bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gastrointestinal tract is the place where encephalitogenic T cells develop in the spontaneous EAE mice (101.11)
Authors: Ito Naoko , Boppana Sridhar , Huang Hui , Dhib-Jalbut Suhayl , Ito Kouichi 
Published: January 2023

Abstract
Multiple sclerosis (MS) is an autoimmune disease exhibiting features of demeylination and axonal loss in the central nervous system (CNS). Although CNS-specific Th1 and Th17 cells have been suggested to initiate the disease, it is still unknown how these effector T cells develop in MS patients. To address this question, we have generated transgenic mice that express T cell receptor (TCR) genes specific for myelin basic protein (MBP) and HLA-DR2a genes that were isolated from an MS patient. The humanized MBP-TCR Tg mice developed spontaneous EAE. Interestingly Th1 and Th17 cells developed in the mesenteric lymph nodes and the colon more efficiently than in other lymphoid organs in the spontaneous EAE mice, and their development was much lower in the gastrointestinal (GI) tract of healthy MBP-TCR Tg mice. This data suggests that MBP-specific T cells differentiate into Th1 and Th17 encephalitogenic T cells in the colon and migrate into the CNS from mesenteric lymph nodes. Alternatively, MBP-specific Th1 and Th17 encephalitogenic T cells develop in the other lymphoid organs and preferentially migrate into the gut. Interestingly, CD4 T cells infiltrates in the CNS of spontaneous EAE mice expressed gut-homing receptors in addition to CNS-homing receptors. These data suggest that the GI-tract may be an important site for the differentiation of encephalitogenic T cells in spontaneous EAE mice.
VSV infection ameliorates autoimmune disease in FcγR2B deficient mice (101.14)
Authors: Kole Hemanta , Deane Jonathan , Scott Bethany , Bolland Silvia 
Published: January 2023

Abstract
We have investigated whether infection by pathogens affects the development of autoimmune diseases such as lupus. We tested the effect of infection with vesicular stomatitis virus (VSV) on two mouse strains that spontaneously develop lupus disease. Infection of VSV in lupus prone FcγR2B-/- (R2) mice significantly reduced autoantibody titers and inflammatory cytokines and chemokines in serum, reduced glomerulonephritis, and improved survival. In contrast, VSV infection in R2yaa mice, which develop a more aggressive lupus disease, showed slightly reduced auto-antibody titers in the serum without any major changes in serum cytokines and chemokines, kidney glomreulonephritis, or survival. Characterization of immune cell phenotypes in VSV infected R2 mice showed that B cell development in the bone marrow was not affected whereas germinal center, plasma, and IgG producing mature B cell numbers were reduced. Additionally, VSV infected R2 mice had lower number of follicular helper T cells and CD11c+ cells in the spleen. Compared to uninfected mice, microarray analysis of naïve resting B cells from VSV infected R2 splenocytes showed up-regulation of several candidate genes including a non receptor type protein tyrosine phosphatase, PTPN22 that has been shown to be associated with Lupus and other autoimmune diseases. Studies of the functional implications of Ptpn22 overexpression in VSV-infected R2 B cells are in progress.
Susceptibility to infection in systemic lupus erythematosus: clues from a murine model. (101.3)
Authors: Lieberman Linda , Tsokos George 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) patients invariably display defects in both innate and the adaptive branches of the immune system, contributing to inflammation and organ damage. Nevertheless, infection is a leading cause of death in patients suffering from SLE. Though SLE patients are treated with immunosuppressive drugs, the high rates of infection suggest that inherent defects in host immunity may contribute to their increased susceptibility. The mechanisms responsible for the increased susceptibility of SLE patients to infection are unclear, but the observed defects in cytokine production and T cell subsets in these patients would intimate that they have a less robust immune response to infection. We have developed a murine model to study the relationship between infection and SLE pathogenesis and preliminary data supports an increased susceptibility of SLE-prone mice to infection. B6.MRL/lpr mice infected intraperitoneally with the obligate intracellular parasite Toxoplasma gondii succumbed to infection acutely. The mechanism behind this susceptibility is not clear. There was no increase in parasite burden or decrease in serum cytokines in the infected SLE-prone mice as compared to the wild type controls. The activation status of various immune cells was normal in the infected SLE mice, but a defect was observed in antigen-specific IFN-γ production. Further studies will elucidate the mechanism responsible for the increased susceptibility of SLE-prone mice to infection.
Development of autoreactive CD8+ T cells in Aire-deficient mice (101.38)
Authors: Ji Niannian , Forsthuber Thomas 
Published: January 2023

