bluuebunny/crossref_metadata_2025_split huggingface dataset:
TLR1/2 ligand Neisseria meningitidis PorB accelerates, antigen presenting cell activation
Authors: Lisk Christina , Reiser Michael , Mosaheb Munir , Wetzler Lee 
Published: January 2023

Abstract

Background
Vaccines are a powerful tool for preventing the transmission of diseases, however very few take advantage of specific mechanistic knowledge. In order for newer and better vaccines to be developed, a greater understanding of adjuvant mechanism and immune system priming needs to be achieved. Our laboratory has focused on the natural adjuvant, PorB, a pore forming protein isolated from Neisseria meningitidis. This protein has been shown to be a TLR2 agonist with potent adjuvant activity. PorB also increases antigen-specific antibody titers and T cell proliferation when co-administered with an antigen.

Hypothesis
In this study, we hypothesized that PorB increases intracellular trafficking of antigen, ovalbumin (OVA), faster than OVA alone in bone marrow derived dendritic cells (BMDCs).

Methods
Isolated BMDC from BL6 mice were divided into 3 groups – PBS control, fluorescently labeled OVA (used antigen control), and OVA+PorB. Stimulation lasted 0, 0.5, 1, 2, or 4 hours. Cells were then stained with early endosome antigen 1 (EEA1) and lysosome-associated membrane protein 1 (LAMP1) to track the labeled OVA.

Results
This experiment showed that OVA uptake was increased within BMDCs stimulated with PorB. Specifically, OVA co-localized with EEA1 and LAMP1 more frequently than OVA alone. OVA co-localization was also present earlier in stimulation when PorB was present compared to OVA alone.

Conclusion
These insights of how BMDCs traffic antigen with adjuvants can allow for more efficient antigen presentation, lymphocyte responses, and, overall, better vaccines.
Immuno-proteomic interrogation of antigen presentation during Dengue infection reveals novel and HLA haplotype-specific MHC-I antigens
Authors: Swaminathan Kavya , Lund Peder J , Olsson Niclas , Marceau Caleb , Carette Jan , Davis Mark M , Elias Josh E 
Published: January 2023

Abstract
Dengue (DEN) virus infection is a leading cause of hospitalization and death in the developing world and broadly effective vaccines and therapies remain elusive. Identifying infection-specific peptide antigens would open new avenues for developing T cell based interventions. Past efforts towards mapping viral antigens used computational predictions that only partially reflect actual antigens presented by the major histocompatibility complex (MHC). To identify DEN-specific antigens without relying on error prone predictions, we developed an immuno-proteomics approach for interrogating antigen presentation in DEN infected B-lymphocytes. This approach enabled three fundamental findings; First, we identified 86 viral MHC-I antigens (59 novel), and mapped them to presentation hotspots in the DEN genome. Second, we discovered post-translationally modified viral and host antigens and antigens derived from alternate reading frames. Predicting these antigens using computational methods alone would be infeasible. Third, we found antigens responsible for HLA-haplotype dependent immune responses against DEN infection: we genetically engineered B-lymphocytes to express HLA alleles associated with either strong or weak DEN-immune responses and identified corresponding allele specific antigens. Together these discoveries let us assay the immunogenic potentials of an unprecedented range of DEN-specific antigens. Ex-vivo assays including ELISPOT and HLA tetramer staining supported our identification of immunogenic antigens in DEN-specific CD8+ T cells. These antigens have potential as both diagnostic tools to characterize DEN-specific T cell immunity, and serve as candidates for designing effective DEN vaccines.
The modulation of cathepsin activities by HIV protease inhibitors alters the processing and cross-presentation of pathogens
Authors: Le Gall Sylvie , Kourjian Georgio , Rucevic Marijana , Berberich Matthew J , Boucau Julie 
Published: January 2023

