bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multivariate Transcriptome Analysis of CXCR5-CXCL13 signaling in Unmutated and Mutated CLL
Authors: Griffen Tiara L , Young Corey , Dill Courtney D. , Carey Kaylin , Adebayo Olayinka , Nunez Sha'kayla , Lillard James W 
Published: January 2023

Abstract
Chronic Lymphocytic Leukemia (CLL) is characterized by the appearance of mature-appearing B cells in the blood, bone marrow, and lymph nodes, but the molecular pathogenesis of CLL is incompletely known. Chemokines and their receptors contribute to the progression of several malignancies. CXCR5 and CXCL13 are produced by cells in the CLL microenvironments, which promote disease progression. There is a gap in understanding the molecular mechanisms involved in CXCL13-CXCR5 interactions during CLL. Together, this provided the rationale to test the hypothesis CXCR5-CXCL13 signaling contributes to the growth, metastasis, and survival of CLL. The role of CXCR5, CXCL13, and associated genes was investigated by conducting Weighted Gene Network Co-expression (WGCNA) and upstream regulator, canonical pathway, and gene interaction analyses of International Cancer Genome Consortium (ICGC) transcriptomes with quantitative and qualitative clinical traits identified in CLL patients (n=203). The WGCNA-designated blue module, co-expression network, contained CXCL13 and 2088 other genes, which significantly correlated (R2=0.31, p= 3e–05) with IGHV-unmutated CLL status. This network included CXCL13-CXCR5 driven genes, e.g., SYK, ATM, JAK1, STAT1, LTB, LTB4R, MAPK, PLC, PIK3, and WNT genes, which mediate survival, stemness, and metastasis of CLL. CXCR5 was found in the WCGNA grey module, which included other CLL-driver genes, e.g., IGHV, MYC, and ZAP-70. This module was significantly associated with stage A, relapse, and IGHV-mutatedCLL cases. Among the top canonical pathways of the grey module were BCR- and PIK3/Akt-signaling. Taken together, our data suggest clinical significance of the CXCL13-CXCR5 pathway in CLL progression.
IL-22 reduces the mortality of type 2 diabetes mellitus (T2DM) mice infected with Mycobacterium tuberculosis
Authors: Tripathi Deepak , Radhakrishnan Rajesh Kumar , Thandi Ramya Sivangala , Paidipally Padmaja , Devalraju Kamakshi Prudhula , Neela Venkata Sanjeev Kumar , Tvinnereim Amy R. , Valluri Vijaya Lakshmi , Vankayalapati Ramakrishna 
Published: January 2023

Abstract
IL-22 play an important role in protective immune responses against bacterial infections including Mtb and maintains homeostasis by regulating excess inflammation. IL-22 can also regulate glucose homeostasis, suggesting IL-22 pathway as a novel target for therapeutic intervention. Previously, we developed a mouse model of type 2 diabetes mellitus (T2DM) and found that pathological immune response enhances mortality of Mycobacterium tuberculosis (Mtb) infected T2DM mice. In the current study, we determined the role of IL-22 during Mtb infection in T2DM mice. We found innate lymphoid 3 cells (ILC3) are the major source for IL-22 and IL- 22 production was significantly reduced in the lungs and serum of T2DM mice infected with Mtb. Recombinant IL- 22 or adoptive transfer of ILC3 cells prolonged the survival of Mtb infected T2DM mice. Recombinant IL-22 prevented neutrophil accumulation near alveoli, reduced the serum insulin level and improved the lipid metabolism. Recombinant IL-22 also prevented neutrophil-mediated epithelial cell damage by inhibiting elastase production by neutrophils. Further, we found serum IL-22 levels were significantly less in tuberculosis (TB) patients with T2DM compared to TB patients without T2DM. Our findings suggest that IL-22 produced by ILC3 cells is essential to inhibit excess inflammation, epithelial cell damage in T2DM mice infected with Mtb.
IL-17D promotes anti-bacterial immunity in Group A Streptococcus infection
Authors: Washington Allen , Valderrama Andres , Nizet Victor , Varki Nissi , Bui Jack D 
Published: January 2023

