bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aptamer-based screening of cerebrospinal fluid for protein biomarkers of multiple sclerosis
Authors: Soomro Sanam , Hughes Samuel , Greenberg Benjamin , Hanly John , Mohan Chandra 
Published: January 2023

Abstract

Background
Multiple sclerosis is a degenerative autoimmune disease marked by the presence of physical, mental, and psychiatric symptoms. Diagnosis is often made very late in the disease. Hence, there is a need for better diagnostic and prognostic biomarkers as well as new therapeutic targets. In this study, MS patients’ CSF was interrogated for potential diagnostic biomarkers using an aptamer based screen.

Methods
The CSF of 6 MS, 10 neurological disease controls (NC), and 8 healthy controls (HC) were subjected to an aptamer based screen of 1128 unique human proteins. Dysregulated proteins were selected using group wise fold change (FC) and Mann Whitney tests. A subset of the elevated proteins was chosen for validation by ELISA in a set of pilot CSF samples (11 MS and 6 HC).

Results
The aptamer-based screen showed 12 proteins to be elevated in MS vs HC CSF and 22 proteins to be elevated in MS vs NC CSF (FC &gt; 1.3 P &lt; 0.05). Among these, IP10, ITAC, BAFF, and LGMN were elevated in MS CSF but not NC, compared to healthy controls (FC &gt; 1.25 P &lt; 0.1). Of the ELISA-validated proteins, BCMA, IP-10, CD48, and MMP9 showed elevation in MS CSF in comparison to healthy CSF, while LGMN did not. I-TAC and MMP-7 could not be detected by ELISA.

Conclusion
An ultra-sensitive and comprehensive aptamer-based biomarker screening platform has uncovered several elevated proteins in MS CSF, including chemokines, cytokines, and B-cell drivers. Although validation is still in progress, the identified proteins show promise as diagnostic markers or therapeutic targets for MS.
Type 2 innate lymphoid cells impair IL-33-mediated tumor suppression
Authors: Long Alan W. , Dominguez Donye , Qin Lei , Zhang Minghui , Fan Jie , Zhang Bin 
Published: January 2023

Abstract
Although a number of studies have recently explored the contribution of the adaptive immunity in interleukin 33 (IL-33)-mediated antitumor effects, the involvement of innate immunity has been weakly characterized. Using Rag1−/− mice (lacking T and B lymphocytes), we show here that either systemic administration of recombinant IL-33 or ectopic expression of IL-33 in melanoma cells is sufficient to significantly delay tumor growth independent of adaptive antitumor immunity. We have demonstrated that IL-33-mediated antitumor effects rely on expansion and activation of NK cells. Concurrently, IL-33 also promoted the expansion of active type 2 innate lymphoid cells (ILC2s), via its receptor, ST2. Elevated ILC2 presence coincided with decreased NK activation and cytotoxicity, and resulted in increased tumor growth, indicating a protumor role for ILC2s. IL-33-induced ILC2 activity elicited greater expression of the immunosuppressive ecto-enzyme CD73. Removal of CD73 from ILC2s in culture with NK cells resulted in markedly increased activation levels in NK cells, providing a potential mechanism by which ILC2s may suppress NK cell-mediated tumor killing. Thus, our data reveal an important contribution of IL-33-induced ILC2 to tumor growth by weakening NK cell activation and tumor killing, independent of adaptive immunity.
The immune enhancement activity of exopolysacharide from marine bacteria on the IBDV immune response induced by B87 vaccine
Authors: He Xiumiao , Wei Ping 
Published: January 2023