Abstract
Autoimmune regulator (Aire) regulates the transcription of a myriad of self antigens in the thymus, which is important for the process of central tolerance to eliminate autoreactive T cells and to prevent autoimmune pathology. Aire-deficient mice (aire-/-) have previously been shown to develop multi-organ autoimmune disorder. We were interested in investigating the role of Aire for autoreactive CD8+ T cells using aire-/-Ia-/- mice. We found that CD8+ T cells were increased in aire-/-Ia-/- mice as compare with their aire+/+ or heterozygous littermates. Furthermore, aire-/-Ia-/- mice showed significantly lower body weight as compared with their littermates. Immune infiltrates mainly composed of CD11c+ cells and CD8+ T cells were found in various tissues of aire-/-Ia-/- mice, especially in liver, lung, pancreas and stomach. Autoantibody was detected in the serum of aire-/-Ia-/- mice directed against gastric tissue and was determined to be predominantly IgM. Collectively, our study shows that autoreactive CD8+ T cells arise on the background of Aire-deficiency are capable of initiating and promoting autoimmunity in the absence of CD4+ T cells.
Mapping the epitope in Epstein Barr Virus nuclear antigen-1 that elicits cross-reactivity with dsDNA (101.43)
Authors: Yadav Pragya , Ebegbe Roland , Anam Adiba , Mumbey-Wafula Alice , Gottlieb Paul , Spatz Linda 
Published: January 2023

Abstract
Several studies have shown an association between Systemic Lupus Erythematosus (SLE) and the Epstein Barr Virus (EBV). Our laboratory recently demonstrated that BALB/c mice injected with the major EBV nuclear antigen, EBNA-1, developed antibodies to EBNA-1 that cross-react with double stranded DNA (dsDNA). We generated monoclonal antibodies (MAbs) to EBNA-1 from EBNA-1 injected mice and demonstrated by anti-dsDNA ELISA, dsDNA affinity columns, and Crithidia luciliae assays, that these antibodies cross-react with dsDNA. Studies are underway to determine the pathogenicity of these MAbs. We have been mapping the epitope in EBNA-1 that serves as a peptide mimotope for dsDNA. We now demonstrate that the mimotope is contained within the carboxyl region of the EBNA-1 protein, between amino acids 459 and 607. This region contains well-defined secondary structure, which suggests that the basis for the cross-reactivity with dsDNA could be due to a conformational epitope in EBNA-1. Studies are in progress to further map this cross-reactive epitope. Identification of this epitope may help in designing diagnostic and therapeutic strategies that can mask the epitope from the immune system following EBV infection and thereby prevent the development of antibodies that cross-react with dsDNA.
Susceptibility to autoimmune myocarditis is associated with strain-dependent differences in IL6 receptor expression on naive CD4+ T cells (101.5)
Authors: Chen Ping , Baldeviano G. , Ligons Davinna , Talor Monica , Barin Jobert , Rose Noel , Daniela Cihakova 
Published: January 2023

Abstract
The goal of this study is to identify non-H-2 loci controlling differential susceptibility to experimental autoimmune myocarditis (EAM). A.SW and B10.S mice share the same MHC (H-2s) haplotype, yet A.SW are susceptible to EAM, while B10.S are resistant. We have identified a locus on Chromosome 1 (termed Eam1) that is important in determining susceptibility to myocarditis. In this study we have found that naive A.SW mice had a higher percentage of CD4+ T cells in their spleens, and CD4+ T cells from naive A.SW had great potential to differentiate towards the Th17 pathway than that from naive B10.S mice. To examine why T cells from A.SW mice more readily develop a Th17 phenotype, we assessed the cytokines and related receptors needed for Th17 induction. Level of IL-6 did not differ in the hearts of A.SW and B10.S mice. However, IL6Rα expression was greater on naive A.SW CD4+ T cells compared to B10.S mice, no difference was found for TGF-βRI expression. B10.A.Eam1 congenic mice were generated where Eam1 was derived from A.SW and the rest of the genome was of B10.S origin. The percentages of CD4+ T cells and IL-6Rα expression were intermediate on B10.A.Eam1 congenic mice, highest on A.SW and lowest on B10.S mice. Our data suggest that a higher percentage of CD4+ T cells in A.SW mice together with increased expression of IL6Rα and the tendency of CD4+ T cells to differentiate towards a Th17 phenotype contribute to heightened susceptibility to autoimmune myocarditis in A.SW mice.
Deletion of IL-6 in a murine model of primary biliary cirrhosis leads to exacerbated autoimmune cholangitis and lymphomas (101.6)
Authors: Zhang Weici , Tsuda Masanobu , Yang Guo-Xiang , Tsuneyama Koichi , Rong Guanghua , Ridgway William , Ansari Aftab , Flavell Richard , Coppel Ross , Lian Zhe-Xiong , Gershwin M. Eric 
Published: January 2023

