bluuebunny/crossref_metadata_2025_split huggingface dataset:
Macrophages show distinct profiles and origins between the exocrine and endocrine pancreas (HEM3P.279)
Authors: Calderon Boris , Epelman Slava , Carrero Javier , Unanue Emil 
Published: January 2023

Abstract
Islets of Langerhans contain myeloid-derived cells with important features and properties. Our studies have shown islet myeloid cells to play a central role in retaining diabetogenic T cells during early stages of autoimmune diabetes and the initiation of the inflammatory process. We have studied in-depth the phenotype of the islet myeloid cells in the NOD and non-diabetic mouse strains. The major phagocyte in non-inflamed islet is a macrophage (MΦ) identified by cell markers as well as by gene expression analysis. Under steady state, islet MΦ did not arise from circulating monocytes: parabiosis of CD45.1 with CD45.2 mice showed minimal mixing of islet MΦ. Ccr2-/- mice showed no impairment in the number of islet MΦ. In sum, islet MΦ are self-maintained. Ongoing experiments indicate a slow replication rate. Lineage tracing using a Flt3-cre reporter mouse showed MΦ in the exocrine pancreas and in the islets of the adult mouse to derived from different lineages. Majority of the exocrine pancreatic MΦ were yolk sac/fetal liver-derived, while islet MΦ were bone-marrow derived. Islet MΦ required the expression of CSF-1, while exocrine pancreatic MΦ did not. Absence of islet MΦ in CSF-1 deficient mice resulted in reduced β-cell mass and impaired glucose tolerance, highlighting a symbiosis role between islet MΦ and β-cells for islet homeostasis. Current studies are aimed to replace the islet MΦ, since MΦ are involved in many diseases and represents an attractive therapeutic target.
The role of plasma gelsolin in cardiopulmonary bypass induced acute lung injury in infants and young children: a pilot study (HUM1P.310)
Authors: Shu Qiang , Shi Shanshan , Chen Chi , Zhao Dongyan , Liu Xiwang , Cheng Baoli , Wu Shuijing , Lin Ru , Tan Linhua , Fang XiangMing 
Published: January 2023

Abstract
Background Acute lung injury induced by CPB (CPB-ALI) is a common and serious complication. Infants and children are more prone to CPB-ALI. The purpose of this study was to investigate the perioperative changes of plasma gelsolin (pGSN) in patients ≤3 years of age undergoing cardiac surgery with CPB, and determine whether pGSN are associated with the occurrence and severity of CPB-ALI. Methods 77 patients ≤ 3 years of age with CHD were enrolled and assigned to ALI and non-ALI groups according to the American-European Consensus Criteria. Plasma gelsolin and total protein were measured at 8 perioperative time points. Results 27 patients developed CPB-ALI. The normalized pGSN (pGSNN) of ALI group decreased significantly at 6 hours after CPB (p=0.046), which was much earlier than that of non-ALI group (p=0.009); The pGSNN of ALI group before CPB (p=0.001), 6 hours after CPB (p=0.001) and 48 hours after CPB (p=0.032) were all significantly lower than those of non-ALI group; PGSNN before CPB was the only independent risk factor predicting the occurrence of CPB-ALI (OR, 1.069; 95%CI, 1.001-1.035; p=0.033) with an AUC of 0.753 (95%CI, 0.626-0.880); The optimal cutoff value of pGSNN before CPB was 2641.8. Conclusions Patients developing CPB-ALI had lower plasma gelsolin reservoir and a much more amount and rapid consumption of plasma gelsolin early after operation; PGSNN before CPB was a useful early and sensitive predictor of CPB-ALI in infants and young children.
A pathogenic role for SHP-1 activity in macrophages (HUM1P.321)
Authors: Watson Neva , Massa Paul 
Published: January 2023

Abstract
Microbial infections elicit inflammatory responses that eradicate infection and remove damaged cells. Regulation of these events is critical as excessive inflammation may cause substantial bystander tissue destruction in the process of pathogen clearance while a deficient response may be insufficient to clear infections and damaged cells. Defective clearance of dying cells can trigger devastating chronic inflammatory diseases, and we report an unanticipated role for SHP-1 in facilitating this process. SHP-1 restricts innate immunity to pathogens, and therefore mice lacking SHP-1 suffer macrophage-mediated destruction of myelin in the CNS following infection with Theiler’s murine encephalomyelitis virus (TMEV). To the contrary, we have discovered that although resistant to CNS disease, TMEV-infected wild type animals develop a severe debilitating skeletal muscle disease not seen in SHP-1-/- mice. We show that SHP-1-mediated restriction of macrophage responses in WT mice corresponds with insufficient clearance of damaged tissue and increased muscle dysfunction. As SHP-1 controls macrophage phagocytic activity, our data suggests that increased macrophage activity in SHP-1-/- mice restricts muscle disease through rapid clearance of infected and damaged myofibers. These findings demonstrate a unique role of SHP-1 in exacerbating rather than resolving disease pathology by inhibiting clearance of cellular debris. These data suggest novel therapies for chronic inflammatory diseases.
Genomic polymorphism of CD209 gene is associated with sickle cell disease in African children (HUM2P.328)
Authors: Thomas Bolaji , Navarro Kristen , Guindo Aldiouma , Li Yi , Diallo Dapa 
Published: January 2023