Abstract
Infectious bursal disease (IBD), which is caused by infectious bursal disease virus (IBDV), is a fatal or immunosuppressive disease of young chickens. Immunization is still an important way to prevent the outbreak of the disease. The purpose of this study was aimed to investigate the immune enhancement activity of two kinds of exopolysacharide (EPS), on the IBDV immune response induced by an IBD vaccine (B87).
B87 vaccine plus EPS or B87 only were performed twice (at 7 and 14-day old) on commercial Three-Yellow-Chickens. The antibodies and IL-1 level were evaluated after immunization. The vvIBDV challenging was performed at 28-day old. The protection were assessed at 3 and 7 days post infection (dpi).
The results showed that IBDV antibodies and IL-1 level in 04 EPS+B87 and 09 EPS+B87 groups were significantly higher than B87 group. Further, the IL-1 level in groups received EPS only were significantly higher than the group received PBS only. High levels of IBDV antibody and IL-1 lasted at least for 5 weeks. After challenged with vvIBDV, the morbidity in 04 EPS+B87 and 09 EPS+B87 groups was 20%, lower than any other. The BBIX of bursa and thymus in 04 EPS+B87 and 09 EPS+B87 groups were significantly higher than the B87 group but lower than negative control, suggested that either the 04 and 09 EPS might have the ability to repair the immune organ damages induced by B87 vaccine. The trend of T cells (both CD4+ and CD8+) and B cells number, and the viral load, at 3 and 7 dpi, respectively, were consistent with the changing trend in BBIX value. We concluded that either 04 or 09 EPS showed the activity of immune enhancement in Three-Yellow-Chickens, the combination of EPS and B87 could induce higher titers of anti-IBDV antibody and protect chickens from vvIBDV challenge.
Analysis of dendritic cell activation by differential filovirus GP concentration in virus-like particle vaccines
Authors: Charley Krystal R. , Clarke Elizbeth , Bradfute Steven 
Published: January 2023

Abstract
Filoviruses, specifically ebola- and marburgviruses, can cause severe hemorrhagic fever in humans. Currently, there are no US licensed vaccines available against filoviruses. An important filovirus protein required for cellular entry is glycoprotein (GP). GPs are also used as vaccine antigens that can trigger antibody production, which makes them an important factor in vaccine development. Distinct vaccine platforms are made in different cell types, such as mammalian and insect cells. Different glycosylation patterns and GP distribution in virus-like particles (VLPs) were observed by our lab in GPs expressed in mammalian cell lines, but comparative data is needed to determine how differential filovirus GP concentration in the VLP platform affects the immune response in vaccination. We hypothesize that differential filovirus GP concentration will yield diverse results in immunogenicity and will provide insight into specifically how we can utilize GP concentration to improve vaccine development. We are using ebolavirus GPs to develop VLPs by transfecting 293T (mammalian) cells with VP40, a structural protein, and GP DNA from the different filoviruses. Preliminary results show that changing the amount of GP in transfection appears to affect the amount of VLPs generated and the relative amount of GP compared to VP40. We are currently adding the VLPs to dendritic cells (DCs), a key subset of innate immune cells, to measure activation by flow cytometry. We expect to measure how differential filovirus GP concentration in VLPs affects DC activation. This will result in broad significance in development of filovirus vaccine platforms.
An interferon-inducible mitochondrial circuit implicated in cell death, regulated by miRNAs, and conserved in vertebrates uncovered by evolution-guided studies
Authors: Hancks Dustin , Elde Nels 
Published: January 2023

Abstract
Genomes are shaped by selective pressure imposed by pathogens. For instance, over evolutionary time direct-binding of immune factors, such as pattern-recognition receptors, by pathogen-encoded inhibitors can leave a historical record of this pressure as elevated rates of amino acid replacement across closely related species - a hallmark of positive selection. We hypothesized that positive selection could be leveraged to ascribe novel immune functions to poorly characterized genes. Using signatures of positive selection similar to those observed in critical antiviral genes (e.g. APOBEC3G, PKR), we carried out an evolution-guided screen to identify novel immune factors. Our top-candidate is a small mitochondrial protein strongly induced by interferon in human and mouse cells, conserved to zebrafish, and encoded by a poxvirus. Loss-of-function analysis uncovered a defect in staurosporine-induced cell death in the presence of interferon in the absence of this factor. Unexpectedly, this defect appears due to a miRNA, which is perfectly conserved (22/22nt) in certain fish species, encoded by the ISG mRNA. This miRNA targets a highly-conserved sequence in its paralog, a factor also rapidly evolving; a constitutively expressed mitochondrial protein that interacts with the OXPHOS complexes and conserved to yeast. Strikingly, another paralog and a related miRNA (that targets the same microRNA response element in the other paralog) are upregulated in response to hypoxic stress. These data allude to a vertebrate-specific circuit implicated in cell death that is induced by distinct types of cellular stress (e.g. infection, hypoxia), regulated by related miRNAs, implemented by mitochondrial paralogs and antagonized by viruses.
Development of a computational model to quantify antigenic similarity between Dengue viruses
Authors: Smith Brittany K. , Fremont Daved H. 
Published: January 2023

