bluuebunny/crossref_metadata_2025_split huggingface dataset:
LILRA3 protein is constitutively expressed in normal serum and increased in patients with active rheumatoid arthritis (49.11)
Authors: Tedla Nicodemus , Chandra Vasudha , An Hongyan , Bryant Katherine 
Published: January 2023

Abstract
Leukocyte immunoglobulin-like receptor A3 (LILRA3) belongs to a family of cell surface receptors that have activating or inhibiting functions in leukocytes through their intracytoplasmic immunoreceptor tyrosine-based activating motifs (ITAMs) and inhibitory motifs (ITIMs). LILRA3 lacks transmembrane and cytoplasmic domains, suggesting that it may be secreted. Although LILRA3 function is unknown, its high structural homology to activating LILRA1 and A2 indicate that it may act as antagonist or agonist to these receptors. Clinically, LILRA3 may have a role in a number of immune-related diseases. A recent finding showed that individuals who lack the LILRA3 gene have a higher incidence of multiple sclerosis, suggesting that LILRA3 may regulate inflammatory responses. However to date, expression studies of LILRA3 have been limited to mRNA. Here we developed an ELISA to detect LILRA3 protein in serum. To investigate whether LILRA3 plays a role in chronic inflammation, we examined its expression in serum and synovial fluid of patients with rheumatoid arthritis (RA). For the first time, we demonstrate LILRA3 protein expression in serum with increased levels in serum and synovial fluid of patients with RA compared to osteoarthritis or normal subjects. The level of LILRA3 in RA correlated with disease activity score. These findings indicate that LILRA3 may play a role in the pathogenesis of RA.
Autoimmune Transcriptional Profiles in Early Rheumatoid Arthritis Peripheral Blood Cells (49.12)
Authors: Olsen Nancy J , Ligon John , Davis Laurie S 
Published: January 2023

Abstract
Blood samples from early rheumatoid arthritis (RA) patients were examined for unique transcriptional profiles. Whole blood (WB) was collected in PAXgene Blood RNA tubes (Qiagen) from seropositive early RA patients with mean disease duration of 28 weeks, established RA patients (n=2) and healthy controls (HC; n=5). Total RNA purified on Qiagen columns was assessed by Human 6-BeadChip Illumina arrays for expression of 26,098 annotated genes, &gt;21,000 ESTs and 1550 control transcripts. Differentially expressed transcripts were identified using GeneSpring 7.3.1 (Agilent). Of 33,318 transcripts passing filtering, 678 were differentially regulated at least 2 fold in RA vs. HC and 600 were statistically significant by Welch ANOVA analysis (p&lt;0.05). Most (592) were significant by Benjamini and Hochberg false discovery rate multiple testing (p&lt;0.05) and 28 were significant after more stringent Bonferroni family-wise error analysis. Transcripts strongly expressed in early RA included RNA helicases (DDX3), synthases (PGS1), adaptor proteins (PIK3AP1), membrane proteins (CD107b), and signal transduction molecules (DUSP1, FRAT2). A majority of transcripts (18/29) previously identified as RA class predictors were upregulated in early RA. Real-time PCR carried out to confirm gene expression in a larger early RA cohort suggests unique patterns in early RA and lupus. Prospective studies will be of interest to determine gene expression patterns correlating with phenotypes.
QTL associated with collagen-induced arthritis in CXB mice. (49.13)
Authors: Marshall Dana Robin 
Published: January 2023

Abstract
B6 mice are of intermediate susceptibility to collagen-induced arthritis (CIA) while Balb/c mice are resistant but are, in turn, highly susceptible to proteoglycan-induced arthritis. Antigen presentation is H-2 directed but the disease that results is thought to be driven by regions outside of the MHC therefore, CXB mouse strains afford the opportunity to look at the influence of these regions on CIA. H2-b CXB strains are predicted to show variation in disease parameters relative to B6, depending on which Balb/c chromosome regions are present. 9/13 CXB strains are H-2b while one has a recombined H-2 region (CXB9). The four H-2d strains were crossed with C57Bl/6ByJ to generate heterozygous F1 mice that could present collagen via the B6-contributed H-2b locus. A range of incidence and severity of disease was seen across the strains, and mice were assigned to susceptibility groups based on collected parameters, including incidence. QTL analysis using WebQTL, has identified regions on chromosomes 13, 15 and 19, that correlate with susceptibility to CIA. Genes in these regions include some associated with inflammation via TGFá and IL-8, and a T-cell gene linked to rheumatoid arthritis in humans. Additionally, 3/14 identified genes are relatively specific to chondrocytes, with cartilage being the target tissue for autoimmune arthritis. These data are encouraging in that autoimmune disease involves some type of immune deregulation that in certain individuals, acts on a specific target. This model may, therefore, lend clues as to why cartilage becomes a specific target for immunological attack.
DR1001 presents ‘altered-self’ peptides by accepting citrulline in its binding pockets (49.20)
Authors: James Eddie A , Moustakas Antonis K , Bui John , Papadopoulos George K , Kwok William W 
Published: January 2023