Abstract
Sickle cell disease (SCD) presents with multiple complications and marked variability in severity among individuals and possible underlying differences in ethnic-specific disease pathogenesis. The CD209 gene otherwise called DC-SIGN encodes a transmembrane receptor and is expressed on the surface of dendritic cells with multiple studies showing association between its variants and susceptibility to infections. In SCD, vaso-occlusive crises and infections are common occurrences, and the role of CD209 is currently unknown. We examined the genotypic and allelic diversity of CD209 gene and determined its association with SCD in African children. Genomic DNA from 145 children (HbSS) and 244 controls (HbAA) were analyzed for polymorphic variants of CD209 by PCR-RFLP. All SNPs follow Hardy-Weinberg equilibrium (P&gt;0.05). There was a significant difference in both genotypic and allelic frequencies (P=0.004 and P=0.015 respectively) of a promoter variant in CD209, DC-SIGN1-336 between SCD and controls. Additionally, genotype GG variant is less frequent (10.3% versus 22.1%) and significantly associated with sickle cell disease (OR=0.3868; P=0.0010) and this reduced frequency reveals an impaired or reduced capacity to mount an immune response to infectious pathogens. The implications of this finding for delineating disease co-morbidity or as genetic modifiers of SCD pathophysiology, and its significance in African American children with SCD will be explored
A “reduced function” PTPN22 variant modulates the Toll-like receptor-driven type 1 interferon response in systemic lupus erythematosus (HUM2P.329)
Authors: Wang Yaya , Yamamoto Ami , Gillespie Emily , Fazeli Parastoo , Peterson Erik 
Published: January 2023

Abstract
Most systemic lupus erythematosus (SLE patients) exhibit whole-blood increased expression of type I interferon (IFN)-inducible transcripts, known as the "IFN signature". A variant allele of the PTPN22 gene is associated with increased risk of SLE. We recently demonstrated that PTPN22-encoded lymphoid tyrosine phosphatase (Lyp) promotes Toll-like receptor (TLR)-driven type 1 IFN production and type I IFN-dependent host defense and immunoregulation. Further, the disease-associated variant LypR620W (“LypW”) shows reduced function in promoting TLR-driven type 1 IFN-dependent immunity. Here we report that PBMC from LypW carrier SLE patients exhibit reduced type 1 IFN and type 1 IFN-inducible gene expression upon TLR7 activation. The percentages of plasmacytoid dendritic cells (pDC) producing IFNα, as well as the per-cell production of IFNα, are decreased LypW carrier SLE patients. Notably, we found that similar numbers of LypW carriers and non-carriers in SLE patients exhibit elevated IFN gene signatures in whole blood. Together, these data indicate that LypW SLE patient display reduced mononuclear cell capacity for TLR-induced type 1 IFN, despite exhibiting increased systemic type 1 IFN signaling. The findings raise the possibility that autoimmune phenomena in LypW SLE patients may reflect defective type 1 IFN-dependent host defense. Further, they suggest that therapeutic strategies to boost type 1 IFN-driven processes may benefit the LypW carrier subgroup of SLE patients.
Circulating CD4+ T cells in narcolepsy patients react to hypocretin and cross-react with hemagglutinin from an influenza strain linked to increased narcolepsy incidence (HUM2P.336)
Authors: Mellins Elizabeth , Macaubas Claudia , Jiang Wei , De la Herrán-Arita Alberto , Kornum Birgitte , Mahlios Joshua , Hou Tieying , Mignot Emmanuel 
Published: January 2023

