bluuebunny/crossref_metadata_2025_split huggingface dataset:
Not just showboating: Shp1 may keep B cells afloat during gammaherpesvirus infection
Authors: Johnson Kaitlin E. , Mboko Wadzanai P. , Lange Philip T. , Tarakanova Vera L. 
Published: January 2023

Abstract
Gammaherpesviruses (GHVs) are ubiquitous pathogens that establish lifelong infections. Importantly, GHVs manipulate B cell differentiation to establish latency, and are associated with several types of B cell lymphomas. Specifically, GHV infection stimulates an abnormal germinal center expansion, and germinal center B cells are thought to be the target of malignant transformation. Thus, defining host factors that affect the germinal center response during GHV infection may offer insights into the biology of viral latency and lymphomagenesis. Shp1 is a tyrosine phosphatase that acts as a negative regulator of immune cell activation, including B cells. Therefore, we hypothesized that Shp1 opposes GHV-driven germinal center expansion. Surprisingly, our studies utilizing a mouse model of B cell-specific Shp1 deficiency have discovered that Shp1 may be required to sustain the abnormal germinal center expansion characteristic of GHV infection.
In mice with B cell-specific Shp1 deficiency we observed a significant reduction in germinal center B cells along with decreased viral loads during early stages of chronic GHV infection. Further evidence suggests that total loss of Shp1 in B cells disrupts the delicate balance of proliferation and apoptosis during germinal center expansion, resulting in an increased level of apoptosis. Based on these data, we hypothesize that Shp1 prevents hyper-activation, and subsequent cell death, of germinal center B cells during GHV infection. Ongoing studies are examining the mechanism by which Shp1 mediates B cell survival.
TBE vaccine and post TBE disease Abs drive antibody dependent enhancement of Zika infection
Authors: Demina Anna Vladimirovna , Edri Avishay , Fridman Lilach , Rouvinski Alex , Lobel Leslie , Hertz Tomer 
Published: January 2023

Abstract
Tick-borne encephalitis (TBE) virus belongs to the Flaviviruses, such as Zika, Dengue, Yellow fever viruses (YFV), etc. Antibody dependent enhancement (ADE) was first described between Dengue 1–4 viruses. Recently the ADE phenomenon was extended to include additional Flaviviruses that are phylogenetically close to Dengue: Zika and YFV. All arthropod borne Flaviviruses are antigenically related, however, the existence and extent of ADE between mosquito-borne and tick-borne Flaviviruses were never addressed. In order to explore ADE associated pathogenesis of sera cross-reactivity, we studied human sera from patients with acute TBE (n=30), vaccinated against TBE (n=76) and a control group without antibodies (Abs) to Flaviviruses (n=30). ELISA assays were used to profile the IgG and IgM serological repertoires to TBE and cross-reactivity to Zika antigen (Ag). Viral plaque assays (VPA) were used to test if TBE Abs cause ADE during infection with Zika virus. Flow cytometry (FACS) was used to measure ADE of Zika infection in U937 cells in the presence of the sera with TBE Abs. We found that 25% of TBE vaccinated subjects and 47% of acute TBE subjects had cross-reactive Abs to Zika Ag in ELISA. Furthermore, serum from 37/40 (92%) TBE positive subjects caused ADE in the VPA assay and 58/60 (96%) caused ADE using the FACS assay. The magnitude of Zika ADE correlated with the titer of TBE Abs. Thereby we demonstrate, that previous vaccination or infection with TBE significantly increases the risk of ADE upon a secondary infection with Zika virus. These results highlight that presence of cross-reactive Abs induced by previous exposure even to a very distantly related Flaviviruses by vaccination or infection dictates the risk of ADE upon secondary infection.
Plasmacytoid dendritic cells prime anti-viral T cells during acute HIV-1 infection but deplete and impair anti-viral T cells during chronic HIV-1 infection
Authors: Li Guangming , Ma Jianping , Cheng Liang , Zhang Liguo , Su Lishan 
Published: January 2023

