bluuebunny/crossref_metadata_2025_split huggingface dataset:
When signals get crossed: the consequences of dual allergen- and influenza-mediated signaling in mast cells
Authors: Temple Rachel Mary , Amiel Eyal , Obar Joshua J 
Published: January 2023

Abstract
Despite the many advances in our understanding of viral infections, influenza A virus (IAV) continues to impose a significant heath burden and presents a serious threat for a worldwide pandemic. Severe IAV infection is characterized by a cytokine storm. Recent evidence indicates mast cell activation is a key initiator of this cytokine storm during severe IAV infection. During the 2009 H1N1 pandemic, asthma was the most common co-morbidity among hospitalized individuals suggesting a potential interplay between pre-existing mast cell disease and IAV infection. Experimental data examining the cross-talk that can occur during dual FcɛRI and IAV stimulation of mast cells is lacking. Here we show that signaling through FcɛRI concurrent with IAV infection (A/WSN/33) augments the mast cell response resulting in a highly synergist enhancement of cytokine synthesis and release by these cells in vitro. Surprisingly, while IAV induced cytokine production by A/WSN/33 is dependent on the MAVS pathway, using bone marrow cultured mast cells from MAVS and STING knockout mice, we determined this synergistic effect can occur independent of MAVS signaling and the STING adaptor. Furthermore, the synergy can be observed as early as 1 hour PI, prior to significant viral replication. These data suggest an early signaling event is responsible for the synergy. Our data supports a role for the lipid mediator sphingosine-1-phosphate, which is known to be important during allergen stimulation, and as our data demonstrates, is essential for proper IAV activation of mast cells. Taken together, our data suggest that IAV may incite asthmatic exacerbation through enhanced cytokine production from mast cells receiving two distinct stimuli simultaneously.
Dysregulation of ERK signaling in CD4-expressing cells induces osteochondromas
Authors: McGargill Maureen Ann , Wehenkel Marie , Corr Maripat , Guy Clifford S , Edwards Benjamin A , Calabrese Christopher , Pages Gilles , Pouyssegur Jacques , Vogel Peter 
Published: January 2023

Abstract
ERK1 and ERK2 are serine/threonine kinases critical for the proliferation and development of many cell types. Mice with a germline deletion of Erk1 bred to mice with a conditional deletion of Erk2 mediated by CD4cre (DKOCD4 mice) exhibit a profound block in T cell development in the thymus. Surprisingly, 80% of DKOCD4 mice spontaneously developed osteochondromas by 28 weeks of age. Histological analysis of these lesions revealed excessive accumulation of hypertrophic chondrocytes originating from the growth plates in the bone, but no mononuclear infiltrate indicative of inflammation. As the majority of CD4+ cells are T cells, we investigated whether these lesions were caused by deletion of Erk2 in T cells by breeding the DKOCD4 mice to Rag1−/− mice. Unexpectedly, osteochondromas still appeared in DKOCD4Rag1−/− mice. In fact, osteochondromas developed faster and were more severe in DKOCD4Rag1−/− mice compared to DKOCD4 mice, indicating that deletion of Erk2 in other cell types mediates excess cartilage accumulation. Furthermore, the addition of T cells to DKOCD4Rag1−/− mice delayed development of osteochondromas, showing that T cells play an important role in regulating cartilage homeotstasis. Furthermore, the development of the osteochondromas appears to be influenced by changes in the microbiota, as DKOCD4 mice treated with an antibiotic cocktail have a delay in osteochondroma development, while mice housed in non-specific pathogen free conditions had accelerated onset of tumors. Together these data suggest that Erk plays a critical role in a CD4+ cell type other than T cells, possibly an innate lymphoid cell, to alter cartilage growth. In addition, we present a novel role for T cells in regulating cartilage homeostasis.
Lupus T and B cell cross-reactivity between the human Ro60 autoantigen and Ro60 orthologs from the human microbiota
Authors: Greiling Teri , Dehner Carina Anja , Renfroe Stephen , Chen Xinguo , Vieira Silvio Manfredo , Ruff William , Goodman Andrew , Wolin Sandra , Kriegel Martin A 
Published: January 2023

