bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinctive innate immune signatures at the injection site predict the adjuvant-mediated boost of adaptive responses towards a flu subunit vaccine. (106.9)
Authors: Cortese Mario , Caproni Elena , Tritto Elaine , Muzzi Alessandro , Monaci Elisabetta , Baudner Barbara , Seubert Anja , O'Hagan Derek , De Gregorio Ennio 
Published: January 2023

Abstract
Vaccine adjuvants activate specific innate immune pathways which boost the adaptive responses to co-administered antigens, but the efficacy of adjuvants is often antigen-dependent. Recently, several human studies have shown that oil-in-water emulsions such as MF59 are superior to alum in enhancing the response to flu subunit vaccines. However, the mechanism of action of flu adjuvanticity is not fully understood. In this study we wanted to identify the innate immune signatures that are associated to adjuvanticity to flu subunit vaccine in the mouse model. First, we immunized mice with seasonal trivalent flu antigens or tetanus toxoid (TT) mixed with MF59, alum or three TLR-dependent adjuvants: CpG (TLR9), resiquimod (TLR7/8) and Pam3CSK4 (TLR2). All adjuvants were similarly efficient in inducing an adaptive immune response to TT. By contrast, MF59 and, to a lesser extent, Pam3CSK4 enhanced the antibody responses to HA. In order to correlate innate immune gene signatures induced by the vaccine adjuvants with the ability to boost flu adaptive responses, we performed microarray analysis with the same set of adjuvants both in vitro in mouse splenocytes and in vivo in mouse muscle and draining lymph nodes. In summary, we show that strong activation of innate immunity in the muscle, but not in draining LNs, and local recruitment of CD11b+ blood cells at injection site by MF59 and TLR2 vaccine adjuvants correlate with their ability to enhance antibody responses to flu antigens.
Rituximab treatment reduces organ-specific T cell effector responses and ameliorates Experimental Autoimmune Encephalomyelitis (107.3)
Authors: Monson Nancy , Cravens Petra , Hussain Rehana , Harp Christopher , Cummings Matthew , de Pilar Martin Maria , Lyons Jeri-Anne , Lovette-Racke Amy , Cross Anne , Racke Michael , Stuve Olaf , Shlomchik Mark , Eagar Todd 
Published: January 2023

Abstract
Recent clinical trials have established B cell depletion by the anti-CD20 chimeric antibody rituximab as a beneficial therapy for patients with relapsing-remitting multiple sclerosis (MS). However, the impact of rituximab on T cell responses remains largely unexplored. In the experimental autoimmune encephalomyelitis (EAE) model of MS in mice that express human CD20, rituximab administration rapidly depleted peripheral B cells. EAE severity was reduced in a therapeutic model and EAE symptoms were not observed in a preventive model. B cell depletion was also associated with diminished Delayed Type Hypersensitivity (DTH) and a reduction in T cell proliferation and IL-17 production during recall immune response experiments. While rituximab is not considered a broad immunosuppressant, our results indicate a role for B cells as a therapeutic cellular target in regulating encephalitogenic T cell responses in specific tissues.
Synergy between TLR3 and IL-18 promotes IFN-y dependent TRAIL expression in human liver NK cells (108.6)
Authors: Orloff Mark , Tu Zhengkun , Hamalainen-Laanaya Heli , Crispe Nicholas 
Published: January 2023

