bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigating molecular bases for mucosal mast cell motility and interactions in the gut (140.13)
Authors: Lee Jinmin , Williams Rebecca , Blum Lisa , Appleton Judith , Baird Barbara , Holowka David 
Published: January 2023

Abstract
Mast cells function as effector and immunomodulatory cells in innate and adaptive immune responses, and they are the primary mediators of immunoglobulin E (IgE)-dependent allergic disorders. Although homing of mast cell progenitors is relatively well studied, little is known about mature mast cell motility and migration in tissue. Our recent studies have characterized novel polarization and motility of mucosal mast cells in culture, including the RBL-2H3 cell line and rat bone marrow-derived mast cells. Motility of these cells depends on several properties, including Ca2+ homeostasis. Preliminary evidence indicates a role for store-operated Ca2+ entry in this process. RBL-2H3 mast cells undergo adhesion and motility on cultured monolayers of rat intestinal epithelial cells, and they exhibit occasional transepithelial migration under these conditions. Intestinal infection of animals by parasitic nematodes, including Trichinella spiralis, induces local mastocytosis. Using multiphoton confocal microscopy of ex vivo intestinal tissue from infected rats, we have been able to visualize fluorescently labeled and adoptively transferred mast cells in the epithelial layer of jejunal villi.
Cyclophilin A synergizes with MIP-2 to augment pro-inflammatory leukocyte recruitment (140.5)
Authors: Heine Shannon , Olive Denise , Okwumabua Ifeanyi , Bukrinsky Michael , Constant Stephanie 
Published: January 2023

Abstract
Chemokines contribute to inflammatory responses by inducing leukocyte migration and extravasation. Extracellular cyclophilins are a group of alternative chemokines that can be elevated during inflammation, and we have previously shown that their inhibition reduces neutrophil infiltration by &gt;40% in a mouse model of LPS-induced acute lung inflammation. Given the presence of many other chemokines during this inflammatory response, the observed potent contribution of cyclophilins led us to investigate whether they might function in a synergistic partnership with concurrent chemokines. To test whether cyclophilin A (CypA) can work with other chemokines in vivo, recombinant extracellular CypA was co-delivered with intranasal LPS and lung neutrophil numbers were examined at a time point when two classical chemokines, MIP-2 and KC, but not CypA, are present. The addition of CypA induced a significant increase in early neutrophil recruitment that was greater than the additive recruitment induced by LPS and CypA alone. Boyden chamber chemotaxis assays in which purified mouse neutrophils were incubated with various combinations of CypA plus MIP-2 or KC were used to show that CypA had the capacity to synergize with MIP-2, but not KC, to induce augmented neutrophil migration. These findings provide a potential explanation for why the inhibition of cyclophilin activity in vivo has such a great impact on cell recruitment.
Particulate Allergens Exacerbate Allergic Asthma via Extended Localization within Lipid Raft Enriched Compartments in Mast Cells (141.19)
Authors: Jin Cong , Shelburne Christopher , Li Guojie , Potts Erin , Riebe Kristina , Sempowski Gregory , Foster Michael , Abraham Soman 
Published: January 2023

Abstract
Numerous epidemiological studies have related the exacerbation of allergic asthma with exposure to increased ambient particles from air pollutants. However, the mechanism by which particulate allergens (pAg) exacerbate allergic asthma remains undefined. To evaluate this, we modeled environmental pAg induced allergic asthma by exposing mice to polystyrene beads coated with natural allergen extracts. Compared to equal amounts of soluble allergen extracts (sAg), pAg triggered markedly enhanced airway hyper-responsiveness and pulmonary eosinophila in allergen sensitized mice. The cellular basis for this effect was determined to be mast cells (MCs), as both airway allergic responses were attenuated in MC deficient mice compared to MC sufficient mice. The divergent responses of MCs to pAg versus sAg were due to differences in the termination rate of IgE/FcϵRI initiated signaling. Following ligation of sAg, IgE/FcϵRI rapidly shuttled into a degradative endosome/lysosome pathway. However, following ligation by pAg, IgE/FcϵRI migrated into lipid raft enriched compartments and subsequently failed to follow a degradative pathway, which resulted in a prolonged signaling and heightened synthesis of proinflammatory mediators. These observations highlight the overlooked contributions of the particulate nature of allergens and mast cell endocytic circuitry to the aggravation of allergic asthma.
Suppression of liver injury through inhibition of MyD88 signaling in a mouse model of fulminant hepatitis by 18β-glycyrrhetinic acid (142.11)
Authors: Xu Jingwei , Zhang Yanyun 
Published: January 2023

