bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anti-inflammatory activity of algal oils containing Docosahexaenoic Acid (DHA) and omega-6 Docosapentaenoic Acid (DPAn-6) (101.5)
Authors: Nauroth Julie Marie , Van Elswyk Mary , Liu Ying , Arterburn Linda 
Published: January 2023

Abstract
Background: Studies have shown anti-inflammatory activity associated with fish oil and ascribed this effect to the long-chain omega-3 fatty acids DHA and especially eicosapentaenoic acid (EPA).
Objective: The purpose of this study was to examine the anti-inflammatory effects of DHA-rich algal oils which contain little or no EPA and determine the contribution of their individual constituent fatty acids, particularly DHA and DPAn-6.
Results: The effects of feeding DHA-rich Martek DHA-T™ algal oil and DHA/DPAn-6-rich Martek DHA-S™ algal oil on rat carrageenan-induced hind paw edema was examined. The S-oil was more effective at reducing edema than the T-oil, suggesting that DPAn-6 has anti-inflammatory properties. We next tested the in vitro effects of the individual pure fatty acids on reducing LPS-stimulated IL-1β and TNF-α secretion by human peripheral blood mononuclear cells. The relative potency was DPAn-6 (most potent) &gt; DHA &gt; EPA. All three fatty acids were effective at reducing by &gt;50% neutrophil fMLP-mediated migration in vitro. Further in vivo analyses demonstrated that feeding pure DHA and EPA ethyl esters (EE) reduced paw edema and the combination of DHA/DPAn6-EE which mimics algal oil was more potent than the combination of DHA/EPA-EE which mimics fish oil.
Conclusions: DHA, DPAn-6, and EPA have anti-inflammatory activity in vitro and in vivo. Algal S-oil containing the combination of DHA and DPAn-6 shows potential for use in anti-inflammatory applications.
Human umbilical cord blood (UCB) derived CD133 cells demonstrate homing capability in vasculogenesis and evoke a proliferative response as well as IL-4 and IL-10 cytokine production in vitro (102.3)
Authors: Fanning Laura R. , Finney Marcie R. , Winter Daniel G. , Greco Nicholas J. , Kozik Margaret M. , Laughlin Mary J. 
Published: January 2023

Abstract
Homing, IL-8 production and immunogenicity are aspects of CD133 cells, a population of stem cells, which may augment postnatal angiogenesis therapy. CD133 cells were isolated from UCB mononuclear cells (MNC) by magnetic bead selection (Miltenyi) and analyzed by flow cytometry. CD133 cells showed co-expression of KDR (3.5%), CD105 (22.7%), CXCR4 (8.7%), HLA-DR (57.6%) and HLA-ABC (66.5%), suggesting CD133 cells are capable of presenting alloantigen. We next performed 3H-thymidine incorporation MLR using adult peripheral blood (AB) MNC stimulated by irradiated UCB CD133 (46939 ± 2764 cpm) and MNC (49548 ± 2018 cpm). MLR studies with CSFE-stained responder cells confirmed equivalent rates of cell division. The observed proliferation was not an artifact of CD133 cell selection. Preliminary comparison studies of cytokine production of IL-4 and IL-10 increased when AB MNC were stimulated by CD133 as compared to UCB MNC (IL-4: 141±45.7pg/mL and IL-10: 964±538pg/mL,). Additionally, UCB CD133 production of IL-8 was elevated as compared to MNC (103±380 pg/mL). Transwell migration to SDF-1 (100ng/mL) demonstrated a 1.8 ± 0.7 fold increase compared to basal media, correlating with CXCR4 expression. In summary, UCB CD133 cells demonstrate homing capability, potential cellular recruitment (IL-8 production) demonstrate TH2 skewing and induce AB MNC proliferation relevant to angiogenesis and cellular therapeutics.
TGFbeta1 is not essential for generation and maintenance of natural Treg cells (128.10)
Authors: Bommireddy Ramireddy , Babcock George F , Singh Ram R , Doetschman Thomas 
Published: January 2023