Abstract
Toll-like receptor 3 (TLR3), which recognizes double-stranded RNA (dsRNA), was the first identified antiviral TLR, and because dsRNA is a universal viral molecular pattern, TLR3 has been assumed to have a central role in the host response to viruses. Natural killer (NK) cells are a component of innate immunity against viral infections through their rapid cytotoxic activity and cytokine production. The synthetic dsRNA polyinosinic-polycytidylic acid (poly I:C), a mimic of a common product of viral infections, is known to rapidly up-regulate their in vivo functions; however, intrahepatic NK cells’ ability to respond to dsRNA is still mostly unknown. Our results show that poly I:C activates liver NK cells directly in the context of cytokines found in the liver, i.e: poly I:C plus inflammatory cytokines (IL-18, IL-12, and IL-2) induced NK cell IFN-g production and TRAIL expression, and anti-inflammatory cytokines (TGF-β and IL-10) inhibit NK cell IFN-γ production. Neutralization of IFN-g blocks poly I:C plus inflammatory cytokines-induced NK cell TRAIL expression, suggesting that IFN-g is an autocrine differentiation factor for these cells. A better understanding of the intrahepatic NK cell activation against viral infection may help in the design of therapies and vaccines for the control of viral hepatitis.
CpG ODN induced NK cell IFNγ production is positively regulated by IL-12 producing neutrophils and suppressed by IL-10 producing B cells (108.8)
Authors: Guillon Laura , Haddad Evette , Chow Mindy , Cohen Carla , Takei Fumio 
Published: January 2023

Abstract
CpG-containing oligodeoxynucleotides (CpG ODN) stimulates spleen cells in vitro and induces IFNγ secretion mostly from NK cells, whereas purified NK cells are not stimulated by CpG ODN. IL-12 neutralization inhibits NK cell IFNγ production, and IL-12 knockout mouse spleen cells stimulated with CpG ODN produce very little IFNγ, indicating that IL-12 is required. Depletion of macrophages and DC has no effect, whereas neutrophil depletion dramatically decreases both IL-12 and IFNγ production by spleen cells, indicating that neutrophils are a key source of IL-12. NK cells in B cell-deficient mouse spleen secrete higher levels of IFNγ than wild type spleen cells, and B cell depletion enhances NK cell IFNγ production, indicating that B cells are suppressive. CD5+ B cells secrete IL-10 in response to CpG ODN. The neutralization of IL-10 increases IFNγ and IL-12 production by CpG ODN-stimulated spleen cells, and B cell-deficient splenocytes produce more IL-12 than WT splenocytes. Furthermore, exogenously added IL-10 effectively inhibits CpG ODN-induced IL-12 production by purified neutrophils, and IL-12/IL-18 induced stimulation of purified NK cells. Therefore, CD5+ B cells produce IL-10 and suppress CpG ODN-mediated NK cell IFNγ production by inhibiting neutrophil IL-12 production as well as by directly acting on activated NK cells themselves.
An activating mutation in CD45 generates a novel murine model of hemophagocytic disorders in the context of a MHC Class 1 restricted TCR. (109.11)
Authors: Tibbetts Rachelle , Lam Viola , Cresalia Nicole , DeGraaf Fleur , Goren Nira , Wong Lawrence , Hai Si-Han , Mills Robyn , Roque Alfonso , Arthur Weiss , Hermiston Michelle 
Published: January 2023

Abstract
Hemophagocytic syndromes encompass a spectrum of life-threatening disorders characterized by severe systemic inflammation and mechanistically are not well understood. We inadvertently generated a novel mouse model that shares many characteristics of these hyperinflammatory conditions. Expression of a single activating point mutation (E613R) in the receptor protein tyrosine phosphatase CD45 results in a lupus-like phenotype on a mixed C57Bl/6 (B6)-129/Sv genetic background. However, CD45E613R mice on an inbred B6 background show no stigmata of disease despite inappropriate regulation of signals emanating from CD45’s substrates, the src family kinases. Surprisingly, introduction of a MHC class I restricted T cell receptor specific for ovalbumin (OT1) into B6 CD45E613R mice results in a severe hyperinflammatory disease reminiscent of hemophagocytic syndromes. Disease is maintained in RAG1 deficient CD45E613R/OTI mice implicating myeloid and/or CD8 T cells in disease pathogenesis. Using an adoptive transfer approach, we find CD45E613R/OT1 CD8 T cells are necessary and sufficient for this phenotype. Further analysis of CD45E613R/OT1 T cells indicates that they are inappropriately activated, secrete excessive levels of interferon gamma, and have defective cytolytic function. These intriguing results support further analysis of the role of src family kinase mediated signaling networks in hemophagocytic disorders.
VDUP1 inhibits NF-κB activity via association with HDAC1 and HDAC3 (109.14)
Authors: Park Young-Jun , Suh Hyun-Woo , Jung Haiyoung , Yoon Suk-Ran , Choi Inpyo 
Published: January 2023