Abstract
Fulminant hepatitis, develops secondary to infection, toxin or immune mediated attack, is a rare but potentially fatal disease. However, the molecular mechanisms underlying are not well known. 18β-glycyrrhetinic acid (GA), the major bioactive component of licorice root extract, has a protective effect on hepatic injury and exhibits anti-inflammatory activity. Here we investigate the potential role of GA in a mouse model of fulminant hepatitis induced by injection of Propionibacterium acnes (P. acnes) and LPS. GA or vehicle control was administered intraperitoneally daily 1 d after P. acnes priming. The results revealed that GA treatment significantly improved mouse mortality and ameliorated liver injury through inhibition of the activation and proliferation of liver-infiltrating CD4+ T cells and the production of serum pro-inflammatory cytokines such as IFN-γ and TNF-α. However, GA exhibited no direct effect on the proliferation of liver-infiltrating CD4+ T cells, but by reduced recruitment of CD11c+B220- DC precursors into the liver, which is mediated by the inhibition of MIP-1α expression in Kupffer cells by GA. More importantly, GA inhibited the activation of Kupffer cells by down-regulating MyD88 expression and its down-stream signal NF-κB activation. Taken together, our results suggest that GA exhibits anti-inflammatory effects through inhibition of MyD88 signaling in a mouse model of fulminant hepatitis.
Beclin-1 is required for T cell-mediated immune responses (143.19)
Authors: Kovacs Jeffrey , Li Changyou , Lu Binfeng 
Published: January 2023

Abstract
Beclin 1, the mammalian homologue of the yeast Atg6, regulates macroautophagy (autophagy) in eukaryotic cells and plays a critical role in the regulation of cell death and survival in various types of cells. Beclin 1 is expressed in T cells. However, its role in T cell-mediated immune responses remains unknown. We have found that mice with Beclin-1 deletion in T cells have profound deficiencies in mounting T dependent immune responses. Autophagy is abolished in Beclin 1 deficient T cells. We observed that, upon activation, Beclin 1 deficient T cells undergo programmed cell death. Mice with Beclin 1 deletion in T cells fail to mount T cell-dependent humoral immune responses to KLH and are resistant to experimental autoimmune encephalomyelitis. Our work establishes a crucial role of Beclin 1 in autoimmunity.
Self reactive B cells that do not exhibit higher BAFF dependency for survival (143.42)
Authors: Nikbakht Neda , Manser Timothy 
Published: January 2023