Abstract
Interleukin (IL)-17D is a cytokine in the IL-17 family that is conserved in vertebrates and invertebrates. In contrast to IL-17A, which is expressed in T cells, IL-17D is expressed broadly in non-immune cells. IL-17D can promote immune responses to cancer and viruses in part by inducing chemokines that recruit natural killer cells and neutrophils. Although bacterial infection can induce IL-17D in other species, the role of mammalian IL-17D in anti-bacterial immunity has not been determined. In order to ascertain whether IL-17D has a role in mediating immunity against bacterial infections, we studied intraperitoneal infection by Group A Streptococcus (GAS) S. pyogenes in wild-type (WT) and IL-17D-deficient mice. We found that there was more weight loss and decreased survival in mice deficient in IL-17D compared to WT animals after GAS infection. In addition, IL-17D deficient animals had increased bacterial burden in the kidney and peritoneal cavity after GAS infection compared to WT animals. In WT animals, IL-17D transcript could be induced by GAS infection, correlating with increased levels of the chemokine CCL2 and neutrophil recruitment. Notably, GAS-mediated induction of IL-17D seemed to require live bacteria, indicating that pattern recognition did not mediate induction of IL-17D. Altogether, our results demonstrate a role for IL-17D in sensing replicating bacteria and inducing immune responses important in clearing bacteria in distant organs.
A directly GP130-targeting small molecule ameliorates collagen-induced arthrites by inhibiting IL-6/GP130 signalling and Th17 differentiation
Authors: Kim Hee Jung , Park Yeon-Hwa , Heo Tae-Hwe 
Published: January 2023

Abstract
Rheumatoid arthritis is a chronic inflammatory disease that is characterized by joint destruction and inflammation by T helper 17 (Th17) cells. Interleukin-6 (IL-6) is secreted in cells such as macrophage or synovial fibroblast and induces the differentiation and function of Th17 cells that increase lymphocytic infiltration in the joint. LMT-28 suppresses IL-6 signaling through direct binding to glycoprotein-130, and alleviates inflammatory disease (such as rheumatoid arthritis, inflammatory bowel disease) in previous study. The purpose of this study is to assess whether LMT-28 would potently inhibit Th17 differentiation, and the mechanism of LMT-28 that attenuates rheumatoid arthritis through IL-6 signaling pathway. LMT-28 reduced the arthritis score and showed protective effects against bone and cartilage destruction in collagen induced arthritis (CIA) mice. In mice with CIA, LMT-28 markedly decreased the serum levels of IL-6, TNF, and IL-1β compared with each vehicle treated group. Moreover, LMT-28 attenuated Th17 cell activation in lymph nodes of CIA mice. We demonstrated that LMT-28 suppressed differentiation of Th17 in mouse splenocytes and human PBMCs. Additionally, LMT-28 inhibited the phosphorylation of GP130, STAT3, and ERK induced by Hyper IL-6 in human fibroblast-like synoviocytes(FLS). Collectively, these results suggested that LMT-28 inhibits differentiated/activated-Th17 cells in rheumatoid arthritis by blocking activation of the STAT3 pathway.
An autoimmune disease risk SNP, rs2281808, in SIRPG is associated with reduced expression of SIRPγ and heightened effector state in human CD8 T-cells
Authors: Sinha Sushmita 
Published: January 2023

Abstract
Multiple GWAS studies have shown that the SNP rs2281808 TT variant, present within the SIRPG gene, is associated with autoimmune diseases, such as type 1 diabetes. However, the role of SIRPγ in human T-cells is not known, neither is the functional significance of TT variant. Here we investigated SIRPG genotypes and their effects on the fate and function of human T-cells. We found that the presence of T variant resulted in reduction of SIRPγ expression on T-cells. Functionally, SIRPγlow CD8 T-cells in CT and TT individuals existed in a heightened effector state with lower activation threshold and had greater expression of genes and molecules associated with migratory and cytotoxic potential. Further, SIRPγlow CD8 T-cells were deficient in transcription factors associated with long-term functional memory formation. Our study reveals biological consequences of the SNP rs2281808 and provides novel insights into the potential mechanisms by which SIRPγ might regulate human immune responses.
Reduced gravity contributes to Neutrophil to Lymphocyte Ratio shifting and promotion of the Oxidative Stress Response
Authors: Paul Amber M , Mhatre Siddhita D. , Cekanaviciute Egle , Schreurs Ann-Sofie , Tahimic Candice G.T. , Globus Ruth K , Crucian Brian , Bhattacharya Sharmila 
Published: January 2023