Abstract
The role of plasmacytoid dendritic cells (pDCs) in human immunodeficiency virus type 1 (HIV-1) infection and pathogenesis is likely important but remains unclear. We have developed a monoclonal antibody that specifically depletes human pDCs in humanized mice (hu-mice) in vivo. When pDCs were depleted before/during acute HIV infection, the expression of type I interferons (IFN-I) and anti-viral interferon-stimulated genes (ISGs) was severely diminished, accompanied with a significantly up-regulated HIV-1 replication. Interestingly, we found that the anti-viral T cell response is completely abolished in the absence of pDC. We also observed an accelerated decrease of CD4/CD8 T cell ratio. However, when pDCs ablation occurred during chronic HIV infection, numbers of total human leukocytes and T cells were increased and T cell immune function was partially rescued in spite of a higher level of viral replication. We conclude that pDCs suppress HIV infection and replication as well as priming anti-viral T cell response in primary HIV infection. However, during chronic infection, pDCs promotes HIV-1 disease progression, including T cell depletion and immune exhaustion. These findings suggest that pDCs, in addition to suppressing HIV-1 infection, play distinct roles during acute and chronic phases of HIV-1 infection.
Reciprocal regulation of lung resident alveolar macrophage function and repopulation by β-catenin and PPAR-γ dictates host morbidity and tissue recovery from respiratory viral infection
Authors: Zhu Bibo , Huang Su , Jiang Li , Zhang Ruixuan , Sun Jie 
Published: January 2023

Abstract
Acute respiratory viral infections, such as influenza and respiratory syncytial virus infections, cause severe morbidity and mortality in children and the elderly worldwide. Lung resident alveolar macrophages (AM), residing in the alveolar space, have been recently shown as a critical regulator of host antiviral defense and the maintenance of normal lung function during acute respiratory viral infection. However, relatively less is known about the molecular regulation of AM function and repopulation in situ, and the roles of AM in the restoration of lung homeostasis at the recovery stage following pathogen clearance. Here we show that two reciprocally regulated transcription factors in AM, β-catenin and PPAR-γ, oppositely modulate host diseases and recovery following respiratory viral infection. AM β-catenin ablation results in reduced morbidity, accelerated inflammation resolution and recovery; while AM PPAR-γ deletion or constitutive β-catenin activation leads to enhanced diseases and impaired recovery following influenza and respiratory syncytial virus (RSV) infection. Mechanistically, β-catenin and PPAR-γ oppositely regulate AM antiviral, inflammatory, reparative, and immunological gene programs. Further, β-catenin and PPAR-γ distinctly modulate AM proliferation and repopulation, thereby regulating tissue recovery following infection. Strikingly, combined deficiency reveals that the main functions of β-catenin and PPAR-γ are based on mutual antagonism. Our data have revealed the critical roles of a transcriptional circuit in balancing rMΦ function and regeneration for the proper restoration of normal tissue homeostasis following infection.
Atypical Xist RNA Localization to the Inactive X in a Female-biased Murine Model of Systemic Lupus Erythematosus
Authors: Martin Anna R. , Syrett Camille M. , Myles Arpita , Atchison Michael L. , Anguera Montserrat C. 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is a severe autoimmune disease that affects women nine times more than men. The genetic basis for this bias is the X-chromosome, where the greatest concentration of immunity related genes on any chromosome can be found. Females have two X chromosomes (XX), and through a process, known as X-chromosome inactivation (XCI), silence one of their X-chromosomes randomly to have a similar level of X-linked gene expression as males (XY). In XCI, XIST RNA, a long non-coding RNA, is expressed from the future inactive X (Xi) and is bound to it in cis by the transcription factor YY1. As XIST coats the Xi, it recruits heterochromatin modifiers to condense and silence it. Previous research has shown that human SLE patient B cells exhibit altered localization of XIST RNA, thus indicating that they have partial reactivation of the Xi. To explore this relationship, we worked with NZB/W F1mice, which are a well-characterized murine model of SLE that also displays a female bias. The hypothesis of our study is that due to reduced expression of YY1, NZB/W F1 mice have altered Xist RNA localization leading to increased expression of X-linked genes in splenic B cells. Preliminary results using qPCR indicate that the concentration of YY1 is reduced across all stages of disease in NZB/W F1 when compared to age-matched wild type (WT) mice. Using Xist RNA FISH, we have observed that the activated B cells of late stage disease NZB/W F1 mice have decreased localization of Xist RNA to the Xi when compared to WT. In addition, we observed that the expression of TLR7 and CXCR3, two x-linked genes, are increased in diseased NZB/W F1 when compared to age-matched WT.
A comprehensive phenotyping program for the MRL-lpr mouse lupus model
Authors: Schile Andrew , Petrillo Melissa , Vovk Andrey , French Richard , Leighton Krystal , Dragos Zala , Hagarman James , Strobel Marjorie 
Published: January 2023