Abstract
The pro-survival cytokine BAFF was recently proposed to regulate peripheral immunological tolerance within the B cell lineage. Studies conducted in two different model systems of B cell autoimmunity demonstrated a selective elimination of autoreactive B cells upon BAFF depletion. These observations led to a model positing a higher dependency of autoreactive B cells on BAFF. We tested this model by exploiting our experimental system in which targeted Ig heavy chain knock-in transgenic mice (HKI) produce large numbers of B cells that are dually reactive to foreign (Ars) and self (DNA) antigens. HKI B cells do not exhibit the classical features of anergy, escape central tolerance mechanisms, and gain access to normal follicular locales. We show that mature, naïve, autoreactive HKI B cells are out-competed in the presence of a polyclonal repertoire. However, this is not due to a higher dependency of HKI B cells on BAFF for survival. In addition, excess BAFF does not rescue HKI B cells from selective elimination. These findings suggest that some autoreactive B cells can fully develop while in competition with non-autoreactive cells for normal levels of BAFF, but remain at a competitive disadvantage for other trophic factors that regulate peripheral stability. As such, our data indicate the existence of parallel peripheral tolerogenic mechanisms that may act through BCR signaling and at further stages of differentiation such as those that take place in germinal centers.
IL-17 downregulates p50 and p105 to sustain efficient active NF-κB signaling responses in the splenic B cells of autoimmune BXD2 mice (143.48)
Authors: Xie Shutao , Hsu Hui-Chen , Wu Qi , Li Jun , Yang PingAr , Ding Yanna , Mountz John 
Published: January 2023

Abstract
Constitutively active NF-κB signaling with increased expression of p50 is associated with many autoimmune diseases. In autoimmune BXD2 mice, there is dramatically higher p50 in splenic B cells, compared to B6 B cells (&gt;10.0-fold, p&lt;0.01). Surprisingly, both p50 and p105 in BXD2 B cells are significantly lower than those in B cells from BXD2-Il17ra-/- mice, indicating IL-17 downregulates them in B cells. Consistent with it, administration of AdIL-17RA:Fc which blocks IL-17RA signaling, resulted in significantly increased p50 and p105 and decreased phospho-p65 in splenic B cells, leading to decreased autoantibody production in BXD2 mice. In contrast, administration of AdIL-17A exhibited opposite effects. Stimulation of BXD2 B cells with IL-17 led to cytoplasmic translocation of p50 from the nucleus while p65 was phosphorylated and translocated to the nucleus. In BXD2-Il17ra-/- B cells, there is increased localization of p50 and p105 in the nucleus, compared to BXD2 B cells. The enhanced nuclear p50 and p105 in BXD2-Il17ra-/- B cells are associated with dramatically decreased LPS induction of NF-κB response genes including Rgs which are essential for development of autoreactive germinal centers, indicating higher p50 and p105 inhibit these genes expression in BXD2-Il17ra-/- B cells. The results suggest IL-17 downregulate p50 and p105 to sustain efficient active NF-κB signaling responses in autoreactive BXD2 B cells and result in increased production of pathogenic autoantibodies.
Expansion of CD3+/CD4+/CD25+/Foxp3+ T cells in rapamycin-treated lupus patients (143.52)
Authors: Perl Andras , Lai Zhi-Wei , Telarico Tiffany , Bartos Adam , Miklossy Gabriella , Hanczko Robert , Francis Lisa , Tily Hajra , Ramos Irene , Garcia Ricardo , Phillips Paul , Jimah John , Doherty Edward 
Published: January 2023

Abstract
Activation and death pathway selection of T cells are regulated via the mitochondrial transmembrane potential (Δψm). Systemic lupus erythematosus (SLE) patients’ T cells exhibit persistent Δψm elevation or mitochondrial hyperpolarization (MHP) and ATP depletion which predispose them to pro-inflammatory death via necrosis. Here, we examined the role of the mammalian target of rapamycin (mTOR), which serves as a sensor of MHP, in T cell activation in 34 female SLE patients and 30 female controls matched for age and ethnicity. MHP and mitochondrial mass was most robustly (1.6-2.0-fold; p= 0.0027) increased in CD3+/CD4-/CD8- cells. The prevalence of Foxp3+ cells within the CD4+/CD25+ compartment was reduced in SLE patients (37.05 ± 3.0 %) relative to controls (48.37 ± 2.5 %; p = 0.0014). mTOR activity, as measured by the accumulation of pS6 protein, was increased &gt; 1.5-fold in CD3+ T cells (p=0.012) and CD19+ B cells (p=0.006). Relative to healthy controls (3.18 ± 0.39%), the frequency of Foxp3+/CD4+/CD25+ cells was reduced in 6 lupus patients (1.70 ± 0.42%; p=0.021) prior to rapamycin treatment. In vivo treatment with rapamycin increased the frequency of Tregs from 1.50 ± 0.45% to 2.8 ± 0.59% (p=0.040) while the SLEDAI scores were reduced in 5 SLE patients from 22.4 ± 5.7 to 16.7 ± 2.8 (p=0.017).These data identify the in vivo expansion of Tregs as a potential mechanism of action that may contribute to the therapeutic efficacy of rapamycin in SLE.
Therapeutic Potential of in vitro Expansion of Foxp3+ Tregs Utilizing GM-CSF-treated Bone Marrow Dentritic Cell Precusors in Experimental Myathenia Gravis (143.6)
Authors: Sheng Jianrong , Prabhakar Bellur , Meriggioli Matthew 
Published: January 2023

