bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct patterns of dendritic cell cytokine release stimulated by beta-glucans and Toll-Like receptor agonists (98.33)
Authors: Huang Haibin , Ostroff Gary R. , Levitz Stuart M. 
Published: January 2023

Abstract
β-glucans (βGs) derived from fungal cell walls have potential uses as immunomodulating agents and vaccine adjuvants. Yeast glucan particles (YGPs) are purified Saccharomyces cerevisiae cell walls treated so they are &gt;80% β1,3-D-glucan and free of mannan and proteins. YGPs stimulated secretion of the proinflammatory cytokine TNF-α in wild type murine bone marrow-derived myeloid DCs (BMDCs), but did not stimulate IL-12p70 production. A purified soluble βG, scleroglucan, also stimulated TNF-α in BMDCs. These two βGs failed to stimulate TNF-α in dectin-1 (βG-receptor) knockout BMDCs. Co-stimulation of wild-type BMDCs with βGs and specific TLR ligands resulted in greatly enhanced TNF-α production but decreased IL-12p70 production compared with TLR ligands alone. The up-regulation of TNF-α and down-regulation IL-12p70 required dectin-1, but not IL-10. Similar patterns of cytokine regulation were observed in human monocyte-derived DCs (hDCs) co-stimulated with YGPs and, the TLR4 ligand, LPS. Finally, co-stimulation of BMDCs with the TLR9 ligand, CpG, and YGPs resulted in upregulated secretion of IL-1α and IL-10, downregulated IL-1β, IL-6 and IP-10, and had no significant effects on IL-12p40, KC, MCP-1 or MIP-α, compared with CpG alone. Thus, βGs have disparate effects on cytokine responses following DC stimulation with TLR ligands.
CCR7/CCL19 Mediates T Lymphocyte Expression of EDG-1 (98.8)
Authors: Shannon Laurie A , Byers Melissa A , Fassold Brian C , Roth Megan , Calloway Psachal , Zhang Elizabeth Y , Vines Charlotte M 
Published: January 2023

Abstract
C-C Chemokine Receptor 7 (CCR7) regulates migration of naïve T cells to lymph nodes, via chemotaxis to the ligand, CCL21. Approximately 72 hours after lymph node entry, Endothelial Differentiation Gene 1 (EDG-1) is up-regulated on T cells and mediates lymph node egress. It is unclear how EDG-1 expression is up-regulated. We hypothesized that lymph node egress occurs in response to CCR7 receptor interaction with dendritic cells presenting the second CCR7 ligand, CCL19. To test this hypothesis, we used murine or human T cells, stimulated with CCL19 and found that EDG-1 mRNA was up-regulated at 24, 48, and 72 hours. The cells displayed increased migration to EDG-1 ligand S1P over the same time period confirming surface expression of EDG-1. Extracellular Regulated Kinase 5 (ERK5) can mediate transcription of Kruppel-Like Factor 2 (KLF-2). KLF-2 directly mediates transcription of EDG-1. To determine if the hypothesized ERK5-KLF-2-EDG-1 pathway was active in our system, we assayed murine and human T cells for changes in ERK5 and KLF-2. We found that stimulation with CCL19 led to increased phosphorylation and expression of ERK5 at 24, 48, and 72 hours. Similarly, KLF-2 levels were increased over the same interval. Taken together, our data suggests that after lymph node entry of T cells via CCR7/CCL21, T cells exit the lymph nodes via EDG-1 in response to activation of T cell CCR7 by CCL19 on activated dendritic cells.
Dissecting the antimicrobial activity of CCL28 through protein mutagenesis (98.9)
Authors: Liu Bin , Wilson Eric 
Published: January 2023

Abstract
Some chemokines have been shown act as antimicrobial proteins in vitro, suggesting that they may contribute directly to innate immune protection. Based on the study of defensins and other antimicrobial peptides (AMPs), it has been proposed that the characteristics of cationicity, hydrophobicity and amphipathicity of the AMPs determine the killing activity of these peptides. However, amino acid characteristics necessary for the antimicrobial activity of chemokines have not been elucidated. Using mouse CCL28 we have determined the primary sequence features required for antimicrobial activity of this chemokine. Our data demonstrate, through the use of successive truncations, that the holoprotein (108 amino acids) is necessary for full antimicrobial activity of CCL28. Consecutive truncations resulted in an almost complete loss of activity following the removal of the 24 C terminal amino acids. Charge reversal as well as positive charge to neutral charge mutations, support the hypothesis that positively charged amino acids are essential for the antimicrobial activity of CCL28. Finally, the antimicrobial activity of chimeric proteins in which the N-terminus of CCL5 or CCL27 was fused with the C terminus of CCL28 suggest that although the C terminal region of CCL28 is essential for antimicrobial activity, the interaction of the N and C terminal regions of CCL28 is necessary for optimal antimicrobial activity. These experiments are the first to investigate the role of primary structure in the killing activity of an antimicrobial chemokine.
PDCD4-deficient NOD mice are resistant to type 1 diabetes (99.12)
Authors: Ruan Qingguo , Kameswaran Vasumathi , Chen Youhai H 
Published: January 2023