Abstract
MRL/MpJ-Faslpr/J (MRL-lpr) mice develop an autoimmune disease resembling systemic lupus erythematosus, a disease affecting &gt; 1.5 million Americans. The causative mutation, Faslpr, promotes survival of self-reactive lymphocytes, leading to immune proliferation, lymphadenopathy, emergence of anti-DNA antibodies, and fatal immune complex glomerulonephrosis. Like all spontaneous autoimmunity models, MRL-lpr colonies are susceptible to inadvertent selective pressure when mice with absent or delayed phenotypes are bred. We will explain a program for promoting genetic and phenotypic integrity within MRL-lpr breeding colonies. In addition to confirmation of genetic background and Faslpr genotype, breeder phenotypes were assessed at the conclusion of the breeding period. White blood cell counts (WBC) were used to measure lymphoproliferation: at 17 weeks of age, median WBC (103 cells/μL) was 14.2 for females (range = 3.4 – 97.3; N=155) and 10.5 for males (range = 3.7 – 51.4; N=125). Urinalysis to characterize renal damage at 18 weeks of age showed a median albumin/creatinine ratio of 623 for females (range = 1 – 22806; N=163) and 95 for males (range = 1 – 6013; N=123). Median spleen weights (grams) at 18 weeks of age were 0.5464 in females (range = 0.1112 – 2.1348; N=177) and 0.4410 in males (range = 0.2078 – 1.5516; N=135). We will describe a scoring system for clinical signs present at gross necropsy, including appearance of fur/skin, lymph nodes, and organs. We will show that phenotypic integrity can be ensured over time by breeding mice from lineages showing optimal disease development criteria. This program has value beyond breeder assessment, as it can be applied to MRL-lpr mice on study and at conclusion.
BCAP promotes Lupus-like disease and regulates IFNα production in pDC
Authors: Chu Talyn , Waterman Hayley , Gessay Griffin , Hamerman Jessica A. 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) severity is correlated with elevated serum type I interferons (IFN), mainly IFNα, which is produced in large amounts by pDC in response to nucleic acid sensing by TLR7 and TLR9. TLR7 and TLR9-induced IRF7 translocation to the nucleus and subsequent IFNα production by pDC is dependent on phosphatidylinositol-3 kinase (PI3K), but how PI3K regulates this process remains undefined. We showed that B cell adaptor for PI3K (BCAP) links TLRs to PI3K activation in macrophages, thus we asked if BCAP plays a role in pDC IFNα production and SLE pathogenesis. We show BCAP promoted many aspects of TLR7-driven lupus-like disease including interferon-stimulated gene expression in blood. BCAP promoted TLR7 and TLR9-induced IFNα production in pDC, and BCAP−/− mice produced significantly less serum IFNα after injection of TLR9 agonist than WT mice, consistent with a pDC IFNα defect. TLR-induced IFNα production in pDC involves dual signaling pathways that run in parallel and converge upon the phosphorylation and activation of IKKα. There is a TLR-independent pathway initiated by nucleic acid recognition at the plasma membrane that involves Dock2-mediated activation of Rac1, required for phosphorylation of IKKα. The TLR-dependent pathway occurs upon nucleic acid recognition by endosomal TLR7 or 9 and leads to MyD88 activation. BCAP regulated IFNα production independently of the TLR-MyD88 pathway and both BCAP and PI3K were required for CpG DNA-induced early actin remodeling, a readout of Rac1 activation, and IKKα phosphorylation in pDC. Our data suggest BCAP and PI3K specifically regulate the TLR-parallel pathway in pDC. Overall, we show a novel role for BCAP in regulating IFNα production in pDC and SLE pathogenesis.
N-Glycanase 1 Deficiency Triggers Innate Immune Activation Through Dysregulated Mitophagy
Authors: YANG KUN , YAN NAN 
Published: January 2023