Abstract
We have previously shown that regulatory T cells (Tregs) generated in vivo by the selective activation of particular subsets of dendritic cells (DCs) in response to low-dose granulocyte-macrophage colony-stimulating factor (GM-CSF) have the capacity to prevent and reverse experiemental autoimmune myasthenia gravis (EAMG). To further understand the underlying mechanisms of GM-CSF-induced Treg mobilization, we studied the effects of GM-CSF on T cell/DC co-cultures using matured splenic DCs as well bone marrow (BM) - derived DC precursors in vitro. Compared to splenic DCs, bone marrow-derived DC precursors, when cultured in the presence of GM-CSF, gave rise to a population of CD11c+CD11bhighCD8α- DCs (BMDCs) which were able to expand Foxp3+ regulatory T cells (Tregs) in the absence of TCR stimulation. Additionally, the BMDCs secreted high levels of TGF-β which was required for adaptive differentiation of naive T cells to Foxp3+ Tregs upon TCR stimulation. Adoptive transfer of expanded Tregs effectively suppressed ongoing EAMG. These results strongly indicate that BMDCs differentiated in the presence of GM-CSF can expand natural Tregs and induce adaptive Tregs through different mechanisms. Expansion of polyclonal and antigen-specific Tregs in vitro using this strategy may represent an effective treatment for restoring immune tolerance and ameliorating EAMG.
Immunostimulatory characteristics and in vivo trafficking of a primary dendritic cell-based vaccine for coccidioidomycosis. (144.23)
Authors: Awasthi Shanjana , Vilekar Prachi , Lagisetty Pallavi , Awasthi Vibhudutta 
Published: January 2023

Abstract
Dendritic cell (DC)-based vaccines have shown promising results in cancer and infectious diseases. Success of the DC-vaccine depends on multiple factors including host genetic background, trafficking through tissues, interaction and activation of naïve immune cells. We studied the immunostimulatory ability and trafficking of DC-vaccine in BALB/c mice, extremely-susceptible to Coccidioides infection. DC-vaccine was prepared by transfecting DCs with a plasmid DNA encoding Coccidioides-Ag2/PRA-cDNA (protective epitope). Secreted cytokine/chemokines were measured by cytometric bead array, and T cell activation was studied by flow-cytometry after DC-vaccine-lymphocyte co-culture. For trafficking studies, syngeneic BALB/c mice were intranasally injected with DC-vaccine expressing Coccidioides-Ag2/PRA and HSV-1-thymidine kinase (PET-reporter gene). On day 2 and 7 of DC-vaccination, PET imaging was performed 2h after intravenous injection of radiolabeled probe F-18-labeled 2'-fluoro-2'-deoxy-1β-D-arabinofuranosyl-5-iodouracil. Mice were sacrificed, and major organs and blood were collected. Organs- and blood-associated F-18 radioactivity was determined. Our results suggest that DC-vaccine secretes MCP-1 chemokine, activates T cells and traffics through lung, thymus and liver. Biodistribution data suggest an accumulation of F-18 radioactivity in all organs (except intestine) with more pronounced increase in lung, thymus and blood (p&lt;0.005) of DC-vaccinated mice as compared to control.
Conventional splenic dendritic cells regulate development of graft-versus-host disease. (145.10)
Authors: Askew David , Eid Saada , Guardia-Wolff Rocio , Pierce Elizabeth , Cooke Kenneth 
Published: January 2023

