bluuebunny/crossref_metadata_2025_split huggingface dataset:
Therapeutic role of the novel checkpoint regulator VISTA in murine autoimmune disease models. (P5174)
Authors: Ceeraz Sabrina , Sergent Petra , Schned Alan , Burns Christopher , Noelle Randolph 
Published: January 2023

Abstract
Negative checkpoint regulators are critical in triggering the immune response and in the clinic, therapeutics targeting the CTLA-4 and PD-L1 pathway have been successful in treating human cancers and marginal therapeutic efficacy noted in autoimmune diseases. Our lab recently identified a novel checkpoint regulator termed V-region Immunoglobulin-containing Suppressor of T cell Activation (VISTA). VISTA is structurally distinct from other members of the Ig superfamily. This study aimed to determine the therapeutic efficacy of VISTA in autoimmunity is effective. To address this, we investigated the role of a VISTA Ig fusion protein (VISTA-Ig) in autoimmune disease models of Multiple Sclerosis (Experimental Autoimmune Encephalomyelitis (EAE)) and Systemic Lupus Erythematosus (SLE). In sick EAE mice, therapeutic treatment with VISTA-Ig suppressed disease severity compared with untreated mice in vivo. In the lupus prone mouse strain NZBW-F1 which closely resembles human SLE, the prophylactic and therapeutic effect of VISTA-Ig was studied. Prophylactic treatment with VISTA-Ig prevented the onset of proteinuria and weight loss compared with untreated mice and therapeutic treatment reversed proteinuria in sick mice. Clinical evaluation of kidneys from the VISTA-Ig treated group showed minimal to mild glomerulonephritis compared with untreated mice. In conclusion we demonstrate that VISTA-Ig is a novel effective therapeutic in treating established autoimmune diseases.
Role of IL-22 in tissue regeneration in autoimmunity (P5164)
Authors: Singh Bhagirath , Hill Thomas , Krougly Olga , Qian Alexander , Bellemore Stacey , Lee-Chan Edwin , Nikoopour Enayat , Hill David 
Published: January 2023

Abstract
The various cell types in our bodies are constantly regenerating but at a different rate. In autoimmune diseases cells once destroyed can regenerate. However, immune system once activated continues to target and destroy these cells. Thus, tissue regeneration remains a challenge in these diseases. Cytokines play a major role in immune regulation, inflammation, tissue injury and autoimmunity. We have shown that immunostimulation by mycobacterial adjuvants such as BCG vaccine as well as complete Freund’s adjuvant (CFA) can prevent the autoimmune process and can stimulate tissue regeneration. These adjuvants induce regulatory Th17 (Treg17) cells and stimulate expression of Regenerative (Reg) genes such as Reg1 and Reg2 in pancreatic islets. Th17 cells also produce Interleukin-22 (IL-22) that has been shown to stimulate This is probably mediated through STAT3/ERK signaling. Reg gene expression. Blocking of IL-22 prevented the expression of Reg genes in vivo. In this study we explored the cell types that express Reg genes following IL-22 treatment by using RT-PCR analysis and by histological staining. Our hypothesis is that the Reg gene expression drives the islet regeneration following tissue injury by autoimmunity in type 1 diabetes. These approaches offer alternatives to tissue transplantation in autoimmunity.
CTL-promoting effects of IL-21 counteract murine lupus and outweigh B cell stimulatory effects (P5147)
Authors: Rus Violeta , Nguyen Vinh , Tegla Cosmin , Chen Ching , Rus Horea 
Published: January 2023

Abstract
IL-21 promotes autoimmunity in the chronic graft versus host disease (cGVHD) model through both B and CD4 T cell intrinsic mechanisms. To determine the importance of IL-21R signaling in CD8 T cells in murine lupus, we assessed the effect of IL-21 administration on autoimmune parameters in the DBA-into-F1 model of cGVHD. In addition, the effect of IL-21R deficiency on CD8 T cells was assessed in the B6-into-F1 model of acute (a) GVHD using IL-21R sufficient and deficient donor (d) cells. cGVHD mice that received rmIL-21 exhibit attenuated autoimmune parameters with respect to host B cell expansion, anti-ssDNA autoAb production and renal disease along with enhanced dCD8 expansion and donor anti-host CTL activity. Phenotype of aGVHD induced with IL-21R-/- donor cells converted from an acute to a chronic pattern characterized by increased autoAb production, decreased host B cell elimination, impaired CTL activity and decreased dCD4 and dCD8 cell expansion. In both models, IL-21R signaling on dCD8 cells resulted in increased dCD8 expansion, granzyme B level and IFNg expression. These results suggest that lack of IL-21/IL-21R interaction on CD8 T cells converts acute to chronic GVHD, while in cGVHD, IL-21 administration counteracts the humoral component by enhancing CTL generation and host B cells elimination. Therefore, IL-21R signaling on CD8 T cells attenuates disease phenotype in murine lupus, thus opposing the enhancing effects of IL-21R signaling on CD4 T cells and B cells.
Suppression of IL-17 and GM-CSF production in T cells by immunomodulator ameliorates the pathogenesis of autoimmune neuroinflammation (P5150)
Authors: McMickle Anthony , Xie Li , Chen Jing , Awar Nadia , Nady Soad , Sredni Benjamin , Drew Paul , Yu Shiguang 
Published: January 2023