Abstract
Spaceflight can cause immune system dysfunction, such as elevated white blood cells (WBC) and polymorphonuclear neutrophils (PMN), along with unchanged or reduced lymphocyte counts. A high PMN to lymphocyte ratio (NLR) can acts as a poor prognosis in cancer and a biomarker for subclinical inflammation however, the NLR has not been identified as a predictor of astronaut health during spaceflight. CBC data collected on board the International Space Station (ISS) was repurposed to determine the granulocyte to lymphocyte ratio (GLR) in humans and the NLR in rodents. The results displayed a progressive increase in GLR and NLR during spaceflight and at landing. The mechanism for increased NLR was assessed in vitro using the microgravity-analog, rotating wall vessel (RWV), with human WBCs. The results indicated that simulated microgravity led to increased GLR and NLR profiles, and production of reactive oxygen species (ROS) and myeloperoxidase (MPO). Interestingly, simulated microgravity increased the number of matured PMNs that showed impaired phagocytic function, while treatment with tert-Butyl hydroperoxide (TBHP), also reduced PMN phagocytosis. In addition, 30-days of simulated microgravity (hindlimb unloading) in mice, indicated an increased NLR and MPO gene expression, which were mitigated in mitochondrial catalase overexpressing transgenic mice, suggesting ROS scavenging is essential for maintaining homeostatic immunity. Collectively, we propose that the health status of astronauts during future short- and long-term space missions can be monitored by their NLR profile, in addition to utilizing this measurement as a tool for oxidative stress response countermeasure development to restore homeostatic immunity.
Identification of T-cell subsets associated with muscle strength in people with cancer: A pilot study
Authors: Narsale Aditi , Moya Rosa , Ma Jasmin , Anderson Lindsey , Wu Daniel , Garcia Jose , Davies Joanna D 
Published: January 2023

Abstract

Background
Immune deficiency and muscle wasting are both associated with poor prognosis in people with cancer. Survival and quality of life can be improved by attenuating either the immune response or muscle mass, suggesting a relationship between them. Previous data show that mice injected with precursor CD4 T cells maintain muscle mass by restoring immune homeostasis. These data are consistent with the hypothesis that robust anti-cancer T cell immunity leads to improved muscle health. As a first step, this study aims to determine if circulating T cell subsets correlate with muscle strength in people with cancer.

Methods
The frequency(freq) of T cell subsets was quantified in 11 men with gastrointestinal cancer, and 9 men without cancer, using flow cytometry. Total PBMC protein and gene expression was analyzed using qPCR and Western blots. Clinical measures were assessed using: DEXA scan (body composition); Hand-grip (HGS) test and Knee extension test (Muscle Strength); Stair Climb test (Performance) and Karnofsky and ECOG scales (functional impairment). Data was analyzed using Spearman’s correlation and ANOVA.

Results
Our data show significant correlations between i) higher freq of CD8 naïve and EM T cells, and lower freq of CD8 CM T cells with stronger HGS, ii) lower freq of Tregs with greater lean mass index, iii) lower freq of CD8 cells expressing CD95 with greater Stair Climb Power, iv) higher freq of CD197+CD45RA+ T cells and greater knee extension strength, and iv) higher expression of CD4 in whole blood with greater functional impairment in people with cancer.

Conclusions
We have identified significant correlations between levels of T cell populations and muscle strength, performance, and body composition in people with cancer.
Increased expression of CD40 and CD40L in acute coronary syndrome patients: association with genetic variants in western Mexican population
Authors: Martinez-Fernandez Diana Emilia , Padilla-Gutiérrez Jorge Ramón , Casillas-Muñoz Fidel , Valdés-Alvarado Emmanuel , Parra-Reyna Brenda , Aceves-Ramírez Maricela , Muñoz-Valle José Francisco , Valle-Delgadillo Yeminia 
Published: January 2023

Abstract
Acute coronary syndrome (ACS) belongs to the clinical entities characterized by obstruction of a coronary artery. In its etiology, inflammation contributes significantly trough the activation of immune cells by co-stimulatory molecules as CD40 and CD40L. The purpose of this work was to explore the changes of mRNA and circulating soluble levels of CD40-CD40L in ACS patients and association with genetic variants in a western Mexican population.
320 ACS patients and 300 individuals with similar age than cases without ischemic cardiopathy were recruited. Genotype determination was made using TaqMan SNP genotyping assays. CD40 and CD40L mRNA expression in whole blood samples were quantified using TaqMan Gene Expression Assays. Soluble levels were measured in plasma by enzyme-linked immunosorbent assay.
We did not find evidence of association between on CD40 (rs1883832, rs4810485 and rs11086998) and CD40L (rs3092952 and rs3092920) genetic variants and susceptibility to ACS nor changes in their mRNA expression (p&gt;0.05), although rs1883832 and rs4810485 affected significantly sCD40 circulating levels (p=0.005; p=0.015, respectively). Circulating soluble levels were higher in ACS patients; specifically sCD40L was higher in male patients with unstable angina compared to female patients (p=0.016).
Our results showed genetic variants affect soluble levels of CD40 although the CD40 and CD40L polymorphisms are not associated with susceptibility to ACS in western Mexican population. CD40L mRNA expression, sCD40 and sCD40L plasma levels were higher in ACS patients even when they are under pharmacological treatment, which suggests an active role of the CD40-CD40L system in the immunopathogenesis of acute coronary syndrome.
The Th2 cytokine IL-4 mediates loss of skin γδT cells in atopic dermatitis
Authors: Wang Jocelyn , Fu Yongyao , Kaplan Mark H 
Published: January 2023

