bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunogenetic analysis of autoimmune hepatitis in Alaska Native People
Authors: Ferrante Andrea , Kennedy Stephanie N. 
Published: January 2023

Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease, in which a multiplicity of genes, operating alone or in concert, determines the risk that environmental factors act as a trigger of an adaptive immune response against liver self-antigens. Susceptibility to AIH is conferred by genes of the human leukocyte antigen (HLA) system, especially alleles of class II HLA molecules (HLAII). Genetic risk is also conferred by immune-related genes outside the HLA region, whereas the environmental triggers are not known. Though AIH has a global occurrence, its prevalence among Alaska Native People (AN) is the highest reported in the literature, yet efforts to understand the causes of such a high prevalence have been limited. To identify potential risk factors in this population, we have determined by Next-Generation Sequencing HLAII haplotypes and variants of CTLA-4, AIRE, TNFA*2, and VDR expressed in 48 AN AIH patients. The most common HLA alleles identified are HLA-DRB1*04:01:01, HLA-DRB1*14:01:01 and HLADQB1*03:01:01. The most common haplotype is HLA-DRB1*04:01:01, DQB1*03:01:01. DRB1*0401 and 1401 are significantly more represented in the affected cohort than in the general AN population (DRB1*0401: 0.427 vs 0.114; DRB1*1401: 0.104 vs 0.032; p&lt;0.01), as well as DQB1*0301 (0.615 vs. 0.381, p&lt;0.01). Significant SNPs have also been identified for CTLA-4 (+49A/G, G=52.1%, more represented in our cohort than in the general population) and VDR (FokI polymorphism, F allele frequency = 71.9% vs. general population 62.5%). Self-antigen presentation by the identified HLAII alleles in the context of reduced tolerance associated with the above polymorphisms might explain development of disease.
Prevention of LPS-induced lung inflammation by PLAG administration via blocking of IL-6-STAT3-MIP-2 pathway
Authors: Lee Ha-Reum , Shin Su-Hyun , Yoo Nina , Yoon Sun Young , Kim Joo Heon , Nah Seong-Su , Kim Myung-Hwan , Sohn Ki-Young , Kim Heung-Jae , Chong Saeho , Han Yong-Hae , Kim Jae Wha 
Published: January 2023

Abstract
Neutrophil plays a key role in the innate immune system through as the first leukocyte to be migrated to the acute inflammatory region. Lung inflammation is an acute respiratory failure and links closely to excessive neutrophil recruitment and severe mortality. The intranasal LPS introduced mice were shown the over-flowed neutrophils into bronchoalveolar. PLAG is a synthetic monoacetyldiacylglycerol (acetyl-DAG). DAG is a lipid second messenger for PKC activator which is associated with an important for cellular functions. The transmigrated neutrophils in alveolar by LPS stimulation were completely blocked by PLAG administration. LPS-induced cell migration associated factors such as IL-6, MIP-2 and S100A8/9 were decreased by addition of PLAG. STAT3 phosphorylation which related to neutrophil migration was significantly down regulated in PLAG dieted mice. Interestingly, the selectivity of PLAG in the ameliorating of excessive neutrophil migration was verified when compared with PLAG analogues and metabolites. Post treatment of PLAG has also therapeutic effect on LPS-induced lung inflammation. These data could be utilized as a most potential therapeutic agent for lung inflammation through regulation of neutrophil transmigration via blocking of IL-6-STAT3-MIP-2 pathway.
Research of MFG-E8, OPG and SOCS-3 on preeclampsia
Authors: Ilhan Fulya , Atabay Hatice , Ozkan Zehra Sema , Doni Nebiye Yentur , Can Sevim Tuncer 
Published: January 2023

