bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differentiation of Peyer’s patch M cells does not require signals from B cells: evidence from a mouse model of acute antibody-mediated depletion of B cells (90.1)
Authors: Knoop Kathryn , Butler Betsy , Kumar Nachiket , Williams Ifor 
Published: January 2023

Abstract
Microfold (M) cells are antigen-sampling cells in the epithelium covering Peyer’s patches (PP) and other mucosal lymphoid tissues. The previously demonstrated reduction in the number of PP M cells in B cell deficient mice (e.g. JH null and muMT models) led to a model proposing that B cells provide critical signals supporting M cell differentiation, but the specific B cell-derived factors involved in this process remain to be identified. We used an alternate model of acute antibody-mediated B cell depletion in human CD20 transgenic mice to reassess the role of B cells in PP M cell differentiation. Transgenic mice and nontransgenic littermates were treated with 1 mg of rituximab (anti-human CD20) every 4 days for a total of 4 doses. The status of PP M cells was analyzed 16 days after the start of treatment. Rituximab treatment led to loss of ≥94% of B cells from the spleen and PP of human CD20 transgenic mice. Whole mount staining of PP with the UEA-I lectin revealed that the number and pattern of UEA-I+ M cells per follicle was essentially unchanged in mice depleted of B cells (86 M cells/follicle in CD20 transgenic mice vs. 88 M cells/follicle in nontransgenic mice). We conclude that the acute depletion of B cells from PP of adult mice does not impair the normal differentiation of PP M cells. The modest decrease in the density of PP M cells observed in B cell deficient mice may be a consequence of abnormal embryonic PP development rather than lack of a B cell-derived factor.
Roquin-mediated regulation of intestinal inflammation (90.13)
Authors: Schaefer Jeremy , Montufar-Solis Dina , Klein John 
Published: January 2023

Abstract
Peripheral CD4+ (Th17) and CD8+ (Tc17) T cells that secrete the interleukin 17 proinflammatory cytokine play a central role in the host immune response during acute infection; however, aberrant expression of IL-17 has been implicated in a number of autoimmune and chronic inflammatory conditions. The RING finger E3 ligase, Roquin, promotes the degradation of gene transcripts in a microRNA-mediated decay process. Roquin-deficient mice develop chronic inflammation due to excessive ICOS expression. However, the role of Roquin in controlling other T cell activation signals and proinflammatory molecules has yet to be examined. Colonic intraepithelial lymphocytes (cIELs) from IL-10-/- mice, a model of human inflammatory bowel disease, and the EL4 T cell lymphoma line, were used to evaluate the contribution of Roquin in curtailing IL-17-mediated inflammation. In vitro-cultured CD4+ and CD8+ cIELs from IL-10-/- mice with severe inflammation were high producers of IL-17; conversely, Roquin expression was decreased. In IL-10-/- cIELs cultured with recombinant mouse IL-10, IL-17 expression was significantly reduced and Roquin expression was increased. Thus, during IL-10-induced immune regulation, Roquin and IL-17 are differentially modulated with Roquin expression being amplified while IL-17 is inhibited. These findings suggest a link between IL-10 and Roquin in the regulation of IL-17, and they may have significance for developing immunotherapies to control intestinal inflammation.
Dissecting the effects of microflora and antibiotics on immune and metabolic compartments in the gut (90.7)
Authors: Shulzhenko Natalia , Morgun Andrey , Dzutsev Amiran , Matzinger Polly 
Published: January 2023

Abstract
Because germ-free animals are difficult to generate and maintain, antibiotic-treated animals are often substituted in studies designed to determine the role of the normal microflora in health and disease. To determine the extent to which antibiotic (AB) treatment mimics the germ-free condition, and to ascertain the direct effects of AB on the host, we orally treated conventional and germ-free (GF) mice with a combination of four antibiotics for one month and performed microarray analysis of terminal ileum. We observed a decrease in the expression of T lymphocyte genes in both AB-treated and GF mice whereas B-lymphocyte transcripts had much higher expression in AB-treated and conventional than in GF mice. This result was confirmed at the cell number level in the tissue. Among the direct effects of antibiotics independent on flora, we found a decrease in the expression of genes related to mitochondrial functions and cell division. Concordantly, we detected lower amounts of mitochondria and a higher rate of cell death in the gut epithelial cells of AB-treated than of control mice. In conclusion, we found that antibiotics treatment only partially recapitulates the GF condition for mucosal immune system being able to mimic the germ-free status of mucosal T lymphocytes but not of B lymphocytes. In addition, antibiotics have some major direct effects decreasing energy metabolism in the host tissue independently on flora elimination.
The role of MyD88 in the synergy between FcϵR1, TLR4 and ST2 in mast cells. (91.5)
Authors: Collington Sarah , Zaidi Asifa , LaRosa David , Ali Hydar 
Published: January 2023