Abstract
Narcolepsy, a disorder characterized by daytime sleepiness, cataplexy, and REM sleep abnormalities, is caused by the loss of ~70,000 hypothalamic neurons that produce the wake-promoting neuropeptide hypocretin (HCRT). The strong association of narcolepsy with HLA DQA1*01:02/DQB1*06:02 (DQ0602) has led to the hypothesis that narcolepsy is an autoimmune disease, but direct evidence has been lacking. We recently reported discovery of circulating CD4+ T cells reactive to two homologous DQ0602-binding HCRT epitopes (HCRT56-68, HCRT87-99) in narcolepsy patients, but not in DQ0602+ healthy control subjects. Based on epidemiologic evidence linking narcolepsy with the 2009 H1N1 influenza A strain (pH1N1) we measured levels of circulating HCRT56-68, HCRT87-99 reactive T cells in narcolepsy patients who had received the seasonal influenza vaccine (containing pH1N1) and found them to be increased. We identified a pH1N1-specific hemagglutinin epitope with homology to the narcolepsy-associated HCRT epitopes; in vitro stimulation of narcolepsy CD4+T cells with this epitope increased the frequency of HCR-reactive T cells. To directly test for molecular mimicry between the HCRT and pH1N1 epitopes, we have used tetramer staining and single cell TCR sequencing. We conclude that narcolepsy is associated with an autoimmune response to HCRT, which can be triggered by cross-reactive T cell responses to pathogen-derived peptides.
Fluvastatin-mediated suppression of IgE-induced cytokine production can be enhanced by TGFβ1 (HYP3P.403)
Authors: Haque Tamara , Abdul-Qayum Amina , Ryan John 
Published: January 2023

Abstract
Fluvastatin, an HMG-CoA reductase inhibitor known for its role in the treatment of hypercholesterolemia and cardiovascular disease, has recently been shown to play a role in the immune response. Given the critical role that mast cells play in allergy and inflammatory diseases such as asthma, we assessed the effect of Fluvastatin on mast cell function. We also examined the impact of TGFβ1, a cytokine we have previously shown capable of limiting mast cell function, in combination with Fluvastatin. We find that Fluvastatin suppresses IgE-mediated cytokine production in mouse mast cells. Prior exposure to TGFβ1 enhanced the effects of Fluvastatin, such that the IC50 for Fluvastatin-mediated suppression was 3-4-fold lower in the presence of TGFβ1 than in its absence. Interestingly, this effect was found for IgE-induced production of IL-6 and TNF, while TGFβ1 did not alter the suppressive effects of Fluvastatin on IL-13 or MCP-1. Current experiments seek to unravel the mechanism behind this selective effect of TGFβ1.
SPE-7 but not Epsilon-26 anti-dinitrophenyl-Immunoglobulin E induces antigen-dependent thermal hyperalgesia accompanying equivalent inflammatory responses during passive cutaneous anaphylaxis reactions in mice (HYP3P.405)
Authors: Chatterjea Devavani , Ashbaugh Alyssa , Tonc Elena , Mack Madison , Martinov Tijana , Sykes Akilah 
Published: January 2023

Abstract
Sensitization of mast cells with SPE-7 anti-DNP-IgE alone initiates inflammatory cytokine production in vitro. In contrast, ε26 anti-DNP IgE does not induce inflammatory cytokines independent of antigen-stimulation. We tested these two anti-DNP IgE clones in our model of murine thermal hyperalgesia. We found pronounced hind paw hyperalgesic responses lasting to at least 6 hours following antigen challenge 24 hours after sensitization with SPE-7 but not ε26. SPE-7/DNP did not induce greater levels of mast cell degranulation in the hind paw. Differential hyperalgesic responses were accompanied by otherwise equivalent inflammatory changes measured including histamine release, neutrophil influx, expression of TNF-α, IL-1β, and IL-6 genes and changes in levels of TNF-α, IL-1, and IL-6 proteins. Inflammatory responses and hyperalgesia were dependent on antigen challenge and were not detected in sham-challenged mice. Hyperalgesia responses or other inflammatory changes were not detected in the hind paw tissue post-sensitization in the 24 hours prior to antigen challenge. We demonstrate a novel behavioral, antigen-dependent difference between reactions mediated by these IgE antibody clones in vivo in mice. We are currently further investigating the inflammatory cytokine milieu and measuring changes in mRNA and protein levels of nociceptive signaling molecules provoked by IgE/Ag-induced cutaneous anaphylaxis to elucidate the mechanisms underlying this differential pain outcome.
TGFβ1 inhibits IL-33-mediated mast cell activation: a role for genetic background (HYP3P.408)
Authors: Ndaw Victor , Kolawole Elizabeth , Ryan John 
Published: January 2023

