bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted Deletion of Cannabinoid Receptors 1 and 2 Results in Enhanced Inflammation and Exacerbated Immune Response Phenotype to Influenza Challenge (92.10)
Authors: Karmaus Peer , Chen Weimin , Kaplan Barbara , Kaminski Norbert 
Published: January 2023

Abstract
In previous studies, mice lacking cannabinoid receptors 1 and 2 (CB1-/-CB2-/-) showed reduced lung viral burden after a single instillation of mouse-adapted A/PR8/34 influenza compared to C57Bl/6 (WT) mice. In this study we investigated potential mechanisms involved in the differences in viral burden. In a kinetic study, CB1-/-CB2-/- and WT mice were challenged with A/PR8/34 and 1, 3, 5 and 7 days post infection (dpi) several immune parameters were assessed. In the bronchoalveolar lavage fluid, increases in neutrophils and macrophages were observed in response to viral challenge, and both populations were increased in CB1-/-CB2-/- mice as compared to WT at 3 dpi. Furthermore, increases in T cell activation as assessed by CD69 and IFNγ production were observed in CD4+ and CD8+ T cells from CB1-/-CB2-/- compared to WT as early as 3 dpi. To determine potential factors involved in modulating the outcome of the T cell response we performed a low density mouse immune panel gene array on lung RNA 1 and 3 dpi. Differences in chemokine and inflammatory cytokine levels, with enhancement in CB1-/-CB2-/- compared to WT were observed. In a repeat study we observed CD4+NK1.1+CD44- and NK1.1+CD4-CD8- producing significant amounts of IL-17 in CB1-/-CB2-/- over WT at 3 dpi. Overall, these studies suggest an enhanced inflammatory response in CB1-/-CB2-/- leading to faster T cell kinetics and a more robust immune response, thereby limiting viral replication.
Characterization of the monocyte response in the influenza-infected lungs. (92.12)
Authors: Gorski Stacey , Kim Taeg , Sun Jie , Braciale Thomas 
Published: January 2023

Abstract
Influenza virus infection of the respiratory tract triggers a rapid and vigorous innate immune response. Monocyte/macrophages make up a large fraction of this inflammatory infiltrate and are the major contributors to lung inflammation associated with infection. The monocyte population can be defined as CD11b+Ly6G-Dx5-SiglecF-, and subsets can be further discriminated based on Ly6C expression levels. Here we show rapid accumulation of Ly6Chi monocytes in the infected lungs during the inductive phase of the host immune response, resulting in the predominant if not exclusive accumulation of the Ly6Chi monocyte population at the peak of the inflammatory response. The Ly6Chi monocytes are potent producers of TNF alpha and their presence during early infection strongly correlates with overall lung inflammation. Ly6Chi monocytes slowly decline during the recovery phase following virus clearance, resulting in an accumulation of a Ly6Clo monocyte subset. The presence of this Ly6Clo subset, and the subsequent down-regulation of TNF alpha production in the Ly6Chi subset, strongly correlates with recovery (e.g. weight gain and reduced inflammation) in this mouse model of influenza infection.
The role of different virus-specific effector memory T-cell subsets in response to influenza A/H3N2 and pandemic A/H1N1 strains in older compared to young adults (92.2)
Authors: Zhou Xin , McElhaney Janet 
Published: January 2023

Abstract
Age-dependent changes in the cellular immune response have been mainly described in CD8+ T cells, with relative sparing of CD4+ T cells. However, a potential compensatory role for CD4+ T cells in the presence of severe effector functional defects in CD8+ T cells in older adults has not been described. We show that effector memory (CD45RA-CCR7-) and effector (CD45RA+CCR7-) CD8+ T-cell subsets in older compared to young adult PBMC responding to influenza A/H3N2 challenge have limited cytolytic activity against influenza-infected autologous targets. In contrast, effector CD4+ T-cell subsets in older adults demonstrate cytolytic activity in response to influenza challenge and share similar phenotypic and functional characteristics with virus-specific T cell subsets from young adults. Furthermore, we identified influenza virus-specific CD45RA+CCR7-CD25+CD127+ T-cell subsets in both CD4+ and CD8+ T cells , observed the limited effector T cell reponse in healthy young adults who received seasonal influenza split-virus vaccine. We conclude that CD4+ T cells may provide a compensatory response to influenza infection when CD8+ T cells become compromised during the aging process.
Preventing lung immunopathology during a heterologous infection by functional inactivation of cross-reactive influenza A memory T cells (92.20)
Authors: Wlodarczyk Myriam , Kraft Anke , Chen Hong , Kenny Laurie , Selin Liisa 
Published: January 2023