Abstract
Development of autoimmune diseases is associated with heightened protein translation. However, the mechanism of translational regulation and the roles of translation factors in the pathogenesis of autoimmune diseases are not clear. Programmed cell death 4 (PDCD4) is a translation factor that inhibits cap-dependent translation by binding to eIF4A. It is also a newly identified target of micro-RNA 21 that regulates immune responses. To determine the roles of PDCD4 in type 1 diabetes (T1D), we generated PDCD4-deficient NOD mice. We report here that PDCD4-deficient NOD mice are resistant to T1D, and PDCD4-deficient lymphocytes and macrophages produce increased levels of both anti-inflammatory (such as IL-4 and IL-10) and pro-inflammatory cytokines (such as IL-17, IFN-gamma and TNF-alpha). Additionally, PDCD4-deficient NOD mice are also resistant to high dose streptozotocin-induced diabetes, and over-expression of PDCD4 in islet beta cells induces apoptosis and cell cycle arrest, which appear to be related to reduced AP-1 activation. Thus, PDCD4 may regulate the development of autoimmune diabetes by targeting both inflammatory cells and pancreatic beta cells.
A key role for Fas ligand expressed on B cells in initiation of autoimmune diabetes (99.17)
Authors: xiao zuoxiang , Li Meng , Schneck Jonathan P. , Hamad Abdel Rahim A. 
Published: January 2023

Abstract
Type-1 diabetes (T1D) is an organ specific autoimmune disease that affects children. T, B and dendritic cells infiltrate islets in the early stage of disease leading to insulitis followed by islet destruction and hyperglycemia. Development of T1D in non-obese diabetic (NOD) mice is completely inhibited by gld or lpr mutations of Fas and FasL, respectively, even though mutant mice develop T cell lymphoproliferation and the Fas pathway is not essential for T cell activation. Recently, we have shown heterozygous gld mutation (gld/+) provides complete protection without causing lymphoproliferation. Using NOD-gld/+ mouse as a model, we found that the protection is not due to deletion of autoreactive T cells or switching of T helper polarization. Islet-reactive BDC2.5 TCR transgenic CD4 T cells transferred into NOD-gld/+ mice were efficiently primed in the pancreatic lymph nodes but failed to accumulate in the pancreas. FasL deficiency selectively reduced expression of CD40 and frequency of B cells in the pancreas. Transfer of wild type B cells into NOD-gld/+ mice results in mobilization of endogenous T cells particularly CD8 T cells and of co-transferred BDC2.5 T cells resulting in severe insulitis. These results provide the first evidence that B cells play an essential role in gld-mediated protection from T1D and that expression of functional FasL on B cells is key for initiation insulitis.
Supported by grants from AHA and JDRF.
Allogeneic neonatal blood transfusion ameliorates autoimmune diabetes in unconditioned non-obese diabetic mice by functionally deleting pathogenic T cells (99.19)
Authors: Jayaraman Sundararajan , Ajani Shahnaz , Garza Rebecca , Jayaraman Arathi , Kwon Steve , Prabhakar Bellur , Holterman Mark 
Published: January 2023