Abstract
The use of allogeneic hematopoietic stem cell transplant (HSCT) to treat hematologic malignancies is associated with the development of graft-versus-host disease (GVHD), a frequently fatal complication that limits successful outcomes. The treatment of GVHD often requires potent immunosuppressive drugs and can predispose to relapse of the original cancer and the development of opportunistic infection. Understanding how GVHD is initiated may help to identify targets for therapeutic interventions that do not require wholesale suppression of the immune response. Prior studies have shown that host antigen presenting cells (APCs) are critical to GVHD induction. We examined how functionally distinct host splenic DC subpopulations (CD4+ vs. CD8+) regulate the development of GVHD mediated by donor CD4+ T cells. When compared to purified Balb/c CD4+ DCs, we found that Balb/c CD8+ DCs significantly increased C57BL/6 CD4+ T cell proliferation and cytolytic activity in vitro. To control the source of T cell stimulation for in vivo HSCT studies, we created chimeric Balb/c mice that have C57BL/6 APCs (C57BL/6 → Balb/c). Subsequently, we found that transplantation of C57BL/6 CD4+ T cells stimulated ex vivo by CD8+ Balb/c DCs resulted in more robust GVHD (survival, clinical score, pathology) compared to T cells activated by CD4+ DCs. Targeting specific DC-T cell interactions early in HSCT may help to control the severity of GVHD without requiring wholesale suppression of the immune system.
Cytotoxic class I tetramers inhibit CTL priming and alter immunodominance hierarchies in the HY model system (145.33)
Authors: Murray Sabrina , Miller Keith , Young Ellen , Vincent Benjamin , Steele Shaun , Buntzman Adam , Collins Edward , Frelinger Jeffrey , Hess Paul 
Published: January 2023

Abstract
The CD8+ cytotoxic T lymphocyte (CTL) response is a major effector mechanism in allograft rejection. In this study, we used the well-established murine HY-reactive immune response as a rejection model. Sensitization of B6 females with male bone marrow generated robust Db-Uty and Db-Smcy tetramer-positive CTLs that produced IFN-gamma, TNF-alpha, and granzyme B. We hypothesized that treatment of female mice with Db-Uty or Db-Smcy tetramers coupled to the ribosome-inactivating toxin, saporin, would selectively delete naïve cognate T cells and prevent priming of CTL responses. As expected, administration of the cytotoxic tetramers prior to immunization dramatically reduced the HY -specific CTL population at the peak of expansion and permitted the survival of adoptively-transferred, HY peptide-pulsed female cells. Interestingly, elimination of one CTL population magnified T cell reactivity against the remaining dominant epitope, demonstrating that the relative amplitude of these responses depends, in part, on competition between CD8+ T cells during priming. These data suggest that cytotoxic class I tetramers could be useful to dissect or manipulate T cell immunodominance hierarchies.
Over-expression of FGL2 leads to indefinite graft survival without the need for immunosuppression. (145.37)
Authors: Bartczak Agata , He William , Shalev Itay , Mendicino Michael , Urbanellis Peter , Zhang Jianhua , Ma Max , Khattar Ramzi , Adeyi Oyedele , Phillips James , Grant David , Levy Gary 
Published: January 2023