Abstract
Natural CD4+CD25+FOXP3+ Treg cells serve as powerful regulators of autoimmunity. Hence, there has been a great deal of interest in understanding their regulation. TGFβ1 is considered to be required for peripheral maintenance of Treg cells. However, we demonstrate an increase in the percentage of FOXP3+ Treg cells in the spleens and thymi of Tgfb1−/− mice. Despite this abundance of Treg cells, Tgfb1−/− mice develop a marked expansion of activated T cells in their lymphoid organs, suggesting that activated Tgfb1−/− T cells may not be amenable to suppression any more. However, we demonstrate that Tgfb1−/− T cells do remain responsive to the suppressive effect of TGFβ1 in vitro, suggesting that the absence of TGFβ1 production by Treg cells likely leads to their loss of regulatory function. Finally, we show that whereas Tgfb1−/− mice that express a chicken OVA-specific TCR transgene (DO11.10) have an increase in Treg cells, there are no detectable CD4+CD25+ T cells in the spleens of DO11.10 Rag1−/− mice that have no self-reactive T-cells, regardless of whether they express Tgfb1. This suggests that Treg-cell generation is self-antigen dependent and that TGFβ1 is not required for Treg-cell generation and maintenance. We contemplate that TGFβ1 is likely required for the regulatory function of Treg cells to prevent activation of T cells and autoimmunity.
Therapeutic potential and the mechanism of action of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) in established Experimental Autoimmune Myasthenia Gravis (128.13)
Authors: SHENG JIAN RONG , Prabhakar Bellur S , Meriggioli Matthew N 
Published: January 2023

Abstract
Dendritic cells (DCs) are potent antigen presenting cells responsible for priming naïve T cells in an immune response. Distinct subpopulations of DCs play a central role in immune regulation by preferentially inducing immunity or tolerance. Recently, we observed that the selective activation of particular subsets of DCs utilizing fms-like tyrosine kinase receptor 3 ligand (Flt3-L) and granulocyte-macrophage colony-stimulating factor (GM-CSF) had profound effects on the induction of Experimental Autoimmune Myasthenia Gravis (EAMG). Treatment with GM-CSF effectively suppressed the induction of EAMG, and down-modulated anti-AChR T cell and antibody responses. These effects were associated with the activation of CD8α- DCs, the enhanced production of suppressive cytokines such as IL-4 and IL-10, and the mobilization of CD4+CD25+ and Foxp3+ regulatory T cells (Tregs). Based on these observations, we hypothesized that the selective activation of DC subsets using GM-CSF can skew ongoing anti-AChR immune responses in favor of a Th2 polarization and mobilize antigen-specific CD4+CD25+ and Foxp3+ Tregs capable of suppressing established EAMG. In the present study, we evaluated the therapeutic potential of GM-CSF by examining its effectiveness in the treatment of established disease, and its ability to suppress ongoing autoimmune responses in active EAMG. We are continuing to understand the mechanisms of Treg induction and modes of action in the GM-CSF induced suppression of ongoing EAMG, with regard to antigen specificity and duration of induced tolerance.
A Novel Role for PTEN as a Regulator of T Cell Tolerance (128.27)
Authors: Buckler Jodi L. , Walsh Patrick T. , Turka Laurence A. 
Published: January 2023

Abstract
The lipid phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome ten) is a key negative regulator of the PI3K pathway. Recent studies characterizing T cell specific PTEN deficient mice (PTENΔT) suggest that in addition to its role as a tumor suppressor, PTEN also plays a key role in regulating self-tolerance. Our studies have identified a novel mechanism by which PTEN regulates peripheral T cell tolerance. Initial studies revealed that in the absence of PTEN, TCR signals alone, without CD28 costimulation, are sufficient to activate CD4+ T cells both in vitro and in vivo. Importantly, uncoupling T cells from the requirement for costimulation renders them refractory to anergy/tolerance induction. Ongoing studies in which PTENΔT mice were bred onto a TCR transgenic background suggest that the skewing the repertoire away from self-specificities prevents the development of autoimmune serology, suggesting that TCR signals are necessary for the onset of the autoimmune disease observed in these mice. Together, these data suggest that negative regulation of TCR signals by PTEN imposes a requirement for costimulation and in doing so plays a critical role in the maintenance of T cell tolerance.
Activation-induced split anergy: a mechanism of persistence of autoimmune T cells (128.28)
Authors: Dubey Shweta , Wadhone Pallavi , Wang James , Singh Ram Raj 
Published: January 2023