Abstract
Dengue virus (DENV) causes dengue fever, the most prevalent arthropod-borne viral illness in humans. Globally, four DENV serotypes cause an estimated 100 million new cases of dengue fever and 250,000 cases of dengue hemorrhagic fever per year. DENV serotypes differ by 25 to 40 percent in the envelope (E) protein. Although primary DENV infection results in life-long immunity to the infecting serotype, subsequent infection with a different serotype increases risk of severe disease. It has been argued that this is due to weakly neutralizing, cross-reactive antibodies that mediate viral uptake by Fc receptor-bearing cells. The unique role of DENV antibody cross-reactivity in disease outcome necessitates characterization of viral antigenic similarity and resulting disease pathogenesis.
Inspired by influenza models, we are developing a model that incorporates sequence data, neutralization titers and structural information to quantify antigenic similarity between circulating DENV strains. We first identify important E protein antigenic positions by considering sequence conservation and correlation with cross-reactivity. Amino acid similarity at antigenic positions is then combined with structural data to calculate antigenic variance. The objectives of this study are to (1) identify E protein sequence positions and structural properties (epitopes) associated with antigenic variation and (2) introduce a model to quickly predict antigenic distance between DENV strains that can be assessed by neutralization experiments. We expect many antigenic positions to be located in epitopes described in the Immune Epitope Database, although some distant positions may exert allosteric affects by altering E protein structure or dynamics.
Role of Type I IFN signaling in induction of humoral response induced by viral vectored vaccines
Authors: Liu Fengliang , Niu Qingli , Liang Yuejin , Sun Jiaren , Hu Haitao 
Published: January 2023

Abstract
HIV vaccine candidates based on different viral vectors (adenovirus and poxvirus) have been tested in human efficacy trials but were associated with distinct vaccine outcomes. In particular, the vaccine regimen tested in RV144 trial involving poxvirus (ALVAC) vectored HIV vaccine provided a modest protection, which was associated with vaccine-induced HIV envelope-specific IgG antibody response. Our recent study examining host innate immunity to different viral vectors demonstrated that distinct from Ad5, the poxvirus vector can stimulate strong type-I interferon (IFN) response. In this study, we aimed to understand the impact of type I IFN signaling on generation of HIV vaccine-specific humoral immune response induced by poxvirus vectored vaccines. Here we used poxvirus vectored vaccine (MVA-HIV) that is capable of triggering type-I IFN response as a vaccination model. Prime-boost immunization of MVA-HIV in mice demonstrated that compared to wildtype mice, type I IFN receptor-deficient mice produced significantly lower levels of total and HIV gp120-specific IgG after vaccination. Consistent with the antibody response, type-I IFN signaling deficiency also resulted in lower levels of memory B cells as compared to those in WT mice, although the levels of germinal center B cells were comparable between WT and KO mice. Furthermore, our study also provided evidence that type-I IFN signaling may be involved in the generation of vaccine-specific CD4 T-cell response, including induction of HIV gp120-specific T follicular helper (Tfh) cells. Altogether, our data suggest that type I IFN signaling plays an important role in viral vector vaccination by promoting the generation of vaccine-specific humoral response and Tfh response.
Nmp4-deficiency protects mice from influenza A virus infection
Authors: Yang Shuangshuang , Adaway Michele , Sun Jie , Bidwell Joseph P. , Zhou Baohua 
Published: January 2023

Abstract
Severe influenza A virus infection typically triggers excessive and detrimental lung inflammation with massive cell infiltration and hyper-production of cytokines and chemokines. Discovering research models to alleviate lung damage without compromising viral control is critical. Here we identify that the lack of transcription factor-nuclear matrix protein 4 (Nmp4) protects mice from acute influenza virus infection by modulating the early stage inflammation. Upon infection, Nmp4-deficient mice lose only 5% body weight compared to 20% for the wild type (WT) mice. Furthermore, Nmp4-deficiency significantly reduces the recruitment of neutrophils and macrophages in the bronchoalveolar lavage fluid and lung parenchyma. Consistent with the fewer innate cells in the airways, influenza infected Nmp4-deficient mice have significantly decreased expression of cytokines and chemokines, such as IL-1β, TNF, IFN-γ, and MCP-1. However, Nmp4-deficient mice show similar viral control and adaptive immune responses to the WT mice with comparable virus specific CD8 T cells, CD4 T cells and anti-viral antibodies. Taken together, our data suggest that loss of Nmp4 protects mice from immune-driven lung damage without affecting viral clearance and may serve as a therapeutic target for severe influenza infection.
Nod2 is a negative regulator of arthritogenic T cell responses in SKG mice
Authors: Napier Ruth J. , Lee Ellen J. , Vance Emily E. , Snow Paige E. , Dawson Clare , Stenzel Peter , Davey Michael P. , Sakaguchi Shimon , Rosenzweig Holly L. 
Published: January 2023

