bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distant homolog identifies novel viral immune evasins from herpesvirus proteome (VIR5P.1031)
Authors: Xu Bin , Wu Ling , Zhai Lu , Li Feng 
Published: January 2023

Abstract
Viruses have evolved a number of mechanisms to avoid host immune responses. Herpesviruses have been known as a rich source in viral evasion genes including homologs mimicking the structures and functions of host immune proteins. Using a rapid high throughput computational structural mimicry analysis, we have screening the whole proteome of human herpesviruses that includes nearly 2,000 proteins. We discovered a number of novel distant viral homologs in herpesvirus proteome that are previously uncharacterized. This includes homologs involving MHC class I pathways and NK immune defense, or chemokine and cytokine mimics. Sequence identities between viral mimics and native host ligands/receptors can be as low as 9-25%. Two novel distant homologs are of particular interests as they are predicted to be involved in MHC class I modulation. These novel homologs are being expressed and produced and are undergone further characterization to determine their structural and functional characteristics and their roles in viral immune evasion. From these herpesviral homologs and their predicted structures, we hypothesize that herpesviruses utilize a variety of binding mechanisms to regulate a class of key MHC I molecules including MICA/B.
Cytomegalovirus and early-life irradiation synergize to erode protective immunity in aging (VIR5P.1034)
Authors: Pugh Jason , Sukhina Alona , Smithey Megan , Nikolich-Zugich Janko 
Published: January 2023

Abstract
Susceptibility to infectious disease increases with age, making it one of the leading causes of death in people over 65. The immune aging process may be accelerated by the presence of life-long latent infections, such as cytomegalovirus, that put a constant burden on the immune system. Theories of biological aging also suggest that immune cells may have defective functions in old age because of a lifetime of self-renewal, and DNA damage related senescence, among other factors. Sub-lethal whole-body irradiation results in dose-dependent death of immune cells throughout the body, forcing some peripheral self-renewal of surviving immune cells. We exposed mice to various sub-lethal irradiation doses (0Gy - 4Gy) in youth, and followed them for life. Some mice were also given life-long murine cytomegalovirus (MCMV) to reflect the most common latent virus in human populations. At the end of life, mice were vaccinated against, and then infected with, a potentially lethal dose of West Nile Virus (WNV). Neither MCMV, nor any dose of sub-lethal irradiation, independently altered survival following vaccination and WNV infection. However, mice that received a combination of 4Gy of irradiation in youth, and life-long MCMV infection, were less likely to survive WNV challenge. Mechanisms and implications for radiobiology, immune aging, and vaccine efficacy will be discussed.
Dysregulated immune responses in lupus-prone mice facilitate Th1-cell immunity against influenza A (BA12P.103)
Authors: Slight-Webb Samantha , Crowe Sherry , Anderson Jourdan , James Judith 
Published: January 2023