Abstract
HLA-DRB1*1001 (DR1001) is associated with rheumatoid arthritis, containing the shared epitope (residues 70-74) within its third hypervariable region. It has been suggested that shared epitope alleles bias T cell selection and amplification, perhaps favoring the recognition of common self-peptides. However, the binding motif of DR1001 and its epitopes remain relatively uncharacterized. One recent paper inferred a binding motif for DR1001 by aligning the sequences of eluted peptides, but only two epitopes were available to validate these findings. The objective of this study was to assess the capacity of DR1001 to present RA associated self-peptides. This was accomplished by defining high affinity non-self epitopes, characterizing amino acids (including citrulline) that can bind at DR1001 anchor positions and using this information to predict putative citrullinated epitopes within RA associated proteins. We identified 15 novel DR1001 restricted epitopes using class II tetramers. Using two of these as a template, we defined the amino acid preferences for each peptide binding pocket. Citrulline was accepted at positions 4, 7 and 9. Based on the observed binding preferences we identified several arginine containing sequences from within RA associated proteins that would be expected to bind after citrullination. For 12 of these, we synthesized unmodified and citrullinated versions and measured their binding to DR1001. Five sequences bound to DR1001, implicating these as potential 'altered-self' epitopes.
Analysis of SLAM family receptors 2B4, CS1 and NTB-A in patients with Systemic Lupus Erythematosus (SLE) (49.22)
Authors: Mathew Stephen O , Kim Jong R , Pertusi Raymond M , Patel Rahul K , Mathew Porunelloor A 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease, characterized by the improper regulation of B lymphocytes that leads to the production of auto-antibodies. Several studies have identified a genetic susceptibility region called Sle 1 in mice and some human subjects. Recently, genomic characterization of the Sle1b locus, identified a highly polymorphic cluster of genes coding for the signaling lymphocyte activation molecule (SLAM)-related receptors (SRRs). 2B4 (CD244), CS1 (CD319, CRACC) and NTB-A are members of SRRs and are expressed on NK, T, B cells and monocytes. The aim of this study was to investigate expression of members of the SRRs in peripheral blood mononuclear cells (PBMC) from patients with SLE. We analyzed PBMC from forty-six patients with SLE and thirty-one healthy individuals. The surface expressions of 2B4, CS1, and NTB-A on T cells, B cells, NK cells, and monocytes were analyzed by flow cytometry. 2B4 expression was upregulated on T cells but down-regulated on NK cells and monocytes in patients with SLE. B cells from patients with SLE significantly overexpressed CS1 compared to B cells from healthy controls. The surface expression of NTB-A was upregulated on T cells and monocytes, but down-regulated on B cells in patients with SLE. Our results suggest that altered expression of SRRs may be related to the abnormal B cell hyperactivity in patients with SLE. (Research supported by grants from Texas Higher Education Board and UNTHSC).
The Epigenome of SLE (49.26)
Authors: Sullivan Kathleen E , Zhang Zhe , Song Li , Petri Michelle A 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is a polygenic disorder affecting 1:1000 adults. Recent data have implicated interferons in the pathogenesis. We examined H4 acetylation and gene expression in monocytes from patients with SLE to define alterations to the epigenome. Monocytes from 14 controls and 24 patients were used for analysis by chromatin immunoprecipitation for H4 acetylation and gene expression arrays. H4 acetylation is significantly altered in monocytes from patients with SLE. Although there was a relationship between increased H4 acetylation and gene expression the two gene sets were not concordant. The most significant relationship for both genes with increased H4 acetylation and increased gene expression was the potential for transcriptional regulation by IRF1. Alpha-interferon was a significant contributor to gene expression patterns in SLE, but the greatest concordance was seen in the enrichment of certain transcription factor binding sites upstream of genes with increased H4 acetylation in SLE and genes with increased H4 acetylation after alpha-interferon treatment. We conclude that SLE is associated with a globally altered epigenome. Multiple lines of evidence implicate the interferon pathway. Altered epigenetic patterns could contribute to the perpetuation of disease by molding the gene set competent for expression.
SR16951, a new small molecule antagonist of MCP-1 for the treatment of autoimmune diseases (50.13)
Authors: Lam Jennifer S , Alt Carsten , Bernard Claude , Laborde Edgardo , D'Andrea Annalisa 
Published: January 2023