Abstract
Atopic dermatitis (AD) is a common Th2-biased chronic inflammatory skin disease. Major clinical manifestations include erythema, severe itchiness, and dry skin that impose a burden on patients and impairs their quality of life. Extensive research has been conducted to identify possible underlying mechanisms and develop therapeutic approaches. γδT cells, an understudied T cell population, play important roles in maintaining skin integrity in both human and mice. They are among the first responders to epithelial wounding and are a source of keratinocyte/fibroblast growth factors that promote wound repair. Hence, we wanted to investigate their behavior during wounding in an AD-like environment. Using a mouse model, we observed that γδT cell numbers are drastically decreased in atopic skin. Multiple factors contribute to this decrease, including insufficient activation, less proliferative capacity and increased cell death. These changes in γδT cell function are IL-4 dependent. Administration of IL-4 to wild type (WT) mice resulted in significant loss of γδT cells, and Il4−/− mice in the AD model showed numbers of γδT cells similar to WT controls. We further observed that the levels of keratinocyte/fibroblast growth factors are lower in AD animals, suggesting that loss of γδT cells could compromise re-epithelialization and repair following wounding. Collectively, our data indicate that in an atopic environment, γδT cells decrease drastically in an IL-4 dependent fashion, which may contribute to the aberrant wound healing process in AD animals.
Nerve growth factor receptor expression marks activated human perivascular adventitial fibroblasts in distinct perturbed states
Authors: Barron Alexander Michael Shuford , Ho Jonathan Dale , Mantero Julio C. , Bhawan Jag , Browning Jeffrey L 
Published: January 2023

Abstract
Vascular alterations are common in human autoimmune skin diseases, including systemic sclerosis and discoid lupus. Much is known about endothelial cell, pericyte and vascular smooth muscle cell activation. In contrast, the adventitial layer of the vascular unit is less well explored. This compartment serves as a reservoir for leukocytes and mesenchymal stem cells, and appears to play important sentinel and remodeling roles. We recently demonstrated that the compartment, as well as the perivascular adventitial fibroblasts, expand in the skin of systemic sclerosis, discoid lupus, and dermatitis patients. Vascular cell adhesion molecule-1 (VCAM) display marked activated adventitial fibroblasts in discoid lupus and dermatitis, and correlated with perivascular T cell infiltration. Here we demonstrate elevated expression of Nerve growth factor receptor (NGFR) by perivascular adventitial fibroblasts in the skin of systemic sclerosis patients but not control subjects. Adventitial NGFR expression occurred without elevated VCAM indicating a distinct activation state. Conversion to the NGFR+ state was also observed in the absence of large, perivascular leukocyte infiltrates. In systemic sclerosis, NGFR was more common than VCAM on perivascular adventitial fibroblasts. Conversely, in discoid lupus lesions, VCAM was more common than NGFR on adventitial fibroblasts suggesting two distinct activation programs. Similar adventitial NGFR staining was seen in both pathological (e.g. hypertrophic and keloid) and normal reparative skin wounds. Our data indicate that elevated NGFR expression can identify an activated perivascular adventitial fibroblast in disease.
Kinetics of immune cell responses in the multiple low dose streptozotocin mouse model of type 1 diabetes
Authors: Luo Zhengkang , Soläng Charlotte , Blixt Martin , Carlsson Per-Ola , Sandler Stellan , Singh Kailash 
Published: January 2023