Abstract
Immune recognition by T cells relies on the presentation of pathogen-derived peptides by infected cells but the persistence of chronic infections calls for new approaches to modulate immune recognition. Pathogen uptake in phagosomes initiates infection of macrophages and leads to the priming of T cell responses by dendritic cells. The original degradation of antigens is performed by pH-dependent endolysosomal cathepsins. We show that HIV protease inhibitors (PIs) prescribed to HIV-infected persons variably modulate cathepsin hydrolytic activities in human antigen presenting cells (APCs), dendritic cells and macrophages, and CD4 T cells, three cell subsets infected by HIV. Two HIV PIs acted in two complementary ways on cathepsin activities: They directly enhanced procathepsin maturation and increased cathepsin hydrolytic activities. They indirectly altered regulators of cathepsin functions by inhibiting Akt kinase activities, reducing NADPH oxidase 2 (NOX2) activation, lowering phagolysosomal ROS production and pH, which altogether led to enhanced cathepsin activities. HIV PIs modified endolysosomal degradation and epitope production of proteins from HIV and other pathogens in a sequence-dependent manner. They altered cross-presentation of antigens by dendritic cells and epitope-specific T cell-mediated killing by up to 2.5-fold. HIV PI-induced modulation of antigen processing partly changed the self MHC-peptidome displayed by primary human cells. This first identification of prescription drugs modifying the regulation of cathepsin activities and the MHC-peptidome may provide an alternate therapeutic approach to modulate immune recognition in immune disease beyond HIV.
New insights into rheumatoid arthritis by whole transcriptome profiling of autoreactive B cells
Authors: Mahendra Ankit , Yang Xingyue , Qiu Peng , Park Daechan , Coarfa Cristian , Agarwal Sandeep K , Varadarajan Navin 
Published: January 2023

Abstract
B cells are important in the pathogenesis of rheumatoid arthritis (RA). By utilizing a flow-cytometric assay to reliably detect the low frequency of autoreactive B cells (ABC) in the blood of RA patients, we performed RNA sequencing of citrulline-specific ABCs and compared them with hemaglutinin (HA) specific B cells. To the best of our knowledge, this is the first complete transcriptome map of human ABCs in autoimmunity, and our data shows a specific up regulation of amphiregulin (AREG) (q-value = 3.1×10−12, fold-change = 250); a member of the EGF growth factor of ligands. Also, the receptor signaling pathways associated with AREG including EGF mediated signaling (FDR q-value = 0.06) and the NRG1 mediated signaling (FDR q-value = 0.03) were enriched, supporting an important role for AREG. Consistent with the well-recognized role of TNF in RA, our RNA-seq data revealed highly significant enrichment of both the TNF pathway (FDR q-value = 0.02) and genes that are targets of TNF (FDR q-value = 0.08) in ABCs from RA patients. Comparisons of our differential expression gene analyses with known risk loci of RA (SNPs) identified genes with decreased expression including TNFAIP3 (leading to inflammatory responses), and REL (anti-apoptotic); and increased expression including CCR6 (maturation and differentiation), and ETS1 (development and maturation) within ABCs than HA specific B cells. Ig sequencing of ABC show normal mutational targeting frequencies but increased somatic hymermutation. In aggregate, our results indicate that the pro-inflammatory nature of IL15 and TNF mediated signaling might promote a feed-forward loop promoting the altered differentiation of ABCs through the AREG-TNF signaling axis, which in turn promotes inflammation.
Anti-nuclear antibodies in autoimmune prone mice are protective against HIV
Authors: Schroeder Kristin M , Strauch Pamela , Harper Michael , Pelanda Roberta , Santiago Mario L , Torres Raul M 
Published: January 2023