Abstract
FGL2 is an effector molecule of CD4+CD25+FoxP3+ T regulatory cells (Treg) which exerts its effect through binding to FcγRIIb and FcγRIII on APC. Mice deficient in fgl2 show impaired Treg activity associated with increased immune reactivity and development of autoimmune glomerulonephritis. In a fully mismatched model of heart allotransplantation where recipients were treated with recombinant FGL2, graft survival was extended significantly but grafts were rejected following cessation of treatment. To further explore the function of FGL2, we generated an FGL2 over-expressing mouse (fgl2Tg) using a conditional, double reporter cre/lox expression system. These mice express 1000-fold higher levels of FGL2 in plasma compared to wildtype mice. The high levels of FGL2 do not appear to adversely affect mouse development. Treg isolated from the fgl2Tg mice have increased suppressive activity in vitro and effector T cells isolated from fgl2Tg mice are hyporesponsive to alloantigens. In vivo, fully mismatched hearts transplanted into fgl2Tg mice survived indefinitely without the need for immunosuppression. These data demonstrate that FGL2 is an important effector immunosuppressive molecule of Treg which has therapeutic implications for transplantation and autoimmune disease.
central tolerance induction by adoptive transfer of donor dendritic cells (145.5)
Authors: Yamano Tomoyoshi , Goto Masafumi , Abe Ryo , Kishimoto Hidehiro 
Published: January 2023

Abstract
The principal function of DCs is to promote T cell activation and differentiation into effecter T cells by presenting foreign Ags and providing costimulatory signals. DCs also play a critical role in maintaining not only peripheral but also central tolerance. Central tolerance is established by negative selection of developing T cells that have high-affinity TCRs for self-peptide-MHC complexes expressing on DCs or mTECs. We studied whether i.v. injection of allogeneic DCs that are obtained BM culture with Flt3L (FLDCs), GM-CSF(GMDCs) or allogeneic B cells could home to the recipient thymus. We found that only FLDCs could traffic to the recipient thymus. In MLR assay, splenic T cells and mature thymocytes which were recovered from donor FLDCs infused mice, have poor proliferative activity in response to donor APCs, whereas the responses of T cells against third party APCs were as same as control mice. The MHC classI Ld specific 2C thymocytes were selectively deleted after intravenous injection of BALB/c FLDCs. Furthermore, adoptive transfer of donor FLDCs showed significant prolonged donor skin graft. FLDCs transfer was also able to prolong the donor islet graft and prevented the mice from streptozotocin induced diabete mellitus. These results show that i.v injection of FLDCs induces donor specific both central and peripheral tolerance.
Inhibition of the primary antibody response to transfused allogeneic platelets (145.8)
Authors: Gilson Christopher , Zimring James 
Published: January 2023

Abstract
Alloantibodies are a clinically significant sequela of platelet (PLT) transfusion, potentially rendering patients refractory to ongoing transfusion support. PLTs are restricted to the peripheral circulation, where antigens are primarily sampled by the spleen and liver. We hypothesized that the primary antibody (Ab) response to allogeneic PLTs depends upon CD4 T cell help in the splenic microenvironment. C57BL/6 recipients (H-2b) transfused four times weekly with 1x108 leukoreduced BALB/c (H-2d) PLTs developed anti-donor Ab by day 28 (15/15 mice). Adoptive transfer of CFSE labeled CD4+ TCR75 cells, a TCR transgenic specific for a peptide from Kd presented by I-Ab, augmented the Ab response by day 14 to a single transfusion (9/9). TCR75 division by day 5 was exclusive to the spleen and not the liver or lymph nodes. Anti-donor Ab was undetectable in CD4 depleted recipients (0/15). Splenectomized recipients did not develop detectable anti-donor Ab (0/13) and adoptively transferred TCR75 cells did not divide or rescue the Ab response (0/9). The non-responsiveness in splenectomized animals was not due to donor specific tolerance as these recipients responded robustly to subsequent donor whole blood (6/6). Enhanced alloimmunization by adoptive transfer and abrogation by depletion supports the critical role for CD4 T cell help. Failure of TCR75 proliferation in splenectomized recipients suggests that an intact spleen is required, but the liver insufficient, for PLT alloimmunization.