Abstract
Mast cells are well established as important effector cells in allergic reactions. Cross-linking of the high affinity IgE receptor (FcϵRI) on mast cells by allergen causes degranulation leading to the release and generation of a variety of inflammatory mediators. IL-33 and lipopolysaccharide (LPS) are members of the IL-1 family that use MyD88 as an adaptor molecule for signalling. Alone, IL-33 and LPS are unable to cause mast cell degranulation but they can induce cytokine generation. In addition, IL-33 and LPS synergise with antigen/IgE for cytokine production in mast cells. IL-33 and LPS-induced cytokine production was abolished in MyD88-deficient (MyD88-/-) bone marrow-derived mast cells (BMMCs). Surprisingly, antigen/IgE-mediated cytokine production was also substantially reduced in MyD88-/- BMMCs. However, MyD88 had no effect on FcϵRI expression, calcium mobilisation or degranulation. The synergy between IL-33 and antigen/IgE in IL-13 production by BMMCs was shown to be MyD88-dependent. Similarly, MyD88 was required for cytokine production in LPS and antigen/IgE stimulated BMMCs. The synergy between LPS and antigen/IgE for cytokine generation also required p38 MAP kinase activation. These findings suggest that MyD88 signalling in mast cells could provide a novel target to modulate allergic diseases.
Plasmacytoid dendritic cells kill virus-specific CD8 T cells during lethal dose influenza virus infections (92.1)
Authors: Legge Kevin , Langlois Ryan 
Published: January 2023

Abstract
Our previous studies have shown that the reduction in CD8 T cell immunity observed during high-dose influenza virus infection (IAV) is mediated via lymph node (LN) dendritic cells (DC) that express FasL and drive FasL:Fas (DC:T) induced apoptosis. However, the specific DC subset(s) within the LN and the additional factors required for DC mediated elimination of IAV-specific CD8 T cells remain unknown. Here, we demonstrate that plasmacytoid DC (pDC) accumulate to greater numbers within the LN of lethal, compared sublethal, dose IAV infected mice. Further our findings show that lethal, but not sublethal dose, pDC drive elimination Fas+ CD8 T cells and that this elimination occurs in the absence of protective cognate IAV-peptide-MHCI:TCR interactions. Together our results suggest that pDC play a heretofore unknown role in limiting the CD8 T cell response therein increasing mortality during high dose IAV infections.
Botanical medicines and their effects on the replication of influenza A virus and the influenza A virus-induced production of inflammatory mediators (92.14)
Authors: Cecil Chad , Oyegunwa Akinbolade , Kandhi Vamsikrishna , Eads Dawn , Hansen Rebecca , Sikes Michael , Scholle Frank , Petty Ian , Davis Jeanine , Cech Nadja , Laster Scott 
Published: January 2023

Abstract
Experiments are underway to evaluate plant extracts, and their constituents, for the ability to inhibit influenza A virus replication and the influenza A virus-dependent production of cytokines, chemokines and inflammatory lipids. Terameprocol (TMP), or tetra-O-methyl-nordihydroguaiaretic acid, produced by the creosote bush (Larrea tridentata), did not inhibit the growth of several strains of influenza A virus. In contrast, TMP strongly inhibited production of several inflammatory mediators including TNF-α, MCP-1, and PGE2 from infected cells. Our experiments show that TMP’s effects on cytokine and chemokine production stem from effects on the ability of NF-κB to bind DNA while effects on prostaglandin production stem from a direct inhibitory effect on the activity of COX-2. We found that extracts of Echinacea purpurea are also able to block production of TNF-α and PGE2 from infected RAW 264.7 cells, although wide variation in effectiveness is seen among plants from different locations. These effects were also seen with purified alkylamides found in Echinacea extracts, although different alkylamides displayed different activities. As with TMP, Echinacea extracts did not display an inhibitory effect on the growth of influenza A virus. Finally, extracts of Goldenseal (Hydrastis canadensis), and its primary alkaloid berberine, inhibited both influenza A virus replication and production of inflammatory mediators. Studies on the mechanisms underlying these effects are underway.
CD4 T-cells mediate enhanced immunopathology during influenza infection (92.22)
Authors: Verhoeven David , Farber Donna 
Published: January 2023