Abstract
IL-33 is a recently discovered cytokine that functions as an alarmin member of the IL-1 family that plays a critical role in Th2 responses and mast cell activation. Numerous recent studies have demonstrated IL-33-mediated function via the T1/ST2 receptor on mast cells to elicit cytokine production and adhesion, as well as enhancing IgE-mediated degranulation. However, because of reported pro- and anti-inflammatory effects, the role of IL-33 in the pathogenesis of allergic diseases is not completely understood. In this study, we found that TGFβ1 suppresses IL-33-mediated production of TNFα, IL-6 and MCP-1, and reduces T1/ST2 receptor expression on mast cells. These responses were concentration-dependent. Consistent with our previous work, we found that bone marrow-derived mast cells (BMMC) from 129/Sv mice were more resistant to TGFβ1 treatment than C57BL/6 BMMC. We propose that TGFβ1 regulates mast cell homeostasis, and that this feedback suppression may be dependent on genetic context, predisposing some individuals to atopic disease.
Novel characterization of lethenteron japonicum complement C3 involved in immune response (INM2P.429)
Authors: Li Qingwei , Pang Yue , Zan Qi , Ba Wei , Pei Guangying 
Published: January 2023

Abstract
As an important model organism for the research of adaptive immune system, lampreys have been recognized as the key of the discovery of immune factors. In this paper, we discovered a novel immune factor named LjC3-like which participated in immune deposition and clearance. Datas indicated that the transcript and protein expression of LjC3-like was distributed in immune associated tissues, such as marrow, gill, kidney, intestines. A part of LjC3-like cDNA from lamprey liver, was successfully constructed and expressed in E.coli Rosatte and obtained anti-LjC3 polyclonal antibody. Flow cytometry analysis and laser scanning confocal microscopy revealed the existence of LjC3 in leukocytes and myelocyteson, especially in cytoplasm. The functional interaction between VLRB and LjC3 were demonstrated by coimmunoprecipitation in parallel with western blot assays. Furthermore lamprey serum destroyed target cells while the deposition of LjC3-like on their surface was detected. These results show novel characterization of LjC3-like, which lay a foundation to further research the vertebrate immunology , bring to the rethink of immune system in the lowest vertebrates.
Antibacterial and pro-resolving mechanisms in lung diseases: role of C-type lectin receptors (INM2P.430)
Authors: Sharma Jyotika , Sharma Atul , Steichen Anthony , Jondle Christopher , Binstock Brandilyn , Mishra Bibhuti 
Published: January 2023

Abstract
Lower respiratory tract infection with bacteria can lead to sepsis development, a complex immune disorder with systemic hyperinflammation. There are currently no effective therapies for sepsis. To understand the function of specific pulmonary components in regulation of immune responses in this immune disorder, we utilize an acute pulmonary bacterial infection model of Klebsiella pneumoniae (KPn). Nosocomial infections with this opportunistic pathogen account for 5-20% of Gram-negative sepsis cases. C-type lectin receptors (CLRs), expressed mainly by myeloid cells, can shape immune responses in diverse pathological conditions. However, their role in development of pneumonic sepsis is unknown. Our preliminary analysis of a panel of CLRs showed an upregulated expression of two CLRs, Clec4d and Clec4e in the lungs of KPn infected mice. While the wild-type mice were able to resolve a sublethal pneumonic KPn infection, the Clec4d-/- and Clec4e-/- mice displayed increased susceptibility with a progressive increase in bacterial burden, hyperinflammatory response and massive accumulation of neutrophils in lungs. Importantly, we show that coordinated function of Clec4d and Clec4e in neutrophils during bacterial pneumonia, and in a chronic lung disease, leads to control of bacterial growth and hyperinflammation by regulating phagocytosis and efferocytosis (clearance of dead cells). Our studies provide novel insights into regulation of inflammatory derangements in immune disorders.
Actin confinement of activating receptors does not dictate natural killer cell licensing (INM2P.431)
Authors: Thomas Louis , Long Eric 
Published: January 2023