Abstract
We show that transfusion of unconditioned, pre-diabetic non-obese diabetic mice with newborn blood containing multiple Sca-1+ stem/progenitor subsets derived from allogeneic diabetes-resistant mice can prevent diabetes. Diabetes protection was characterized by enhanced glucose-induced insulin release and diminished cellular infiltration of islets. Allogeneic neonatal blood transfusion induced only transient hematopoietic microchimerism, which did not correlate with the level of protection obtained. Splenocytes derived from cured mice failed to transfer diabetes into immunodeficient NODscid mice, indicating deletion/inactivation of diabetogenic T cells by transfused neonatal blood cells. Diabetes cure did not result in alloantigen-specific T cell unresponsiveness as assessed by T cell proliferation. Paradoxically, T cell anergy to allogeneic antigens was displayed by a majority of diabetic but not cured mice that received newborn blood cells. These results indicate that deletion/inactivation of diabetogenic T lymphocytes is instrumental in preventing the progression of insulitis to overt diabetes by allogeneic newborn blood cell transplantation.
Double-stranded RNA protects against antigen-induced arthritis via the type I interferon receptor (99.23)
Authors: Magnusson Mattias 
Published: January 2023

Abstract
Viral infections may contribute to different forms of arthritis. Both viral components, e.g. dsRNA and host-derived anti-viral agents, e.g. type I interferons (IFN), can induce arthritis if present in a joint. This joint inflammation is transient and mediated by antigen-independent (innate) immunity. In order to study the impact viral components may have on the development of antigen-dependent arthritis, dsRNA was administered systemically during the activation of antigen-induced arthritis.
The methylated bovine serum (mBSA)-induced arthritis model used consists of two s.c. immunizations with mBSA in Freund's incomplete adjuvant one week apart, followed by intraarticular injection of mBSA alone three weeks after the first immunization. The importance of IFN-signalling in the onset of mBSA-induced arthritis was studied (1) by using mice deficient for the IFN receptor (IFNAR ko, strain 129) and (2) by including the IFN-activator viral dsRNA in the immunizations.
Administration of dsRNA during the immunizations with mBSA inhibited arthritis development and severity in wt, but not in IFNAR ko mice (p&lt;0.05). This protection was accompanied by lower levels of anti-mBSA-specific IgG in serum (p&lt;0.05). This anti-inflammatory effect of IFN-signalling contrasts the potent arthritogenic properties dsRNA and IFN have if present in the joint and underscores the opposing effects IFN signalling may have locally/systemically and on innate/adaptive immunity.
Grant resources for this work includes The King Gustav V 80-years foundation and the Swedish Physicians Society
Smoking and nicotine exposure delays development of arthritis in animal model (99.24)
Authors: Lindblad Sofia Silfverswärd , Mydel Piotr , Jonsson Ing-Marie , Senior Robert M , Tarkowski Andrej , Bokarewa Maria 
Published: January 2023

Abstract
Recent results of epidemiological studies indicate smoking as an environmental risk factor for development of rheumatoid arthritis (RA). The aim of this study was to evaluate the role of smoking and nicotine in the pathogenesis of arthritis using an animal model.
DBA/1 mice were exposed to cigarette smoke for 16 weeks prior to immunization with collagen type II (CII) and through the whole course of experiment. In a separate experiment DBA/1 mice were subjected to nicotine in drinking water from the day of immunization with CII until the end of experiment. Severity of arthritis was evaluated clinically and morphologically and compared to control mice. Levels of specific anti-CII antibodies as well as of autoantibodies (aCCP and RF) and cytokines were evaluated.
Clinical evaluation of arthritis showed a delayed onset of arthritis in smoking mice as compared to non-smoking (p&lt;0.05). Histological index and weight changes were comparable between both groups, however smoking mice were gaining weight faster than non-smoking (p&lt;0.05). Additionally, smoking mice had decreased ability to produce antibodies (aCCP and anti-CII) as compared to non-smoking (p&lt;0.05). Similar results were obtained in the mice exposed to nicotine. Nicotine had a direct anti-inflammatory effect diminishing cytokine production by stimulated spleenocytes in vitro.
Neither smoking nor nicotine exposure aggravates development of CII-induced arthritis in mouse model.
A new mode of TNF-[alpha] inhibition by microRNA (99.26)
Authors: Frenzel Laurent , Semaan Noha , Alsaleh Ghada , Wachsmann Dominique , Gottenberg Jacques-Eric , Sibilia Jean 
Published: January 2023

