bluuebunny/crossref_metadata_2025_split huggingface dataset:
Longitudinal Immune and Genomic Monitoring Reveals Signatures of Immune-related Adverse Events in Cancer Patients Receiving Checkpoint Inhibitor Therapy
Authors: Khan Shaheen , Moses Angela , Imam Marjaan , Wakeland Edward K , Arana Carlos , Fattah Farjana , Li Quan-Zhen , von Itzstein Mitch , Hsieh David , Popat Vinitha , Barnes Spencer , Xie Yang , Khan Saad , Gerber David 
Published: January 2023

Abstract
Despite the remarkable success of immune checkpoint inhibitor (ICI) therapy, a significant number of patients develop severe and unpredictable immune-related adverse events (irAEs) affecting a wide variety of organs. Concerns over irAE have led to the exclusion of patients with autoimmune disease from ICI clinical trials. Role of host genetic and immune factors in mediating irAEs remain unclear and it is not clear if the manifestations of irAEs is associated with response to therapy. Here, we use multi-faceted approach to characterize changes in host immune system in 200 patients receiving ICI therapy at baseline and post immunotherapy. In addition, we assessed genetic predisposition to autoimmunity using the Illumina SNP array and via targeted resequencing of over 150 immunoregulatory loci including the HLA region. In this meeting, we will present our initial genetic data, serum cytokine and autoantibody profiles and RNA sequencing on peripheral blood mononuclear cells (PBMCs) at baseline and post immunotherapy in patients with and without irAEs. Our preliminary findings suggest that patients who developed irAEs have lower baseline levels and greater post-treatment increases in key interferon gamma inducible cytokine/chemokine levels. Our autoantibody profiling data reveals unique sets of autoantibodies associated with specific irAEs. We will present a comprehensive analysis of immune and genetic correlates of irAEs and response to therapy. We hope our study can help gain insight in to the mechanisms underlying irAE and to identify biomarker signatures predictive of irAEs and/or response. These findings may ultimately help identify high-risk patients, customize therapy, expand use of immunotherapy and prevent toxicities.
Cervical Cancer induces NLRP3 inflammasome activation in human peripheral blood monocytes
Authors: Fernandes Fernanda Pereira , Leal Vinícius Nunes Cordeiro , Pontillo Alessandra 
Published: January 2023

Abstract

Background
Chronic inflammation plays an important role in tumorigenesis of HPV-associated cervical cancer (CC). However the role of inflammasome on CC has not been yet elucidated.

Aim
To investigate the interplay between inflammasome and CC to determine the contribution of inflammasome activation in the progression of CC.

Methods
Inflammasome activation was analyzed in SiHa, Caski, C33 cells lines in monolayer and spheroids cultures representing the CC model. The cell lines was also co-cultured with human monocytes isolated from Healthy donors (HD). Peripheral blood mononuclear cells (PBMC) of patients with CC or precursor lesions (CIN) were also stimulated to evaluate inflammasome activation.

Results
The co-culture of CC cell lines and monocytes induced an increased production of IL-1ß in spheroids model. The culture with the specific NLRP3 inhibitor (MCC-950) showed that the IL-1ß is derived from monocytes through NLRP3 receptor activation. These results indicated that CC is able to activate NLRP3 inflammasome and IL-1ß production in monocytes, however how it happens it still remains unclear. CC conditioned medium was not able to activate monocytes suggesting that possibly a physical interaction between cancer cells and monocytes is needed. Moreover whether IL-1ß production is beneficial or not for the tumor control is still debated. IL-1ß production is higher in LPS-induced CC PBMC than in CIN PBMC.

Conclusion
Our finds suggests that CC is able to activate NLRP3 inflammasome and IL-1ß production in monocytes, and IL-1ß production is higher in patients with CC.
Noncanonical NF-κB signaling is suppressed through the negative regulation of the essential kinase NIK and attenuation is associated with eosinophilic esophagitis pathogenesis
Authors: Allen Irving C , Morrison Holly , Eden Kristin , Brown Stephan , Hart Michael , McGowan Emily 
Published: January 2023