Abstract
Anergy and apoptosis are major pathways of T cell tolerance. Impairments in these mechanisms are believed to contribute to the development of autoimmune diseases such as SLE and arthritis. Here we analyzed features of T cell anergy, activation and activation-induced cell death in lupus-prone and MHC-matched healthy mice. Unexpectedly, lupus mice exhibit reduced calcium flux, IL-2 production and proliferation in spleen cells upon anti-CD3 stimulation. Such T cell hyporesponsiveness is abrogated upon ionomycin stimulation, suggesting a specific impairment in TCR signaling pathway. This suggests that autoimmune T cells exhibit features of anergy, rather than resistance to it. In contrast, autoimmune T cells produce higher levels of pro-inflammatory cytokine interferon-gamma, and exhibit features of activation, i.e., increased activation markers. Consistently, quantitative gene expression analyses show lower Il2, but higher Ifn-g, mRNA in lupus T cells than in controls. Further, lupus T cells exhibit increased constitutive phosphorylation of ZAP-70 and other T cell signaling molecules, which do not increase upon anti-CD3 stimulation. Finally, lupus T cells resist apoptosis upon specific TCR signaling. Thus, autoimmune T cells display features of activation as well as anergy. Such split anergic T cells display resistance to activation-induced cell death. These data lead us to posit that persistent in vivo T cell activation results in subsequent induction of anergy that manifests as impaired responsiveness to TCR mediated signaling and prevents T cells from undergoing activation-induced cell death. Thus, induction of anergy may actually prevent autoreactive T cells from being eliminated. Ongoing experiments will delineate mechanisms underlying this novel mechanism of autoimmune T cell persistence.
Central Histamine H3 Receptor Signaling Negatively Regulates Autoimmune Inflammation (129.31)
Authors: Teuscher Cory , Subramanian Meena , Noubade Rajkumar , Gao Jian Feng , Offner Halina , Zachary James F. , Blankenhorn Elizabeth P. 
Published: January 2023

Abstract
Histamine is a ubiquitous regulator of diverse physiologic processes including inflammation, immune modulation and neurotransmission. Four subtypes of histamine receptors are currently recognized and genetic and pharmacological studies have shown that the H1 and H2 receptors play a role in susceptibility to experimental allergic encephalomyelitis (EAE), the primary autoimmune model of multiple sclerosis. Histamine H3 receptor (H3R), which is not expressed in hematopoietic cells, is a presynaptic auto- and hetero-receptor. Here we show that H3RKO mice develop significantly more severe acute phase clinical disease and neuropathology compared to wild-type controls. In H3RKO mice this is preceded by disruption of the blood brain barrier and increased chemokine/chemokine receptor expression in peripheral T-cells. These data are consistent with inhibition of H3R-mediated neurogenic control of cerebrovascular tone and T-cell function. Additionally, genetic studies indicate that an H3R polymorphism leading to differential expression of H3R isoforms underlies eae8, a locus controlling disease associated weight loss, a phenotype known to be regulated by central H3R activity.
The role of regulatory T cells in the NZB disease (130.10)
Authors: Scaglione Brian , Salerno Erica , Langer Jerome A. , Pan Manjing , Raveche Elizabeth 
Published: January 2023

Abstract
Regulatory T cells (Tregs) play an important role in protection against autoimmune disease. These CD4+ CD25+ Foxp3+ T cells are also known to be potent inhibitors of antitumor immune responses. The NZB mouse is a murine model for both autoimmune diseases such as SLE, since high levels of autoantibodies are present, as well as a model of human CLL, due to the expansion of malignant B-1 cells. In this study, we examined the role of Tregs in the onset of these disease manifestations. Flow cytometric analysis of spleen, lymph node, and peritoneal cells showed increased levels of CD4+ CD25+ Foxp3+ Tregs in 12 to17-month old NZB mice with a B cell malignancy identified by IgM+ CD5+ B220 dull cells as compared to healthy C57Bl/6 controls. Furthermore, ex vivo treatment of cells from these tissues with IFN-α, which has been known to increase autoimmune symptoms in NZB mice, led to a decrease in the levels of Tregs 48 hours post treatment. These results indicate that while the levels of Tregs found in NZB mice may suppress a more severe autoimmune disease, they might also contribute to the development of the B cell malignancy.
(Funded in part by a grant from the Alliance for Lupus Research to JAL).
The role of B-cell subsets in pristane-induced lupus (130.14)
Authors: Barker Tolga , Lee Pui Y. , Weinstein Jason , Nacionales Dina C. , Kelly-Scumpia Kindra M. , Sobel Eric S. , Reeves Westley H. , Satoh Minoru 
Published: January 2023