Abstract
Preeclampsia is a specific disease and closely associated with systemic inflammatory response. The aim of this study is research to possible role of some inflammatory factors and the controlling factor in inflammation in the etiology of preeclampsia or reflection of this situation on placental tissue. Three parameters were included in the study regarded as potential risk factors: Milk Fat Globul Epidermal Growth Factor-8 (MFG-E8); is an endometrial epithelial proteins and regulates inflammation and apoptosis. MFG-E8 is an important in the development of endometrium and chorionic villus. Osteoprotegerin (OPG); is pro-angiogenic factor, it can be important for plasental angiogenesis. Suppressor of cytokine signaling-3 Receptor (SOCS-3) has a role on prevents the inflammation. Serum and placental tissue samples were used as materials. Control group is composed of 50 healthy women volunteers with no history of preeclampsia and 28–34th weeks of pregnancy. The experimental group consisted 40 preeclamptic women in 28–34th week of pregnancy. All of the measurement analyzed through the ELISA (Enzyme-Linked Immuno Sorbent Analysis) method and findings evaluated comparatively. MFG-E8, SOCS-3 and OPG levels analysed with ELISA in the serum and placental tissue. OPG levels in serum raised and displayed statistically significant difference with respect to control group (p&lt;0.01). In respect to the serum MFG-E8 and SOCS-3 are not observed any difference between two groups. MFG-E8 tissue levels are statistically significantly low in preeclamptic group with respect to healthy control group and that there is no changes in the levels of SOCS-3 (p&lt;0.01).
Pinpointing IL-23-target cells in autoimmunity and inflammation using novel mouse models
Authors: Yang Yi 
Published: January 2023

Abstract
Interleukin-23 is the first cytokine linked to proinflammatory Th17 cells. Although IL-23 is dispensable for the differentiation of Th17 cells in vitro, it is absolutely required for their late maturation and acquisition of pathogenicity in vivo. IL-23 signaling promotes and exacerbates autoimmunity in many disease settings. On the contrary, IL-23 protects mice from pathogen-induced infection. Key cellular mediators of IL-23 in various immune responses remain to be understood since the receptor of IL-23 (IL-23R) is expressed by multiple immune cells. To elucidate the major cellular mediators of IL-23 in both pathogenic and beneficiary immune responses, we developed IL-23R conditional knock-out and IL-23R conditional knock-in mice. These mice allow us to turn on/off IL-23R expression in desired cell types by crossing with lineage-specific Cre-recombinase mice. To understand the significance of Th17 cell-intrinsic and –extrinsic IL-23R signaling in vivo, we examined these mice in various diseases. Interestingly, we found that CD4-autonomous IL-23R signaling is necessary and sufficient for the development of EAE. In contrast, IL-23R mediated protection against Citrobacter rodentium, a mucosal pathogen, is not impaired in CD4 T cell-specific IL-23R deficient animals. Thus, our data suggests a contrasting requirement for the IL-23-Th17 axis in CNS vs. mucosal sites. These novel mice shall be valuable in studying IL-23 responses in other diseases.
Evaluation of the Inflammatory Response in Non-human Primate (NHP) Models of Poly-trauma
Authors: Vernon Philip J , Schaub Leasha , Grossman Heather , Glaser Jacob , Sheppard Forest 
Published: January 2023

Abstract

Background
Trauma is a leading cause of mortality, with those surviving their initial injuries remaining at risk for death due to deleterious inflammation. Preclinical investigations of immunomodulatory therapeutics are hindered by the limitations of available animal models. We sought to develop a translatable poly-trauma model in NHPs to facilitate future translational immunotherapeutic evaluation.

Methods
NHPs (n=24) were randomly assigned to: 60min hemorrhage shock alone(n=8) or in combination with laparotomy (n=8) ± femur fracture (n=8), resuscitation and 24hr survival. Blood was collected at baseline (BLSN), end of shock (EOS), end of resuscitation (EOR), T=360min and T=24hr; lung tissue was collected at T=24hr. Blood and tissue cytokines were quantified by a 23 plex multiplex. Results reported as mean±SEM, Statistics: Two-tailed T-Test, with p&lt;0.05 significant.

Results
Circulating IL-6, IL-10, IL-15, MCP-1, TGFa and VEGF were significantly elevated in all models as early as EOS; IL-1RA, IL-15, TNFa, IL-6, IL-10, MCP-1, TGFa and IL-5 were significantly increased as early as EOS and directly correlated with injury severity. Lung tissue G-CSF, IL-1b, IL-RA, IL-6, IL-10, IL-15, IL-17A, IL-18, MCP-1, sCD40L, TGFa and VEGF were significantly elevated and directly correlated with injury severity.