Abstract
Eosinophilic esophagitis (EoE) is an allergic disease of the esophagus driven by T cell and eosinophil responses to dietary allergens, resulting in chronic mucosal inflammation. NF-κB signaling is a master regulator of gene transcription and drives diverse biological processes of relevance to EoE. NF-κB activation occurs through either canonical or noncanonical pathways. In general, there is a relative paucity of knowledge regarding noncanonical NF-κB regulation and signaling. Previously, we have shown that mice with hyperactive noncanonical NF-κB signaling are more susceptible to Th1/Th17 mediated experimental colitis and cancer. Conversely, mice with attenuated noncanonical NF-κB signaling spontaneously develop EoE. The objective of our current study is to translate these findings from mouse models to human patients. Clinical specimens were collected from a cohort of 16 EoE patients and representative controls. Gene expression and protein analysis revealed a significant decrease in p52, RelB, and chemokines specifically associated with noncanonical NF-κB signaling correlated with EoE. However, we also identified a significant change in several mediators that should increase noncanonical NF-κB signaling upstream of the essential kinase NIK. Thus, our data suggest a disconnect between pathway activation and p52/RelB mediated gene transcription, with NIK functioning as a key regulatory target. Further analysis identified 6 regulatory proteins that target NIK in EoE patient specimens and robustly attenuate downstream noncanonical NF-κB signaling. Together, these data demonstrate the significance of this understudied pathway in human EoE and identify potential targets for future therapeutic strategies.
Absence of SIRPα signaling drives TLR9-induced hemophagocytic lymphohistiocytosis-like disease independent of IFN-γ in mice
Authors: Kidder Koby , Bian Zhen , Shi Lei , Liu Yuan 
Published: January 2023

Abstract
The non-physiological phenomenon whereby macrophages phagocytose healthy host cells is a hallmark of severe inflammatory disorders such as hemophagocytic lymphohistiocytosis (HLH). The mechanisms underlying the nascence of hemophagocytic macrophages, however, remain largely unknown. Under healthy conditions, macrophages are non-hemophagocytic and therefore do not eat healthy host cells, owing to the inhibitory myeloid receptor SIRPα. However, we previously showed that, unless inflammatory stimulation via TLR agonists or certain pro-inflammatory cytokines is also provided, the mere absence of SIRPα does not drive macrophages to become hemophagocytic. Here we show that hemophagocytic macrophages may arise under inflammatory conditions given an absence of SIRPα signaling and thereby lead to a severe inflammatory state reminiscent of HLH. SIRPα-knockout (Sirpα−/−) mice injected with the TLR9 agonist CpG rapidly developed characteristics of HLH, e.g., hemophagocytosis, anemia, thrombocytopenia, leukopenia, hepatosplenomegaly, hyperferritinemia, hypertriglyceridemia, and hypercytokinemia, with much greater severity than wild-type mice. Interestingly, IFNγ, a putative driver of HLH, was dispensable in the immunopathology of TLR9-driven HLH in Sirpα−/− mice, as IFNγ neutralization did not ameliorate any symptoms of HLH. As with CpG, other TLR agonists (Poly I:C, LPS, Zymosan) or cytokines (TNFα, IL-6, IL-17A) induced hemophagocytic macrophages that incurred severe HLH in Sirpα−/− mice. Together, these findings implicate that a pre-disposing loss of SIRPα signaling under inflammatory conditions may give rise to hemophagocytic macrophages that drive an HLH-like disease independent of IFNγ.
Repeated exposures to the environmental allergen methylisothiazolinone reduce viability of fibroblasts derived from allergic sites in response to allergen challenge in vitro
Authors: Chatterjea Devavani , Blum Melissa , Koehler Jennifer 
Published: January 2023

Abstract
Chronic, unexplained vulvar pain or vulvodynia affects 8% of women of reproductive age, and is more common with histories of yeast infections and allergies. We have established mouse models of localized, provoked genital pain driven by repeated labiar and vaginal exposures to allergens such as oxazolone, dinitrofluorobenzene and the common chemical preservative methylisothiazolinone (MI). Pain sensitivity is concomitant with tissue mast cell increases and reduced when mast cells are reduced by chemical degranulation or topical phytocannabinoid treatment. Vulvar fibroblasts from patients show altered inflammatory responses in vitro.to repeated topical application of the allergenic cosmetic preservative methylisothiazolinone (MI) to the murine vaginal canal produces long-lasting contact hypersensitivity. Here, we have optimized methods to grow skin and vaginal canal fibroblasts from outbred Swiss mice that are responsive to lipopolysaccharide and zymosan treatment in vitro. We also show that in vitro MI treatment reduces the viability of derived fibroblasts in a dose-dependent manner, with a more robust effect on cell lines derived from MI-treated skin, indicating that previous exposure to MI in the skin primes fibroblasts to undergo cell death upon future exposures. Our data suggest that fibroblasts may become more sensitive to allergens as a result of previous exposures, which could contribute to the development of chronic allergic and pain sensitivity after repeated low dose chemical exposures.
Microarray analysis of human abdominal aortic aneurysm (AAA) detected altered gene expression profiles including H19
Authors: Lu Song , Li Liping , White John V , Zhang Xiaoying , Nwaneshiudu Ifeyinwa , Ntaoula Nectaria , Lin Wanlu , Solomides Charalambos , Gaughan John , Monos Dimitri , Oleszak Emilia , Platsoucas Chris D 
Published: January 2023