Abstract
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE) is a common animal model for MS. A number of studies provide evidence that IL-17-producing T cells (Th17 cells) play a dominant role in the pathogenesis of MS and EAE. Recent work by others further indicated that the ability of Th17 cells to induce EAE is dependent on granulocyte-macrophage colony-stimulating factor (GM-CSF). Therefore, targeting Th17 cells and/or inhibiting production of GM-CSF has potential therapeutic options for EAE and MS. Our current studies demonstrated that AS101 (a small, non-toxic organotellurium compound used in the treatment of cancer), inhibits Th17 cell differentiation and reduces GM-CSF production in T cells by inhibiting activation of the transcription factors Stat3, RORγt and NFAT, and up-regulating activation of ERK and SOCS3 expression. Furthermore, administration of AS101 in vivo reduces the severity of chronic EAE and inflammatory cell infiltration into the CNS. These studies will provide insights concerning the possible use of AS101 in clinical treatment of MS.
Blockade of CSF-1 and IL-34 in mouse model of inflammatory arthritis and colitis show a pathogenic role for IL-34 (P5160)
Authors: Lin WeiYu , Delarosa Donnie , Young Judy , Lee Dave , Jeet Surinder , Huang Zhiyu , DeVoss Jason , Chen Yongmei , Wu Yan , Caplazi Patrick , Austin Cary , Martin Flavius 
Published: January 2023

Abstract
Colony-stimulating factor1 (CSF1) and IL34 signaling through their receptor (CSF1R) promotes monocyte and macrophage (Mf) differentiation, proliferation and migration. Mf activation through CSF1/IL34 and CSF1R signaling is associated with a broad spectrum of pathologies. Therapeutic monoclonal antibodies (mAb) against CSF1 and CSF1R or specific inhibitors of CSF1R kinase activity have been tested in the animal models and some human trials. To date there are no reports on IL34 or dual CSF1 and IL34 blockade as a therapeutic strategy for targeting myeloid driven diseases. Here we describe neutralization of both CSF1 and IL34 using specific mAb in collagen induced arthritis (CIA) and DSS-induced colitis mouse models. The efficacy of the dual blockade was superior to the single blockade of CSF1 or IL34 in both models. In CIA treatment was started at day 31 post disease induction and continued for 7 weeks. Anti-CSF1 plus anti-IL34 combination therapy reduced arthritis severity comparable to anti-TNF therapy. Mechanistic studies showed reduction of Mf and monocytes in the joint of dual Ab treated group. Dual blockade of CSF1 and IL34 decreased colon histology score in colitis mice. The mice with colitis produced higher CSF1 and IL34 in serum and colon tissue compared with the controls. In conclusion, blocking CSF1 and IL34 by specific mAb could be an effective therapy for myeloid driven inflammatory disease.
An evidence for a potential linkage between Acanthamoeba infections and multiple sclerosis (P4551)
Authors: Massilamany Chandirasegaran , Jamerson Melissa , Madayiputhiya Nandakumar , Nandakumar Renu , Marciano-Cabral Francine , Sejbaek Tobias , Illes Zslot , Reddy Jay 
Published: January 2023