Abstract
NF-κB subunits are important regulators of apoptosis or cellular responses triggered by tumor necrosis factor TNF-α. Termination of nuclear NF-κB action is regulated by histone deacetylase (HDAC) corepressor proteins. However, the molecular mechanism that leads to the termination is not fully understood. Here, we examined the functions of VDUP1, a negative regulator of thioredoxin, in TNF-α-mediated NF-κB activation. VDUP1 level was markedly reduced by TNF-α stimulation, concomitant with elevated NF-κB activation. Furthermore, Enforced VDUP1 overexpression suppressed strongly the increased NF-κB activity. In addition, the overexpresion of VDUP1 resulted in the robust suppression of TNF-α-activated NF-κB activity via association with HDAC1 or HDAC3. Collectively, we identified VDUP1 as a new component of the corepressors by demonstrating its ability to repress NF-κB activation, during which HDAC1 and HDAC3 interact with NF-κB p65 to suppress the NF-κB activity
Selenoprotein K knockout mice exhibit deficient calcium flux in immune cells and impaired immune responses (109.23)
Authors: Hoffmann Peter , Huang Zhi , Hoffmann FuKun , Hashimoto Ann , Verma Saguna , Kumar Mukesh , Roe Kelsey 
Published: January 2023

Abstract
Selenoprotein K (Sel K) is a selenium-containing protein for which no function has been identified. We found that Sel K is an endoplasmic reticulum (ER) transmembrane protein expressed at relatively high levels in immune cells and is regulated by dietary selenium. Sel K-/- mice were generated and found to be similar to WT controls regarding growth and fertility. Immune system development was not affected by Sel K deletion, but specific immune cell defects were found in Sel K-/- mice. Receptor-mediated Ca2+ flux was decreased in T cells, neutrophils, and macrophages from Sel K-/- mice compare to controls. Ca2+-dependent functions including T cell proliferation, T cell and neutrophil migration, and Fcγ-receptor-mediated oxidative burst in macrophages were decreased in cells from Sel K-/- mice compared to controls. West Nile virus (WNV) infections were performed and Sel K-/- mice exhibited decreased viral clearance in the periphery and increased viral titers in brain. Furthermore, WNV-infected Sel K-/- mice demonstrated significantly lower survival (2/23; 8.7%) compared to WT controls (10/26; 38.5%). These results establish Sel K as an ER-membrane protein important for promoting effective Ca2+ flux during immune cell activation and provide insight into molecular mechanisms by which dietary selenium enhances immune responses.
MicroRNA regulation of helper T cell cytokine production and proliferation (109.29)
Authors: Steiner David , Thomas Molly , Blelloch Robert , Ansel K. 
Published: January 2023

Abstract
MicroRNAs have been implicated as important regulators of many aspects of immune cell function. We and others have previously shown that deletion of the microRNA biogenesis enzymes Dicer and Drosha from T cells results in abnormal cytokine production and decreased proliferation of CD4+ T cells ex vivo. However, the role of individual miRNAs in this phenotype remains poorly understood. We conducted a screen for miRNA function in primary T cells and report the identification of individual miRNAs that can independently rescue the defects of miRNA-deficient helper T cells. Multiple members of the miR-17 and miR-92 families rescued proliferation while miR-29 rescued the aberrant IFN-γ expression by these cells. Repression of IFN-γ by miR-29 involved the regulation of both T-bet and Eomes, two transcription factors known to induce IFN-γ production. These results represent a novel screening strategy for miRNA function in primary T cells and further demonstrate the impressive regulatory capability of individual miRNAs in the immune system.
Tyrosine phosphorylation of 3BP2 regulates BCR-mediated activation of NFAT. (109.3)
Authors: Sada Kiyonao , Nakashima Kenji , Ogi Kazuhiro , Chihara Kazuyasu 
Published: January 2023

