bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of vasoactive intestinal polypeptide signaling augments T cell activation by plasmacytoid dendritic cells: implications for cellular immunotherapy
Authors: Li Jingxia , Li Jian-Ming , Waller Edmund K 
Published: January 2023

Abstract

Introduction
Murine models of allogeneic hematopoietic stem cell transplant (allo-HSCT) have shown that adding donor plasmacytoid dendritic cell (pDC) to allogeneic HSC and T cell grafts can: 1) augment the graft-versus-leukemia (GvL) activity of T cells by inducing donor Th1 polarization; and 2) limit the subsequent development of graft-versus-host disease (GvHD) through interferon gamma-licensed IDO production by pDC. Vasoactive intestinal polypeptide (VIP) is an immunosuppressive neuropeptide, which may regulate activation of allo-specific T cells, making it a potential target for regulating GvHD and GvL in allo-HSCT.

Methods and results
We used a model system of indirect presentation by pDC of a I-Ed derived allo-peptide (EaP 52–68) to transgenic T cells expressing the TEa TCR. The effect of blocking VIP signaling from pDC was assessed with VIP-knockout (KO) pDC or by adding a VIP antagonist, VIPhyb. Peptide-primed pDCs from VIP-KO mice increased expression of activation markers (CD69 and CD71) and stimulated TEa T cell proliferation compared with pDCs from WT mice. Similar results were observed in T cells cultured with VIPhyb treated pDCs. T cells proliferated more when cultured with BM VIP-KO pDCs than splenic VIP-KO pDCs.

Conclusions
These data indicate a novel role for VIP signaling in T cell activation and proliferation in response to indirect antigen presentation. These data support published data on the role of donor pDC in modulating the GvHD activity of T cells and indicate important functional differences in pDC activity according to their source. Ongoing experiments support the immune regulatory effect of VIP on GvHD and GvL in murine allo-HSCT.
Are the extracellular IgV and IgC domains of butyrophilin 3A1 required for prenyl pyrophosphate stimulation of human Vγ2Vδ2 T cells?
Authors: Morita Craig T , Wang Hong 
Published: January 2023

Abstract
Vγ2Vδ2 T cells play important roles in human immunity to pathogens and in cancer immunotherapy by responding to isoprenoid metabolites such as (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) and isopentenyl pyrophosphate (IPP). The immunoglobulin superfamily protein, butyrophilin 3A1 (BTN3A1), is required for prenyl pyrophosphate stimulation. Our mutational studies and the work of others has shown that HMBPP and IPP compounds are not antigens but instead are sensed molecules that bind to the intracellular B30.2 domain of BTN3A1. How this binding is detected by the Vγ2Vδ2 TCR is unclear. One possibility is that HMBPP binding alters the conformation and/or distribution of the extracellular domains (ECD) of the BTN3A1 dimer allowing direct binding to the Vγ2Vδ2 TCR or to another molecule that binds the Vγ2Vδ2 TCR. Alternatively, the Vγ2Vδ2 TCR could bind to a molecule that is recruited by the intracellular B30.2 domain upon HMBPP binding. To distinguish between these mechanisms, we mutagenized 32 residues on the surfaces of the IgV and IgC domains of BTN3A1 to alanine and tested the mutant proteins for their ability to mediate prenyl pyrophosphate stimulation of Vγ2Vδ2 T cells. Mutagenesis of residues in the IgV and IgC domains had no effect whereas mutagenesis of the B30.2 binding site abrogated Vγ2Vδ2 T cell responses to HMBPP. Therefore, these findings do not support direct binding to the Vγ2Vδ2 TCR (or to another protein) by the ECD of BTN3A1. Instead, Vγ2Vδ2 TCR recognition may be to a protein recruited to the B30.2 domain upon HMBPP binding. Identification of this second protein will help clarify the puzzling process of human Vγ2Vδ2 T cell receptor recognition.
Transporter associated with antigen processing (TAP) dependencies and cell surface peptide occupancies of HLA-B allotypes
Authors: Geng Jie , Raghavan Malini 
Published: January 2023