Abstract
The cytosolic N-glycanase 1 (Ngly1) is an evolutionarily conserved de-glycosylating enzyme, which plays a critical role in the quality control of newly synthesized glycoproteins. Misfolded N-glycoproteins retro-translocated from endoplasmic reticulum lumen to cytosol are deglycosylated by Ngly1 prior to proteasome degradation. Mutations in the human NGLY1 gene are associated with a severe rare congenital disorder characterized by global development delay, neurological abnormalities and liver diseases. The pathogenesis of the NGLY1-associated disease remains largely unknown. In this study, we observed an aberrant innate immune activation in both human and mouse Ngly1−/− cells, as evidenced by elevated expression of interferon-stimulated genes that are collectively known as the ‘type I interferon gene signature’. Using pharmacological inhibitors and RNAi knockdown, we identified the cytosolic DNA sensing pathway as the key innate immune pathway activated in Ngly1−/− cells. We also found that Ngly1−/− cells exhibited fragmented mitochondria and mtDNA leakage into the cytosol, which likely serve as the source for self DNA sensed by the innate immunity. Mitochondria are dynamic organelles, and aged or damaged mitochondria are cleared through mitophagy. We found that mitophagy was impaired in the absence of NGLY1. Together, our data reveal the first evidence of immune dysregulation associated with NGLY1 deficiency, as well as defects in mitophagy that likely lead to accumulation of damaged mitochondria, mtDNA leakage into the cytosol and activation of cytosolic DNA sensing pathway.
Lipocalin 2 deficiency exacerbates collagen antibody induced arthritis in mice
Authors: Lopez Maria , Meyers Keya R. , samuels janaiya , Shashidharamurthy Rangaiah 
Published: January 2023

Abstract
Rheumatoid arthritis (RA) is associated with elevated levels of a numerous acute phase proteins (APPs), including lipocalin 2 (Lcn2), that drive/dampen the inflammatory response. Lcn2, a 25KDa innate immune protein is known to be significantly up regulated during various inflammatory disorders including antibody-mediated arthritis such as rheumatoid arthritis (RA). However, its biological role remains unclear. Herein we have demonstrated that Lcn2 levels were significantly upregulated during collagen antibody induced arthritis (CAIA). Lcn-2-knockout mice (Lcn2KO) developed more severe serum-induced arthritis compared to wild-type (WT) mice. Histological analysis revealed extensive tissue and bone destruction in Lcn2KO mice compared to WT mice. Furthermore, we have observed reduced immune cell infiltration in Lcn2KO mice compared to WT mice. These studies suggest a crucial role of Lcn2 in resolution of arthritic inflammation, making it a promising target in designing better therapeutic strategies for the treatment of rheumatoid arthritis.
An upregulation of TLR7 in renal dendritic cells is associated with glomerulonephritis across multiple B6. Sle1-associated strains.
Authors: Fairhurst Ann-Marie 
Published: January 2023

Abstract
Toll-like receptors (TLRs) 7 and 9 are important innate signalling molecules with opposing roles in the development and progression of Systemic Lupus Erythematosus (SLE). While multiple studies support a dependency on TLR7 for disease development, genetic ablation of TLR9 results in severe disease with glomerulonephritis (GN) by a largely unknown mechanism. In the present study we show that the autoimmune phenotypes exhibited by TLR9-deficient Sle1 mice (Sle1TLR9−/−) mice are akin to those shown by the Sle1Tg7 strain, a model with a 2-fold increase in TLR7 expression. These include increased autoantibody titers, systemic immune activation and glomerulonephritis (GN). Kidney disease in Sle1TLR9−/− mice is associated with an increase in renal CD11b+CD11c+MHC+F480− dendritic cells (DC). These cDCs have higher levels of TLR7 protein with a corresponding increased ability to stimulate T cell proliferation following R848 exposure. Our analyses of TLR7 using flow cytometry in the Sle1Tg7 and Sle123 murine lupus models indicated similar increases in protein expression within cDCs, suggesting their importance across multiple model systems.
Genetic ablation of TLR9 in Sle1 mice also resulted in increased TLR7-reactive RNA/anti-RNA-associated autoantibodies, indicating that TLR9 is required for B cell tolerance to RNA-associated antigens.
In summary, the increase in TLR7-reactive immune complexes (IC) and the concomitant enhanced expression of their receptor, promotes Inflammation and Disease in Sle1TLR9−/− mice.
CD40 expression on specific antigen-presenting cells mediates experimental autoimmune encephalomyelitis
Authors: Lu Ying , Hodes Richard J. 
Published: January 2023