Abstract
Influenza viruses are a primary cause of respiratory tract infections causing the highest number of hospitalizations and mortalities out of any viral respiratory pathogen. In patients with systemic lupus erythematosis (SLE), infections remain a major cause of morbidity and early mortality. Despite the availability of vaccines, only antigenically related infections are prevented and vaccines may be less effective in some SLE patients. Whether infectious disease risk results from SLE-associated innate and adaptive immune defects or from immunosuppressive medication effects (or both) remains unknown. Using a murine model of SLE, we show MRL-lpr/lpr mice infected with influenza A PR8/34 H1N1 have delayed morbidity and decreased cellular infiltration into the lung compared to MRL/MPJ and C57BL/6 control mice. In addition, we show that lupus-prone mice accumulate more pulmonary IFNγ and TNFα virus-specific CD4+ and CD8+ T cells to clear infection. However, MRL-lpr/lpr mice have increased levels of IL-10 compared to controls limiting pulmonary inflammation. We further show that influenza virus did not increase production of lupus-specific autoantibodies or total IgG in SLE mice. These data suggest that the activated immune response of lupus-prone mice assists in the control of influenza A virus without worsening of disease symptoms.
Intricate interplay of cytokines determine the progression of SLE-like disease in BXSB.Yaa mice (BA12P.104)
Authors: Jain Shweta , Adkins Elisabeth , McPhee Caroline , Christianson Gregory , Sproule Thomas , Shin Dong-Mi , Roopenian Derry , Morse Herbert 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is a complex multi-organ disease that affects mostly females. It is caused by several environmental, genetic and stochastic factors. BXSB.Yaa is a recombinant inbred strain of mice with major manifestations that parallel those of human SLE, thereby making it a model system to investigate genetic and non-genetic determinants of disease initiation and progression. The Yaa mutation in male results due to translocation of a 4Mb chromosomal region, including Tlr7 gene, from X to the Y chromosome, making them susceptible to disease. The disease pathogenesis involves an intricate interplay of key cytokines such as IL-21, IL-6, Type I interferon (IFN) and IL-10. Enhanced expression of IL-21 by CD4-T (Tfh) cells expands autoreactive B cells that differentiate into plasmablasts and secrete autoantibodies. IL21 also promotes the development of CD8-T cells and NK cells which retard early disease development. Gene expression profiles of cells from young IL-21R deficient BXSB.Yaa mice revealed an “IFN signature” similar to human SLE females. Purified plasmacytoid dendritic cells (pDCs) from male mice produced higher levels of Type-I IFN than females. Type I IFN further stimulates IL6 producing B cells that drives differentiation of CD4 Tfh cells. IL6 also contributes to accelerated mortality in BXSB.Yaa mice. Moreover, BXSB.Yaa mice express IL10 and ablation of IL10 in these mice results in accelerated mortality.
CD275/ICOSL-independent germinal centers and autoantibody in autoimmune-prone RasGRP1-deficient mice (BA13P.125)
Authors: Barrington Robert , Buhlmann Janet , Wang Xiaogan , Bartlett Amber , Lim Bing , Smith William 
Published: January 2023

Abstract
Lymphopenia results in favorable microenvironments for the expansion and activation of autoreactive lymphocytes. Mice deficient in guanine nucleotide exchange factor Rasgrp1 (KO) are T lymphopenic early in life and develop a lymphoproliferative disorder with features of human SLE. Our previous work revealed that autoreactive B cells lacking RasGRP1 break tolerance early during development as well as during germinal center responses, suggesting both T cell-independent and -dependent mechanisms are responsible. To understand whether T cells are involved in the breach of tolerance in germinal centers, we examined T effector cells in KO mice. In addition to the expected increase in Th1 cells, the frequency and number of Th17 cells were also elevated in KO mice. Th17 cells were positive for CXCR5 and Bcl-6, localized to germinal centers and upregulated levels of CD278/ICOS coordinately with the appearance of germinal centers, all attributes of T follicular helper cells (Tfh17). To determine whether CD278-CD275 interactions were required for the development of Tfh17 cells and for autoantibody, we crossed KO and CD275-deficient mice. Interestingly, KO mice lacking CD275 formed germinal centers with an elevated frequency of Th17 cells and similar titers of autoantibodies. From these data, we suggest that CD278-CD275 interactions are not required for germinal centers and autoantibody production in mice lacking RasGRP1.
IL-13Rα1 plays a role in CD4+ T cell stimulation by antigen presenting cells and affects CNS autoimmunity (BA14P.213)
Authors: Khairallah Marie-Therese , Ellis Jason , Chen Weirong , Miller Mindy , Ukah Tobechukwu , Zaghouani Habib 
Published: January 2023

Abstract
Multiple sclerosis (MS) and its animal model, experimental allergic encephalomyelitis (EAE), are immune-mediated inflammatory diseases of the central nervous system (CNS) triggered by activation of myelin-reactive Th1 and Th17 cells. Both IL-4 and IL-13 cytokines are regarded as anti-inflammatory cytokines against the disease but the mechanism by which these cytokines exercise modulatory function remains largely unknown. Since the heteroreceptor (HR) comprising IL-4 receptor alpha (IL-4Rα) and IL-13Rα1 is shared by both cytokines, we envisioned that IL-4 and IL-13 utilize the HR to drive disease modulation. The findings indicate that mice, in which the heteroreceptor has been made non-functional by gene deletion exhibited earlier onset and more severe disease symptoms when induced for EAE with myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide. In addition, MOG-specific T cell responses had increased IL-17 but reduced IFNγ production relative to heteroreceptor sufficient mice. Intriguingly, the HR-deficient mice had increased T regulatory cells relative to HR-sufficient animals. These findings suggest that the HR plays a role in the development of Tregs and regulate their function toward pathogenic cells in a subset specific manor.
Absence of IFNγ increased brain pathology in EAE-susceptible DR3DQ8 HLA transgenic mice through secretion of IL-17 and induction of pathogenic monocytes/microglia into the CNS (BA14P.202)
Authors: Mangalam Ashutosh , Luo Ningling , Luckey David , Papke Louisa , Smart Michele , Giri Shailendra , Rodriguez Moses , David Chella 
Published: January 2023