Abstract
The responsiveness of an individual Natural Killer (NK) cell is calibrated by licensing (aka education), a process that depends on inhibitory receptor binding to major histocompatibility complex (MHC) class I. Previous data suggested that unlicensed NK cells have decreased responsiveness because the mobility of their activating receptors is hindered by actin. To test this hypothesis, we compared activating receptor-induced calcium mobilization in licensed and unlicensed human NK cells before and after actin depolymerization by Latrunculin. Licensed NK cells mobilized more calcium following stimulation by single or multiple activating receptors, as compared to unlicensed cells. Notably, the amplitude but not the induction of calcium mobilization was different. Actin depolymerization elevated the amplitude of calcium mobilization and accelerated calcium induction in both licensed and unlicensed NK cells. Therefore, licensed NK cells mobilized more calcium than unlicensed cells even after actin depolymerization. Furthermore, actin depolymerization resulted in faster lateral mobility of activating receptors in both licensed and unlicensed NK cells. Ongoing studies are evaluating the movement of activating receptors by single particle tracking. In conclusion, the results of our study show that actin-dependent confinement of activating receptors is not the only determinant of reduced responsiveness by unlicensed NK cells.
Soluble IP4 limits NK cell effector functions by controlling PI3K signaling (INM2P.434)
Authors: Sauer Karsten , Park Eugene , Siegemund Sabine , French Anthony , Wahle Joseph , Sternberg Luise , Rigaud Stephanie , Jonsson Helena , Yokoyama Wayne , Huang Yina 
Published: January 2023

Abstract
NK cells have important functions in cancer immunosurveillance, BM allograft rejection, fighting infections and reproduction. NK cell-based therapies are promising blood cancer treatments. Overcoming their limited efficacy requires a better understanding of the molecular mechanisms dampening their effector functions. NK cells recognize and kill pathogen-infected or tumor cells through invariant NK cell receptors (NKR). Two second-messenger pathways downstream of NKRs are required for NK cell maturation and effector responses: PIP3-generation by PI3K, and generation of DAG and IP3 by PLCγ. IP3 plays a key signaling role by mobilizing Calcium, but can also be converted into soluble IP4. We and others previously showed that IP4 can act as a soluble analog of the PI3K lipid-product PIP3 and control PIP3-mediated protein membrane recruitment and activation in thymocytes and granulocytes. Here, we show data which suggest a novel IP4 function in promoting NK cell terminal differentiation and acquisition of a mature NKR repertoire. However, in mature NK cells, IP4 limits NKR induced IFNγ secretion, granule exocytosis and target-cell clearance, in part by inhibiting the PIP3 effector Akt. This identifies IP4 as an important novel regulator of NK cell development and function, and expands our understanding of the therapeutically important mechanisms dampening NK cell responses. Our results further suggest that PI3K regulation by soluble IP4 is a broadly important signaling paradigm.
Covalently coupled immunostimulant heterodimers (INM2P.419)
Authors: Mancini Rock , Tom Janine , Esser-Kahn Aaron 
Published: January 2023

Abstract
We report increased stimulation of dendritic cells via heterodimers of immunostimulants formed at discrete molecular distances. Many vaccines present spatially organized agonists to immune cell receptors. These receptors cluster suggesting that signaling is increased by spatial organization and receptor proximity, but this has not been directly tested for multiple, unique receptors. In this study we probe the spatial aspect of immune cell activation using heterodimers of covalently attached immunostimulants including pyrimido[5,4-b]indoles, imidazoquinolines, palmitylated peptides, lipoteichoic acids, and CpG oligonucleotides.
Lung MDSC-derived IL-10 in resolution of inflammation during bacterial pneumonia (INM2P.420)
Authors: Chakraborty Krishnendu , Khare Anupriya , Raundhal Mahesh , Poe Stephanie , Morse Christina , Huff Rachael , Ray Anuradha , Ray Prabir 
Published: January 2023

Abstract
Bacterial pneumonia remains a significant burden worldwide. Although an inflammatory response in the lung is required to fight against pathogenic microorganisms, persistent inflammation leads to collateral tissue damage and precipitates acute lung injury. Recently we have shown that interleukin (IL)-10 is essential for resolution of lung inflammation with Klebsiella pneumoniae, a bacterium commonly associated with hospital-acquired pneumonia. Although IL-10-/- mice cleared bacteria, they displayed increased morbidity with progressive weight loss and persistent lung inflammation in the later phase after infection. A source of tissue IL-10 was found to be resident CD11b+Gr1(Ly6G)intF4/80+ cells resembling myeloid-derived suppressor cells (MDSCs). These cells efficiently efferocytosed apoptotic neutrophils, which was aided by IL-10. However, our ongoing studies show that IL-10 production from lung MDSCs can be negatively regulated during pneumonia. Previous studies have documented increased levels of the lipid cardiolipin, which is generated from the mitochondria of dead cells, in the lungs of patients with severe pneumonia. We have observed that cardiolipin blunts pulmonary IL-10 production thereby compromising the efficiency of the MDSC-IL-10 system to dampen inflammation. Considering the important role of IL-10 in limiting inflammation and tissue damage, our study identifies new targets for maintaining IL-10 expression during resolution of inflammation in pneumonia.