Conclusion
Increases in cytokines identified in all models are consistent with those reported in human trauma studies. Cytokines strongly associated with injury severity score (ISS) in humans directly correlated with model severity (IL-6 and IL-10). These models have uncovered cytokine responses not characterized in poly-trauma (IL-15), demonstrating their utility in identifying novel targets for human investigation.
Modeling cytokines and chemokines through a rooted correlation network
Authors: Qeadan Fares , Dwivedi Sunita , Page Kimberly , Gravitt Patti 
Published: January 2023

Abstract
Several studies have investigated the role of cytokines/chemokines in infection and chronic and autoimmune diseases using different statistical models. Generally, only two mediators are evaluated at a time, by comparing group-specific mean concentration differences. Restricted pairwise analysis from a large array of markers which inherently operate at a systems level to regulate immune response ignores important inter-correlation structures, compromising clinical and epidemiological inference. We propose the use of a rooted correlation network as a novel statistical method which allows group-specific comparisons of a panel of soluble immune markers while adjusting for the interaction complexity.
We examined soluble immune markers in luminal fluid samples from 90 HPV infected female participants with and without soil transmitted helminth (STH) co-infection in Peru. We constructed a lower triangular correlation matrix using Spearman’s correlation with Sidak adjustment for both the STH-infected and -uninfected women. Rooted correlation network was constructed for the cytokines and chemokines that were insignificant in the non-helminth group but became significant in the helminth one. The generated cytokine network demonstrated statistically significant association of Th2 pathway cytokines with the canonical Th2 cytokine IL-4. Using this new statistical model, we demonstrate that the female genital tract of STH-infected women reveals polarization towards Th2 immune response (IL-25, IL-21, IL-5, IL-10, IL-8, and IL-31) in comparison to STH-uninfected women, which was not easily recognizable when using standard bivariate methods with multiple comparisons.
Macrophage migration inhibitory factor-induced autophagy is involved in thrombin-mediated endothelial cell hyperpermeability
Authors: Yeh Trai-Ming , Chao Chiao-Hsuan 
Published: January 2023

Abstract
Sepsis is a disease in which systemic inflammation-induced vascular leakage and disseminated intravascular coagulation lead to multiple organ failure. Despite a high mortality andmorbidity, there is currently no specific drug for sepsis. Thrombin, a serineprotease that mediates key sepsis-related pathologies, both activates coagulation cascades and acts as a mediator to induce vascular hyperpermeability and inflammation. It is known that thrombin can induce endothelial cells to secrete macrophage migration inhibitor factor (MIF) and MIFcan cause endothelial hyperpermeability via autophagy. However, it is unclearwhether MIF-induced autophagy is involved in thrombin-mediated vascular hyperpermeability. Herein, we show that thrombin treatment induced hyperpermeability, which was accompanied by VE-cadherin translocation in the human microvascular endothelial cell line (HMEC-1). Additionally, thrombin could induce MIF secretion and autophagy in HMEC-1 cells. Inhibition of MIF by its antibody or inhibitors could reduce thrombin-induced endothelial hyperpermeability and autophagy. However, inhibition of autophagy prevented only endothelial hyperpermeability, not MIF secretion. Finally, both MIF and autophagy inhibitors reduced thrombin- induced vascular leakage in vitro. Together, our data suggest that MIF-induced autophagy is involved in thrombin-mediated endothelial cell hyperpermeability. Further studies designed to test whether autophagy inhibitors could prevent endothelial barrier dysfunction in sepsis may provide potential therapeutic modalities to reduce sepsis-related mortality.
The role of the interleukin-12/STAT4 axis in breast cancer
Authors: Nunez Angel R 
Published: January 2023

Abstract
Breast cancer (BC) is one of the leading causes of cancer-related deaths among women worldwide. Interleukin-12 (IL-12) has demonstrated anti-cancer effects in vitro and in vivo. IL-12 signaling occurs mainly through STAT4, and it induces anti-tumorigenic actions such as promotion of apoptosis, differentiation of T helper 1 (Th1) cells, increasing immune cell’s cytotoxicity and preventing angiogenesis. The role of the IL-12/STAT4 axis in human breast cancer has not been studied thoroughly. Our aim was to assess if the IL-12/STAT4 pathway is differentially expressed and contribute to a pro-tumor environment in BC. We hypothesize that genetic and molecular impairments lead to a downregulation of the IL-12/STAT4 axis and are associated with breast cancer risk. mRNA and protein levels of key IL-12/STAT4 molecules were measured using peripheral mononuclear blood cells (PBMCs) from BC patients and non-BC controls. Interleukin-12 B (IL12B), STAT4 and interferon gamma (IFNG) expression was lower in BC samples when compared with the controls. These results suggest that the IL-12/STAT4 axis pathway is differentially expressed in BC, and prompts more specific analyses such as whether this is BC subtype-specific.
Low-dose gamma radiation does not mitigate inflammatory cytokine responses in a murine model of Benzo[a]pyrene-induced lung cancer
Authors: Bruce Veronica R , Gott Katherine , Scott Bobby , Wilder Julie 
Published: January 2023