Abstract
Influenza infection generates robust CD4 T-cell memory that cross-reacts conserved epitopes between viral strains. We previously determined that influenza specific-memory CD4 T-cells have protective properties but enhance earlier morbidity. In this study, we found that Rag2-/- mice with memory CD4 T-cell specific for influenza A/PR/34/8 (PR8) and challenged with PR8 exhibited increased weight loss, had lower pO2 levels associated with greater lung epithelial damage, and died sooner than mice without flu memory or with naïve CD4 T-cells. To further define the immunopathologic nature of memory CD4 T-cell, we utilized adoptive transfers of PR8-specific memory into congenic hosts and challenged these mice with the heterosubtypic strain of influenza HK-X31. We determined that mice with influenza specific-memory CD4 T-cells had greater initial influenza-associated morbidity with enhanced epithelial damage in lungs despite lower viral titers as compared to primary infection. CD4 T-cell memory was associated with increased proliferation and recruitment of X31-specific effector CD4 T-cells during heterosubtypic challenge and enhanced flu specific interferon-γ and IL-17 responses. Memory CD4 T-cells tended to cluster together in the lungs during a secondary challenge possibly concentrating antiviral cytokines and further damaging the epithelium. This study clearly establishes the mechanisms driving a dual protective/immunopathologic role for CD4+ T-cell memory during infection.
Development and Maintenance of Antiviral Antibody Secreting Cells in Response to Influenza Virus Infection (92.3)
Authors: Wolf Amaya , Mozdzanowska Krystyna , Metzgar Michele , Quinn William , Bram Richard , Cancro Michael , Erikson Jan 
Published: January 2023

Abstract
Respiratory infection with influenza virus (flu) induces long-lasting protective humoral immunity. Although flu-specific antibody secreting cells (ASCs) increase post infection (p.i.) and are present in various organs, including the lung, it is unclear what signals promote their maintenance and/or survival. We determined that flu-specific ASCs were maintained in the lung up to half a year p.i.. These cells were not proliferating as they failed to incorporate BrDU. With the hypothesis that BLyS-family members may be important for ASC maintenance, we investigated the B cell response to flu in TACI-/- mice. TACI has been implicated in the T-independent type II response, but its role in anti-viral immunity is unknown. WT and TACI-/- mice exhibited a similar anti-flu B cell response at day 8 p.i., however, by day 33p.i., TACI-/- mice had significantly lower anti-flu antibody levels in the serum and locally in the lung. TACI deficiency did not affect flu-specific ASC numbers in spleen and lung-draining mediastinal lymph nodes. In contrast, it resulted in drastically reduced ASCs in lung and bone marrow. The results of our study will be discussed in the context of protection and possible implications for vaccine development.
Inhibiting the Inflammatory Response Following Influenza Virus Infection utilizing Sphingosine-1-phosphate receptor 1 signaling (92.4)
Authors: Teijaro John , Walsh Kevin , Rosen Hugh , Oldstone Michael 
Published: January 2023