Abstract
Among all the genetic factors linked with multiple sclerosis (MS), MHC class-II molecules show the strongest association. Generation of HLA class-II transgenic mice has helped to elucidate the role of HLA class-II gene in MS. We have shown that the human HLA-DR3 (DRβ1*0301) gene predisposes to proteolipid protein (PLP)-induced EAE, whereas HLA-DQβ1*0601 (DQ6) was resistant. We also showed that the DQ6 molecule protects from EAE in DR3DQ6 double transgenic mice by producing anti-inflammatory interferon gamma (IFNγ). To further confirm the role of IFNγ in protection, we generated DR3DQ8 mice lacking IFNγ (DR3DQ8.IFNγ-/-). Immunization with PLP91-110 peptide caused atypical EAE in DR3DQ8.IFNγ-/- mice characterized by ataxia and spasticity, hallmarks of brain-specific disease. Severe brain specific inflammation and demyelination in DR3DQ8.IFNγ-/- mice with minimal spinal cord pathology further confirmed brain-specific pathology. Severe disease in DR3DQ8.IFNγ-/- mice was due to increased encephalitogenicity of CD4 T cells and its ability to produce higher levels of IL-17 and GM-CSF compared to DR3DQ8 mice. Further, areas with demyelination showed increased presence of CD68+ inflammatory cells suggesting an important role for monocytes/microglia in causing brain pathology. Thus, our study supports a protective role for IFNγ in inflammatory and demyelinating disease through down regulation of IL-17 and induction of neuro-protective factors in the brain by monocytes/microglial cells.
Differential regulation of T cell responses and disease severity by mycoplasma and its superantigen in autoimmune diabetic mouse (BA15P.228)
Authors: Mu Hong-Hua , Nourian Maziar 
Published: January 2023

Abstract
Infection has been extensively documented as a serious problem causing high mortality and morbidity in diabetic populations. M. arthritidis produces a potent superantigen (SAg) MAM, which has been shown to be at least partially responsible for the septic shock induced in certain susceptible mouse strains. In the present study, we have investigated how diabetic immune cells respond to the M. arthritidis and MAM SAg. By using two well-defined animal models of diabetes, STZ and NOD mice, we found that STZ mice infected with M. arthritidis developped severe lethal toxicity and the immune cells predominantly produces pro-inflammatory cytokines TNFalpha, IL-6, IL-1β, chemokines CCR2/4 and Tbx21, a Th1-related transcription factor; while MAM-activated T cells from NOD mice display a mixture of Th1 and Th17 profiles which are associated with the elevated levels of ICOS molecule and a unique transcription factor LSF (tcfcp2). Since ERK, a signaling protein of MAPK family, is reported to be responsible for the phosphorylation of LSF in T cell activation, thus we propose a novel ERK-LSF-ICOS signaling cascade that is required for the Th1/Th17 development in NOD mice in response to MAM. Our findings further suggest that the inhibition of these molecules might be potentially therapeutic in the alleviation of mortality and morbidity in diabetic individuals with severe infections.
In autoimmune-prone NOD mice, altered DC subsets induce aberrant activation of CD4 T cells, yet DCIR2+ DCs can still induce tolerance. (BA15P.218)
Authors: Tarbell Kristin , Price Jeffrey , Rahir Gwendoline , Beauchamp Nicole , Zhao Yongge , Dong Matthew 
Published: January 2023