Abstract
Low-dose radiation has been reported to modify the immune system and may lead to lung cancer suppression. In a series of short-term studies, A/J mice were injected i.p. with a carcinogen, Benzo[a]pyrene (B[a]P), and/or whole-body irradiated with low-dose gamma radiation (LDR). We previously reported that B[a]P promoted a pro-inflammatory cytokine response (IL-1β, IL-6, IL-17, TNF-α) whereas LDR promoted an anti-inflammatory response (IL-4, IL-10) and increased IL-2 in supernatants of Concanavalin A-stimulated splenocytes. Consequently, we enumerated cytokine-producing cells via intracellular flow cytometry and examined cytokine production capacity by median fluorescence intensity (MFI) analysis. In the spleen, B[a]P enhanced IL-1β and IL-17 producing Gr-1+ and CD19+ cells. Although B[a]P and LDR enhanced IL-6, or IL-2, IL-4, and IL-10 production respectively, the corresponding cell types were unidentifiable. MFI was not affected by either B[a]P or LDR. In the lung, B[a]P increased IL-1β production in CD19+ and CD4+, IL-6 in CD4+, IL-17 in Gr-1+ and CD19+, and TNF-α in CD19+ and CD8+ cells. B[a]P also increased IL-4, IL-10, and IL-13 expressing CD4+ cells, and IL-10 expressing CD8+ cells. Increased MFI was observed for several of these cells types. Neither cytokine producing cell numbers nor MFI were affected by LDR. Although we observed B[a]P-mediated anti-inflammatory cytokine production in the lung, we postulate that this is a tissue specific response to ease inflammation through feedback mechanisms. Finally, we found no evidence that LDR mitigates B[a]P-mediated inflammatory cytokine responses in either tissue. We believe it is unlikely that LDR suppresses B[a]P-mediated cancer suppression through immune modulation.
Establishment of tissue-resident macrophage core and tissue specific programs during embryogenesis
Authors: Mass Elvira , Ballesteros Ivan , Farlik Matthias , Halbritter Florian , Klughammer Johanna , Bock Christoph , Geissmann Frederic 
Published: January 2023

Abstract
Tissue resident macrophages develop during embryogenesis, are maintained independently of hematopoietic stem cells during adulthood, and display tissue-specific functions and phenotypes. To understand the genetic program that drives macrophage differentiation from distinct progenitors and their tissue-specific identity, we performed a systematic spatio-temporal analysis of macrophage development in mice. Transcriptional and in situ analyses revealed that a core macrophage program is established very early and within a short time window and is conserved throughout fetal development and in adult macrophages. A new genetic mouse model supports the transcriptional data as it allows to specifically label differentiating macrophages, and therefore targets adult macrophages in all tissues. Interestingly, immediately after colonization of the target tissue, we could identify tissue-specific macrophage programs that are maintained until adulthood. Additionally, we identified a novel transcriptional regulator, which is expressed in early fetal liver macrophages, and whose inactivation results in an impaired Kupffer cell development. In summary, we present a macrophage developmental atlas, identify novel tissue-specific markers and transcriptional regulators, and show that tissue specialization is mainly influenced by ontogenetic gene expression programs.
Expression and function of Olig2 in eosinophils
Authors: Chung Il Yup , Hwang Sae Mi , Uhm Tae Gi 
Published: January 2023