Abstract
HIV broadly neutralizing antibodies (bnAbs) recognize conserved regions of the HIV envelope trimer, are capable of neutralizing up to 90% of cross-clade HIV strains in vitro, and have auto- and poly-reactive specificities. Multiple bnAbs, with different specificities for HIV envelope, have been reported to recognize autoantigens, such as membrane phospholipids, histones, and human ubiquitin ligase 3. Further, bnAb CH98 has been identified in an HIV infected individual with systemic lupus erythematosus (SLE) and was found to recognize both dsDNA and the CD4 binding site, as well as neutralize HIV strains of multiple clades in vitro. From this data, our lab hypothesized that both central and peripheral B cell tolerance checkpoints inhibit potentially neutralizing HIV-Ab responses, and that autoimmune prone individuals are capable of mounting neutralizing Ab responses. In order to further investigate this, we immunized age-matched, wild type and SLE prone strains of mice with HIV envelope proteins in adjuvant. We found that a subset of SLE prone mice neutralized multiple heterologous HIV strains 14 days post immunization, which was not observed in wild type mice. This neutralizing Ab response positively correlated with age and total serum IgM levels. SLE prone mice produced envelope-specific IgG of similar magnitude and isotypes as wild type mice, following envelope immunization. Using an array with 92 autoantigens, we found that the subset of SLE prone mice, which neutralize HIV, produce higher levels of histone H2A and dsDNA reactive IgM, as compared to the non-neutralizing SLE and wild type mice. Lastly, in vivo and in vitro studies show that activation of the autoimmune B cells by adjuvant is required for this neutralization activity.
The role of plasma cell precursors in a mouse model of lupus
Authors: Rosean Timothy R , Loo William , Erickson Loren D 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease, which occurs when terminally-differentiated B cells, called plasma cells (PC), secrete anti-nuclear antibodies (ANA). Once formed, PCs persist in the bone marrow for the lifetime of the host, but the mechanisms of this long-term persistence are poorly understood. Our lab and others have identified a novel subset of terminally-differentiated B-lineage cells. These cells, called plasma cell precursors (PCpre) are a post-germinal center cell population, which are both long-lived and capable of self-renewal. While PCpre do not actively secrete antibody, they can terminally differentiate into mature, long-lived PCs. The role of PCpre in the production of ANA has yet to be elucidated. To understand the role of PCpre in autoimmunity, our lab utilized the congenic New Zealand Black Autoimmunity 2 (NBA2) mouse strain, which develops B cell abnormalities similar to SLE. NBA2 mice develop significantly higher frequencies and numbers of PCpre compared to controls. PCpre from NBA2 mice express the transcription factors IRF-4, BLIMP-1, and XBP-1 that are known to be upregulated in PC. In addition, PCpre express high levels of B220 and MHC class II. Adoptive transfer of PCpre cells from NBA2 mice into B6 controls results in ANAs in recipient mice by day 14, demonstrating the pathogenic potential of PCpre in mouse models of SLE. Furthermore, these PCpre are capable of long-term survival as they persist in the recipient for at least 40 days. Based on these findings, we hypothesize that PCpre are involved in the renewal of the PC niche in the NBA2 model of SLE. Current research is focused on the mechanisms by which PCpre undergo proliferation and terminal differentiation.
Dnase1L3 trafficking is redirected from secretion to the nucleus in lupus-prone mice
Authors: Abbott Kennady N , Wu Wenbo , Shi Guilan , Salter Russell , Keyel Peter 
Published: January 2023

Abstract
Pediatric-onset Systemic Lupus Erythematosus (SLE) is linked to a deficiency of the endonuclease Dnase1L3. Dnase1L3 can function extracellularly as a barrier to transfection or localize to the nucleus of macrophages to cleave DNA during apoptosis, though the mechanism by which Dnase1L3 protects from pediatric-onset SLE is unknown. Two polygenic lupus murine models, MRL-lpr and NZB/W F1, bear the activity-reducing T89I mutation in Dnase1L3. Dnase1L3 T89I has an eight-fold decrease in barrier-to-transfection activity, while the endonuclease activity is only decreased two-fold compared to the wildtype, providing a tool with which to dissect Dnase1L3 trafficking in SLE. We hypothesized that Dnase1L3 T89I localizes to the nucleus, which decreases barrier-to-transfection activity and enhances SLE onset. We transfected HEK cells with wild type or T89I Dnase1L3, and determined the subcellular localization of Dnase1L3. We found that the majority of wild type Dnase1L3 is secreted from the cell, while Dnase1L3 T89I showed increased nuclear localization. Since Dnase1L3 alters inflammasome function, we tested whether inflammatory stimuli alter Dnase1L3 trafficking. LPS treatment of cells transfected with Dnase1L3 T89I reduced its nuclear localization. Altered Dnase1L3 trafficking may impair inflammasome function, since macrophages from NZB/W F1 mice secreted less IL-1β than wild type mice. Overall, the increase in nuclear localization of Dnase1L3 T89I suggests that barrier to transfection or extracellular nuclease activity may promote IL-1β release and protect against pediatric-onset SLE.
Chronic Interferon-gamma expression triggers a female bias in the development of primary biliary cholangitis
Authors: Young Howard A , Leung Patrick , Tsuneyama Koichi , Valencia Julio , Hodge Deborah L , Kim Seohyun , Back Tim , Karwan Megan , Merchant Anand , Feng Dechun , Gao Bin , Park Ogyi , Gershwin M Eric , Bae Rachel 
Published: January 2023