Abstract
Human Ro60 is an RNA binding protein that is commonly targeted in systemic autoimmunity. We identified Ro60 orthologs that are conserved in a subset of skin, oral, and gut commensal species. Since anti-Ro60 antibodies are the earliest autoantibodies detected in lupus patients, we hypothesized that commensal Ro60 orthologs may trigger autoimmunity via autoepitope cross-reactivity in genetically susceptible individuals. While Ro60-producing gut commensals were common among both healthy controls and lupus patients, only antibodies from 4 Ro60-positive lupus patients, but not Ro60-negative subjects, co-immunoprecipitated Ro60 and its bound Y RNA from the Ro60-containing skin commensal P. propionicum. This suggests antibody cross-reactivity between human Ro60 antibodies and commensal Ro60. Next, Ro60-specific CCR6+ and CCR6- CD4 memory T cells clones from lupus patients were generated using a T cell library assay. Ro60 CCR6+ T cell clones proliferated in response to P. propionicum, demonstrating T cell cross-reactivity with commensal Ro60. Finally, germ-free mice monocolonized with B. thetaiotaomicron, a Ro60 ortholog-containing gut commensal, produced fecal anti-human Ro60 IgA antibodies (n=4, p=0.04), linking anti-Ro60 commensal responses in vivo with the generation of human Ro60 autoantibodies. In summary, Ro60 autoimmune T and B cells from human lupus patients cross-reacted with commensal Ro60 in vitro and commensal Ro60 triggered anti-Ro60 antibodies in vivo. Taken together, these data suggest that colonization with autoantigen ortholog-carrying species may sustain chronic autoimmunity in patients. This concept could lead to development of novel therapeutic approaches targeted at the human microbiota.
TLR7 responsiveness of human transitional B cells
Authors: Giltiay Natalia V , Shu Geraldine , Wang Ting , Marken John , Durcan Laura , Clark Edward A 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is a complex autoimmune disease that is known to be associated with B cell hyperactivity and production of autoantibodies (Auto-Abs) against nucleoproteins. Auto-Abs reactive to RNA-containing antigens are found in a fraction of SLE patients, particularly those with severe disease activity. Toll-like receptor 7 (TLR7), an intracellular TLR that recognizes ssRNA, has been highly implicated in the generation of pathogenic anti-RNA autoantibodies in SLE; however, the cellular origin of anti-RNA Ab–secreting cells is not well defined. We have found that increased expression of TLR7 in TLR7Tg mice results in activation of their newly-formed (NF) transitional B cells which upon stimulation produced class-switched IgGs, including anti-RNA auto-Abs. Subsequent analysis of the B cell compartment in SLE patients revealed a correlation between the levels of TLR7 expression and increases in the frequencies of circulating CD20+CD27−CD10+CD38highCD24high NF B cells. SLE patients with dysregulation of NF B cells were also more likely to have Sm/RNP auto-Abs. IFNa treatment induced more than a 10-fold increase in the mRNA expression of TLR7, UNC93B and IRF7 in NF B cells isolated from umbilical cord blood. Furthermore, IFNa-primed NF B cells became highly responsive to in vitro stimulation with TLR7 ligand-R848 and differentiated into CD27+CD38hiCD24lo plasmablasts in the absence of any other stimuli. Human NF B cells are enriched in polyreactive specificities and increases of NF B cells have been described in SLE patients. Our studies suggest that human NF B cells might be an important source of auto-Ab-secreting cells and provide a new link between innate IFNa and TLR7 signaling and B cell activation in SLE.
MDSCs enhance Th17 differentiation and disease progression through arginase-1 production in patients with systemic lupus erythematosus
Authors: YI HUANFA , Wu Hao , Zhen Yu , Ma Zhanchuan , Li Huiumin , Yang Yong Guang 
Published: January 2023

Abstract
Expansion of myeloid-derived suppressor cells (MDSCs) has been documented in some murine models and patients with autoimmune diseases, but the exact role of MDSCs in this process remains largely unknown. Although MDSCs are supposed to be immunosuppressive, previous studies have shown that these cells may also enhance Th17 responses via an IL-1-dependent mechanism in murine autoimmune models, such as experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). However, the role of MDSCs in the development of autoimmune responses in human remains largely unknown. Current study investigates this question in patients with systemic lupus erythematosus (SLE). We found that patients with active SLE (n=32) had a significant increase in HLA-DR−CD11b+CD33+ MDSCs, in the peripheral blood compared to healthy controls (HCs; n=25). The frequency of MDSCs was positively correlated with the level of serum arginase-1 (Arg-1) activity, Th17 responses and disease severity in SLE patients. Consistently, in comparison with MDSCs from HCs, MDSCs from SLE patients exhibited significantly elevated Arg-1 production, and increased potential to promote Th17 differentiation in vitro in an Arg-1-dependent manner that is likely mediated by multiple mechanisms involving RORgt, RORa and mTOR. Moreover, in a humanized SLE model, MDSCs were essential for the induction of Th17 responses and the associated renal injuries and the effect of MDSCs was Arg-1-dependent. Our data provide direct evidence demonstrating a pathogenic role for MDSCs in human SLE, and suggests that targeting MDSCs or Arg-1 may offer novel therapeutic strategies for the treatment of SLE and other Th17 cell-mediated autoimmune diseases.
Complement-tagged basophils and eosinophils in Systemic Lupus Erythematosus (SLE)
Authors: Liu Chau-Ching , McCarty Berryhill E. , McGeary Meaghan , Manzi Susan , Ahearn Joseph M. 
Published: January 2023