Abstract
CD40 is a cell surface receptor that belongs tothe tumor necrosis factor receptor (TNFR) family and serves as a costimulatory molecule on the antigen presenting cells (APCs). The interaction between CD40 on B cells and its ligand CD154 on activated T helper cells is known to be essential for the development of thymus-dependent humoral immunity. Administration of blocking anti-CD40L antibody or CD40 gene knockout make mice resistant to experimental autoimmune encephalomyelitis(EAE), an animal model of human multiple sclerosis (MS), but the complex cellular interactions mediating the role of CD40 in EAE are not fully understood. We are using conditional CD40 knockout mice to selectively delete CD40 on specific APC populations and evaluate the effects by recombinant human MOG (rhMOG) induced EAE, a model is both T cell and B cell dependent. We found that conditional knockout of CD40 on B cells or dendritic cells led to significantly reduced severity of EAE. Studies of the mechanisms mediating CD40 function in immune response and CNS immunopathology are underway.
Myeloid NF-κB signaling contributes to pathogenesis of immune-mediated nephritis
Authors: Chalmers Samantha A. , Garcia Sayra , Shum Justine , Herlitz Leal , Putterman Chaim 
Published: January 2023

Abstract
Immune-mediated glomerulonephritis is a serious end organ pathology that affects patients with systemic lupus erythematosus (SLE). A common murine model used to study lupus nephritis (LN) is nephrotoxic serum nephritis (NTN) in which mice are passively transferred nephrotoxic antibodies. We have previously shown that macrophages are important for the pathogenesis of LN. To further investigate the mechanism and determine if the contribution of macrophages is mediated via the NF-κB pathway we created B6 mice which had RelA knocked out in myeloid cells, thus inhibiting classical NF-κB signaling in this cell lineage. We induced NTN in this strain to assess the importance of macrophage derived NF-κB signaling in contributing to disease progression.
Myeloid cell RelA knock out (KO) mice injected with nephrotoxic serum had significantly ameliorated proteinuria (p&lt;0.01) and serum BUN levels (p&lt;0.05) compared to control injected wildtype B6 mice (WT). Inhibiting myeloid NF-κB signaling also decreased inflammatory modulators within the kidneys. We measured significant decreases of IL-1a, IFNg, and IL-6 in kidneys from KO mice, but higher IL-10 expression. Flow cytometry revealed decreased numbers of kidney infiltrating classically activated macrophages in KO mice as well. Analysis of renal histopathology is pending.
Taken together, our studies indicate that macrophage NF-κB signaling is instrumental in the contribution of this cell type to the pathogenesis of NTN. Our results suggest that while approaches which decrease macrophage numbers can be effective in immune mediated nephritis, more targeted treatments directed at modulating macrophage signaling and/or function could be beneficial, at least in the early stages of disease.
Macrophage dependent pathways modulate the pathogenesis of cytokine storm syndrome
Authors: Mahajan Sahil , Decker Corinne , Mellins Elizabeth , Faccio Roberta 
Published: January 2023

Abstract
Cytokine storm syndromes (CSS) are life-threatening conditions characterized by excessive activation of T cells, accumulation of well-differentiated macrophages in various organs and exuberant release of inflammatory cytokines. CSS are associated with a wide variety of infectious and noninfectious diseases, often occurring in patients with familial hemophagocytic lymphohistiocytosis and systemic juvenile idiopathic arthritis (sJIA). Although increased number of macrophages is observed in CSS, their role in disease initiation has never been investigated. Here we report that depletion of macrophages at disease onset decreases lethality and limits CSS in two clinically relevant animal models. Mechanistic studies reveal that phospholipase C gamma 2 (Plcʏ2) is critical for macrophage responses during CSS. To dissect how Plcʏ2 induces macrophage activation during CSS, we evaluated two Plcʏ2 downstream pathways, namely calcium and diacylglycerol (DAG). Calcium and DAG levels are tightly controlled by expression of Tmem178, a Plcʏ2-dependent protein and negative regulator of calcium fluxes, and Dgkζ, an enzyme converting DAG into phosphatidic acid, respectively. Intriguingly, by using Tmem178−/− or Dgkζ−/− mouse models, we discovered that calcium and DAG exert opposite effects, with increased calcium augmenting macrophage activation and CSS severity while accumulation of DAG limiting these excessive inflammatory responses. Importantly, macrophages exposed to plasma from sJIA patients that are at risk of developing CSS show skewing toward increased calcium and reduced DAG, via modulation of Tmem178 and Dgkζ expression. In conclusion our data indicate a potential role for macrophage-based therapies for CSS.