Abstract
Nod2 is a pattern recognition receptor known for its role in antimicrobial immunity. Intriguingly, NOD2 appears to have a role outside of infection, as a single point mutation in this molecule leads to 100% incidence of an inflammatory arthritis called Blau Syndrome. Here we investigate the role of Nod2 in regulation of arthritogenic CD4+ T cells in SKG mice. SKG mice have a mutation in ZAP-70 that results in altered thymic selection and spontaneous production of arthritogenic T cells. Nod2−/− SKG mice have exacerbated arthritis and increased numbers of CD4+IL-17+ (Th17) cells that co-produce TNF and GM-CSF compared to SKG mice. Additionally, Nod2−/− SKG mice have augmented levels of IL-17A in their joint synovial fluid. Exacerbated disease in Nod2−/− SKG mice is independent of sex or SKG-mediated dysbiosis as shown by co-housing studies, but dependent on the skg-mutation. Naïve (non-arthritic) Nod2−/− SKG mice have similar numbers of conventional CD4+ T cells with unaltered Treg frequency or function compared to SKG mice. However, CD4+ T cells isolated from naïve Nod2−/− SKG mice produce increased levels of pro-inflammatory cytokines (IL-17, IFNγ) in response to TCR-dependent or -independent stimulus. Furthermore, transfer of CD4+ T cells isolated from naïve Nod2−/−SKG mice into lymphopenic (Nude) recipients results in worsened arthritis compared to an analogous transfer of SKG-CD4+ T cells. These data suggest a previously unappreciated function of Nod2 as a negative regulator of the proinflammatory capacity and pathogenesis of autoreactive CD4+ T cells in SKG mice. Understanding how Nod2 participates in immune tolerance mechanisms will contribute to our knowledge of the pathophysiology of autoimmunity and arthritis.
Reduction of autoantibody in SLE by probiotic exopolysaccharide-induced inhibitory dendritic cells
Authors: Kalinina Olga , Knight Katherine L. 
Published: January 2023

Abstract
Exopolysaccharide (EPS) secreted by a commensal bacterium, Bacillus subtilis, induces alternatively-activated, anti-inflammatory M2 macrophages that protect mice from T cell-dependent inflammatory disease induced by the enteric pathogen Citrobacter rodentium. We tested the activity of EPS on dendritic cells (DCs), and found that in vitro, EPS not only induced the expression of inhibitory molecules, PDL1 and PDL2, but also that these DCs inhibited alloreactive T cell activation and proliferation in mixed lymphocyte reactions (MLR). We also found that in vivo injection of EPS resulted in the generation of DCs expressing PD-L1 and PD-L2. To test if the EPS-induced DCs are inhibitory in vivo, we used a model that mimics Systemic Lupus Erythematosus (SLE) and tested if the level of autoantibody was decreased. We injected Bm12 cells into EPS-treated C57BL/6 mice to induce SLE-like symptoms, and found that the titer of autoantibodies was significantly decreased in the EPS-injected mice compared to control mice. We conclude that EPS can generate inhibitory DCs both in vitro and in vivo, and we suggest that these DCs have the potential to protect from SLE and other autoimmune diseases.
Arginine methylation drives inflammatory T cell responses and autoimmunity
Authors: Webb Lindsay M. , Savardekar Himanshu , Jablonski Kyle A. , Amici Stephanie A. , Li Linsen , Li Chenglong , Baiocchi Robert A. , Guerau-De-Arellano Mireia 
Published: January 2023