Abstract
Cell-bound complement activation products (CB-CAPs) on erythrocytes, reticulocytes, platelets, and lymphocytes have been recognized as biomarkers for SLE diagnosis, monitoring, and prognosis and to render such cells dysfunctional. Recently, basophils have been shown to contribute to the development of lupus nephritis and presence of eosinophils in the urine has been reported as a potential biomarker for lupus nephritis. This study was based on the hypothesis that basophils and eosinophils bearing C4d may serve as valuable biomarkers and participate in lupus pathogenesis.
To verify this hypothesis, a pilot study investigating basophil-bound and eosinophil-bound C4d levels was conducted using blood samples taken from 103 patients with SLE, 23 patients with other immune-inflammatory diseases, 17 patients with asthma or allergic rhinitis, and 17 healthy individuals. Peripheral blood leukocytes were isolated, and basophils and eosinophils therein were detected and analyzed for surface-bound C4d by flow cytometry.
Preliminary results showed that basophil-bound C4d (Baso-C4d) and eosinophil-bound C4d (Eos-C4d) levels were significantly elevated in patients with SLE, compared to patients with other immune-inflammatory diseases, patients with asthma/allergy, and healthy controls (all p &lt; 0.05). As diagnostic tools, Eos-C4d and Baso-C4d, respectively, were 29% sensitive/96% specific and 22% sensitive/96% specific in differentiating SLE from other immune-inflammatory diseases. The results obtained indicate that Baso-C4d and Eos-C4d may serve as specific markers for SLE diagnosis and possibly for SLE global/organ-specific disease activity.
Autoantibody-mediated generation of platelet-bound C4d in Systemic Lupus Erythematosus (SLE)
Authors: Liu Chau-Ching , Schofield Travis , Manzi Susan , Ahearn Joseph M. 
Published: January 2023

Abstract
Premature and accelerated onset of atherothrombotic disease is prevalent in patients with SLE. Most, if not all, atherothrombotic diseases are likely to involve platelets and the complement system in some capacity. Previously, we discovered that platelets bearing complement activation product C4d (P-C4d) are present in approximately 20% of SLE patients and are significantly associated with anti-phospholipid (aPL) antibody positivity and stroke in SLE patients. The goal of the present study was to elucidate the role of aPL and other platelet-reactive autoantibodies in the generation of P-C4d.
To determine the association between P-C4d and aPL, the level of P-C4d in 180 SLE patients was measured by flow cytometry. Serum level of aPL, including anti-cardiolipin (aCL) and anti-b2 glycoprotein I (anti-b2GPI) antibodies, in these patients was measured by enzyme-linked immunosorbent assays. To investigate the role of aPL, and possibly other autoantibodies as well, in mediating the generation of P-C4d, in vitro 2-step transfer experiments using normal platelets in combination with plasma or immunoglobulin derived from SLE patients were performed. The results showed that the presence and levels of serum aCL and anti- anti-b2GPI were highly specific for SLE patients with positive P-C4d. The plasma and immunoglobulins purified from SLE patients who were positive for P-C4d and aCL/anti-b2GPI were able to induce C4d deposition on normal platelets in vitro. The capacity of SLE plasma in inducing P-C4d appeared to correlate proportionately to the serum aCL levels. Collectively, the results demonstrate that both aPL, particularly aCL, and other platelet-reactive autoantibodies participate in mediating the generation of P-C4d in SLE patients.
Increased cytokine expression of mesangial cells through altered glycosphingolipid catabolism in lupus nephritis
Authors: Nowling Tamara K , Sundararaj Kamala , Angel Peggi , Drake Richard 
Published: January 2023