Abstract
Human leukocyte antigens (HLA) class I molecules comprise a highly polymorphic heavy chain complexed to beta2-microglobulin (β2m). The heterodimers bind and display short peptides on the cell surface for intracellular surveillance by cytotoxic T cells. Peptides that assemble with HLA class I molecules are typically derived from the cytosol of cells, whereas the assembly of HLA class I occurs within the ER lumen. The transporter associated with antigen processing (TAP) is essential for peptide transport from the cytosol into the ER. In this study we showed that frequently occurring HLA-B variants display distinct patterns of TAP dependencies. Some HLA-B allotypes are detectable at significant levels in TAP-deficient and TAP-inhibited cells. Such allotypes are predominantly peptide-occupied in TAP-sufficient cells, but display higher percentages of empty protein in cells with inhibited or dysfunctional forms of TAP. TAP activity is known to be blocked by many viral proteins and in some cancers. Our findings indicate TAP dependency-influenced variations in cell surface expression and peptide occupancies of HLA-B allotypes under pathoglocical conditions.
Association of functionally distinct ERAP1 variants with prognosis in HPV positive cancer.
Authors: Reeves Emma , King Emma , Elliott Tim , Thomas Gareth , James Edward N 
Published: January 2023

Abstract
Human papillomavirus (HPV) infection accounts for 5% cancers worldwide, with cervical carcinoma and squamous cell carcinoma of the head and neck (SCCHN) being most common. HPV can enable immune evasion, with 50% of HPV+SCCHN having reduced pMHC I expression, correlating with fewer tumor infiltrating lymphocytes (TIL) and a worse clinical outcome. Polymorphisms in the endoplasmic reticulum aminopeptidase1 (ERAP1), a key component of antigen processing, trimming N-terminally extended peptides for MHC I, are associated with prognosis and outcome in cervical carcinoma. We have previously demonstrated ERAP1 to be highly polymorphic, forming distinct allotypes with functional differences. Here we investigate the contribution of ERAP1 in the pathogenesis of SCCHN.
We identified a number of novel ERAP1 allotype pairs (both chromosomal copies) from HPV+ SCCHN. Assessment of trimming function revealed a range of abilities to generate the model epitope SIINFEHL from individual amino acid or AIVMK precursors. Furthermore, the ability to generate HPV-16 E6/E7 specific epitopes also demonstrated varying trimming phenotypes. Interestingly, the overall ability to generate the final epitopes (model and HPV) in TILLOW patients was poor, whereas TILHIGH patients efficiently generated them. This difference revealed ERAP1 gene sequence and function stratifies with TIL levels and prognosis. These results demonstrate that the successful presentation of HPV-16 E6/E7 epitopes at the cell surface depends on the ERAP1 allotype pairs expressed within an individual. Furthermore, the allotype pairs correlate with levels of tumor infiltrate, suggesting ERAP1 activity as an indicator of prognosis in HPV+ SCCHN patients.
ERAP1 deficiency protects HLA-B27 transgenic rats from arthritis
Authors: Tran Tri M , Gill Tejpal , Hong Sohee , Bennett Joshua , Colbert Robert A 
Published: January 2023

Abstract
HLA-B27 (B27) confers a strong predisposition to spondyloarthritis (SpA). Rats transgenic for B27 (B27-TG) develop SpA-like disease with gut inflammation and arthritis. Common variants in ERAP1, which trims peptides for HLA class I in the ER, have been associated with SpA. We sought to determine how ERAP1 loss-of-function affects SpA-like disease in rats. Part of the first exon of ERAP1 was deleted using a TALEN, resulting in complete loss of ERAP1 expression in cells from ERAP1−/− animals. Strains were crossed to generate cohorts of B27-TG with ERAP1+/+, ERAP1+/−, and ERAP1−/− genotypes. B7-TG rats and WT rats with ERAP1+/+, +/− or −/− were used as controls. B27+ males with either ERAP1+/+ or ERAP1+/− genotype developed arthritis with a frequency of 28% (5/18), and 35% (8/23), respectively, with comparable arthritis severity scores (2.0) and age of onset (4.1 months), whereas only 13% (2/15) of rats with an ERAP1−/− genotype developed arthritis with a lower arthritis score (0.75). Only 13% of B27+ERAP1+/− females developed arthritis (arthritis score of 0.75), while ERAP1+/+ and ERAP1−/− females remained healthy. Furthermore, B7-TG and WT rats were healthy regardless of the ERAP1 genotype. All B27+ rats developed gut inflammation with no differences in clinical colitis, although histology scores were slightly higher in the complete absence of ERAP1 (7.0) compared to ERAP1+/+ (5.0) with p&lt;0.05. Taken together, complete absence of ERAP1 protected B27-TG rats from arthritis, no appreciable difference in gut inflammation, suggesting different effects on pathogenic mechanisms involved in arthritis and colitis. This novel model provides an opportunity to better understand the mechanism(s) by which HLA-B27 contributes to SpA pathogenesis
Participation of plasmacytoid dendritic cells and NKT cells in the mouse model of lupus induced by non-bilayer phospholipid arrangements
Authors: Saldivar Carla Elizabeth Landa , Reséndiz Albany , Zárate Luz Angela , Hernández Teresa , Sánchez Sandra , Flores-Romo Leopoldo , Wong-Ramírez Carlos , Baeza-Ramírez Isabel , Wong-Baeza Carlos 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease where animal models are used to study its pathogenesis. We have developed a mouse model of an autoimmune disease that resembles human lupus by the injection of liposomes bearing non-bilayer phospholipid arrangements (NPA). We detected the presence of IgG antibodies against NPA in the serum of mice with lupus and patients with SLE. In this work, we determined by citofluorometry the presence of plasmacytoid dendritic cells (pDC) the main producer of type I interferons, and of NKT cells in the secondary lymphoid organs of mice 30 and 60 days after the injection of liposomes with or without NPA induced with 8 mM promazine. In both groups of mice injected with liposomes bearing NPA a significant increase of pDC cells (5-fold) was found which correlates with the high concentration of type I interferon previously detected in this mouse model of lupus and in patients with SLE. A significant increase of NKT (3-fold) was detected at 30 days, specifically in the NKT subpopulation CD4+ that is known to cooperate with B cells in response of lipid antigens; this increase suggests its probable involvement in adaptive immune responses, which lead to the production of anti-NPA IgG antibodies. The increase of pDC and NKT cells found by cytometry in secondary lymphoid organs in this work, suggests their involvement in the formation of anti-NPA IgG antibodies and the development of the disease resembling human lupus.
Neutrophils modulate the progression of B cell auto-reactivity in systemic lupus erythematosus
Authors: Bird Anna Kathleen , Rangel-Moreno Javier , Meednu Nida , Hossler Jennifer , Anolik Jennifer 
Published: January 2023

