bluuebunny/crossref_metadata_2025_split huggingface dataset:
Indoleamine 2,3-dioxygenase 2, a novel mediator of pathogenic autoantibodies in autoimmune arthritis (BA12P.110)
Authors: Merlo Lauren , Pigott Elizabeth , DuHadaway James , Grabler Samantha , Metz Richard , Prendergast George , Mandik-Nayak Laura 
Published: January 2023

Abstract
Several autoimmune disorders, including rheumatoid arthritis (RA), are associated with altered activity of the immunomodulatory enzyme indoleamine-2,3-dioxygenase (IDO). However, the precise contributions of IDO function to autoimmunity remain unclear. We examined the effect of two different IDO enzymes, IDO1 and IDO2, on the development of autoimmune arthritis in the KRN preclinical model of autoimmune arthritis by comparing the effects of both genetic knockout models and chemical inhibitors of IDO on joint inflammation. We find that IDO2, but not IDO1, is critical for arthritis development, providing the first direct evidence of separate in vivo functions for IDO1 and IDO2. Specifically, IDO2 knockout mice display decreased joint inflammation relative to wild-type mice due to a reduction in pathogenic autoantibodies and antibody secreting cells. Notably, IDO2 appears to specifically mediate autoreactive, but not normal B cell responses, as total serum Ig levels are not altered and IDO2 ko mice are able to mount productive antibody responses to model antigens in vitro and in vivo. Reciprocal adoptive transfer studies confirmed that autoantibody production and arthritis are modulated by IDO2 expression in a cell type extrinsic to the T cell. Future work will define the relevant cell types for IDO2 activity. Our results provide the first insights into the previously unknown function of IDO2 by defining its pathogenic contributions to autoantibody-mediated autoimmunity.
Superoxide-deficient macrophages exhibit an M2 phenotype to prevent autoimmune diabetes. (BA12P.105)
Authors: Padgett Lindsey , Burg Ashley , Lei Weiqi , Tse Hubert 
Published: January 2023

Abstract
Type 1 diabetes (T1D) is an autoimmune disease culminating in β-cell destruction by inducing reactive oxygen species (ROS), pro-inflammatory cytokines, and islet-infiltrating leukocytes. We recently demonstrated the importance of NADPH oxidase (NOX)-derived ROS synthesis in T1D, as Non-Obese Diabetic (NOD) mice unable to generate superoxide (NOD.Ncf1m1J) were highly T1D resistant. Therefore, we hypothesized that dampened ROS synthesis within NOD.Ncf1m1J mice contributes to blunted pro-inflammatory M1 and/or enhanced anti-inflammatory M2 macrophage responses. During spontaneous T1D progression, islet-resident NOD.Ncf1m1J macrophages exhibited an enhanced M2 phenotype in contrast to age-matched NOD with a significant (p &lt; 0.01) increase in M2 macrophage transcripts (Ccl17, Retnla, Cd206, Arg1), and a significant (p &lt; 0.01) decrease in M1 transcripts (Cxcl10, Ccl5, Nos2, and Tnfa). To confirm that redox status influenced macrophage differentiation, pre-activated diabetogenic BDC-2.5 CD4 T cells, which recruit pro-inflammatory M1 macrophages to destroy β-cells, were transferred into NOD.Rag.Ncf1m1J recipients possessing superoxide-deficient antigen presenting cells. We observed a decrease in IL-1β-expressing, islet-infiltrating M1 macrophages and enhanced Arginase-1-expressing M2 macrophages compared to NOD.Rag. Our results demonstrate the importance of ROS in M1 macrophage differentiation; thus, targeting macrophage redox status may represent a promising therapy in halting T1D.
Toll-like receptor 4 agonistic monoclonal antibody reverses new onset type 1 diabetes (BA12P.106)
Authors: Bednar Kyle , Tsukamoto Hiroki , Wu Yuehong , KImoto Masao , Ridgway William 
Published: January 2023