Abstract
Previously we demonstrated that glycosphingolipid (GSL) levels and neuraminidase (NEU) activity are altered in the kidneys and/or urine of lupus mice and human patients with nephritis compared to their non-nephritic counterparts and healthy controls. We also showed that sterol regulatory element-binding protein (SREBP)-1 expression is increased in the kidneys of nephritic lupus mice and altered GSL levels were observed in the glomerular region. Therefore, we hypothesized that NEU-mediated GSL catabolism is regulated by SREBP-1 and contributes to the production of cytokines by mesangial cells (MC) leading to renal inflammation in lupus nephritis. We now show co-localization of GSL lactosylceramide (LacCer) with MCs and increased expression of IL-6, IFNγ and other cytokines following addition of LacCer to cultured MCs. Primary MCs from pre-nephritic lupus mice stimulated with heat aggregated IgG (a mimic of immune complexes), LPS, or lupus serum showed elevated GSL levels, IL-6 production, MCP-1 expression and Neu1 expression. We now demonstrate that SREBP-1c expression is significantly upregulated in the kidney prior to overt nephritis compared to healthy controls. Over-expressing SREBP-1c in a MC line upregulated Neu1 promoter activity by two-fold, increased endogenous NEU1 expression and increased LacCer levels. Moreover, over-expressing either NEU1 or SREBP-1c significantly increased IL-6 production. Together these results suggest that MC activation leads to increased cytokine expression in part through NEU-mediated GSL catabolism regulated by SREBP-1c in lupus nephritis.
Stromal cells from inflamed lymph nodes modulate B cell surface CD23 expression
Authors: Bottaro Andrea , Kuzin Igor , Sims Etty , Koshkareva Yekaterina , Bernstein Steven , Burack Richard , Schwarz Edward 
Published: January 2023

Abstract
CD23 is a trans-membrane protein belonging to the C-type lectin family, widely expressed in the immune system. Originally identified as the low-affinity receptor for IgE, CD23 was later shown to also bind CD21, MHCII and various integrins, and to have pleiotropic roles, including modulation of cell proliferation, differentiation, Ig and cytokine secretion. Expression of membrane CD23 (mCD23) is regulated at least in part by its shedding from the cell surface via activity of metalloproteinases, the most important of which is ADAM10. Interestingly, secreted CD23 (sCD23) isoforms can exert immunomodulatory functions as soluble factors. B cells upregulate mCD23 and serum sCD23 levels have been found to be elevated in inflammatory and autoimmune conditions, including rheumatoid arthritis, and in B cell chronic lymphocytic leukemia. However, the mechanisms responsible for CD23 modulation on B cells are still unclear. Here we show that mCD23 is upregulated on mouse and human B cells found in inflamed lymphoid tissues. Furthermore, in vitro experiments demonstrate that B cell mCD23 upregulation is strictly dependent on soluble signals provided by stromal cells from inflamed, but not non-inflamed lymph nodes, and can be reversed by ADAM10-specific inhibitors. We propose therefore that the balance between B cell mCD23 and sCD23 expression in inflammatory conditions is modulated by microenvironmental signals provided by stromal cells within lymphoid tissues.
Effects of different treatment regimens on T cell function in acute HIV infection.
Authors: Clutton Genevieve Tyndale , Xu Yinyan , Fernandez Maria Abad , Crooks Amanda , Turner Blair , Maponga Nicole , Cope Anna , Fiscus Susan , McGee Kara , McKellar Mehri , Kuruc JoAnn , Ferrari Guido , Margolis David , Hicks Charles , Eron Joseph , Gay Cindy , Goonetilleke Nilu 
Published: January 2023

Abstract
In HIV-infected individuals, anti-retroviral therapy (ART) is effective in maintaining low viral loads, restoring CD4+ T cell counts, and prolonging life. However, chronic inflammation and immune dysfunction persist even after years of successful ART. Previous studies have suggested that early initiation of ART may result in improved immune reconstitution, but whether more rapid suppression of viral load during early treatment also improves immunological outcomes is unknown. In this study we compare the effects of two regimens initiated during acute infection on T cell phenotype and function. Regimen 1 (n=30) is a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen and Regimen 2 (n=30) combines an integrase strand transfer inhibitor (INSTI) with nucleoside reverse transcriptase inhibitors (NRTIs). NRTIs and NNRTIs inhibit reverse transcription of viral RNA to DNA in the infected cell, while INSTIs block integration of viral DNA into the host genome. Since Regimen 2 targets multiple stages of the viral life cycle, we hypothesize that more rapid viral suppression may be achieved with this treatment schedule. In a cross-sectional study performed 96 weeks after treatment initiation, we are comparing the effects of the two regimens on T cell activation (CD25, CD69, CD38, HLA-DR), exhaustion (PD-1, Tim-3, CD160, T-bet, Eomes), and proliferation using standardized flow cytometry panels. This study will provide valuable insights into the relationship between viral decay kinetics and immune preservation during acute infection, informing the design of future ART regimens.
Ficolins promote fungal clearance during the early stage of pulmonary infection with Aspergillus fumigatus.
Authors: Genster Ninette , Cowland Jack , Cramer Elisabeth , Rosbjerg Anne , Pilely Katrine , Garred Peter 
Published: January 2023