Abstract
The central feature of systemic lupus erythematosus (SLE) pathogenesis is loss of immunologic self-tolerance. Here, we address a current controversy regarding whether neutrophils influence the development of B cell auto-reactivity SLE. While both human and murine lupus neutrophils produce factors known to fuel adaptive immune dysregulation, including type I interferon, B cell survival factors, and extracellular traps (a putative source of self-antigen), some studies have contended that neutrophils in peripheral lymphoid organs (PLO) suppress B cell activation and differentiation. In order to ask whether neutrophils exert regulatory or deleterious effects on loss of B cell self-tolerance and immune activation, we compare changes in SLE progression following neutrophil depletion in the NZB/W lupus model, either during or after establishment of disease. Following depletion early in disease, we observe pronounced acceleration of proteinuria, anti-dsDNA titers, and germinal center formation. However, neutrophil depletion after onset of overt disease pathology (including proteinuria) does not strongly alter SLE progression, implicating neutrophils as playing a protective role only apparent during disease onset. To elucidate the specific mechanisms underlying neutrophil effects on B cell auto-reactivity, we examine the cytokine profile of neutrophils in direct proximity to B cells in PLO during several stages of disease. With progression of disease, we observe an influx of interferon-alpha-producing neutrophils in direct proximity to B cells in PLO. These data delineate a shifting balance of both regulatory and activating roles for neutrophils in auto-reactive B cell activation/proliferation during SLE progression.
TNF receptor type 2 (TNFR2) in the maintenance of gut microbiota and autoimmune disease susceptibility
Authors: McKarns Susan C , Miller Patrick G. , Franklin Craig , Ericsson Aaron C , Bonn Michael B 
Published: January 2023

Abstract
Tumor necrosis factor (TNF) antagonism is therapeutic for some inflammatory autoimmune disorders such as Crohn’s disease and rheumatoid arthritis. However, TNF blockade inexplicably exacerbates CNS autoimmunity, including multiple sclerosis. We now demonstrate that selective TNFR2 deficiency augments spontaneous autoimmunity in female, but not male, myelin oligodendrocyte glycoprotein (MOG)–specific 2D2 TCR transgenic mice. Disease in TNFR2−/− 2D2 mice correlates with CNS lymphocyte infiltration and increased myelin oligodendrocyte glycoprotein–induced IL-17, IFN-γ, and IgG2b production. Attenuated disease in TNF−/− 2D2 mice relative to TNFR2−/− 2D2 mice identified distinctive roles for TNFR1 and TNFR2. Antibiotic treatment eliminated spontaneous autoimmunity in TNFR2−/− 2D2 mice to suggest a role for gut microbiota. Illumina sequencing of fecal 16S rRNA identified a distinct microbiota profile in male TNFR2−/− 2D2 mice that associated with disease protection. While Akkermansia muciniphila, Sutterella sp., Oscillospira sp., Bacteroides acidifaciens, and Anaeroplasma sp. were selectively more abundant in male TNFR2−/− 2D2 mice, Bacteroides sp., Bacteroides uniformis, and Parabacteroides sp. were more abundant in affected female TNFR2−/− 2D2 mice. Overall, selective TNFR2 blockade appears to target commensal bacteria–host immune dysbiosis to potentiate autoimmunity in genetically susceptible female mice. Under this paradigm, microbes likely contribute to an individual’s response to anti-TNF therapy. This model provides a foundation for host immune–microbiota-directed measures for the prevention and treatment of CNS-demyelinating autoimmune disorders.
TLR2 tolerance in EAE
Authors: Anstadt Emily J , Fujiwara Mai , Nichols Frank , Clark Robert B 
Published: January 2023