Abstract
TNF-α, is a major cytokine implicated in rheumatoid arthritis (RA). TNF-α expression is regulated both at the transcriptional and the postranscriptional levels and recent data demonstrated that miRNAs are implicated in TNF-α response in macrophages. LPS-activated synoviocytes fibroblast-like (FLS) isolated from RA patients express TNF-α mRNA but they do not release TNF-α. This inhibition is due to a rapid degradation of TNF-α mRNA. We demonstrated previously that miR-346, which is overexpressed in LPS-activated FLS inhibits Bruton's tyrosine kinase (Btk) expression, which controls TNF-α stability. In fact, transfection of antisense oligonucleotides targeting miR-346 reestablished Btk and TNF-α expression in activated FLS. We also showed that transfection of miR-346 in THP-1 cells, inhibited TNF-α secretion in response to LPS. Tristetraprolin (TTP) is a protein which inhibited TNF-α synthesis by binding to AU rich elements of TNF-α mRNA. We demonstrated in LPS-activated RA FLS, that inhibition of miR-346 decreases TTP expression. In parallel we also showed that inhibition of Btk by LFMA13 or miR-346, increases the expression of TTP in LPS-activated THP-1 cells which results in inhibition of TNF-α synthesis. These results indicate that Btk controls TNF-α synthesis by regulating TTP expression. In conclusion, our findings provide evidence that miR-346 can act as a negative regulator of inflammation.
Select T Cell Receptor Utilization by CD4+ T Cells in a Murine Model of Systemic Lupus Erythematosus is Similar to Human Disease (99.31)
Authors: Trivedi Sapna , Culpepper Schartess , Zang Yun , Martinez Laisel , Greidinger Eric L , Hoffman Robert W 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease associated with significant morbidity and mortality. We have identified and characterized U1-70kDa small nuclear ribonucleoprotein (70kDa) autoantigen specific T cells in a murine model of autoimmunity when a subset of mice developed kidney disease similar to lupus nephritis. Mice developed proteinuria and histology showed CD4+ T cells associated with glomerular lesions. CD4+ T cells were freshly isolated from kidney and spleen and cultured with autoantigen to generate short-term T cell lines. Following RNA extraction from cell lines and cDNA preparation, a PCR reaction was performed using primers for the TRBV subgroups. The product was purified and underwent cloning and sequencing. T cell epitope mapping revealed that the majority of T cells were directed against antigenic peptides residing within the RNA binding domain of 70KDa. We also found that TCR beta (TRB) V usage was highly restricted among 70kDa reactive T cells which selectively utilized TCR BV subgroups 1 and 8.3 in the kidney and 1,2, 6, 8.1, 8.2, and 8.3 in the spleen and the lung. The TRB third complementary-determining regions (CDR3) had conserved sequence motifs which were shared across different TRBV subgroups. When compared for homology, the TRBV and CDR3 regions used by both murine and human 70kDa-specific CD4+ T cells were highly similar including those CD4+ T cells found at two sites of inflammation; the kidney and lung.
The NIH and Dept Veterans Affairs provided support for this work.
IL-21 Receptor signaling by B-cells is essential for BXSB-Yaa pathogenesis (99.39)
Authors: Bubier Jason A , Sproule Thomas J , Foreman Oded , Spolski Rosanne , Morse Herbert C , Leonard Warren J , Roopenian Derry C 
Published: January 2023

Abstract
IL-21 is a member of the IL-2 cytokine family that exerts potent biological effects on multiple hemopoietic cell types. It is produced by activated CD4 T cells, while its receptor, IL-21R, is found on cells including NK cells, dendritic, T cells and B cells. To investigate the role of IL-21 signaling in autoimmune disease, we addressed whether this cytokine contributes to the severe systemic lupus erythematosus (SLE)-like syndrome developed by BXSB-Yaa mice. We show that BXSB-Yaa CD4 T cells produce IL-21 but lack discriminative T follicular helper cell markers. We also show that BXSB-Yaa mice completely lacking the IL-21R or Igh6 are remarkably resistant to multiple aspects of the prototypic BXSB-Yaa autoimmune disease. Finally, we show that mixed bone marrow chimeric BXSB-Yaa mice lacking IL-21R specifically in the B-cell compartment are similarly resistant. These results suggest that IL-21 produced by a novel population of BXSB-Yaa CD4 T-cells acts through B-cells to evoke multiple features characteristic of severe SLE. The results indicate that IL-21 signaling through B-cells is an essential step in the pathogenesis of this SLE-like autoimmune disease and potentially others. Funded by an Arthritis Foundation grant to JB.
Bruton’s tyrosine kinase and microRNA miR-346 regulate IL-18 release by LPS-activated rheumatoid fibroblast-like synoviocytes (99.52)
Authors: Wachsmann dominique , Alsaleh Ghada , Semaan Noha , Suffert Guillaume , Pfeffer Sebastien , Frenzel Laurent , Gottenberg Jacques-Eric , Sibilia Jean 
Published: January 2023