Abstract
Adaptor protein c-Abl SH3 domain-binding protein-2 (3BP2, also referred to SH3BP2) regulates immune receptor-mediated signal transduction. In this report, we focused on the molecular mechanism of 3BP2 function in B cell receptor (BCR) signaling. Engagement of BCR induces tyrosine phosphorylation of 3BP2. Genetic analysis demonstrated that Syk is critical for BCR-mediated tyrosine phosphorylation of 3BP2. Mutational analysis of 3BP2 revealed that both Tyr183 and Src homology 2 (SH2) domain are necessary for 3BP2-mediated BCR-induced activation of nuclear factor of activated T cells (NFAT). Point mutation of Tyr183 or Arg486 in the SH2 domain of 3BP2 diminished BCR-mediated tyrosine phosphorylation of 3BP2. Endogenous 3BP2 forms complex with tyrosine phosphorylated cellular signaling molecules. Peptide binding experiments demonstrated that only phosphorylated Tyr183 in 3BP2 could form a complex with the SH2 domain(s) of phospholipase C (PLC)-γ2 and Vav1 from B cell lysates. These interactions were represented by using bacterial GST-PLC-γ2 or -Vav1 SH2 domain(s). Furthermore, pull down and far-western experiments showed that 3BP2-SH2 domain directly binds to B cell linker protein (BLNK) following BCR stimulation. These results demonstrated that 3BP2 induces protein complex with cellular signaling molecules through phosphorylation of Tyr183 and SH2 domain leading to the activation of NFAT in B cells.
Cytoskeletal and microtubule machineries in concert with integrins are required for the secretion of eosinophil-associated RNases (110.13)
Authors: Shamri Revital , Young Kristen , Melo Rossana , Ghiran Ionita , Weller Peter 
Published: January 2023

Abstract
Eosinophils, both as end-stage effector cells and as collaborative interacting components of innate immune responses, have the capacity to secrete varied cytotoxic proteins that are stored in their cytoplasmic secretory granules, termed specific granules. Among them are the eosinophil-associated RNases (EARs): the human eosinophil-derived neurotoxin and eosinophilic cationic protein. The mouse EAR family includes at least 13 members, six of which were found to be present in specific granules. In the last decade several studies, both in vitro and in vivo, have revealed a role for eosinophils and their EARs in anti-viral defense. However, the secretion mechanism of EARs is not fully understood, especially in mouse eosinophils. Therefore, our study aimed to understand the mechanism of EAR secretion following physiological stimulation with chemokines. We found that dynamic polymerization of the actin cytoskeleton and microtubules, as well as functional integrins were critical for CCR3-mediated secretion of EARs. However, inhibition of regulatory components of the cytoskeletal machinery, such as Rac1 and ROCK-I and -II, increased EARs secretion in mouse and human eosinophils, suggesting a negative regulation of these effectors on EARs secretion. Collectively, these data suggest a mechanism by which EARs are secreted from eosinophils under physiological stimulation, findings that are pertinent to host defense against RNA viruses and eosinophil-associated diseases.
The Structure and Function of Acute Phase Proteins: C-Reactive Protein and Serum Amyloid A in Innate Immunity (110.21)
Authors: Lu Jinghua , Marjon Kristopher , Marnell Lorraine , Mold Carolyn , Du Clos Terry , Sun Peter 
Published: January 2023