Abstract
TLR2 expression is enhanced in MS and EAE, but its role in these diseases is controversial. In adoptive transfer EAE, exogenous TLR ligands are not administered yet TLR2-deficient mice have been reported to develop attenuated disease. Despite this evidence for a disease-promoting function of TLR2, others have shown the opposite, i.e. that administration of TLR2 ligands can inhibit EAE in WT mice. To understand this paradox we tested the postulate that although TLR2 signaling may be EAE-promoting, repeated TLR2 ligand administration can lead to diminished TLR2 responsiveness (tolerance) and attenuated disease.
To establish our approach, we administered Pam2Cys to SJL/J mice for 5 days and induced TLR2 tolerance that persisted for 4–5 days, reflected in decreased serum TNFα in response to a second TLR2 ligand (p&lt;0.0001 day 1; p&lt;0.01 day 3; p=0.069 day 5). Next, we used this approach to induce TLR2 tolerance in the context of EAE. SJL/J mice received EAE-causing, PLP-reactive LNCs on day 0 and tolerance was induced at various time points. Surprisingly, initiating the TLR2 tolerance protocol at day −2 or day +8 showed no effect on disease. In contrast, initiating the protocol between day +4 and +6 lead to significant inhibition of EAE onset and severity that lasted at least 5 days (p=0.025) and was associated with TLR2 tolerance (p&lt;0.0001).
In sum, we have used TLR tolerance as a novel probe to identify a narrow kinetic window in which TLR2 is required for EAE. Additionally, we have demonstrated the potential use of TLR tolerance as a new therapeutic approach in EAE and MS. Ongoing studies will characterize the relevant TLR2-expressing cells in EAE and the potential role of the microbiome in inducing homeostatic TLR tolerance that regulates autoimmunity.
Gut microbiota dysbiosis in patients with Multiple Sclerosis
Authors: Mangalam Ashutosh K , Chia Nicholas , Chen Jun , Kalari Krishna R , Yao Janet Z , Novotna Martina , Soldan Mateo Paz , Luckey David , Marietta Eric V , Jeraldo Patricio R , Chen Xianfeng , Weinshenker Brian G , Rodriguez Moses , Kantarci Orhun H , Kantarci Orhun H , Nelson Heidi , Murray Joseph A 
Published: January 2023

Abstract
Multiple sclerosis (MS) is an inflammatory and demyelinating autoimmune disease that is known to involve environmental predisposition—an important component of which may be influenced by the GI microbiota. This study was designed to investigate whether gut microbiota may play a role in the etiopathogenesis of MS, by comparing the composition of fecal microbiota in MS patients to that of age- and gender-matched healthy controls. Phylotype profiles of the microbiome populations were generated using deep sequencing of the hyper variable V3–V5 region of the 16S ribosomal RNA (rRNA) gene and high quality sequences were then analyzed for taxonomic composition and clustering (OTU) using QIIME (Quantitative Insights Into Microbial Ecology) and LEfSe (LDA Effect Size). High-throughput multiplexed MiSeq sequencing yielded over 50,000 reads/sample, ensuring detection of both dominant and rare members of the microbiome. Detailed fecal microbiome analyses revealed that patients with MS had a distinct microbial community profile compared to healthy controls. We observed a decreased abundance of taxa involved in metabolism of phytoestrogen and bile acid, both of which play important roles in the maintenance of gut homeostasis and the induction of anti-inflammatory pathways. This study suggests that microbial dysbiosis, particularly a decrease in anti-inflammatory microbes, may lead to an increased pro-inflammatory immune response and subsequent predisposition to the development of MS. In particular, our study consistent with the hypothesis that microbial dysbiosis is a contributing environmental factor involved in the etiopathogenesis of MS.
Influenza infection modulate the extent and duration of inflammation in the central nervous system of EAE pathogenesis
Authors: Chen Qingyun , Liu Yinping , Ni Ke , Lv Aizhen , Xiang Zheng , Zheng Jian , Tu Wenwei 
Published: January 2023