Abstract
Autoimmune liver diseases are characterized by elevated serum levels of IL-6. We have previously reported the development of a PBC-like model in dnTGF-βRII mice engineered to express a dominant negative form of transforming growth factor β receptor (dnTGF-βRII, dnR) under the control of CD4 promoter. By producing a double construct, namely IL-6 deficient mice on the dnTGF-βRII background (dnTGFβRII IL-6-/- mice), we previously reported that such animals manifest improvement in their underlying inflammatory bowel disease but worsening of their biliary infiltrates. To further understand this model, we have studied dnTGFβRII IL-6-/- mice and, in particular, focused on the pathology over a longer period of observation of up to 9 months. Importantly, loss of the IL-6 gene, although it does improve underlying inflammatory bowel disease, dramatically increases lymphoid aggregation, elevates inflammatory liver cytokines and promotes the appearance of activated T cells in liver. Indeed, loss of the IL-6 gene results in lymphomatous lesions in liver, spleen and lung at 6-9 months of age in 7 of 22 male dnTGFβRII IL-6-/- mice. No lesions were found in control dnTGFβRII mice. These data further highlight the promiscuous role of IL-6 and suggest caution in the therapeutic use of anti-IL6R antibody in the treatment of patients with autoimmune disease.
Neutrophil migration to the lung is enhanced in selectin-ligand deficient mice (102.11)
Authors: Onami Thandi , Harp John , Zeng Junwei 
Published: January 2023

Abstract
The first step in leukocyte trafficking into tissues and peripheral organs is mediated by selectin binding. Mice deficient in α1,3 fucosyltransferases-VII and -IV (FtDKO) are unable to synthesize sLex, which is required for E-, P-, and L-selectin binding. We recently reported that due to an inability to enter peripheral lymph nodes, FtDKO mice show increased numbers of T cells in peripheral blood and increased T cell accumulation in the lung. We now report that FtDKO mice show substantial increases in granulocyte populations in peripheral blood, with an ~20-fold increase in Ly6G+Mac-1+ neutrophil populations in the lung parenchyma. To determine whether increased neutrophil localization in the lung influences disease processes, we infected FtDKO mice with influenza. As previously reported, FtDKO mice show impaired neutrophil trafficking to the peritoneal cavity following inflammation due to loss of selectin-mediated binding. However, FtDKO mice show rapid and enhanced neutrophil trafficking to broncho-alveolar regions of the lung following influenza infection. These data suggest that instead of reducing inflammatory cell populations, loss of selectin-mediated binding may paradoxically enhance accumulation of neutrophils in the lung parenchyma, which may in turn facilitate the influx of these cells into broncho-alveolar regions of the lung following inflammation or injury.
Renal dysfunction increases aortic macrophage and lymphocyte accumulation during atherosclerosis development (102.2)
Authors: von Vietinghoff Sibylle , Hertel Barbara , Ley Klaus , Haller Hermann 
Published: January 2023