Abstract
Emerging pathogenic strains of influenza A virus have caused significant morbidity and mortality in humans. During influenza virus infection, severe damage of lung tissue directly correlates with innate and adaptive cellular immune responses in addition to elevated pro-inflammatory cytokine responses. We reported previously that intra-tracheal treatment with a sphingosine analog, AAL-R, inhibits the production of pro-inflammatory cytokines and T cell accumulation within lung tissue without altering B cell responses or viral clearance (Marsolais, et al., 2008). Now we report that intra-tracheal treatment with AAL-R has profound S1P1-specific effects on innate immune responses. AAL-R inhibits neutrophil, NK and macrophage activation and recruitment into the lung via S1P1 signaling. In addition, AAL-R modulation of pro-inflammatory cytokines was also specific to S1P1 receptor signaling, as treatment with an S1P1 specific agonist significantly reduces early pro-inflammatory cytokine production after influenza virus challenge. Finally, we demonstrate that inhibition of T cell accumulation within the infected lung was independent of S1P1 receptor signaling. Here we provide mechanistic evidence for previously unrecognized inhibition of influenza virus innate and pro-inflammatory immune responses via S1P1 signaling. These findings have profound implications for designing therapeutic strategies to mitigate harmful immune responses during pathogenic influenza virus infection.
Uveitis-associated epitopes of retinal antigens are pathogenic in the humanized mouse model of EAU and identify autoaggressive T cells (93.1)
Authors: Mattapallil Mary , Silver Phyllis , Mattapallil Joseph , Horai Reiko , Karabekian Zaruhi , McDowell Hugh , Chan Chi-Chao , James Eddie , Kwok William , David Chella , Caspi Rachel 
Published: January 2023

Abstract
Autoimmune uveitis affects 150,000 Americans annually and is a leading cause of blindness. Pathogenesis is thought to involve T cell mediated responses to retinal proteins, such as retinal arrestin (S-Ag). Susceptibility to autoimmune uveitis is strongly associated with HLA class I and class II, but relatively little is known about the nature of HLA class II alleles and about the epitopes that might be pathogenic in the context of different HLA class II molecules. Using a ‘humanized’ mouse model for experimental autoimmune uveitis (EAU) in HLA transgenic mice, we have identified permissive and non-permissive alleles of the HLA-DR and -DQ genes and characterized allele-specific uveitogenic epitopes. The sequences of these epitopes overlap with some of the previously identified peptides of S-Ag (M and N), which elicit memory responses in lymphocytes of uveitis patients. HLA-DR restricted S-Ag specific CD4+ T cells could be detected in blood and draining lymph nodes of immunized mice using HLA class II tetramers, demonstrating the potential use of this reagent to detect and isolate antigen specific T cells in uveitis patients. Our data provide new insights into the pathogenesis of human uveitis, and may help in the development of antigen specific therapies.
An epitope from Acanthamoeba castellanii induces clinical signs of autoimmune encephalomyelitis in SJL mice by molecular mimicry. (93.25)
Authors: Massilamany Chandirasegaran , Thulasingam Siva , Steffen David , Reddy Jay 
Published: January 2023

Abstract
Autoimmune responses to myelin antigens have been implicated in the pathogenesis of multiple sclerosis (MS), but the mechanisms by which the disease is initiated are unknown. Exposure to environmental microbes has been suspected to initiate the disease by generating autoreactive cells as a result of the release of new antigens, bystander activation and molecular mimicry. We have identified an epitope (aa, 83-95) from Acanthamoeba castellanii (ACA) and it induces clinical signs of experimental autoimmune encephalomyelitis (EAE) in SJL/J mice reminiscent of the disease induced with myelin proteolipid protein (PLP) 139-151 regardless of gender. By using major histocompatibility complex II / IAs tetramers, we demonstrate that both ACA 83-95 and PLP 139-151 generate antigen-specific cross-reactive CD4 T cells and the T cells secrete identical patterns of T helper (Th) 1 and Th 17 cytokines. However, by contrasting the differences in TCR Vβ usage, it was revealed that the T cells from mice immunized with ACA 83-95 showed a higher proportion of Vβ2+ T cells with a corresponding decrease in Vβ17a+ cells and the reverse pattern was observed in mice immunized with PLP 139-151. These results may provide insights into the pathogenesis of multiple sclerosis and ACA-induced granulomatous encephalitis.
T cells, but not TLRs, control Act1-driven autoimmunity (93.28)
Authors: Johnson Angela , Li Xiaoxia , Jorgensen Trine 
Published: January 2023

