified inflammatory biomarkers in swine, using swine whole blood cultures. Blood was collected from 9 male Yorkshire barrows, cultured in vitro. The blood was divided into two groups (stimulated and unstimulated) per each time point. Unstimulated blood was used as control to compare samples treated with l-CGN. Blood was then separated into two fractions, serum collection for ELISA analysis and white blood cells for RNA extraction per time point. We found that l-CGN increased the production MCP-1 in vitro, both on the proteomics level and the genomic level. Conversely, TNF-a and IL-6 demonstrated a decreased or no change in cytokine production when measured via ELISA. Phosphokinase-3, Thrombospondin-1 and Alveolar Macrophage Chemotactic -II showed increased gene expression when normalized to GAPDH. These results also demonstrate that carrageenan initiates an inflammatory response that differs from a typical endotoxin effect, such as LPS stimulation in terms of the pathways and gene products altered.