Abstract
Heterologous immunity may help explain why any respiratory infection can cause a wide range of disease from asymptomatic to extremely severe, even resulting in death. Prior immunity to influenza A led to significantly increased viral load and lung pathology upon LCMV infection, the severity of which varied between genetically identical mice, but did not correlate with viral load. Flu-specific memory CD8 T cells mediated this increased pathology as evidenced by CD8 depletion studies and the observation that disease severity directly correlated with the expansion of two cross-reactive Flu-epitope specific memory CD8 T cell responses during LCMV infection. H2-Kb-restricted IAV-PB1703 and H2-Db-restricted IAV-PA224 responses cross-reacted with LCMV-GP34, and -GP276, respectively. Functionally inactivating these memory populations by peptide tolerization or blocking IFNγ activity greatly decreased lung pathology demonstrating novel therapeutic interventions. Flu-specific memory CD4 T cells mediated the enhanced viral load during LCMV infection as demonstrated by CD4 depletion studies and depletion of the early enhanced Th2 cytokine IL-4. These findings have important implications for understanding and potentially controlling variability in disease outcome during respiratory infections.
Altering hemagglutinin binding to B cells modulates original antigenic sin responses to influenza viruses (92.23)
Authors: Powers Ryan , Kim Jin , Steinhauer David , Jacob Joshy 
Published: January 2023

Abstract
Original antigenic sin is a phenomenon in which exposure to a novel influenza virus strain leads to production of antibodies against a related viral strain encountered in the past. These cross-reactive antibodies are produced at the expense of antibodies against novel epitopes in the current strain. The existence of original antigenic sin has been demonstrated in humans as well as mice, rabbits, guinea pigs and ferrets. Despite the fact that this phenomenon was first described in 1953, the mechanisms involved are poorly understood. We hypothesize that original antigenic sin results from selective activation of B cells, particularly memory B cells specific for cross-reactive antigenic determinants. The hemagglutinin of influenza viruses can bind to all B cells, irrespective of their B cell receptor specificity, via sialic acid binding. Such binding may activate memory B cells better because they have lower activation thresholds than naïve B cells. To test whether original antigenic sin resulted from targeting of the virus to B cells and activation of pre-existing memory B cells specific for influenza strains encountered in the past, we generated influenza viruses whose ability to bind to sialic acid receptors on B cell surfaces is severely diminished. Our results suggest such diminished B cell targeting modulates the induction of original antigenic sin.
IL-15 is required for the migration of influenza-specific effector CD8+ T cells to the lung airways (92.24)
Authors: Verbist Katherine , Cole Charles , Field Mary , Klonowski Kimberly 
Published: January 2023

Abstract
CD8 T cells targeted to conserved viral proteins can provide protection against multiple strains of seasonal and highly pathogenic influenza virus, mediating heterosubtypic immunity. However, in mice this protection declines over time as the number of influenza-specific CD8 T cells in the lung airways falls below a set numerical threshold, despite influenza-specific splenic memory CD8 T cells continually migrating to the lung airways. Thus, understanding how to enhance both the frequency and longevity of the Tmem population in the lung airways is critical to an effective CD8 T cell-mediated vaccine. Since IL-15 regulates the survival of anti-viral CD8 Tmem, we sought to determine whether local deficiencies in IL-15 were responsible for the attrition of influenza-specific CD8 T cells in the lung airways. Using wild type and IL-15 deficient animals, we found IL-15 to be dispensable for both the generation and maintenance of influenza nucleoprotein (NP)-specific CD8 Tmem in all tissues. However, IL-15-/- mice harbored fewer influenza-specific CD8 Teff cells in the airways. Furthermore, influenza-specific Teff migrated to IL-15 complexes in vitro and in vivo. Overall, our studies describe a unique role for IL-15 in regulating the trafficking of CD8 Teff to the lung airways following influenza infection and suggest that using IL-15 complexes as an adjuvant in the mucosa may represent a methodology to prolong protection by lung airway-resident CD8 T cells.
Expression of the orphan nuclear receptor NR4A2 is required for IL-17 production by Th17 cells and the induction of Th17-mediated autoimmunity (93.14)
Authors: Raveney Ben , Oki Shinji , Yamamura Takashi 
Published: January 2023