Abstract
An intraperitoneal (ip) injection of pristane in mice induces a biphasic immune response characterized by an early T-independent phase (increased total IgM, IgM anti-ssDNA peaking at 2 wks) and a later T-dependent phase (increased total IgG, IgG anti-snRNPs, Su, chromatin after 4–6 wks). Although peritoneal B-1 cells are thought to be responsible for the early phase, they disappear after ip pristane. IgG autoantibodies can be produced in SCID mice by transferring peritoneal, spleen, or lymph node cells from pristane-treated mice. To evaluate further the role of B-cell subsets in the two phases of pristane-induced autoimmunity, GFP+ naïve peritoneal, spleen, or bone marrow (bm) cells were transferred ip to T- and B-cell deficient RAG1−/− mice, followed by an ip pristane 3 days later. Autoantibodies and total Ig (ELISA), and the phenotypes of GFP+ cells in the recipients (flow cytometry) were analyzed. At 3 days prior to pristane ip, GFP+ peritoneal B-1 cells (CD19+CD11b+ CD5+ IgM+) were detected in recipients of bm, peritoneal, or spleen cells. Following pristane ip, peritoneal B-1 cells disappeared, as seen in immunocompetent mice. Analysis of GFP+ cells in peritoneal cavity at day 10 revealed the predominance of CD11b+ macrophages in the peritoneal cell recipients whereas T and B cells were predominant in bm or spleen cell recipients. In mice that received GFP+ spleen cells, IgM anti-ss- and -dsDNA dramatically increased at 2–4 weeks after pristane, while the total IgM levels increased in all groups at later time points. We conclude that splenic B cells may be responsible for the early IgM response in pristane model.
Supported by NIH
Intrinsic B cell defect results in abnormal TD antigen response in lupus-prone mice (130.17)
Authors: Niu Haitao , Morel Laurence 
Published: January 2023

Abstract
The response to TD antigen NP-KLH was compared between the lupus-prone B6.Sle1.Sle2.Sle3 (TC) mice and control B6 mice. The amount of anti-NP IgG Abs in TC mice was significantly decreased as compared to B6 mice. In contrast, total anti-IgG Abs and anti-dsDNA Abs were increased compared to B6 mice, indicating that the decreased was specific for the immunization. This corresponds to the known poor immunization response of lupus patients. In addition, germinal center (GC) NP-specific B cells were decreased in TC mice compared to B6 mice, although there was no difference in the total number of GC B cells between the two strains. Co-transfer of purified CD43- B and CD4+ T cells from either B6 or TC mice showed that a TC intrinsic B cell defect was involved. B6.Rag−/− mice transferred with non-T BM cells from immunized TC mice lost anti-NP antibody production unlike transfer with BM cells from B6 mice. In contrast, there was similar Ab production between the two strains when transferred with non-T splenocytes, indicating that long-lived plasma cells in TC mice accumulated in spleen, instead of migrating to BM. In conclusion, lupus-prone mice show a deficient response to NP-KLH, in which NP-specific B cells differentiate differently from autoantigen-specific B cells. This deficiency is due at least in part to a defect in B cell maturation and plasma cell migration. SLE susceptibility loci involved in these defects will be mapped in future.
Novosphingobium aromaticivorans - causative agent or trigger of Primary Biliary Cirrhosis? (130.29)
Authors: Mattner Jochen , Savage Paul B. , Teyton Luc , Wicker Linda , Ridgway William M , Oertelt Sabine M , Gershwin Eric M , Bendelac Albert 
Published: January 2023

Abstract
Undetected bacterial infections elicit strong immune responses that can masquerade into autoimmune diseases. This has recently been proposed for Primary Biliary Cirrhosis (PBC), a liver disease where individuals have signs of chronic immune responses against Novosphingobium aromaticivorans, an ubiquitous xenobiotic-metabolizing microorganism. Humans with PBC exhibit also NKT cell redistribution to the liver. We have obtained evidence that infection of female B6, SJL and NOD congenic mice with Novosphingobium triggers potent and persistent IgG responses to the mitochondrial antigens of PBC and induce biliary duct lesions and portal inflammation resembling PBC in humans. As our previous work has identified microbial glycosphingolipid (GSL) ligands in the cell wall of these Novosphingobium bacteria that trigger NKT cell activation we propose that the striking differences originate from the nature of the innate signals associated with Sphingomonas infection, which recruits NKT cell help for autoreactive B cells, as opposed to TLR signaling alone in the case of other bacteria, which fails to provide similar helper signals.
Vγ4+ γδ T cells act as TH-17 cells in a mouse model of collagen-induced arthritis (130.39)
Authors: Roark Christina , French Jena D. , Taylor Molly A. , Bendele Alison M. , Born Willi K. , O’Brien Rebecca L. 
Published: January 2023