Abstract
We reported previously that LPS-activated synoviocytes fibroblast-like (FLS) isolated from rheumatoid arthritis (RA) patients express IL-18 mRNA but they do not release IL-18. As this inhibition was due to a rapid degradation of IL-18 mRNA, our group has carried out a study to identify miRNAs that could play a role in this "anti-inflammatory" response. As assessed by microarray analysis, 15 miRNAs were overexpressed more than two fold in LPS-activated FLS and among them, we identified one miRNA, miR-346 that had partial sequence complementarity within the 3'-UTR region of the IL-18 mRNA. We then used antisense oligonucleotides molecules to block miR-346 activity; transfection of the inhibitor targeting miR-346 reestablished IL-18 release by LPS-activated FLS. Moreover we also showed that transient transfection of miR-346 in THP-1 cells, inhibited IL-18 secretion by these cells in response to LPS. Using a luciferase assay we showed that miR-346 does not target directly IL-18 mRNA. In search for another target that could explain the effect of miR-346 on IL-18, we also demonstrated that miR-346 inhibited Btk expression at the transcriptional level in LPS-activated RA FLS and that inhibition of Btk expression regulated negatively IL-18 release. These results suggest an important role of miR-346 in the control of IL-18 synthesis and indicate that its expression may be critical to prevent an excessive inflammatory response.
Neuropilin-1 is important for proper suppression of inflammation and autoreactivity (99.6)
Authors: Bynoe Margaret S , Solomon Benjamin D , Chae Wookjin 
Published: January 2023

Abstract
Neuropilin-1(Nrp1) is a surface molecule originally identified for its role in neuronal development. Recently, Nrp1 has been implicated in several aspects of immune function including maintenance of the immune synapse and development of regulatory T cells (Treg). In this study we provide the first evidence for a role of Nrp1 in the pathogenesis of an immune mediated disease, experimental autoimmune encephalomyelitis (EAE), which is an animal model for the central nervous system inflammatory disorder multiple sclerosis (MS). Using a cell type specific deletion system, we observed that the lack of Nrp1 on CD4+ T cells results in increased EAE disease severity. These conditional knockout mice exhibit preferential Th17 lineage commitment and decreased Treg numbers and functionality. Conversely, mice receiving CD4 T cells that were retrovirally transduced with Nrp1 and immunized for EAE developed only mild EAE compared to controls. This suggests that Nrp1 is essential for proper maintenance of peripheral tolerance and its absence can result in unchecked autoreactive responses leading to diseases like EAE and MS. This work was supported by National Institutes of Health Grants AI 57854 and AI 072434 (to MSB).
The IFN-γ / IFN-γ Rα axis is involved in immunoediting of breast cancer that leads to the de novo generation of a novel breast cancer stem cell (BCSC)-like tumor variant and subsequent tumor recurrence (100.12)
Authors: Kmieciak Maciej , Knutson Keith , Manjili Masoud 
Published: January 2023

Abstract
Tumor dormancy remains a major hurdle in the treatment of cancers. Recently, the association between cancer stem cells (CSC) and tumor dormancy has been speculated in variety of cancers. Despite conventional therapies of breast cancer, most of the US deaths are attributed to relapse which is likely due to a failure of current treatment regimens to eliminate breast cancer stem cells (BCSC). We reported IFN-γ-induced HER-2/neu antigen loss and tumor relapse. We performed in vitro and in vivo studies using neu positive mammary carcinoma (MMC) tumors and their dominant negative (dn) IFN-γ Rα MMC sub-line. We showed that IFN-γ producing CD8+ T cells induced the de novo generation of a distinct BCSC variant that differed from conventional BCSC. The novel phenotype: i) is not intrinsically quiescent, ii) is reversible by blocking IFN-γ Rα signaling in the tumor, iii) upregulates serine protease inhibitors (SPI-6/PI-9) and MUC-1 that could render the tumors refractory to granzyme/perforin- and antibody-induced apoptosis, respectively, and iv) downregulates HER-2/neu expression upon emerging under the immune pressure. While HER-2/neu+ conventional BCSC have been shown to be sensitive to HER-2/neu-targeted immunotherapy, these novel BCSC-like phenotypes are refractory to such immunotherapy because of HER-2/neu loss. Identification of such tumor immunoediting pathways and mechanisms is expected to improve immunotherapy of breast cancer, by pathway blocking strategies.