Abstract
Stimulation of CD4+ T cells by antigen targeted in vivo to dendritic cells (DCs) in the absence of inflammation usually leads to tolerance. However, DCs are altered in autoimmune-prone mice such as non-obese diabetic (NOD) mice, a model for type 1 diabetes. We observed altered DC responses in NOD mice to innate immune stimuli such as CpG, which may alter the ability of these DCs to induce tolerance. In addition, determining which antigen presenting cell populations are capable of inducing tolerance in the context of chronic autoimmunity is critical for antigen-specific treatments for autoimmune disease. We recently reported that in NOD mice, DEC-205+ DCs induce effector responses, not tolerance, in autoreactive CD4+ T cells. We now show that DCIR2+ DCs, distinct from DEC-205+ DCs, can be tolerogenic in NOD mice. Beta cell antigen targeted via chimeric antibody to DCIR2+ DCs delays disease induction in a transfer model of type 1 diabetes. DCIR2+ DC stimulation induces partial deletion of autoreactive CD4+ T cells and remaining cells are unable to produce IFN-γ. These disparate T cell outcomes after targeting antigen to DEC-205+ or DCIR2+ DCs are underpinned by differential gene expression in antigen-specific T cells early after stimulation. In conclusion, we have characterized defects in DCs in NOD mice, and the resulting altered T cell responses with the goal of identifying ways to induce tolerance even in the context of autoimmunity.
The transcription factor Bcl-3 represses the function of regulatory T cells leading to the development of colitis (BA15P.223)
Authors: Reissig Sonja , Nikolaev Alexey , Waisman Ari , Hoevelmeyer Nadine 
Published: January 2023

Abstract
The proto-oncogene Bcl-3 (B cell leukemia-3) is a member of the IκB family of NF-κB inhibitors and was originally identified as a component of a chromosomal rearrangement in some B cell lymphomas. In contrast to other IκB proteins, Bcl-3 associates with p50 and p52 homodimers and is predominantly a nuclear protein involved in regulating nuclear NF-κB activity. To understand more about the effects of Bcl-3 on T cells, we have generated a new mouse model, where Bcl-3 is overexpressed specifically in T cells. We could show that mice overexpressing Bcl-3 solely in T cells developed spontaneous colitis accompanied by a massive cell infiltration into the colon. Interestingly, by analyzing regulatory T cells we could demonstrate that these cells were not able to suppress an inflammatory response. Due to the suppressive dysfunction, Tregs of Bcl-3 overexpressing mice expressed less CD25, Foxp3 as well as less of the co-inhibitory molecule CTLA-4. Hence, the loss of suppression of Bcl-3 overexpressing Tregs might result in the development of severe spontaneous colitis. Our data emphasize a novel pathway in the maintenance of viability and suppressive function of Tregs in the gut that critically involves Bcl-3 as a negative regulator, qualifying this protein as an interesting pharmacological target for the treatment of IBD.
Autocrine il-6 drives skin-derived mesenchymal stem cell trafficking via regulating voltage-gated ca2+ channels (CAM5P.243)
Authors: Wang Honglin , Ke Fang , Zhang Lingyun , Liu Zhaoyuan , Yan Sha 
Published: January 2023

Abstract
Mesenchymal stem cells (MSCs) have demonstrated promising therapeutic potential for a variety of diseases including autoimmune disorders. A fundamental requirement for MSC-mediated in vivo immunosuppression is their effective trafficking. However the mechanism underlying MSC trafficking remains elusive. Here we report that skin-derived MSCs (S-MSCs) secrete high levels of interleukin-6 (IL-6). Disruption of the il6 or its signaling transducer gp130 blocks voltage-gated Ca2+ channels (VGCC) critically required for cell contraction involved in the sequential adhesion and de-adhesion events during S-MSC migration. IL-6 directly regulates CaV2.3 encoded by cacna1e of R-type Ca2+ channels through the JAK3/STAT3 pathway. Deletion of il6 or silencing CaV2.3 gene leads to a severe defect in S-MSC’s trafficking and immunosuppressive function in vivo. Thus, this unexpected requirement of autocrine IL-6 for activating CaV2.3 Ca2+ channels uncovers a previously unrecognized link between the IL-6 signaling and the VGCC, and provides novel mechanistic insights for the trafficking and immunomodulatory activities of S-MSCs.
Effect of adiponectin on a disintegrin and metalloproteinase with thrombospondin motifs-9 gene expression in human chondrocytes (CCR5P.257)
Authors: Yaykasli Kursat , Dogan Mustafa , Hatipoglu Omer , Yaykasli Emine , Kaya Ertugrul , Ozsahin Mustafa , Uslu Mustafa 
Published: January 2023