Abstract
We recently observed that Acanthamoeba castellanii (ACA), a free-living amoeba, has the potential to trigger central nervous system autoimmunity by generating cross-reactive T cells for multiple myelin antigens, namely, proteolipid protein (PLP) 139-151 and myelin basic protein (MBP) 89-101. Additionally, the homology model derived for human leukocyte antigen-DR2, complexed with MBP 85-99 and its mimicry epitope, predicts the possibility of generating cross-reactive T cells for human MBP 85-99 in Acanthamoeba-exposed individuals. These observations raise a question whether prior exposure to ACA infection can trigger multiple sclerosis (MS). To address this hypothesis, we extracted DNA from cerebrospinal fluid obtained from MS patients and individuals with other neurological disorders, and subjected them to PCR that amplified a 500 bp fragment of the small subunit 18S rDNA using ACA-specific primer set. We confirmed the identity of PCR products by sequencing. To provide additional evidence for a linkage of ACA to MS pathogenesis, we asked whether anti-human PLP antibody can detect amoebic rhodanese-related sulfurtransferase (RST), since this protein contains the mimicry epitope ACA 83-95 for PLP 139-151. Through western blotting and LC/MS analyses, we noted that PLP antibody binds RST, suggesting that anti-Acanthamoeba immune responses have the potential to target myelin antigens. Collectively, the data suggest a linkage of ACA infection to MS pathogenesis.
Weak TCR signaling due to repeated immunization with antigen is the key for peripheral TCR revision generating aiCD4 T cell: a novel self-organized criticality theory (P4537)
Authors: Shiozawa Shunichi , Uto Kenichi , Tsumiyama Ken 
Published: January 2023

Abstract
The autoimmune disease theory explains that autoreactive clones derive from restricted clones either slipped from thymic selection or reactivated from tolerance, which cannot explain varieties of autoantibody exceeding 140 specificities seen in SLE. We instead show that autoreactive clones newly emerge via de novo TCRalpha but not beta revision at periphery from thymus-passed non-autoreactive clones (PLoS ONE 4(12):e8382,2009). This autoreactive autoantibody-inducing CD4 (aiCD4) T cell stimulates B cells to generate autoantibodies and helps to generate CD8 CTL via antigen cross-presentation and cause SLE. We studied how aiCD4 T cell is produced. Methods: Balb/c mice were immunization 8x with staphylococcus enterotoxin B (SEB), signaling molecules and their phosphorylation were assayed using western blot and antibodies. Results: The chromatin of CD4 T cell V,J region was not acetylated/ H3K4me3-lated and open, thereby facilitating the access of RAG1/2. Upon repeated immunization 8x with SBE, RAG1/2 was up-regulated but CD3zeta, ZAP70, LAT, SLP-76, PLCgamma1 and NFAT1/2 were down-regulated in splenic Vbeta8+CD4 T cell. Instead, re-activation of RAG1/2 was inhibited when TCR signal was augmented vice versa by adding PMA+ionomycin, indicating that loss of TCR signal reactivates RAG1/2 at peripheral lymphoid organ in spleen. Conclusion: Weak TCR signaling due to repeated immunization with antigen re-expresses RAG1/2 at periphery to induce aiCD4 T cell and cause SLE.
Disruption of transient receptor potential melastatin 2 attenuate lipopolysaccharide-induced heme oxygenase-1 expression in mouse macrophages through p38 mitogen-activated protein kinase (P5202)
Authors: Fang XiangMing , Qian XiaoWei 
Published: January 2023

Abstract
Transient Receptor Potential Melastatin 2 (TRPM2) is a member of transient receptor potential channels. TRPM2 mediated Ca2+ entry is an important mechanism for lipopolysaccharide (LPS)-induced cytokine and reactive oxygen species (ROS)-induced chemokine production in monocytes/macrophages. However, whether TRPM2-mediated Ca2+ entry contributes to intracellular protective protein Homo oxygenase-1 (HO-1) production in response to LPS remained unknown. Bone marrow-derived macrophages were isolated from TRPM2 knock-out (KO) mice and wild-type (WT) mice and cultured. After 100ng/ml LPS stimulation, the protein levels of HO-1 and its related signaling molecules p38 MAPK and Nrf2 were measured using immunobloting. Furthermore, in LPS stimulated WT macrophages, the p38 MAPK levels were detected after chelating Ca2+, and the HO-1 levels were evaluated after inhibition of p38 MAPK signaling. In TRPM2 KO macrophages, the expression levels of HO-1 were significantly reduced after LPS stimulation. The levels of phosphorylation of p38 MAPK and Nrf2 nuclear translocation showed the same manner when compared to those in WT macrophages. Chelation of calcium obviously inactivated LPS-induced phosphorylation of p38 MAPK. Inhibition of p38 MAPK signaling completely suppressed HO-1 expression. TRPM2 plays an important role in controlling HO-1 expression in macrophages and thereby may protect against inflammation and tissue oxidant injury.
Pregnancy establishment is influenced by CCR7 and CCR9 (P6360)
Authors: Teles Ana , Zenclussen Ana 
Published: January 2023