Abstract
Previously, we reported that NR4A2, an orphan nuclear receptor, is upregulated by peripheral blood cells during the human autoimmune disease multiple sclerosis (MS), as well as by peripheral blood cells and leukocytes infiltrating the central nervous system (CNS) during experimental autoimmune encecephalomyelitis (EAE). The pathology of MS and EAE is mediated by infiltration of both Th1 and Th17 cells into the CNS, but we reveal that upregulation of NR4A2 observed in CNS-infiltrating leukocytes and peripheral blood cells is most apparent amongst IL-17-secreting CD4+ T cells. Therefore, we examined the role of NR4A2 in the differentiation of these Th17 cells: transfection of naïve T cells with NR4A2 siRNA precludes IL-17 secretion when cultured under Th17 polarising conditions. However, such cells do proliferate and upregulate RORγt to the same extent as fully functional Th17 cells. IL-23 stimulation is critical in licensing IL-17 production by Th17 cells and that this depends on the upregulation of IL-23R by Th17 cells subsequent to autocrine IL-21 signalling. NR4A2 siRNA knock-down in CD4+ T cells prevents IL-21 production under Th17 polarising conditions and consequently such cells do not upregulate IL-23R. Addition of exogenous IL-21 circumvented NR4A2 knock-down, leading to IL-23R upregulation and IL-17 production. Furthermore, NR4A2 appears to be critical in generating Th17-mediated autoimmunity as systemic administration of NR4A2 siRNA prevented EAE induction.
Identification of a critical CYP2E1 epitope in patients with drug-induced liver injury from anesthetics (93.16)
Authors: Njoku Dolores , Li Zhaoxia , Li Haiyan , Ligons Davinna , Rose Noel , Njoku Dolores 
Published: January 2023

Abstract
Susceptible individuals develop immune-mediated drug-induced liver injury (DILI) after receiving halogenated anesthetics, anti-seizure medications, antibiotics or non-steroidal anti-inflammatory drugs. In anesthetic DILI, serum cytochrome P4502E1 (CYP2E1) autoantibodies and diminished CYP2E1 activity assist in confirming the diagnosis, while responsible epitopes are unknown. We hypothesize that anesthetic DILI is initiated by pathogenic CYP2E1 epitopes centered on the Ser129 active site and presented by MHC II molecules in susceptible haplotypes. To test our hypothesis, we identified 15 mer human CYP2E1 candidate epitopes centered on Ser129 that bind to mouse MHC II using competitive inhibition of OVA323 - 329 in I-Ad DO11.10 T cell hybridomas + LS102.9 activation. Next we measured splenocyte T cell proliferation to candidate epitopes using our model of anesthetic DILI in BALB/c mice two weeks following TFA-S100 immunizations. Two CYP2E1 epitopes were detected by competitive inhibition; however, only one epitope Gly113 - Leu135 was recognized by proliferation and human sera ELISA assays. SYFPEITHI prediction of the probability of binding confirmed H2-Ad and H2-Ed haplotypes in BALB/c mice and identified 6 human MHC II haplotypes that could bind this epitope: HLA-DRB1*0101, HLA-DRB1*0301 HLA-DRB1*0401, HLA-DRB1*0701 HLADRB*1101 and HLADRB1*1501. This is the first demonstration of a CYP2E1 epitope and MHC II haplotypes that may increase the risk of developing anesthetic DILI.
Pathogenic Potential of Trypanosoma cruzi-Induced Autoimmunity (93.2)
Authors: Bonney Kevin , Daniels Melvin , Taylor Joann , Epting Conrad , Engman David 
Published: January 2023

Abstract
Chagas heart disease (CHD), caused by the parasite Trypanosoma cruzi, is a potentially fatal myocarditis associated with cardiac autoimmunity. Immunization of A/J mice with heat-killed T. cruzi (HKTC) induces acute cardiac damage and polyantigenic humoral and cellular autoimmunity of a specificity and magnitude similar to that observed in infected mice, yet it does not cause cardiac inflammation. The goal of the present study was to determine the differences between the autoimmune response induced by T. cruzi infection and that initiated by HKTC immunization that may be responsible for the presence or absence of myocarditis. We hypothesized that certain inflammatory conditions or secondary immune stimuli might be required in order for T. cruzi-induced autoimmunity to lead to myocarditis. The antigen specificity, autoantibody titers, and DTH responses to a panel of known cardiac autoantigens were similar in infected and HKTC-immunized mice. However, the HKTC-immunized mice failed to develop the robust Th1/Th17-mediated immune response present in infected mice. This suggested that Th1/Th17 responses may be important for the development of myocarditis associated with live T. cruzi infection. Coadministration of Th1-promoting but not Th2-promoting adjuvants resulted in the development of myocarditis in HKTC-immunized mice, supporting this hypothesis.
HLA alleles not associated with arthritis predispose by forming HLA- DQbeta-DQalpha trans-heterodimer (93.27)
Authors: Taneja Veena , Behrens Marshall , David Chella 
Published: January 2023