Abstract
AAA is often a life-threatening disease with poorly understood pathogenesis. We examined gene expression profiles between AAA and normal aorta specimens by cDNA microarray analysis. AAA wall specimens from 5 patients with AAA and grossly normal aortic walls from 3 transplant donors were employed in this study. Total RNA was extracted from each specimen, RT into cDNA, and labeled with phosphorus α-32P. cDNA probes were then hybridized onto human cardiovascular microarray and analyzed by densitometry. Quantitative differences of some genes were further explored by SYBR green-mediated qRT-PCR analysis. Pairwise comparisons of both microarray and qRT-PCR results were made by Student t-test. Most of the 588 genes studied had similar expression among AAA specimens and control aortas, however, 25 genes were upregulated and 26 downregulated. Expression of MMP-9, TIMP3, collagen 1A1 (COL1A1), COL6A3, COL15A1, decorin, MCP 1, Apo E, Apo D, H19 and others was increased. Expression of COL4A4, biglycan, caveolin 3, galectin 1, LDL receptor-related protein 1, extracellular SOD 3, ANP receptor A precursor and others was decreased. Most qRT-PCR results agreed well with those from microarray analysis, with few exceptions. A number of genes that have been previously postulated to participate in AAA pathogenesis, have been upregulated or their expression has been altered. We also revealed some genes that have not been yet studied in human AAA. Of note, H19, one of the most highly up-regulated transcripts in two mouse aneurysm models, was also significantly upregulated in human AAA. These results indicate that many genes involved in different cellular functions might contribute to the pathogenesis of AAA.
Supported in part by grant RO1 HL64340 from NIH.
Investigating the role of B cell signaling in atherosclerosis
Authors: Ma Shelby , Moriarty Alina , Keeter W. Coles , Waseem Tayab , Gauronskas Phillip Joseph , Galkina Elena 
Published: January 2023

Abstract

INTRODUCTION
Atherosclerosis is an inflammatory disease of the large and medium size arteries. While specific antigens are not well characterized, strong data demonstrate that the immune response is involved in atherogenesis. The role of B cells in atherosclerosis is B cell specific: B2 cells are proatherogenic and B1 and MZ B cells serve as protective. B cell activation is dependent on B cell receptor signaling along with a secondary signal, such as CD45. To date, it is unknown how CD45 signaling regulates activation and functions of B cells in atherosclerosis.

METHODS
We took advantage of a previously characterized transgenic mice that express low levels of CD45 (CD45L/L). We performed adoptive transfer of CD45L/L or WT B cells into B cell-deficient mice injected with AAV-PSCK-9 to induce atherosclerosis. After 16 wks of a western diet feeding aortas were collected and stained with Oil Red O. Spleens from the CD45L/L and WT recipients were analyzed by FACS and isolated splenic B cells were tested in BCR-induced Ca2+ flux, proliferation, and survival assays.

RESULTS and CONCLUSIONS
Our preliminary data demonstrate that low CD45 expression by B cells increases atherosclerosis in the CD45L/L vs WT recipients. Unexpectedly, elevated aortic plaque burden was accompanied by decrease in pathological Tfh cells and a significant elevation in protective B1 B cells in the CD45L/L compared to WT recipients. Future analysis will determine levels of proliferation and activation of B cells in both groups. These results suggest that CD45-dependent activation of B cells impacts the distribution of B cell subsets and highlight a potential role of BCR-related signaling in the regulation of immunity in atherosclerosis.
Defining mechanisms of semaphorin 4A stimulatory action on human Treg cells
Authors: Chapoval Svetlana P , Qi Xiulan , Neuwald Andrew F , Keegan Achsah Dorsey 
Published: January 2023