Abstract
Viral, parasitic or bacterial infections can prevent T1D in NOD mice. The “hygiene hypothesis” proposes that the incidence of autoimmunity is increasing due to decreased immune stimulation in childhood, offering a rationale for stimulation of innate immunity as a treatment for T1D. We demonstrate that a TLR4/MD-2 specific agonistic monoclonal antibody, UT18, can not only prevent T1D, but also reverse new onset T1D (diagnosed by polyuria, weight loss, and elevated blood glucose). UT15, a control TLR4/MD-2 non-agonistic monoclonal antibody, neither prevented nor reversed T1D. In the prevention studies, UT18 treatment resulted in decreased insulitis vs. UT15 treatment. UT18 treatment permanently reversed new onset T1D in 9/13 mice, while UT15 treated mice rapidly progressed to end-stage diabetes (&gt;600 mg/dl). Mice successfully treated with UT18 had less severe islet infiltration and increased insulin positive beta-cell area compared to UT15 controls. Transfer of CD4+ and CD8+ T-cells (from mice successfully treated with UT18) did not cause diabetes for up to 75 days post transfer, whereas cells transferred from UT15 and non-diabetic NOD mice rapidly caused disease. The lack of T cell mediated diabetes transfer suggests that T cell tolerance was restored in new onset diabetic mice treated with UT18. Restoration of T cell tolerance via TLR-4/MD-2 mediated innate immune stimulation is a promising new pathway for treatment of T1D and other T cell mediated autoimmune diseases.
Anti-viral responses to diabetogenic viruses are mediated by superoxide production (BA12P.107)
Authors: Tse Hubert , Padgett Lindsey , Burg Ashley , Lei Weiqi 
Published: January 2023

Abstract
Viral infections may directly trigger the onset of Type 1 diabetes (T1D) by β-cell lysis and/or indirectly via pro-inflammatory cytokines and reactive oxygen species (ROS) by islet-infiltrating leukocytes. We recently demonstrated a crucial role for NADPH oxidase (NOX)-dependent superoxide production in T1D, as NOX-deficient Non-Obese Diabetic (NOD.Ncf1m1J) mice were resistant to autoimmune diabetes, which was partly mediated by diminished pro-inflammatory cytokine and Type I interferon synthesis via dampened macrophage-derived Toll-like receptor (TLR) signaling in response to poly(I:C), a viral RNA mimic. Therefore, we hypothesized that ROS deficiency would diminish anti-viral pro-inflammatory responses and inhibit T1D in response to viral triggers. To define the interplay between redox status and anti-viral responses, we performed infections with Coxsackie B4 (CB4) virus a putative diabetogenic enterovirus associated with T1D induction in both humans and rodents. In the absence of superoxide, NOD.Ncf1m1J macrophages exhibited a 2-fold decrease in TNF-α and IFN-α upon infection due to dampened TLR3 and RIG-I signaling. Corroborating the in vitro results, CB4 infection of NOD.Ncf1m1J mice elicited a 2-fold decrease in TNF-α and IL-1β by pancreas-infiltrating macrophages in contrast to NOD. Future studies will determine if oxidative stress can influence anti-viral responses and uncover novel insights into T1D pathogenesis in response to diabetogenic viruses.
The transcription factor CREMalpha regulates inflammatory T cell subsets in juvenile idiopathic arthritis (BA13P.115)
Authors: Moncrieffe Halima , Ohl Kim , Nickel Helge , Wedderburn Lucy , Tenbrock Klaus 
Published: January 2023

Abstract
The cAMP response element (CRE) modulator (CREM)α binds to genes promoters with CREs and regulates transcription via a chromatin-dependent mechanism. CREMα is important for the T cell pathophysiology of SLE suppressing IL-2 and CD3ζ transcription, but enhances IL-17. Juvenile idiopathic arthritis (JIA) is an autoimmune disease of unknown origin. Th17 cells have a pathogenic role in arthritis and are not controlled by local FoxP3+ regulatory T cells (Tregs). Pathogenic T cells in the inflamed joints of JIA patients have enhanced expression of IL-17, IFNgamma and CD161. CD161+ CD4+ cells also contain FoxP3+ cells that produce proinflammatory cytokines. We observed enhanced CREM expression in JIA patient synovial fluid (SF) T cells and also after culture of healthy donor PBMCs with JIA SF. We furthermore found enhanced expression of CREM in CD4+CD161+ and in CD4+FoxP3+CD161+ cells, which produce inflammatory cytokines. Vice versa Helios+FoxP3+ cells, which are characteristically stable Tregs and do not express inflammatory cytokines, had lower levels of CREM. JIA SF induced IFNgamma, IL-17 and FoxP3 in T cells during incubation, which could be abrogated by CREM siRNA transfection. Within the FoxP3+ population, CREM siRNA reduced CD161+FoxP3+ cells but not Helios+FoxP3+ cells. We thus suggest CREMα overexpression in T cells contributes to T cell pathophysiology in JIA by regulating percentages of inflammatory CD4+ IL-17+ cells, as well as inflammatory CD161+FoxP3+ cells.
CD4+ T regulatory and effector cells display a similar wide range of affinities for self during autoimmune disease (BA13P.129)
Authors: Hood Jennifer , Evavold Brian 
Published: January 2023