Abstract
Atherosclerosis is a chronic inflammatory disease of the artery wall with innate and adaptive immune components. Decreased renal function is a major risk factor for cardiovascular events and mortality. While altered hemodynamics and mineral metabolism have been investigated in detail, the atherosclerotic vascular leukocyte infiltrate in renal impairment has not been systematically explored. This study tested whether moderate renal impairment alters leukocyte composition in the aorta of atherosclerotic mice. Apolipoprotein E deficient (Apoe-/-) mice underwent nephrectomy or sham surgery and were maintained on high-fat diet for 12 weeks. Aortic leukocyte infiltration was determined by immunofluorescence staining and confocal microscopy and by flow cytometry of aortic single cell suspensions. Unilateral nephrectomy significantly increased serum creatinine levels as a measure of renal function but did not alter serum calcium and phosphorous levels. While total blood leukocyte counts were un-altered, the number of aortic leukocytes was significantly increased after nephrectomy. Specifically, aortic B cells and macrophages were increased. Proliferation of aortic macrophages was increased. Aortic en face and root atherosclerotic lesion size were significantly larger in mononephric mice. We conclude that mild renal failure is sufficient to alter inflammatory aortic leukocyte accumulation in atherosclerosis.
Age-associated changes in Non-muscle Myosin IIA and CXCR4 regulates increased migration induced by SDF1 in CD4+ T lymphocytes from elderly human donors. (102.8)
Authors: Cane Stefania , Ponnappan Subramaniam , Sullivan Dennis , Ponnappan Usha 
Published: January 2023

Abstract
Non-muscle Myosin-IIA has varied functions in T cell contractility, migration and cytokinesis. Evaluation of non-muscle Myosin-IIA in CD4+ T cells from the elderly, demonstrated not only altered association of the Myosin heavy chain with the chaperone HSP90, but also increased basal levels of protein expression, and constitutive phosphorylation of the myosin light chains. These alterations manifested as increased actomyosin complex formation in cells from the elderly, as opposed to those from young donors. Additionally, chemotactic migration in response to agonist SDF1, demonstrated increased migration index in CD4+ T cells from the elderly, when compared to those from young donors. As SDF1-mediated migration is clearly dependent on the expression of CXCR4 on T cell surface, we assessed CXCR4 levels in CD4+ T cells from young and elderly human donors. Our results for the first time demonstrate a significant increase in CXCR4 levels on the surface of T cells from the elderly, when compared to those from young donors. As Myosin-IIA regulates both the motility and endocytosis of CXCR4, we hypothesize that alterations in Myosin-IIA may underlie endocytosis of CXCR4 by SDF1 in the elderly. Thus, combined alteration in Myosin-IIA and CXCR4 levels in T lymphocytes may underlie increased motility observed during aging and may impact the strength and duration of interaction with antigen-presenting cells.
Maintenance and homeostatic proliferation of regulatory CD4 T cells occur independent of the thymus and of secondary lymphoid organs (104.7)
Authors: Camirand Geoffrey , Lakkis Fadi , Rothstein David 
Published: January 2023

Abstract
In vivo manipulations that influence regulatory Foxp3+CD4+ T cells (Treg) homeostasis represent a valuable therapeutic mean for balancing immunity and regulation. However, the signals and the anatomical sites of Treg homeostasis are not completely defined. Therefore, we investigated the role of the thymus, and of secondary lymphoid organs (SLO) on Treg homeostasis in steady state. The absolute numbers of conventional CD4 T cells (Tconv) and Treg in spleen, peripheral lymph nodes, bone marrow, blood, liver, and lungs were determined by flow cytometry in euthymic or thymectomized adult wt B6 mice and in mice lacking SLO (splenectomized Lymphotoxin receptor β knockout). Proliferation was measured by EdU incorporation over a period of 3 days prior to analysis. We found that, in wt B6 mice, Treg exhibited a much higher rate of homeostatic proliferation (HP) than Tconv in both lymphoid and non-lymphoid compartments. Thymectomy of adult B6 mice reduced Tconv numbers in all compartments by 30-60%, while Treg numbers remained primarily unaffected (d30 and d60). In absence of SLO or both thymus and SLO, Treg accumulated in non-lymphoid organs, in blood, and in bone marrow in higher numbers and displayed similar rates of HP compared to wt mice. Our data show that Treg homeostasis occurs independently of thymic production and of SLO, suggesting an intrinsic Treg ability to respond to antigens in non-lymphoid tissues.
Intrahepatic inflammatory profiles in HCV/HIV coinfection versus HCV infection (105.10)
Authors: Hu Sishun , Yu Andy , Amet Tohti , Byrd Daniel 
Published: January 2023