Abstract
We had shown previously that semaphorin 4A (Sema4A) suppresses allergic inflammation in mice (Mucosal Immunol., 2012, 5:409-19), regulates human Treg cell stability, and induces the generation of Treg cells in PBMC cultures acting through its Plexin B1 receptor (Immunohorizons, 2019, 3:78–87). Plexin B1 forms functional homodimers or heterodimers with other Plexin B molecules and co-precipitates with Neuropilins (NRPs) in transfected 293T cells. Furthermore, NRPs were shown to stabilize Sema/Plexin interactions. In this study, we sought to identify potential partner(s) for Plexin B1 in mediating Sema4A action. We examined surface expression of Plexin B2, B3, and NRPs 1, 2 in human Treg cells by flow cytometry, and observed that they express NRP-2 but not NRP-1, Plexin B2, or B3. Moreover, culture of PBMC with recombinant human Sema4A-Fc (rhSema4A) in vitro resulted in the downregulation of NRP-2 expression on human Treg cells suggesting a specific ligand-receptor interaction. We propose that Sema4A action on human Treg cells may be mediated by a Plexin B1-NRP-2 complex. Our ongoing research is focused on cryoEM studies of ligand-receptor and receptor-receptor interactions in conjunction with sequence/structure statistical analyses using the DARC (Deep Analysis of Residue Constraints) program (Scientific Reports, in press) with the goal of developing Sema4A-based therapies for allergic disease.
IQ motif-containing GTPase-activating protein 1 is essential for the optimal maintenance of lung ILC2s
Authors: Tayama Shunichi , OKUYAMA YUKO , PHUNG HAI THE , ASAO ATSUKO , KOBAYASHI SHUHEI , KAWABE TAKESHI , TAKANORI SO , ISII NAOTO 
Published: January 2023

Abstract
Group 2 innate lymphoid cells (ILC2s) play critical roles in type 2 immunity and are crucial for pathogenesis of various types of inflammatory disease. IQ motif-containing GTPase-activating protein 1 (IQGAP1) is a ubiquitously expressed scaffold protein that is involved in multiple cellular functions such as cell survival and trafficking. While the roles for IQGAP1 in T and B lymphocytes have been uncovered, the physiological significance of IQGAP1 in innate lymphocytes remains to be elucidated. In the current study, we demonstrate that using bone marrow chimeras, the deficiency of IQGAP1 caused an impaired survival of lung ILC2s in a cell-intrinsic manner and that Iqgap1−/− mice displayed decreased accumulation of ILC2s after administration of papain and thereby reduced pathology of the disease. Moreover, Iqgap1−/− ILC2s showed a significantly enhanced apoptosis as compared to wild-type ILC2s under both steady-state and inflammatory conditions. Together these results identify for the first time that IQGAP1 is essential for homeostasis of ILC2s in the lung.
The Role of Tyrosine Kinase Itk in T helper 17 and T regulatory cells in Hypersensitivity Pneumonitis
Authors: Elmore Jessica , Carter Chavez , Koylass Nicholas , Bennett Amelia , Mead Max , Kim Alexia , Huang Weishan , August Avery 
Published: January 2023

Abstract
The balance of inflammatory and suppressive cytokines is critical in controlling inflammatory responses, and the pro- and anti-inflammatory cytokines IL17A and IL10 has been implicated in numerous pulmonary inflammatory diseases. The tyrosine kinase, Itk, plays a critical role in T cell activation. Itk is required for the development of Th17 cells and their production of IL17A in allergic lung inflammation. Furthermore, Type I regulatory and Foxp3+ T regulatory (Tregs) cells, producers of IL10, are positively and negatively regulated by Itk respectively. Farmer’s lung, a subset of hypersensitivity pneumonitis, develops due to repeated exposure to the bacteria Saccharopolyspora rectivirgula (SR) and is dependent on IL17A and regulated by IL10. Surprisingly, exposure to SR drives robust CD4+ T cell IL17A response even in the absence of Itk, with pulmonary inflammation. Transcriptomic analysis of sort purified WT and Itk−/− IL17A producing CD4+ T cells from SR-exposed mice revealed an enrichment of Notch signaling pathway in the absence of Itk. SR also induced the Itk independent development of a population of IL17A producing Foxp3+ Tregs cells, and a significant decrease in IL10 producing Tr1 cells. These data suggest that Itk regulates the expression of IL10, and pathogenic Th17 cells via Notch signaling. These studies suggest that TCR signaling through Itk differentially regulates the development of inflammatory Th17 cells and suppressive Tregs and Tr1 cells in response to SR exposure. Understanding how Itk modulates the development of Th17/Treg cytokine responses will allow us to better understand the precise role of Itk in the regulating the balance of pro- and anti-inflammatory cytokine production during airway inflammation.
Potential role of thioredoxin-interacting protein in non-IgE mast cell degranulation
Authors: Mendoza Ryan P , Anderson Colin C , Roede James R , Brown Jared M 
Published: January 2023