Abstract
Monocyte Chemoattractant Protein-1 (MCP-1) is a chemokine that plays a role in the inflammatory response by attracting monocytes, memory T cells, dendritic cells, natural killer cells, and endothelial cells to the site of injury. MCP-1 and its receptor, CCR2, have been implicated as potent mediators in a variety of inflammatory and autoimmune diseases, such as multiple sclerosis (MS), rheumatoid arthritis, and atherosclerosis. Thus, the ability to block the actions of MCP-1 can be a powerful therapeutic approach for the treatment of these diseases. Here we report on SR16951, a small molecule antagonist of MCP-1. SR16951 inhibits MCP-1-induced migration of monocytic cells in vitro. Moreover, SR16951 showed a significant effect at preventing and therapeutically ameliorating the clinical symptoms that manifest during Experimental Autoimmune Encephalomyelitis (EAE), a model for MS, and Collagen-Induced Arthritis. In order to gain a better understanding of the mechanism of SR16951, we focused on differences in intracellular signaling events following MCP-1 stimulation in the presence or absence of SR16951. We found that SR16951 inhibits MCP-1-induced phosphorylation of Akt, a downstream target of the PI3K/Akt signaling pathway. These preliminary studies would indicate that SR16951 inhibits MCP-1-induced chemotaxis by interfering with early signaling events that take place after binding of MCP-1 to CCR2.
Immune modulation by chondroitin sulfate and its degraded disaccharide in the development of experimental autoimmune encephalomyelitis (EAE) (50.2)
Authors: Zhou Juhua , Nagarkatti Prakash , Zhong Yin , Nagarkatti Mitzi 
Published: January 2023

Abstract
We attempted to understand the immune modulation mediated by chondroitin sulfate A (CS-A) and its disaccharide degradation product (CSPG-DS) in the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Clinical symptoms in myelin oligodendrocyte glycoprotein peptide (MOG35-55)-induced EAE mice significantly enhanced following CS-A injection, whereas CSPG-DS injection completely inhibited EAE development. When a clinically more severe form of EAE was induced, CS-A accelerated the clinical disease, whereas CSPG-DS significantly delayed EAE. Further studies demonstrated that CS-A up-regulated STAT4 expression, and thus induced interferon-gamma production and Th1 CD4 T cell differentiation. CS-A also up-regulated STAT3 expression and increased IL-17 producing T cell populations. CSPG-DS treatment both in vivo and in vitro decreased tumor necrosis factor - alpha production from splenocytes. In vitro and in vivo assay indicated that CSPG-DS treatment significantly blocked T cell migration, whereas CS-A treatment increased lymphocyte infiltration in the brain when compared to MOG-treated control mice. Our results suggest that while CS-A exacerbates the development of EAE, CSPG-DS administration may be useful in its treatment. (Supported in part by NIH grants R01AI053703, R01ES09098, R01 AI058300, R01DA016545, R01HL058641 and P01AT003961).
The natural antioxidant lipoic acid (LA) alters immune cell function: implications for multiple sclerosis (50.3)
Authors: Salinthone Sonemany , Schillace Robynn V. , Yadav Vijayshree , Marracci Gail , Bourdette Dennis , Carr Daniel W. 
Published: January 2023