Abstract
Multiple sclerosis (MS) starts with increased migration of auto-reactive lymphocytes across the blood-brain barrier, resulting in persistent neurodegeneration. Evidence from clinical and epidemiological studies indicated that viral infections are important in the induction of autoimmunity including MS. Using the experimental autoimmune encephalomyelitis (EAE) as a model for MS, we demonstrated that influenza infection can modulate the development of the central nervous system (CNS) inflammation. It was shown that mice with influenza infection were unable to recover from EAE, exhibiting a long-term chronic disease course. We found that the exacerbated disease after influenza virus infection was due to elevated Th1 cells infiltration into CNS, and this enhancement in the early stage of EAE disease is accompanied by increased CCR5+CD4+, CXCR3+CD4+ T cell and MOG35–55 specific CD4+ T cells localized in the lung and its draining lymph node in influenza virus-infected mice. We also observed much more CD45highCD4+CD44high effector T cell and CCR5, CXCR3, IFNγ expressing Th1 type cells entering the CNS at both acute phase and later stage of EAE disease in influenza virus-infected mice. Finally, the administration of a CCR5 and CXCR3 antagonist inhitibs the Th1 cells infiltration and significantly decreases the difference of clinical disease course between mock and influenza virus-infected mice. Taken together, our data suggested that prior influenza infection may affect subsequent EAE pathogenesis by selectively recruit CCR5 and CXCR3 bearing CD4 T cells into CNS.
The effects of Estrogen on the IFN signature in Lupus
Authors: Lee Michael Hweemoon , Sriram Uma , Chakhtoura Marita , Chain Robert W , Caricchio Roberto , Gallucci Stefania 
Published: January 2023

Abstract
Dendritic cells (DCs) are pivotal immune regulators and are important in the pathogenesis of Systemic Lupus Erythematosus (SLE). We have previously found that DCs from female lupus-prone mice constitutively over-express Type I Interferon (IFN) responsive genes resembling the IFN Signature found in SLE patients. Since this Signature is present in pre-diseased mice, it may contribute to disease pathogenesis. Nucleic acids, major auto-antigens in lupus, are potent stimulators of innate immunity and may contribute to the IFN signature by stimulating DCs through TLR7 and 9. As SLE is ~9 times more likely to affect women than men and the onset of SLE is most often in the reproductive years of women, estrogens have been suggested to affect the IFN response. To investigate the effects of estrogen on the IFN signature, we studied conventional DCs (cDCs), from male and female Sle1,2,3 lupus prone mice or from wild type C57BL/6 mice, generated in media void of sterols with supplemental titrations of 17-beta-estradiol (E2). We have found that DCs from male pre-diseased lupus-prone mice express the IFN Signature found previously in female DCs. Furthermore, E2 stimulation, regardless of the sex of the DCs, modulates the activation of cDCs in response to TLR stimulation. Interestingly, while high levels of E2 in hormone replete conditions were capable of exacerbating the IFN signature, the difference seen between wild-type and Sle DCs in standard conditions indicates both an E2 and E2-independent exacerbation in the activation of Sle DCs.
Chemotaxis to islets based on cellular insulin receptor expression
Authors: Esakov Emily L , Al-Dieri Ali , McInerney Marcia F 
Published: January 2023

Abstract
In the non-obese diabetic (NOD) mouse model, T1D is an autoimmune disease characterized by insulitis and T cell-mediated destruction of pancreatic islet beta cells. Insulin receptor (IR) is a chemotactic receptor capable of driving T cell movement in response to insulin. In published work, purified T cells, obtained from diabetic mice, and sorted into IR positive and negative cells were passaged into irradiated nondiabetic NOD mice. Only recipients that received IR positive T cells had insulitis and diabetes. If the IR expressing cells are moving into the pancreas based on an insulin gradient, then artificially making T cells with high IR expression should allow for movement into the pancreas in mice that are not susceptible to T1D.
A novel transgenic mouse model was made that has a FLAG tagged mouse insulin receptor behind a CD3 promoter for expression on T cells in a mouse not susceptible to T1D development. Transgenic BL/6-CD3FLAGmIR mice were successfully made, and show evidence for T cell trafficking into the pancreas. Although insulitis occurs, no diabetes has developed.
Characterizing IR expression on T cells may be of key importance for understanding the pathogenesis of diabetes. If IR expression is established as a mechanism to move T cells into islets, then down regulation of IR expression specifically in T cells will provide a new therapeutic target to block cell movement into the pancreas, thus preventing T1D.