Abstract
During an acute infection, serum levels of certain proteins will be increased dramatically at the early stage of the infection, which are so-called acute phase proteins (APPs). Among them, C-reactive protein (CRP) and Serum Amyloid A (SAA) are two major APPs in humans and therefore they have long been used as clinical biomarkers to monitor the inflammation and the outcome of therapy. However, the physiological function of CRP and SAA remains to be better characterized. In our study, we have shown that CRP can functionally activate Fc receptors pathways, particularly FcγRs and FcαRI (CD89), resulting in the phagocytosis of microbial pathogens and cytokine secretion, such as IL6, and IL8. The ability of CRP to activate FcγRs and FcαRI defines a novel function for acute phase proteins in inflammatory responses involving neutrophils and macrophages and also highlights the innate aspect of otherwise humoral immunity-associated antibody receptors. Furthermore, SAA was shown to be able to bind Gram-positive bacteria. We have now determined the X-ray structure of SAA at 2.7Å resolution. The natural hexameric SAA structure revealed a dimeric architecture arranged as two trimers. We also discovered that SAA hexamer could undergo a transition to monomers that are able to bind and activate Toll-like receptor 2 and 4. Taken together, our studies highlighted CRP and SAA as the powerful first lines of host immune defense during acute infection.
Systemic decrease in murine collecting vessel lymphatic function during initial stages of inflammation (110.5)
Authors: Aldrich Melissa , Hall Mary , Angermiller Bonnie , Robinson Holly , Sevick-Muraca Eva 
Published: January 2023

Abstract
The effects of inflammation on the lymphatic system are largely unknown, with conflicting reports of enhanced or decreased activity. We imaged murine lymphatic vessels and function using a custom-designed ICCD camera/low-level laser system and an intradermally injected fluorescent dye, indocyanine green, which is rapidly taken up by the lymphatic vasculature. Mice injected with LPS exhibited a drastic, systemic decrease in collecting vessel lymphatic propulsive flow velocity and frequency at 4-24 hours after the inflammatory insult, gradually increasing to normal values by 7 days post-inflammation. IL-6, TNF-alpha, MCP-1, MCP-5, RANTES, and IL-10 levels were increased in plasma at 4-24 hours. Draining lymph nodes retained ICG at 6-7 days post-inflammation, perhaps indicating restriction of afferent and/or efferent lymphatic vessels. This system for non-invasive imaging of the lymphatic system under inflammatory conditions may allow insights into mechanisms of inflammation and its resolution.
Circadian rhythms influence disease severity in a mouse model of sepsis (110.9)
Authors: Walker Wendy , Bozzi Aaron , Fikrig Erol 
Published: January 2023

Abstract
Septic patients have a heightened risk of mortality between the hours of 2 and 6 am. However, the reasons for this are unknown. Circadian rhythms orchestrate many aspects of mammalian physiology, including inflammatory responses. We investigated how circadian rhythms affect the cecal ligation and puncture (CLP) mouse model of sepsis. We found that mice that underwent CLP had a worse sepsis phenotype when the surgery was performed at zeitgeber time (ZT) 19 (2 am) vs. ZT 7 (2 pm): mice exhibited earlier mortality, more severe hypothermia and worse disease score. This was associated with higher levels of serum proinflammatory cytokines and creatine kinase. These data indicate that in the CLP model, the timing of sepsis induction influences the severity of the inflammatory response and the morbidity and mortality that ensue. Our findings imply that it is important to take circadian rhythms into account when treating patients who are at risk of developing sepsis.
Role of BAT3 in modulating the immune response (111.12)
Authors: Grover Ajay , Izzo Angelo 
Published: January 2023