Abstract
Multiple Sclerosis (MS) is an often disabling disease of the central nervous system. Current FDA approved therapies are only partially effective, associated with side-effects and costly. Thus, there is a need for development of novel treatment alternatives for MS. The antioxidant lipoic acid (LA) reduces disease severity and T lymphocyte migration into the spinal cord in a model of MS, experimental autoimmune encephalomyelitis. A pilot clinical trial demonstrated that oral LA is well tolerated in MS patients. Because the mechanism of action of LA is unknown, we sought to determine the effects of LA on immune cell function and identify a signaling pathway that may mediate this response. We discovered that LA stimulates production of cAMP in immune cells obtained from MS patients after oral ingestion of LA. Studies using radiolabeled prostaglandin E2 (PGE2) indicate that LA competes for binding of the PGE2 receptors. LA suppresses the production of interleukin (IL)-2, IL-6 and IL-17 in these cells, and inhibits T cell proliferation. Furthermore, studies blocking activation of the cAMP signaling pathway illustrates that cAMP mediates LA suppression of interferon gamma (IFNγ) production. These novel findings suggest that LA may inhibit immune cell function via the cAMP signaling pathway and has implications for MS therapy.
This work is supported by the Dept. of Veterans Affairs Biomedical Laboratory Research & Development Service.
Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) induces tolerogenic dendritic cells that delay onset of type 1 diabetes by enhancing CD4+CD25+Foxp3+ regulatory T cells (50.33)
Authors: Ganesh Balaji B , Cheatem Donald , Gopisetty Anupama , Bhattacharya Palash , Vasu Chenthamarakshan , Prabhakar Bellur S 
Published: January 2023

Abstract
Impairment in dendritic cell (DC) functions is implicated in defective immune regulation that leads to type-1 diabetes (T1D) in both humans and the established non-obese diabetic (NOD) mouse model. In this study, we examined the roles of DC modulators such as GM-CSF and Flt3-L to affect DC function and prevent T1D development in NOD mice. Both GM-CSF and FLT3-L could suppress the development of T1D if treatment was initiated earlier in life prior to the development of clinical diabetes. However, unlike Flt3-L, GM-CSF was far more effective in suppressing T1D even when administered at later stages of insulitis. Ongoing periodic treatment of NOD mice with GM-CSF prevented the development of T1D and the animals remained healthy until 3 months after cessation of the treatment. Adoptive transfer of CD4+CD25+ T cells from GM-CSF-treated mice could suppress effector T cell response and T1D in NOD-SCID mice, and this suppression was associated with enhanced IL-10 and TGF-β1 production. Moreover, adoptive transfer of GM-CSF-exposed DCs to naive NOD mice resulted in an expansion of Foxp3+ T cells and a significant delay in T1D onset. These results indicate that primarily the GM-CSF renders DCs tolerogenic resulting in subsequent Treg induction and delayed onset of T1D in NOD mice. NIH 1RO1AI058190
Increased susceptibility to colitis in the Vasoactive Intestinal Peptide receptor type 2 (VPAC2) mouse : A negative role for VPAC1 receptor in the induction of intestinal inflammation (50.44)
Authors: Yadav Mahesh , Goetzl Edward J 
Published: January 2023

Abstract
Vasoactive intestinal peptide (VIP) is a prominent neuropeptide with effects on many immune functions which are transduced by VIP G-protein-coupled receptors type 1 (VPAC1) and type 2 (VPAC2) on immune cells. Previous studies have shown that VIP reduces clinical symptoms and inflammation in mouse models of human immune-based diseases such as rheumatoid arthritis, Crohn's Disease, septic shock and multiple sclerosis. We recently demonstrated that VPAC2 knockout (KO) CD4 T cells in the presence of VIP and TGF-b develop into Th17 cells in a cAMP-Protein Kinase A dependent manner. Here we show that increased IL-17 induction in VPAC2-KO CD4 cells is accompanied by a reduced conversion of CD4 T cells into FoxP3+ regulatory T cells. To determine if VPACs play a role in the inflammatory bowel disease (IBD), VPAC2-KO mice were subjected to dextran sulfate sodium (DSS) in drinking water. Compared to wild type (WT), VPAC2-KO mice exhibited rapid and more severe clinical symptoms of colitis and had significantly higher colonic inflammation and increased inflammatory cytokines in colon. Severe colitis in VPAC2-KO mice was ameliorated in the presence of PKA inhibitors. Moreover, VPAC1-KO mice were resistant to the development of DSS-induced colitis. The results demonstrate a new role for VPAC1 which is responsible for increased inflammation in IBD and may provide a new therapeutic target.
The Use of Soluble T Cell Receptors to Identify Ligands for gamma/delta T Cells (78.1)
Authors: Chain Jennifer L , Aydintug M. Kemal , Roark Christina L , Born Willi K , O'Brien Rebecca L 
Published: January 2023