Abstract
We currently have a poor understanding of the immunopathogenesis of accelerated liver damage in HCV/HIV coinfection. Recent studies suggest that ongoing chronic liver inflammation is responsible for the faster liver damage. We therefore used a real-time PCR-based array to study intraheptic inflammation in the liver biopsy specimens from HCV-infected (n=20), HCV/HIV coinfected (n=8) and healthy (n=8) donors. A total of 84 inflammation-related genes encoding inflammatory cytokines, chemokines and their receptors were analyzed. We found that genes encoding CCL19 and CXCR3-associated chemokines (CXCL9, CXCL10, and CXCL11) were significantly up-regulated in both HCV infection and HCV/HIV coinfection when compared with that of liver biopsies from healthy donors. CXCR3-associated chemokine genes were further up-regulated in HCV/HIV coinfection. Meanwhile, 3 genes (CCL25, CRP, and CXCL2) were significantly down-regulated in HCV infection and HCV/HIV co-infection, and CCL25 was further down-regulated in HCV/HIV coinfection. These data were confirmed by in vitro studies using human hepatocyte cell line Huh7.5. Studies of the molecular mechanisms in regulation of these gene activation showed that LPS and viral proteins played significant roles in the changes of intraheptic inflammatory profiles. Our results suggest that the CXCR3-associated chemokines, particularly CXCL10, may play an important role in the immunopathogenesis of accelerated liver damage in HCV/HIV coinfection.
Exhausted CD8 T cells downregulate the IL-18 receptor and become unresponsive to inflammatory cytokines and bacterial coinfections (105.15)
Authors: Zajac Allan , Ingram Jennifer 
Published: January 2023

Abstract
During many chronic infections virus-specific CD8 T cells succumb to exhaustion as they lose their ability to respond to antigenic activation. Combinations of IL-12, IL-18, and IL-21 have been shown to induce the antigen-independent production of IFN-γ by effector and memory CD8 T cells. In this study we have investigated whether exhausted CD8 T cells are sensitive to activation by these cytokines. We show that effector and memory, but not exhausted, CD8 T cells produce IFN-γ and upregulate CD25 following exposure to certain combinations of IL-12, IL-18, and IL-21. This unresponsiveness is associated with downregulation of the IL-18R on exhausted T cells. To evaluate the consequences of IL-18R downregulation on CD8 T cell fate, we tracked IL-18R-/- cells in chronically infected mixed bone marrow chimeras and discovered that the IL-18R-/- cells were preferentially lost during the contraction phase. The antigen-independent responsiveness of exhausted CD8 T cells was also investigated following co-infection with Listeria monocytogenes, which induces the expression of IL-12 and IL-18. Although IL-18R-high memory cells upregulated CD25 and produced IFN-γ, the IL-18R-low exhausted cells failed to respond. Collectively, these findings indicate that as exhausted T cells adjust to the chronically infected environment, they lose their susceptibility to antigen-independent activation by cytokines, which compromises their ability to detect bacterial co-infections.
The role of long-lived plasma and memory B cells in response to challenge with homologous and heterologous West Nile viruses (105.16)
Authors: Purtha Whitney , Bhattacharya Deepta , Diamond Michael 
Published: January 2023

Abstract
Memory B cells (MBC) and long-lived plasma cells (LLPC) are generated after infection, but the significance of each population in conferring protection against secondary challenge remains unclear. Using a mouse model of West Nile virus (WNV) infection, we demonstrate that MBC possess a more cross-reactive repertoire to viral neutralization escape mutants than do LLPC. Through clonal analysis, we found that a high frequency of both MBC and LLPC generated by WNV infection recognize domain III (DIII) of the viral envelope, whereas a substantial fraction of MBC, but not LLPC, continue to recognize DIII with mutations at residues that comprise the neutralizing epitope (DIII-K307E, T330I). Accordingly, a variant virus carrying this mutation (WNV-K307E) was neutralized poorly relative to its wild type counterpart (8.3-fold reduction in EC50 value) by immune serum maintained by LLPC from WNV-immune mice. In contrast, adoptively transferred MBC readily generated antibodies upon WNV-K307E challenge that were not restricted to the wild type neutralizing epitope. These studies have implications on the analysis of protective immunity and evaluation of effective vaccines for viruses that vary at key neutralizing epitopes.