Abstract
Pregnancy establishment and maintenance represents a challenge for the maternal immune system. It has to be alert against pathogens while tolerating paternal alloantigens in fetal structures. The maternal immune system is not only aware of these alloantigens, but it also actively tolerates them to ensure the survival of the fetus throughout pregnancy. Regulatory T cells (Treg) are reportedly involved in this process. They are known to act in both paracrine and cell-contact dependent ways and therefore their cellular localization is essential for their functional ability of suppressing specific immune responses. Chemokines are known coordinators of leukocyte migration and our aim was to understand how these molecules influence Treg recruitment at the feto-maternal interface and interfere with pregnancy success. We found that both CCL21 and CCL25 chemokine ligands are present in the uterus before and during pregnancy and their ligands CCR7 and CCR9 are expressed in Tregs from the uterus and lymph nodes draining the uterine region. CCR7 mediated the homing of Treg to the uterus while CCR9 determined the maturation state of uterine DCs and presence of T effector cells, and both critically interfered with implantation if genetically deleted. Our data provide new insights on the mechanisms of tolerance acquisition during pregnancy.
Diesel exhaust particle induction of IL17A contributes to severe asthma (P6373)
Authors: Brandt Eric , Butsch Kovacic Melinda , Lee Gerald , Gibson Aaron , Acciani Thomas , LeCras Timothy , Budelsky Alison , Khurana Hershey Gurjit 
Published: January 2023

Abstract
The factors that promote IL17A production during the pathogenesis of severe asthma remain undefined. Diesel exhaust particles (DEP) are a major component of traffic related air pollution and are implicated in asthma exacerbation. We assessed the impact of DEP exposure on asthma severity in asthmatic children from the Greater Cincinnati Pediatric Clinic Repository. Among high DEP-exposed children with allergic asthma, 32.2% of the children had severe asthma, compared to only 14.2% in the low DEP-exposed group. Similarly, Balb/c mice co-exposed to DEP and house dust mite extract (HDM) markedly demonstrated enhanced airway inflammation and hyperresponsiveness (AHR) compared to HDM alone. Exposure to DEP alone did not induce classic features of asthma but generated a Th17 response. DEP and HDM co-exposures enhanced pulmonary Th2 and Th17 cell numbers compared to HDM alone. High DEP-exposed children with allergic asthma had elevated serum IL17A levels compared with low DEP-exposed children. Finally, IL17A neutralization alleviated DEP-induced exacerbation of AHR. In conclusion, Th17 cells contribute to DEP-mediated exacerbation of allergen-induced asthma. Neutralization of IL17A may be a useful therapeutic strategy to counteract the asthma promoting effects of traffic related air pollution especially in severe asthmatics.
Racial disparities in the vitamin D-mediated innate immune response following supplementation (P3379)
Authors: Reyes Rachel , Rafison Brandon , Hur Andy , Joyce Peter , Modlin Robert , Liu Philip , Adams John 
Published: January 2023

Abstract
We have previously demonstrated that innate (Toll-like receptor 2/1) and adaptive (IFN-γ) immune signals converge on a common vitamin D-dependent antimicrobial pathway in the human macrophage against Mycobacterium tuberculosis, including activation of CYP27B1 which converts 25D into the active 1,25D hormone as well as expression of antimicrobial peptides cathelicidin and human beta defensin 4. This antimicrobial activity is dependent on the level of extracellular 25D in culture. Therefore, we asked if this antimicrobial response could be recapitulated using sera from 25D deficient subjects before and after vitamin D repletion of the host in vivo. Serum has been collected prospectively from 67 Hispanic/Latino, 12 black and 21 non-Hispanic white, vitamin D-insufficient/deficient (8-29 ng/ml) before and after treatment with 500,000 IU vitamin D3. The mean total serum 25D in all three ethnic groups was 20ng/ml before and rose significantly (p&lt;0.001) after vitamin D3 repletion, with a mean fold-change of 2.0, 2.9 and 3.0 in white, Hispanic and blacks, respectively. Despite the most substantial rise in total 25D in the minority populations, the ability of the sera from white donors to increase IFN-γ-stimulated macrophage cathelicidin was 3-fold (p&lt;0.01) and 2-fold greater (p&lt;0.05) than in cells conditioned in African and Hispanic/Latino American sera, respectively. These data suggest an ethnic/racial disparity in response to vitamin D supplementation.
Increased IL-22-producing cells contribute to liver fibrosis through promoting Th17 migration in chronic HBV patients (P3363)
Authors: Zhang Zheng , Zhao Juanjuan , Fu Yangxin , Wang Fu-Sheng 
Published: January 2023