Abstract
Act1 is a negative regulator of B lymphocyte-activating factor (BAFF) and CD40 signaling and is a key modulator of systemic autoimmunity, since Act1-deficient mice develop symptoms of severe autoimmune disease. As both T cell help and TLR signaling are known to contribute to autoimmune disease, mice deficient in either functional T cells (TCRb/d knockout) or TLR signaling (IRAK4 knockout) were crossed onto the Act1 autoimmune-prone background. Importantly, IRAK4-deficient animals are devoid in all TLR signaling, except TLR3. Splenomegaly, lymphademopathy, hypergammaglobulinemia, antigen-specific autoantibodies and immune complex deposition are all reduced in Act1 / TCRb/d triple deficient mice but not in Act1 / IRAK4 double deficient mice, indicating that T cells but not TLRs are required for Act1-driven autoimmunity. Additionally, as it is known that the numbers of transitional B cells are increased in the absence of functional Act1, preliminary cell population analysis demonstrates that in the absence of T cells, transitional B cells are still increased in number. Taken together, this indicates that early B cell development is not dependent upon the presence of T cells; whereas, the activation of autoreactive B cells is dependent upon T cells. Furthermore, both of these events appear to be independent of IRAK4 and potentially TLR signaling.
Dexamethasone synergistically increases secretion of the anti-inflammatory cytokine interleukin(IL)-10 in murine dendritic cells (DCs) upon viral infection: Potential implication to stress-mediated modification of susceptibility to viral infection. (94.4)
Authors: Ng Sinnie , Li Andrew , Ozato Keiko , Kino Tomoshige 
Published: January 2023

Abstract
Glucocorticoids (GC) are end-products of the HPA axis, which play central roles in stress response, including pathogen infection, and are widely used as therapeutic agents for inflammatory diseases. It is known that stressed condition altered the susceptibility to viral infection. Since it is not known how GC influence the function of DCs upon viral infection, we infected murine DC with Newcastle disease virus (NDV) in the presence of glucocorticoid receptor (GR) ligand dexamethasone (Dex), and examined mRNA expression of 84 genes, which play various roles in the TLR signaling cascade. We found that NDV infection potently induced mRNA expression of 24 genes. Among them, 7 genes (interferon (IFN)-γ, interleukin (IL)-6, IL-10, lymphotoxin A, C-type lectin domain family 4, nuclear factor of κ light chain gene enhancer in B cell inhibitor β and prostaglandin-endoperoxidase synthase 2) were further up- or down-regulated by Dex pre-treatment. Particularly on IL-10, Dex synergistically up-regulated NDV-induced mRNA by 7-fold. The Dex effect was mediated by GR, as inhibitor RU 486 abolished the effect. In contrast to IFN-γ and IL-6, which are Th1 cytokines and response at early time point (6 h), kinetics of IL-10 mRNA showed the highest synergistic effect of NDV and Dex at a later time point (24 h). ELISA results showed consistent results with mRNA expression. Taken together, our study indicates that GC modulate host immunity, altering TLR-related gene expression in DCs.
Improved tumor elimination by anti-tumor T cells that are resistant to adenosine-mediated immunosuppression in tumor microenvironment (95.1)
Authors: Ohta Akio , Kjaergaard Jorgen , Hatfield Stephen , Madasu Manasa , Subramanian Meenakshi , Kini Radhika , Ohta Akiko , Sitkovsky Michail 
Published: January 2023

Abstract
Tumors protect themselves from the anti-tumor immune response. One of the self-protective mechanisms is extracellular adenosine in tumor microenvironment, which inactivates anti-tumor T cells via A2A adenosine receptor (A2AR). Anti-tumor T cells that are resistant to adenosine-mediated immunosuppression should be of significant benefit to improve adoptive tumor immunotherapy. Our previous study demonstrated that addition of an adenosine receptor agonist NECA in CTL culture made the CTL resistant to adenosine-mediated immunosuppression. In this study, we evaluated the efficacy of NECA-treated anti-tumor T cells in MCA205 lung metastasis model. Culture-activated tumor-draining lymph node cells (TDLN) were used as anti-MCA205 effector cells. It was confirmed that NECA treatment of TDLN are less sensitive to A2AR signaling. We transferred either TDLN or NECA-treated effector cells (NECA-TDLN) into tumor-bearing mice 10 days after tumor inoculation. NECA pretreatment improved tumor rejection as indicated by the decreased number of tumor nodules from 118 ± 51 (TDLN) to 21 ± 33 (NECA-TDLN). T cell proliferation in vivo was analyzed after the adoptive transfer of CFSE-labeled effector cells. NECA-TDLN proliferated better than control TDLN in the lung (tumor site) suggesting that adenosine-resistant NECA-TDLN could activate well in tumor microenvironment. Induction of adenosine-resistance by NECA pretreatment might be a novel approach to overcome immunosuppression in tumors.