Abstract
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that is the leading cause of disability in 2 million young adults aged 20–40 worldwide. Heightened pro-inflammatory T helper (Th) 1 and Th17 cell responses and deficient Th2 and regulatory T (Treg) cell responses drive myelin sheath damage and disability in MS. Thus, therapeutic strategies that modulate inflammatory T cell responses would be beneficial to the field. Epigenetic modifications are well known to provide control over cellular phenotype, and pan-methyltransferase inhibitors have been shown to suppress Experimental Autoimmune Encephalomyelitis (EAE), the mouse model of MS. However, the methylation enzyme responsible for this therapeutic effect remains unknown. Protein arginine methyltransferase 5 (PRMT5) is the only enzyme known to catalyze symmetric dimethylation (SDM) on arginine residues of histones, mediating transcriptional repression. Although PRMT5 is a known cancer driver, until recently, there was no known role for PRMT5 in T cells. We found that PRMT5 protein was up-regulated during re-activation of memory human Th1 cells, and that PRMT5-selective inhibitors suppressed inflammatory T cell proliferation. Further, we developed a conditional PRMT5 knockout mouse model in which PRMT5 knockout can be induced in CD4+ T cells. With this model, we genetically validated our findings that PRMT5 drives CD4+ T cell proliferation. Importantly, we translated our findings in vivo by showing that PRMT5 inhibitors suppressed established EAE disease severity. Overall, these data support a role for PRMT5 in pathogenic memory T cell responses and suggest its promise as a potential therapeutic target for autoimmune diseases such as MS.
Level of self-reactivity modulates functional potential of effector T cells in autoimmune diabetes.
Authors: Kong Yuelin , Sprouse Maran , Jing Yi , Bettini Matthew L. , Bettini Maria 
Published: January 2023

Abstract
T cell infiltration and accumulation in pancreatic islets during autoimmune diabetes is largely dependent on TCR specificity for beta cell antigens. However, it is not fully clear whether the level of self-reactivity is an important determinant of T cell function in autoimmunity. We observed that CD5 expression is proportional to the level of self-reactivity based on Nur77-GFP reporter of TCR signaling and insulin tetramer staining of islet infiltrating T cells. Using RNAseq profiling, TCR sequencing, and cell transfer diabetes model we show that CD5 segregates functionally and transcriptionally distinct effector T cells. Transfer of CD5hi islet infiltrating T cells resulted in accelerated diabetes development compared to CD5lo cells (8 weeks vs. 11 weeks post transfer), suggesting that both T cell populations are able to re-infiltrate the pancreas and cause beta cell destruction, but CD5hi T cells exhibit increased pathogenicity. RNAseq analysis showed an increase in expression of Lag3 and FR4 in CD5hi cells, consistent with their increased activation and subsequent induction of regulatory and tolerogenic pathways. However, cell intrinsic negative regulators did not suppress IFNg production in CD5hi T cells, which was significantly higher compared to CD5lo cells. Our findings show that the strength of TCR reactivity to beta cell antigens is an important determinant of T cell pathogenicity in autoimmune diabetes.
Rapamycin suppresses T cell responses in recoverin-induced autoimmune retinopathy and prevents disease progression in the eyes
Authors: Nikoopour Enayat , Lin Cheng-mao , Heckenlively John R. , Lundy Steven K. 
Published: January 2023

Abstract
Autoimmune retinopathy (AIR) causes acute and progressive vision loss in patients. We have established a murine model using the retinal autoantigen, recoverin, to better understand the immunopathology of AIR. Immunization of C57BL6 mice with recombinant mouse recoverin resulted in systemic recoverin-specific Th1 and Th17 cell responses and infiltration of CD4+ and CD8+ T lymphocytes, B lymphocytes, and CD11b+Ly6C+ inflammatory monocytes into the eyes. Treatment of mice with rapamycin at the time of immunization suppressed the induction of recoverin immunity and reduced inflammation in the eyes compared to the untreated group. Rapamycin dampened Th1 and Th17 T cell responses in draining lymph nodes and lowered serum antibody titers toward recoverin. There was a significant decrease in the number of CD4+ T cells and CD11b+Ly6C+ inflammatory monocytes infiltrating the eyes of rapamycin-treated mice. A higher number of CD103+CD8+ tissue resident memory T cells were present in the eyes of rapamycin treated mice. Treatment resulted in a significant decrease in the frequency of CD122+CD69−PD-1−CD8+ and the total number of CD44+CD62L+ memory T cells in lymphoid organs. While adoptive transfer of T cells from recoverin-immunized mice into naïve mice led to pathological changes in the eye, adoptive transfer of T cells from a rapamycin treated group did not result in eye pathology in the recipient. Treatment of mice with rapamycin at later time points after disease induction did not prevent disease, however, transfer of recoverin-specific T cells from those mice into recipient mice failed to induce disease. Our findings indicate rapamycin may be an effective drug for suppression of autoimmune retinopathy in some circumstances.