Abstract
A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) is a family of peptidases. They comprise 19 members, and have several vital functions in organism. ADAMTS-9 with aggrecanolytic activity is responsible for the degradation of the articular cartilage components like aggrecan. Adiponectin is the most abundantly secreted adipokines (adipocytokines), and the characteristic of adiponectin is controversial. It was assumed that adiponectin has anti-inflammatory effect. However, recent studies showed the inflammatory features of adiponectin. It was aimed to evaluate the effect of adiponectin on ADAMTS-9 gene expression in human chondrocytes. Human articular chondrocytes were cultured and exposed by adiponectin at 1, 4, 8 and 12 µg/ml doses. At the end of the incubation, total RNA was reverse-transcribed by random primer. The expression levels of the ADAMTS-9 and β-actin genes were determined using real-time polymerase chain reaction. The ADAMTS-9 gene expression was found to increase after adiponectin incubation at 12 µg/ml dose. The interleukin-1β induced ADAMTS-9 gene up-regulation and the increased serum level of ADAMTS-9 in patients with osteoarthritis (OA) were reported before. Similarly, the putative involvement of adiponectin in OA and rheumatoid arthritis (RA) was demonstrated. Together with these findings, our results suggesting that adiponectin may involve in the degradation of aggrecan by increasing ADAMTS-9 gene expression.
IL-10 and IL-24 expression is regulated by distinct pathways in macrophages and NK cells (CCR5P.252)
Authors: Dabitao Djeneba , Christian Hedrich , Huska Jason , Bream Jay 
Published: January 2023

Abstract
Homologous gene in clusters can be coordinately regulated by shared genomic elements to synchronize biologic functions. Within the Il10 locus which includes Il19, Il20 and Il24, only IL-10 and IL-24 are preferentially expressed by Th2 cells. The extent to which IL-24 is regulated in other IL-10-producing cell types and its role in immunity remains unclear. To determine if these genes share regulatory pathways, we examined IL-24 expression in macrophages and NK cells which are key sources of IL-10. In macrophages, maximal LPS-induced IL-24 expression requires IL-4 and Stat6 while IL-10 induction is largely independent of Stat6. Likewise, in NK cells, IL-10 expression is independent of IL-4 but IL-24 is strongly induced by IL-4 in combination with IL-2 and is dependent on Stat6. We identified 4 putative Stat-binding elements in the Il24 gene and found that each site binds IL-4-induced Stat6 in macrophages and NK cells. Interestingly, these sites also bound Stat4 in IL-12-stimulated NK cells but not in macrophages. In NK cells, IL-24 expression required type I IFN signaling regardless of the stimulation while IL-10 expression required type I IFNs only in macrophages. Histone modifications in Il24 were dependent on IL-4/Stat6 in macrophages but not in NK cells. Our results indicate that although IL-10 and IL-24 are co-expressed in macrophages and NK cells, they are governed by distinct signaling pathways suggesting they are unlikely to share genomic regulatory elements.
Crystal structures of FasL:DcR3 and LIGHT:DcR3 complexes reveal the molecular basis for the broad specificity of DcR3 (CCR5P.255)
Authors: Liu Weifeng , Zhan Chenyang , Nathenson Stanley , Almo Steven 
Published: January 2023

Abstract
Decoy receptor 3 (DcR3) is a secreted TNF receptor discovered in human beings but not in mice. DcR3 is able to neutralize three TNF ligands, LIGHT, FasL and TL1A and further modulate the immune response. For example, neutralization of LIGHT by DcR3 can manipulate the co-stimulatory signal triggered by LIGHT:HVEM interaction or the cell death signal resulted from LIGHT:LTβR interaction. Upon ligation with FasL, DcR3 can block the cell apoptosis pathway commenced by FasL:Fas interaction. Besides, DcR3 binds to TL1A, which can interrupt its interaction with DR3 to boost T cell immunity or induce cell apoptosis in different cell types. Although the remarkable ability of DcR3 to neutralize three different ligands has already been realized, the mechanisms which support the broad specificity of DcR3 remain to be fully defined. Here I present the novel crystal structures of the FasL:DcR3 and LIGHT:DcR3 complexes. Along with the TL1A:DcR3 structure solved in our lab previously, the whole set of the structures of TNF:TNFR complexes engaged by DcR3 was solved. Our results show that the loops of the ligands are the major determinants for the recognition of DcR3. By appropriate conformational alterations of the flexible loops but not the rigid beta-strand sheets, the diverse residues on the loops of different ligands are able to capture the cognate residues on DcR3 by polar contacts and hydrophobic interactions, thus enable the different TNF ligands to bind to the same DcR3.