Abstract
Eosinophils are granulocytes that are associated with homeostasis and type 2 immune responses, allergy and parasitic infection. Olig2 is a basic helix loop helix transcription factor that is known to play a key role in cell fate decision and subsequent differentiation of oligodendrocytes. Herein, we report the expression and possible function of Olig2 in eosinophils. When cord blood (CB) CD34+ hematopoietic stem cells differentiated toward eosinophils during a 24 day culture period, Olig2 protein was expressed only in CB eosinophils at day 24, a time when these cells were considered fully differentiated and matured, while Olig2 protein was not detected at day 18 or at earlier time points. Olig2 protein was also abundantly expressed in human peripheral blood eosinophils, but not neutrophils, monocytes, lymphocytes or CB mast cells. RNA-seq analysis showed that numerous genes, especially those encoding eosinophil surface molecules, were highly upregulated along with OLIG2. Among the genes examined, SIGLEC-8 mRNA and protein were downregulated in parallel with OLIG2 by an Olig2 siRNA or a shRNA. In reporter gene and chromatin immunoprecipitation experiments, an E-box in the first intron was found to stimulate SIGLEC-8 gene transcription and bind Olig2. Occupancy of the E-box by Olig2 was also seen upon differentiation of immature eosinophilic AML14.3D10 cells. Hence, at least one important aspect of eosinophil differentiation is driven by Olig2, a transcription factor that has not previously been reported in normal granulocytes.
Role of Wnt-4 signaling in dendritic cells lineage and differentiation
Authors: Jain Pooja , Scharer Christopher , Kawasawa Yuka , Sreedhar Sreesha , Khan Zafar , Boss Jeremy 
Published: January 2023

Abstract
Dendritic cells (DCs) are important mediators of the innate and adaptive immune responses. The network of genes governing the differentiation of these cells has been a topic of discussion for a long time, mainly because of their similarity to other myeloid lineages such as monocytes and macrophages. In order to gain insights into the characterization of factors that contribute to the lineage restricted progenitors in the bone marrow that govern DC differentiation, we performed epigenetic analyses utilizing next generation sequencing of bone marrow-derived CD11c+ DCs (BMDCs). Fms-like tyrosine kinase 3 ligand (Flt3L) is a hematopoietic growth factor that is crucial to the development and commitment of DCs from the common myeloid progenitor (CMP) to the common dendritic progenitor (CDP), subsequently yielding conventional and plasmacytoid DCs. The combined analysis of the DNA methylome by Reduced Representation Bisulfite sequencing (RRBS) and the transcriptome by RNA-seq identified a hypermethylation and a reduction in gene expression of Wnt-4 signaling. Wnt-4 gene family is implicated in several developmental processes especially in determination of cell fate and embryogenesis. A comparative validation analyses at RNA and protein levels on BM cells, CMPs and BMDCs yielded confirmed changes in Wnt-4 and in another cell-cycle factor, Cyclin-D1. Further studies are being done to identify intersection of DNA methylation/RNA-seq data to see if changes in methylation are correlated with transcription, in the Wnt signaling enabling us to further understand the differentiation and maturation of DC lineages.
Characterization of a novel bone marrow resident cell population with the potential to regulate early hematopoiesis and skeletogenesis.
Authors: Root Sierra Hope , Matthews Brya , Kalajzic Ivo , Aguila H. Leonardo 
Published: January 2023

Abstract
Hematopoiesis and skeletogenesis are tightly regulated with participation of cells from both systems. The main hematopoietic component is the osteoclast, a cell crucial for bone remodeling. However, beyond bone homeostasis, other hematopoietic cells may exist as regulators of hematopoiesis within the bone marrow (BM) microenvironment. Histological analyses of mice expressing cre under the control of Dental Matrix Protein-1 (Dmp-1) promoter and crossed with the reporter strain Ai9, showed a fluorescent (tomato+) dendritic cell–like population interspersed within the BM space. These tomato+ cells were isolated, and showed efficient expression of RANK-L and IL-7, suggesting that they could regulate hematopoiesis. These cells also express surface markers of myeloid lineage including: CD11b, F4.80, CD169, and Ly-6C. In vitro hematopoietic progression assays failed on generating these cells from isolated hematopoietic stem cells. However, they can be generated and expanded ex vivo from CD11b+ tomato negative cells. Furthermore, using a tamoxifen inducible Dmp-1/tomato mouse, hematopoietic tomato+ cells appeared 2 days after tamoxifen treatment. In a transgenic mouse bearing the tamoxifen inducible Dmp-1/tomato plus a transgene allowing the ablation of bone formation after injecting ganciclovir; bone ablation for 16 days followed by tamoxifen two days prior to analysis, showed a compromise in the generation of tomato+ hematopoietic cells indicating that their generation is linked to bone formation. Finally, these cells exist in the BM of late gestation embryos and neonates suggesting a possible fetal origin. Currently we are addressing their phagocytic function and their ability to influence hematopoietic progression.