Abstract
An important issue in autoimmunity research has been the ability to identify the mechanisms that link genetic susceptibility to environmental influences. In most autoimmune diseases, including primary biliary cholangitis (PBC), the serologic hallmarks of disease precede clinical pathology by years, thus making early diagnosis and potential treatment difficult if not unlikely. Thus identifying animal models that present early events becomes essential to understanding disease initiation and progression. Although murine models of PBC have been identified, there are none that fully recapitulate the human disease. Herein we have utilized a novel mouse model exhibiting dysregulation of interferon-gamma (IFNg) expression, characterized by prolonged and chronic expression of IFNg as a result of the replacement of the IFNg 3′ UTR AU-rich element with random nucleotides (designated ARE-Del−/−). These C57 BL/6 ARE-Del−/− mice develop autoimmune cholangitis with a female predominance characterized by upregulation of total serum bile acids, portal duct inflammation, spontaneous production of AMA and increased skin pigmentation. RNA seq data has revealed that female ARE-Del−/− mice have &gt;1000 genes deferentially expressed in hepatocytes compared to control mice, including genes that represent early responses in disease progression. Furthermore, the data indicates that the Type 1 IFN pathway is also involved, implying that Type II interferon interplays with Type I IFNs in the initiation of PBC. Thus persistent IFNg expression, along with Type I and Type II IFN pathway interactions, is critical for the pathogenesis of PBC and recapitulates the sex bias observed in patients.
Next generation sequencing reveals HLA and KIR susceptibility alleles for rheumatoid arthritis
Authors: Geraghty Daniel , Nakanishi Mari , Ide Takeshi , Tanaka Hidenori , Miyazaki Yuki , Saji Hiroh , Inoue Kazuya , Murata Norikazu , Ashida Tsuneo , Hatake Katsuhiko , Ishitani Akiko 
Published: January 2023

Abstract
Previous associations of KIR with rheumatoid arthritis (RA) have been reported in some but not all populations studied, possibly due to limited genotyping in some studies, and gene content homogeneity in some populations. In this study, HLA and KIR typing was carried out, including KIR haplotype and allele typing, using state of the art sequencing methodologies in a re-examination of the association of these gene families with RA in a Japanese cohort. An additional cohort of pollen allergy patients was examined in an effort to distinguish common genetic elements in a phenotype functionally reciprocal to RA. DNAs from 116 RA patients, 167 pollen allergy patients, and 185 healthy controls were examined for KIR haplotype, allele type and HLA class I and II allele types using next generation sequencing (NGS). Association analysis was carried out with healthy controls classified into two groups, positive and negative for allergen specific IgE antibodies, including a pollen allergy group for comparison with RA. Significant results were observed with allele types KIR2DS4*007 and KIR3DL1*00501, which strongly associated with disease, while KIR 3DL1*001 and 3DL1*02901 associated with a protective phenotype. These findings were significant when compared with the IgE positive control group while the IgE-negative group did not demonstrate significance. Given that KIR3DL1 is an inhibitory receptor and the KIR3DL1*00501 allele has been reported as a low expression allele, these findings are consistent with a model of weak suppression of NK cytotoxic activity as a contributing factor in RA. Further support for this model was observed from the reciprocity of the genetic associations between RA and pollen allergy.
Role of the TNF-family cytokine TL1A and its receptor DR3 in systemic autoimmunity and glomerulonephritis
Authors: Meylan Francoise , Hayes Erika , Ferdinand John , Farley Taylor , Richoz Nathan , Gabay Odile , Siegel Richard M 
Published: January 2023

Abstract
DR3 (Tnsfrsf25) is a death domain-containing tumor necrosis factor receptor found primarily on activated T cells and innate lymphocytes. Interaction with its ligand the TNF-family cytokine TL1A plays critical roles in diverse autoimmune disease models in facilitating T cell accumulation at the site of inflammation while the systemic response was unaffected. To determine whether DR3 could play a role in systemic autoimmunity, we studied the role of DR3 in the MLR/lpr mouse model of lupus. Lpr mice have a mutation in the TNF family receptor Fas (CD95, Tnfrsf6) that impair its expression, causing a systemic autoimmune disease that mimics systemic lupus erythematosus (SLE) observed in humans. DR3 deficient lpr mice developed identical degrees of lymphadenopathy, splenomegaly compared to control littermates. Accumulation of autoantibodies was also not dependent on DR3. However, DR3 deficiency significantly protected MRL/lpr mice from IgG and C3 glomerular immune complex deposition and DR3 deficient kidneys had decreased medullary T cell accumulation, decreased periglomerular and medullary macrophage infiltrates, reduced proteinuria and reduced renal pathology. In addition, DR3-deficient CD4+ T cell transfer in a chronic graft-versus-host disease (GVHD) model showed similar levels of autoantibodies and immunoglobulin class switching than with wild-type CD4+ T cells but decreased proteinuria and reduced renal pathology. These findings show that DR3 specifically promotes renal pathology in the MRL/lpr mouse model of lupus nephritis and in chronic GVHD without affecting systemic autoimmunity. Blockade of TL1A-DR3 interactions may be a novel strategy to counter nephritis and other organ damage in human SLE.
Meta-Analysis from Gene Expression Profiles of Lupus Affected Tissues Reveals Novel Immune Cell Contributions
Authors: Grammer Amrie C. , Heuer Sarah , Catalina Michelle , Robl Robert , Madamanchi Sushma , Wanjari Pankhuri , Min Junghwan , Bachali Prathyusha , Kretzler Matthias , Berthier Celine , Suarez-Farinas Mayte , Davis Laurie , Lauwerys Bernard , Houssiau Frédéric , Lipsky Peter 
Published: January 2023