Abstract
We have examined two γδ T cells subsets, Vγ1 and Vγ4, in collagen-induced arthritis. The Vγ4+ subset increases expression of CD44 and loses expression of CD62L after each collagen/CFA injection, suggesting this subset is activated during the disease process. The Vγ1+ subset increases in overall numbers but the surface markers remain unchanged. We depleted the γδ subsets to examine their roles in the disease process. Disease scores and histology revealed a significant reduction in both the severity and incidence of arthritis in mice depleted of Vγ4+cells. Depletion of the Vγ1+ subset had no significant effect. We also noted a significant decrease in the levels of total IgG and IgG2a anti-collagen antibodies in mice that were depleted of Vγ4+ cells. Next, we used intracellular cytokine staining to identify which cytokines were being made by the Vγ4+ cells during the height of their activation. Surprisingly, over 60% of the Vγ4+ cells produce IL-17. In fact, as a population, the Vγ4+ cells contain as many or more IL-17 producers as do all CD4+ αβ T cells together. Thus, depletion of the Vγ4+ subset may reduce IL-17 levels, leading to less severe disease in this model. Finally, preliminary data indicate that the Th-17 Vγ4+ cells in this disease model are preferentially paired with one delta chain and express very limited junctional sequences.
This work is supported by an Arthritis Investigator award from the Arthritis Foundation.
An autoimmune basis in the disease pathogenesis of COPD/Emphysema (130.41)
Authors: Goswami Sangeeta , Barranco Wade , Lee Seung-Hyo , Grudo Ariel , Corry David B , Kheradmand Farrah 
Published: January 2023

Abstract
Chronic obstructive pulmonary disease (COPD) and emphysema are chronic inflammatory diseases of the lung. Chronic exposure to cigarette smoke is the most common cause of COPD/emphysema however the pathogenesis is not fully understood. Innate immune cells like macrophages and neutrophils are thought to be the most critical factor in the disease pathogenesis. However, we have found that lung and peripheral blood T cells in patients with severe emphysema secrete Th1 cytokines and chemokines when stimulated with elastin peptides in vitro and they have increased anti-elastin antibody as compared to controls. Based on these human studies, we tested the hypothesis that elastin peptides can act as self-antigen and induce an autoimmune lung inflammation in mice. Mice were immunized intra-peritonealy with mouse elastin peptides and adjuvants. Like human COPD, we found increased numbers of activated macrophages and neutrophils as well as increased MMP9 and MMP12 in the airway fluid of elastin immunized mice. Hilar lymph node cells of elastin immunized mice produced more IFN-g upon restimulation with elastin peptides. Additionally, elastin immunized mice had increased anti-elastin antibody titer in the serum and increased IFN-g in the lungs. The establishment of the mouse model of elastin-mediated autoimmune lung inflammation will be critical in elucidating the role of adaptive immune system in pathogenesis of COPD/emphysema.
Cardiac Troponin I Induces Severe Autoimmune Inflammation in the Myocardium (130.43)
Authors: Kaya Ziya , Göser Stefan , Andrassy Martin , Buss Sebastian J. , Leuschner Florian , Volz Christian H. , Öttl Renate , Zittrich Stefan , Blaudeck Natascha , Hardt Stefan E. , Pfitzer Gabriele , Rose Noel R. , Katus Hugo A. 
Published: January 2023

Abstract
Cardiac troponins are the most preferred markers of myocardial damage. The fact that they are normally not found in the circulation provides a high level of clinical sensitivity and specificity even when cardiac lesions are small. However, little is known about the long-term effects of the released troponins on cardiac function.
In this study we prepared recombinant murine cardiac troponin I (mc-TnI) and murine cardiac troponin T and used them to immunize mice. We report that A/J mice immunized with mc-TnI developed severe inflammation of the myocardium with increased expression of inflammatory chemokines RANTES, MCP-1, MIP–1, MIP-1ß, MIP-2, TCA-3, and eotaxin and chemokine receptors CCR1, CCR2, and CCR5. The inflammation was followed by cardiomegaly, fibrosis, reduced fractional shortening, and 30% mortality over 270 days. In contrast, mice immunized with murine cardiac troponin T or with the control buffer showed little or no inflammation and no death. Furthermore, we demonstrate that mice preimmunized with mc-TnI before left anterior descending coronary artery ligation showed greater infarct size, more fibrosis, higher inflammation score, and reduced fractional shortening. Overall, our results show for the first time that provocation of an autoimmune response to mc-TnI induces severe inflammation in the myocardium followed by fibrosis and heart failure with increased mortality in mice.