Abstract
Non-IgE mediated pathways of mast cell degranulation result in similar pathological outcomes as IgE mediated degranulation without prior IgE sensitization thereby making it difficult to identify causative agents and develop therapeutics for patients. We have demonstrated that 20 nm silver nanoparticles (AgNP) induce non-IgE mast cell degranulation through an unknown mechanism. However, we have established that this non-IgE response is strain dependent with C57BL/6 bone marrow derived mast cells (BMMCs) being high responders and LP/J BMMCs being low responders. Further, RNA sequencing of high-responder and low-responder BMMCs demonstrated a significant increase in thioredoxin-interacting protein (txnip) in the low-responders after AgNP mediated degranulation. We explored this protein to determine its regulatory potential in non-IgE mast cell degranulation. At 1hr following exposure to AgNP, txnip mRNA levels increased in LP/J but not C57BL/6 which confirmed RNAseq results. Txnip protein levels were similarly decreased in BMMCs from both strains at 1hr; however, there was an increase in the low-responder BMMCs at six hours post-exposure that did not occur in the high-responder BMMCs. siRNA knockdown of txnip resulted in increased BMMC degranulation by AgNP. Txnip is strongly involved in cellular metabolism. Seahorse XfP results demonstrated a lower energy and glycolytically focused phenotype in low-responders compared to high-responders. C57BL/6 have significantly lowered glycolytic capacity after AgNP-mediated degranulation not present in LP/J. Our data suggests that txnip plays a role in non-IgE mediated mast cell degranulation and may modulate cellular metabolism.
M2-like, dermal macrophages are maintained via IL-4/CCL24 mediated cooperative interaction with eosinophils in cutaneous leishmaniasis
Authors: Lee Sang Hun , Chaves Mariana M. , Kamenyeva Olena , Gazzinelli-Guimaraes Pedro H. , Kang Byung Hyun , Pessenda Gabriela , Kaiuska Passelli , Tacchini-Cottier Fabienne M , Kabat Juraj , Jacobsen Elizabeth A , Nutman Thomas B , Sacks David 
Published: January 2023

Abstract
Tissue-resident macrophages (TRMs) maintain tissue homeostasis, but they can also provide a replicative niche for intracellular pathogens such as Leishmania. How dermal TRMs proliferate and maintain their M2 properties even in the strong TH1 environment of the L. major infected dermis is not clear. Here, we show that in infected mice lacking IL-4/IL-13 from eosinophils, dermal TRMs shifted to a pro-inflammatory state, their numbers declined, and disease was attenuated. Intravital microscopy revealed a rapid infiltration of eosinophils followed by their tight interaction with dermal TRMs. IL-4-stimulated dermal TRMs, in concert with IL-10, produced a large amount of CCL24 which functioned to amplify eosinophil influx and their interaction with dermal TRMs. An intraperitoneal helminth infection model also demonstrated a requirement for eosinophil-derived IL-4 to maintain tissue macrophages through a CCL24-mediated amplification loop. CCL24 secretion was confined to resident macrophages in other tissues, implicating eosinophil-TRM cooperative interactions in diverse inflammatory settings.
Suppression of Inflammation of the Cytokine Storm Following Francisella Tularensis Infection is Mediated by Natural Killer T Cell Subsets
Authors: Setzu Nicole R , Spencer Charles T 
Published: January 2023

Abstract
Francisella tularensis is intracellular bacteria which is the causative agent of the disease tularemia. Highly virulent in both humans and animals, it takes only as few as ten microorganisms to cause a lethal infection. The bacteria can enter via direct or indirect routes causing the activations of the host innate inflammatory response to ensue. The function of the bacteria once its entered the host cell is to be opsonized by phagocytic cell, survive and continue to proliferate in the host causing pathogenicity.
The bacteria invade host dendritic cells, neutrophils, and predominately macrophages. This causes a mass inflammatory response resulting in the cytokine storm. Activation of natural killer T cells has been shown to suppress inflammation in in vitro functional assay studies. We know that select populations of NKT cells influence the cytokine storm at the onset of infection. Our hypothesis seeks to determine whether type one versus type two natural killer T cells are inhibiting inflammation. Based on our preliminary results we hypothesize that the type one NKT cells will show cell suppression.