Abstract
Immunologic mechanisms causing tissue damage in autoimmune diseases such as SLE are not fully understood. To gain additional insight, gene expression profiles obtained from lupus affected skin, synovium and kidney were obtained and compared to meta-analyzed data obtained from active lupus B, T and myeloid cells. More than 300 arrays from lupus patients and appropriate controls were analyzed to determine differentially expressed (DE) genes (8279 discoid lupus skin, 5465 synovium, 6381 glomerulus, 5587 tubulointerstitum). Notably, the majority of lupus affected tissue DE genes were detected in more than one tissue and 439 were differentially expressed in all tissues. A variety of approaches assessed the molecular pathways and cellular phenotypes accounting for these common lupus affected tissue DE genes. Curated STRING-based interaction analysis identified a number of pathways including co-stimulation of T cells, activation of B and myeloid cells, antigen presentation, TLR signaling and p38 activation; from a total of 193 IPA-documented pathways, 59 were common to all tissues including p38 signaling, TLR signaling, maturation of dendritic cells, B cell activation and ICOS-ICOSL in T cells. Novel bioinformatics approaches documented that more than 50% of the DE genes in the tissues were associated with immune cell function and 11–18% were unique to the immune system. Further analysis using LINCS and additional novel software highlighted specific molecular pathways of immune cell activation including the JAK/STAT and the IL12 pathways. These results demonstrate the value of comprehensive application of orthogonal curated bioinformatics tools in identifying the role of immune cells in lupus pathogenesis and tissue damage.
Exacerbation of MPTP induced neurodegeneration by a CD4+ effector T cell line specific for N-α-synuclein in a mouse model of Parkinson’s disease
Authors: Wilshusen Rebecca A , Mosley R. Lee 
Published: January 2023

Abstract
Inflammation and oxidative stress play critical roles in PD. Moreover, T cell-mediated immunity regulates innate immunity to control or exacerbate neuroinflammation. We have previously shown in the MPTP mouse model that adoptive transfer of effector T cells (Teffs) which recognize nitrated α-synuclein (N-α-syn) as non-self exacerbates microglial-mediated neuroinflammation with amplified dopaminergic neurodegeneration. The specific mechanisms by which these Teffs modulate neurodegeneration remain enigmatic. However, increasing evidence suggests neurotoxic inflammatory activities have a profound effect on the pathogenesis of PD. Herein, we report on the generation and long-term culture of a N-α-syn specific CD4+ Teff line that induces increased production of reactive nitrogen species from microglia and also intensifies the loss of tyrosine hydroxylase+ (TH+) neurons of MPTP-intoxicated mice. Flow cytometric analysis showed the Teffs line exhibited very distinct expression of CD3 and CD4 cell surface markers and intracellular IL-17a cytokine, suggestive of characteristics consistent with a Th17 cell. Co-culture of the Teffs with a dopaminergic cell line significantly increased cell death of dopaminergic cells in comparison to controls. Lastly, adoptive transfer of the Teffs line to MPTP-intoxicated mice increased the loss of TH+ neurons. Together, these results support the notion that Teffs may play a pivotal role in the progression of neurodegeneration in PD. Further investigation of the mechanisms behind the exacerbation of neurodegeneration caused by Teffs has the potential to advance therapeutic strategies that target neurotoxic mechanisms to attenuate neuroinflammation and ameliorate neuronal loss in PD.