Abstract
HLA-DQB1*0302/DQA1*0301 renders humans and transgenic mice susceptible to develop arthritis while HLA-DQB1*0601/DQA1*0103 has been associated with resistance to arthritis in both. However, some patients of rheumatoid arthritis carry the non-associated alleles. Most of the studies do not take in to account the role of DQA1 alleles. DQB1*0604 generally occurs in linkage with DQA1*0102. To understand the role of trans-heterodimer, we generated DQB1*0604/ DQA1* 0103 transgenic mice lacking endogenous class II molecules. Previous studies have shown that DQB1*0601/DQA1*0103 transgenic mice are resistant to develop collagen-induced arthritis. The DQB1*0604/A1*0103 and DQA1*0103 mice developed severe arthritis and generated antigen-specific response in vitro. The DQB1*0604/ DQA1*0103 could present CII-derived peptides that are not presented by RA resistant DQ6 allele suggesting that trans-heterodimer molecules between two DQB1 and DQA1 molecules may result in presentation of unique antigens and susceptibility to develop arthritis. The data provides a possible explanation for the presence of HLA alleles not associated with arthritis in some patients.
Donor CD8 T cell activation is critical for sex based differences in lupus-like disease in DBA-into-F1 mice. (93.31)
Authors: Foster Anthony , Haas Mark , Puliaeva Irina , Soloviova Kateryna , Puliaev Roman , Via Charles 
Published: January 2023

Abstract
Transfer of DBA splenocytes into BDF1 mice (DBA-&gt;F1) results in donor CD4 T cell mediated lupus-like renal disease that is more severe in females and preceded at day 14 by greater female CD4 T cell engraftment. Donor CD8 T cells have no reported role. To compare sex based differences in donor CD4 T cell function, we transferred CD8 depleted DBA splenocytes and surprisingly observed that greater female renal disease severity and greater day 14 female CD4 engraftment were lost or significantly reduced. Kinetic analyses demonstrated that mice receiving undepleted donor cells exhibited a stronger day 8-12 graft-vs.-host (GVH) and host vs. graft (HVG) responses in males followed by contraction of donor CD8 T cells. The weaker GVH/HVG in females was followed by persistence/increase in donor CD8 T cells. Importantly, sex based differences in GVH/HVG were lost or attenuated in mice receiving CD8 depleted splenocytes, linking sex based differences in day 8-10 GVH/HVG to differences in day 14 CD4 engraftment. We conclude that: 1) donor CD8 T cells enhance the proliferation of donor CD4 T cells in both sexes; and 2) prolonged survival of donor CD8 T cells in females is causally related to greater day 14 engraftment of donor CD4 T cells in females. These results support the novel conclusion that sex based differences in sub optimal donor CD8 CTL activation are critical for shaping sex based differences in donor CD4 T cell engraftment at two weeks and lupus like disease long term.
Increased levels of IgA and IgA deposition in kidney glomeruli of influenza infected ST6Gal I deficient mice (93.38)
Authors: Onami Thandi , Acharya Suneeta , Zeng Junwei , Sangster Mark 
Published: January 2023

Abstract
ST6Gal I, a glycosyltransferase highly expressed by B cells, catalyzes the addition of alpha-2, 6 sialic acid to galactose (Siaα2-6Gal), a modification found on N-linked glycoproteins. Aberrant glycosylation has been associated with the pathogenesis of IgA nephropathy (IgAN), a disease characterized by immune complex deposits in the glomerular mesangium, which can lead to end-stage renal failure in 20-40% of diagnosed patients. Previously, we have shown that ST6Gal I-/- mice infected with influenza A/HKx31 demonstrated profound impairment in the generation of viral-specific humoral responses, although memory IgG responses were mostly normal. We now show that influenza infected ST6Gal I-/- mice had higher levels of influenza-specific IgA and total IgA in sera at memory compared to WT mice. Additionally, we observed increased deposition of IgA in the glomeruli of kidneys of ST6Gal I-/- mice, although no differences were noted in urinalysis. These data suggest that loss of expression of an alpha-2,6 sialyltransferase, together with influenza viral infection, can contribute to increased deposition of IgA in mouse kidney glomeruli, and may contribute to the pathogenesis of one of the most common forms of glomerulonephritis in humans.
Engraftment of peripheral blood mononuclear cells from patients with type 1 diabetes in NOD-scid HLA-A*0201/γc -/-immunodeficient mice (93.5)
Authors: Larry Fatima , Young Ellen , Fudge Elizabeth , Azam Anita , Patel Shipra , Joseph Largay , Warren Byrd , Buse John , Calikoglu Ali , Frelinger Jeffrey 
Published: January 2023