Abstract
Two very distinct types of T lymphocytes, expressing either an alpha/beta (ab) or gamma/delta (gd) T cell receptor (TCR), are involved in immune responses. Knowledge of the antigens that gd T cells recognize and their specific functions lags extensively behind that of ab T cells. The roles of gd cells are poorly defined largely because the antigens recognized by specific gd TCRs are not known. Gd TCRs are typically considered self-reactive, responding to stress-induced host molecules, although some are known to recognize pathogen-derived molecules. Our laboratory has developed a novel technique to detect host-derived ligands on cells using purified, soluble forms of specific gd TCRs as staining reagents. The use of these soluble TCRs (sTCRs) will provide a novel approach to the identification of specific cell surface ligands responsible for activating gd T cells. I propose to use sTCRs to identify the ligands for two common murine gd TCRs, Vg1:Vd6.3 and Vg6:Vd1. sTCRs against these receptors will be used like monoclonal antibodies to screen a retroviral cDNA library made from a ligand-positive cell line. The identification of these ligands will promote further research, leading to a better understanding of the roles of gd cells in a wide variety of immune responses and providing insight into the specificity requirements of the gd TCR.
A cell free antigen processing system identifies immunodominant epitopes (78.19)
Authors: Kim Ae , Hartman Isamu , Sadegh-Nasseri Scheherazade 
Published: January 2023

Abstract
T cell-mediated responses to protein antigen involve recognition of selected antigenic peptides bound to Major Histocompatibility Complex (MHC) molecules. Proteolytic digestion of protein antigens during antigen processing generates many peptide fragments that can potentially bind to MHC molecules. However, only few selected antigenic epitopes induce T cell responses, defined as "immunodominant". Identifying immunodominant epitopes from a given antigen has wide applications in development of peptide vaccines and therapies against infectious diseases, cancer, autoimmune diseases, and allergy. Currently available methods are not efficient in elucidating CD4+ T cell epitopes. Here, we provide a novel approach for identifying the immunodominant epitopes from protein antigens using a cell-free MHC class II antigen-processing assay. Two different novel antigens, Hemagglutinin (HA1) of the A/Vietnam/1203/2004 (H5N1) virus, and a recombinant form of Plasmodium falciparum liver-stage antigen 1 (LSA-NRC) were used to evaluate our assay. HLA-DR1 restricted epitopes from both proteins were identified by mass spectrometry and were tested for their ability to activate T cells in HLA-DR1 tg mice. We observed that the identified epitopes were indeed immunodominant as CD4+ T cells from mice immunized with the proteins proliferated and produced cytokines upon challenge with the identified epitopes at levels comparable to the whole protein. This cell-free assay provides a useful tool for identification of CD4+ T cell epitopes for specific MHC class II alleles.
Vanilloid receptor 1 agonists, capsaicin and resiniferatoxin, induce efficient anti-viral CTL responses by increasing MHC-restricted antigen presentation (78.29)
Authors: Lee Chong-Kil , Lee Young-Hee , Lee Young-Ran , Kang Hyun-Jung , Im Sun-A , Song Sukgil , Kim Kyungjae 
Published: January 2023

Abstract
DCs, like the sensory neurons, express vanilloid receptor 1 (VR1). Here we demonstrate that VR1 agonists, capsaicin (CP) and resiniferatoxin (RTX), increase MHC-restricted antigen presentation in DCs. Treatment of DCs, that were infected with recombinant vaccinia virus (VV) expressing OVA (VV-OVA), with CP or RTX significantly increased MHC class I-restricted OVA presentation. In accordance with the in vitro results, oral administration of CP into VV-OVA-infected mice significantly enhanced MHC class I-restricted OVA presentation, and consequently elicited potent OVA-specific CTL activity compared to untreated controls. The effects of VR1 agonists on the exogenous antigen presentation were also examined in DCs. CP and RTX enhanced MHC class I-restricted, but not MHC class II-restricted, presentation of exogenous OVA. CP and RTX did not affect phagocytic activity, the expression level of total MHC molecules and co-stimulatory molecules on DC, suggesting that they enhance the intracellular processing events of phagocytosed antigens. These results demonstrate that VR1 agonists preferentially increase MHC class I-restricted antigen processing pathways. The present study also shows that oral consumption of CP, a common component of pungent foods, could enhance the efficacy of DC-based anti-viral and anti-tumor vaccines.