Abstract
Interleukin-22 is markedly upregulated in chronic HBV (CHB) infection; however, its functional role in patients with liver fibrosis (LC) remains obscure. We screened mRNA expression in HBV-infected liver tissue vs normal control and found IL-22-associated pathway was significantly changed. We further found that intrahepatic IL-22+ cell counts were significantly increased in HBV-infected patients, especially in LC patients. Further analysis indicated that IL-22 could be produced by various liver-infiltrating lymphocytes, but preferentially produced by IL-22+IL-17a+IFN-γ- Th17 cells in LC patients, which was also positively associated with liver fibrosis severity in CHB patients. We also found human HSCs express high levels of IL-22R. IL-22 exposure increased pSTAT3 expression and fibrotic protein production, and also prevented soluble TRAIL-mediated HSC apoptosis in vitro. Blockade of IL-22 in a HBV-transgenic mice model with T cell-mediated liver fibrosis significantly restricted liver fibrosis progression, and Th17 migration and CCL20 expression. IL-22-treated HSCs secreted CCL20, and blockade of CCL20 preferentially reduced the migration of Th17 cells in vitro. These data suggest that the increased IL-22-producing cells contribute to liver fibrosis through promoting Th17 migration in chronic HBV patients, and may facilitate the rational development of immunotherapeutic strategies targeting IL-22 for the amelioration of liver fibrosis in chronically HBV-infected subjects.
Phosphorylation and the regulation of CD40L mRNA stability by polypyrimidine tract binding protein (P1394)
Authors: Saifuddin Ali , Yang Alex , Covey Lori 
Published: January 2023

Abstract
The expression of the CD40 ligand (CD40L) is controlled at the posttranscriptional level by an activation-induced program of regulated mRNA stability that is dependent on the formation of a cytoplasmic polypyrimidine tract binding protein (PTB)-containing-complex (Complex I) that binds to the 3’UTR of the CD40L mRNA. PTB is expressed as two major spliced isoforms in T cells, PTB-1 and PTB-4, which differ by the inclusion of exon 9 in PTB-4. To understand how these sites influence the function of PTB, mutants were generated at Ser 306 and Tyr 308 in the parent PTB-4 and introduced into Jurkat T cells expressing RNAi-mediated downregulated levels of PTB. Decreased PTB is known to result in an unstable CD40L transcript. We found that mutant proteins were expressed at relatively equal levels to each other and to that of exogenously-expressed wildtype PTB-4. Also, the distribution into the nuclear and cytoplasmic fractions was highly similar to endogenous PTB. We report the effect of the PTB mutations on the stability and cellular distribution of CD40L RNA. Also, comparing the functional activity of PTB-4 with PTB-1, which lacks the targeted phosphorylation sites, revealed distinct differences. Because we have previously demonstrated that PKC affects the PTB-mediated stability of CD40L mRNA, identifying the role of specific phosphorylation sites broadens our understanding of how events during T cell activation regulate expression of this critical co-stimulatory molecule.
T cell correlates of solid protective immunity following immunization of macaques with a live-attenuated trachoma vaccine (P4403)
Authors: Caldwell Harlan , Olivares-Zavaleta Norma , Carmody Aaron , Whitmire Bill , Kari Laszlo 
Published: January 2023

Abstract
Trachoma, caused by Chlamydia trachomatis, is the world’s leading cause of preventable blindness for which a vaccine is needed. We previously described a live-attenuated trachoma vaccine (LATV) in non-human primates (Kari L. 2011 JEM 208: 2217-23). Vaccinated macaques were either solidly or partially protected following challenge with virulent trachoma organisms. Our current goal was to characterize immune responses that correlated with solid protective immunity. Here, we preformed intramuscular boosting of LATV vaccinated macaques and studied the T cell recall response in PBMC by flow cytometry. Both solidly and partially protected macaques exhibited a strong PBMC CD8+ T recall response following intramuscular immunization. Notably, however; only CD8+ T cells from solidly protected macaques strongly proliferated in response to chlamydial soluble antigen (SA) prepared from chlamydial infected cells. The SA contained proteins known to be secreted by chlamydiae into the host cytosol making them logical antigenic targets of cytotoxic CD8+ T cells. The SA expanded CD8+ T cells expressed IFN-γ, granzyme B, and α4β7 integrin implicating them as effectors important to the development of solid protective immunity at the ocular mucosae. Identifying the effector function and antigens recognized by these CD8+ T cells will be the focus of future studies as this information will provide insights into the design of more conventional immunotherapeutic approaches for trachoma control.