Abstract
Type 1 diabetes (T1D) is an autoimmune disease characterized by insulitis followed by CD4+ and CD8+ T cell-mediated destruction of the insulin-producing pancreatic beta cells. Studies have demonstrated the presence of circulating islet-antigen specific CD4+ and CD8+ T cells during the clinical onset of disease. Over the past twenty years non-obese diabetic (NOD) mice have provided a useful tool for understanding human T1D. However, the study of human CD4+ and CD8+ T cell-mediated responses and the development of novel therapeutics for T1D requires an in vivo humanized animal model. In order to develop a model where we could investigate the function of human diabetogenic T cells in vivo we transferred peripheral blood mononuclear cells (PBMCs) from patients with T1D into NOD-scid HLA-A*0201/γc-/- transgenic immunodeficient mice. Following adoptive transfer we examined human T cell survival and homing. We isolated human CD4+ and CD8+ T cells from the pancreatic lymph node, spleen and islets of these mice for up to seven weeks. Our data suggest that this may be a useful humanized mouse model system for studying type 1 diabetes.
IL15-DC activate Th17 and Th1 responses upon encounter with wheat gliadin, the dietary antigen in Celiac disease (93.6)
Authors: Harris Kristina , Fasano Alessio , Mann Dean 
Published: January 2023

Abstract
Celiac disease (CD) is an autoimmune disease triggered by dietary glutens in genetically susceptible individuals. A direct role for IL-15 has been demonstrated in the disease process; however, the relationship between this cytokine and the adaptive immune response that ensues is not clear. Recent studies show that IL-15 drives monocytes into APC with potent proinflammatory potential, termed IL15-DC. Therefore, we examined the immune response of IL15-DC exposed to a digest of wheat gliadin (PTG), the exogenous factor in CD. Using PBMC from healthy donors, we found that IL15-DC secreted IL-1b, IL-6, IL-23, TNFa and CCL20 and produced surface IL-15 in response to PTG. IL15-DC loaded with PTG subsequently activated Th17 and Th1 responses from autologous CD4+ T cells in a contact-dependent and IL-15-dependent manner, respectively. Importantly, lower concentrations of IL-15 augmented Th1 responses induced by PTG in PBMC from CD patients compared to controls. These findings demonstrate that IL-15 supports Th17 and Th1 responses to a dietary antigen that is normally well-tolerated in healthy individuals by generating IL15-DC. These potentially pathogenic immune responses may occur in CD patients and not healthy individuals as a consequence of being hyper-responsive to IL-15 produced in the intestine upon encounter with PTG. Therefore, genetic and/or environmental factors that control IL-15 expression and responsiveness in the intestine likely participate in the pathogenesis of CD.
G-protein coupled receptor kinase-5 mediates Toll-like receptor-4-induced NFκB activation in primary macrophages and in vivo in mice (94.11)
Authors: Shahi Shipra , Patial Sonika , Saini Yogesh , Appledorn Daniel , Lapres John , Amalfitano Andrea , Parameswaran Narayanan 
Published: January 2023

Abstract
Toll-like receptor-4 (TLR4) activated by lipopolysaccharide (LPS) is involved in a number of inflammatory diseases, in part via activation of NFκB pathway. G-protein coupled receptor kinase-5 (GRK5), a serine-threonine kinase originally discovered for its role in desensitization of G-protein coupled receptors has recently been shown to regulate NFκB pathway stimulated by non-GPCRs. This study was undertaken to determine the potential role of GRK5 in inflammatory signaling in primary macrophages and in vivo using GRK5 knockout (KO) mice. We demonstrate here that TLR4-induced IκBα-NFκB pathway is selectively inhibited in primary macrophage from GRK5 KO mice compared to cells from GRK5 wild type (WT) mice. Consistent with the effects on the NFκB pathway, LPS-induced production of many inflammatory cytokines/chemokines (including Interleukin-2, -3, -4, -5, -12, -17, MCP-1, IFNγ, KC, GMCSF and Eotaxin) are inhibited in GRK5 KO macrophages. Confirming this in vitro data, LPS-induced cytokines/chemokines levels in the plasma are also significantly inhibited in the GRK5 KO mice in vivo. Associated with these effects LPS-mediated liver injury is markedly decreased in the GRK5 KO mice. Taken together, our findings demonstrate that GRK5 acts as a positive regulator of TLR4 signaling in vivo and further suggest that these findings could have potential implications for drug development in inflammatory diseases.