Abstract
In type 1 diabetes (T1D), the insulin producing β cells are damaged by immune attacks. It has been hypothesized that the very first response in T1D onset comes from innate immune cells, which further activates the adaptive immune cells to attack the β cells. The kinetics of the infiltration of different immune cells in the multiple low dose streptozotocin (MLDSTZ) induced T1D mouse model is still unclear. Therefore, we used flow cytometry to investigate the proportions of innate immune cells such as neutrophils, dendritic cells (DCs), plasmacytoid DCs (pDCs) and macrophages, and adaptive immune cells (T and B lymphocytes) in thymi, pancreatic draining lymph nodes (PDLNs) and spleens of MLDSTZ mice on days 3, 7, 10 and 21 after the first injection of MLDSTZ. The proportions of DCs and pDCs were increased on day 3 while the proportions of B-1a lymphocytes and neutrophils were increased on day 10 in MLDSTZ treated mice, illustrating that the initial immune response is induced by DCs and pDCs. The proportions of T helper 1, Helios+ T cells and cytotoxic T cells were increased from day 7, suggesting that the innate immune cells precede the adaptive immune cell response in MLDSTZ mice. We also found the proportions of interleukin-35 (IL-35) expressing tolerogenic antigen presenting cells (tolAPCs) were decreased in the spleens of MLDSTZ mice than in control mice on day 21. Furthermore, we found the proportions of IL-35+ tolAPCs were decreased in the peripheral blood mononuclear cells from T1D patients than from healthy controls. Altogether, our data demonstrate a possible sequence of events regarding the involvement of DCs, pDCs, B-1a lymphocytes, neutrophils, and Helios+ T-cells at the early stage of T1D development.
Biochemical and Functional Characterization of the ICOSL TNFR2 Interaction
Authors: Herrera Natalia Guadalupe , Garrett-Thomson Sarah , Almo Steven 
Published: January 2023

Abstract
To evade the immune response, cancers hijack the anti-inflammatory function of T regulatory Cells (Tregs) through blockade of anti-tumor responses carried out by T cells (effector and cytotoxic). Tumor necrosis factor receptor 2 (TNFR2) positive Tregs are highly immunosuppressive and enriched in the tumor microenvironment. Thus, immunotherapies targeting TNFR2 with antagonistic or agonistic antibodies are promising therapeutics for decreasing or increasing Treg cell levels, respectively. TNFR2 is activated by engagement with the cytokine, TNF alpha (TNFa), which leads to cell survival and proliferation through activation of the NFkB pathway, and this is extensively studied in terms of Treg cell proliferation and survival. Using a high-throughput cell-cell based screening approach, the Almo lab identified ICOS ligand (ICOSL) as a novel interacting partner of TNFR2. ICOSL is a costimulatory molecule with wide tissue distribution and with the ability to bind type-I transmembrane proteins CD28, CTLA-4 and ICOSR. ICOSL interactions with these receptors have been implicated in both positive and negative regulation of T cell activity. While TNFa binding to TNFR2 can activate NFkB signaling, it is unclear if ICOSL binding serves a blocking or activating function. We hypothesize the ICOSL-TNFR2 interaction functions as an additional mechanism for activating/stimulating TNFR2+ Treg cells through processes such as survival, cytokine production and expansion.
IL-15-driven clonal expansion of TLR9-primed human B-CLL is characterized by activation of AKT and STAT5, downstream elevation of cyclin D2 and repression of DNA damage response mediators, ATM and TP53BP
Authors: Mongini Patricia K A , Gupta Rashmi , Allen Steven L , Barrientos Jacqueline , Kolitz Jonathan E , Rai Kanti , Chiorazzi Nicholas 
Published: January 2023

Abstract
Clonal expansion of B cell chronic lymphocytic leukemia (B-CLL) is linked to mutagenesis and occurs within lymphoid tissues. CpG DNA (ODN-2006) and IL-15, a cytokine found within stromal cells of B-CLL-infiltrated tissues, manifest striking synergy in promoting in vitro growth of B-CLL cells (J Immunol 195:901–923, 2015). Synergy is in part explained by an ODN-induced, NF-kB (p65)-dependent elevation of IL-15Rα and IL-2/15Rβ (CD122) mRNA and protein (J Immunol 201:1570–1585, 2018). Most recently, we examined the downstream consequences of IL-15 signaling through experiments involving intracellular immunofluorescence staining, pharmacologic inhibitors, RT-PCR, and western blotting. Levels of activated pAKTSer473 and pSTAT5Tyr694 were significantly elevated soon after IL-15 exposure to ODN-primed B-CLL cells; furthermore, STAT5 remained activated throughout cycling. Pharmacologic inhibitors of PI-3K or STAT5 blocked IL-15-driven growth, indicating the functional relevance of these pathways. RT-PCR experiments +/− these inhibitors show that IL-15 signaling in B-CLL is characterized by PI-3K & STAT5-dependent rise in cyclin-D2 and repression of two important DNA damage response (DDR) mediators, ATM and TP53BP1, known to dampen growth and facilitate DNA repair. Repression of the latter two proteins was confirmed by western blotting and immunofluorescence studies. We conclude that IL-15 signaling in TLR9-primed B-CLL can provoke a rapid burst in growth via mechanisms resembling those recently described in CD8 T cells. Nonetheless, because dividing B-CLL cells additionally upregulate the mutagenic enzyme, AICDA (Blood 120: 4802–4811, 2012), these simultaneous events may augment B-CLL mutagenesis.