Abstract
HLA-B-associated transcript 3 (BAT3) also known as Scythe or BAG6, is a nuclear protein that has recently been implicated in the control of apoptosis and in NK-DC cell cross-talk. Here, we demonstrate that BAT3 modulates the immune response by regulating the function of macrophages and dendritic cells. BAT3 is secreted by macrophages and dendritic cells in vitro and extracellular BAT3 down-regulates the production of nitric oxide and proinflammatory cytokines in IFN-γ and LPS stimulated macrophages. Extracellular BAT3 also down-regulates the LPS-stimulated maturation of dendritic cells. The immunodominant Mycobacterium tuberculosis antigen ESAT-6 (early secreted antigenic target-6) up-regulates BAT3 expression in macrophages and dendritic cells in vitro. Intracellular BAT3 regulates ESAT-6 induced apoptosis of macrophages by interacting with the anti-apoptotic protein BCL-2 (B-cell lymphoma 2) indicating that BAT3 may play a role in pathogenesis of tuberculosis. Taken together, the data suggest that BAT3 may exert different immunomodulatory regulations depending on whether it is intra-or extracellular.
New primary immunodeficiency with severe paucity of neutrophil granules despite normal granule protein levels (111.17)
Authors: Ismail Deema , Akuete Kwei , Borregaard Niels , Hostoffer Robert , Tcheurekdjian Haig 
Published: January 2023

Abstract
Neutrophil-specific granule deficiency is a rare congenital disorder, which manifests with severe, recurrent infections and is characterized by the absence of neutrophil specific granules and eosinophil granules. We describe a pathologically distinct primary immunodeficiency characterized by the near absence of all neutrophil granules but sparing of eosinophil granules. The subject is an 8 year old male with infections since birth including recurrent abscesses, chronic cellulitis, recurrent sinopulmonary infections, and profound dental decay. Lymphocyte phenotyping, T-cell and B-cell function, and assessment of neutrophil oxidative burst were normal. Leukocytes appear normal on light microscopy, but neutrophils in peripheral blood and bone marrow examined by electron mocroscopy contained few granules of any kind. Mean (standard deviation) number of granules per neutrophil of subject as compared to control were 1.4 (1.1) and 72.6 (31.4), respectively (p=0.0014). Nonetheless, granule proteins in neutrophil cell lysate were present in amounts comparable to controls. Eosinophils were morphologically normal. This is the first description of an immune deficiency due to near absence of neutrophil granules despite normal granule protein levels. This indicates a defect in granule production as opposed to a defect in granule protein production, which has previously been identified in neutrophil-specific granule deficiency.
The pivotal role of glutathione reductase in host defense against Gram-negative bacteria (111.25)
Authors: Yan Jing , Meng Xiaomei , Wancket Lyn , Lintner Katherine , Wu Haiwa , Nelin Leif , Chen Bernadatte , Smith Charles , Rogers Lynette , Liu Yusen 
Published: January 2023

Abstract
Glutathione reductase (Gsr) is an enzyme that reduces glutathione disulfide to the sulfhydryl form, a major cellular antioxidant. Oxidative burst plays an important role in pathogen killing and initiation of inflammation. Proper redox regulation is crucial for balancing effective pathogen elimination and host preservation. We tested the hypothesis that Gsr plays a critical role in host defense by comparing wildtype (WT) and Gsr- mice after E. coli infection. Compared to WT mice, Gsr- mice exhibited substantially higher mortality, associated with greater bacterial burden, cytokine storm, and striking histological abnormalities. Surprisingly, Gsr- mice displayed increased resistance to LPS. While Gsr- mice exhibited defects in phagocyte mobilization, there appeared no substantial defects in either cell signaling or cytokine production in Gsr- macrophages. The role of Gsr in phagocytic oxidative burst was assessed by both flow cytometry and bioluminescence imaging. The oxidative burst in WT neutrophils after PMA stimulation was sustained for more than 30 min, while oxidative burst was very transient in Gsr- cells (&lt;5 min). Likewise, oxidative burst after E. coli infection was also significantly weaker in the Gsr- neutrophils. Thus, Gsr plays a critical role in host defense against bacterial infection by regulating various immune functions, including facilitation of bacterial killing via sustaining oxidative burst in phagocytes, through maintenance of a delicate redox balance.