Abstract
Aspergillus fumigatus is a fungal pathogen causing severe and usually fatal invasive infections in immunocompromised patients. The Ficolins are pattern recognition molecules of the lectin pathway of complement and in vitro studies suggest a role for ficolins in the defence against A.fumigatus. However, little is known about their significance in fungal infections in vivo. Thus, our aim of the current project was to establish a murine model of pulmonary A. fumigatus infection to study the relevance of ficolins in host protection against A.fumigatus. Wildtype and ficolin knockout mice were infected intranasally with a sublethal dose of A.fumigatus conidia and the lungs were removed at various time points post-infection to assess the fungal load and expression of pro-inflammatory cytokines. In addition, the concentration of pro-inflammatory cytokines was measured in the bronchoalveolar lavage. After 24 hours of A.fumigatus infection, the pulmonary fungal load was significantly higher in ficolin knockout mice compared to wildtype mice. In contrast, no significant difference in fungal load between ficolin knockout mice and wildtype mice was observed after 12, 48 or 72 hours of infection. Interestingly, the increased fungal load in knockout mice 24 post-infection was accompanied by a significantly impaired induction of pro-inflammatory cytokines compared to wildtype mice. These results show that ficolins promote fungal clearance and modulate the pro-inflammatory cytokine response, demonstrating the importance of ficolins during the initial phase of A. fumigatus infections in vivo.
Critical role of LIGHT/TNFSF14 in poly(I:C)-induced acute hepatitis
Authors: Wang Pu , Lu Xiaohua , Zheng Wei , Zou Junhui 
Published: January 2023

Abstract
LIGHT is a member of the TNF superfamily, which is known to be involved in liver pathologies. Toll-like receptor 3 (TLR3) is a critical component of the innate immune response to dsRNA viruses. The polyinosine-polycytidylic acid (Poly(I:C), a TLR3 viral mimetic, induces an acute hepatic injury and mimics a model of viral hepatitis. In this study, we investigated the role of LIGHT in acute hepatitis induced by poly(I:C). The results show that administration of poly(I:C)/D-galactosamine (D-GalN) in mice led to acute liver injury associated with the increased expression of LIGHT in liver. Blockade of LIGHT/HVEM signaling ameliorated liver injury. Pre-treatment with a NF-κB inhibitor dramatically reduced LIGHT expression and liver injury, suggesting the involvement of NF-κB in LIGHT expression in poly(I:C)/D-GalN-induced acute hepatitis.
Netrin-1 mediates macrophage retention in adipose tissue through AGAP-2 interaction with the dependence receptor UNC5B via miR-762 and miR-346
Authors: Mehrpouya-Bahrami Pegah , Zumbrun Elizabeth E. , Zameer Fahran , Nagarkatti Prakash S , Nagarkatti Mitzi 
Published: January 2023

Abstract
Retention of Macrophages in adipose tissue is associated with high expression of neuroimmune guidance cue Netrin-1 and its receptor UNC5B which are involved in chemotaxis. Cannabinoid receptor1 (CB1) receptors are known to regulate the immune response. We have shown previously that treatment of mice with SR141716A, a CB1 antagonist, attenuates obesity. To further investigate the mechanisms, Diet-Induced Obesity (DIO) was generated by feeding C57BL/6J mice with high-fat diet (HFD) whereas their lean, age-matched controls were fed low-fat diet (LFD). HFD-fed mice were treated with either SR141716A (10mg/kg/day) or vehicle by daily oral gavage for 4 weeks starting at week 12. Our data demonstrated that SR141716A suppressed diet intake transiently, however weight loss and reduction in fat mass was persistent. Suppression of pro-inflammatory macrophages was observed in SR141716A-treated HFD-fed group followed by down regulation of Netrin-1 and UNC5B in macrophages. In silico analysis demonstrated that miRs induced by SR141716A regulated several pathways including macrophage migration. miR-762 and miR-346 which were down regulated following SR141716A treatment were found to be complementary to the 3′-UTR of AGAP-2 gene. SR141716A regulated AGAP-2 expression and its association with UNC5B and inhibited UNC5B-provoked macrophage retention in adipose tissue, and subsequently ameliorated insulin resistance. Thus, for the first time we demonstrate that blockade of CB1 receptors leads to altered chemotaxis balance of adipose tissue macrophages leading to amelioration of obesity.