Abstract
The affinity of a T cell receptor (TCR) from a regulatory T cell (Treg) for endogenous self peptide MHC complex is unknown. It is thought that thymic derived Tregs (nTregs) are enriched for high affinity, self-reactive TCRs as an alternative to negative selection. During experimental autoimmune encephalomyelitis (EAE), MOG self-antigen pMHC tetramers identified few (&lt;10%) of the infiltrating CD4+ Tregs and Teffs. The micropipette adhesion frequency assay has previously proven more sensitive for assessing TCR specificity, affinity and frequency of antigen specific cells. Using this assay, it was determined that most of the Tregs and Teffs (&gt;80% each) localized in the central nervous system (CNS) at peak EAE are in fact MOG self antigen specific. Tregs and Teffs possessed similar broad 1000 fold ranges in affinities for MOG with geometric means of 1 and 4 X 10-5 μm4. In the CNS, greater than 90% of the Tregs expressed helios which was consistent with frequencies in the thymus (94%), which suggests an enrichment of nTregs in the CNS during peak EAE. Contrary to the hypothesis that nTregs arise as an alternative to negative selection due to a high affinity for self, our data show that TCR affinity of MOG specific Tregs mimics Teffs with no enrichment of high affinity cells.
Prolonged exposure to type-I IFN inhibits IL-10 signaling in memory and regulatory T cells: a new mechanism contributing to the development of autoimmune diseases (BA13P.130)
Authors: Raimondi Giorgio , Nicholson Yawah , Chen Leo 
Published: January 2023

Abstract
Interleukin 10 (IL-10) is a fundamental immunoregulatory cytokine. Mice with memory T cells (Tmem)- or regulatory T cells (Treg)-specific depletion of the IL-10 receptor (IL-10R) develop fatal autoimmune diseases. However, no correlation is known between pathological conditions and altered IL-10 signaling in T cells. We investigated the influence of prolonged exposure to the supernatant of mouse maturing dendritic cells, exposed to LPS, on the integrity of the IL-10 signaling pathway in Tmem and Treg. Following 36-48h incubation, a block in phosphorylation of STAT3 in response to IL-10, but not in response to IL-6, was evident. This IL-10-specific unresponsiveness was not associated with lower IL-10R expression. Additionally, this inhibition was not induced by IL-6 or IL-1. Instead, incubation with IFN-β impaired IL-10 signaling in both Tmem and Treg. This effect was not blocked by AKT inhibition, suggesting a role for Jak/STAT or other IFN-β-initiated signaling pathways. In NOD mice, a model of human type-1 diabetes (T1D), diabetes development is linked to high levels of type-I interferons in pancreatic lymph nodes (PNC-LN). We analyzed the IL-10 response in T cells from spleen, PNC-LN, other LNs, and pancreata of NOD mice and discovered that starting at 4 weeks of age, Tmem and Treg in PNC-LN and pancreata display suppressed responses to IL-10. Overall, these data reveal a new molecular mechanism that controls the development of autoimmunity and the pathogenesis of T1D.
Pathogenicity of autoreactive Th17 cells is dependent on T-bet expression in non-T-helper cells in experimental autoimmune encephalomyelitis (BA13P.117)
Authors: Kwong Brandon , McGavern Dorian , Lazarevic Vanja 
Published: January 2023

Abstract
Experimental autoimmune encephalomyelitis is a murine model for multiple sclerosis in which autoreactive CD4+ T-helper cells infiltrate the central nervous system (CNS) and initiate autoimmune inflammation. Previous studies have shown that EAE induction via the adoptive transfer of CNS antigen-specific Th17 cells requires T-cell-intrinsic expression of the transcription factor T-bet, but the potential pathogenic role of T-bet expression in non-T-helper cells remains unclear. Using T-bet-ZsGreen reporter mice, we confirmed that multiple non-T-helper cell populations express T-bet in the CNS during active EAE. To assess the pathogenic contribution of T-bet in non-Th cells, we transferred 2D2-transgenic (expressing a CNS antigen-specific TCR) T-bet-/- or WT Th17 cells into T-bet-/- or WT recipient mice. Consistent with previous reports, 2D2 T-bet-/- Th17 cells did not induce significant levels of EAE disease in either T-bet-/- or WT recipient mice, supporting the role for T-bet in CD4+ Th cells. Surprisingly, WT Th17 cells, while fully pathogenic in WT hosts, were unable to induce EAE in T-bet-/- hosts. Our preliminary data suggest that 2D2 WT Th17 cells were unable to breach the blood-brain barrier and infiltrate the CNS parenchyma due to ineffective local re-activation of 2D2 WT cells in the CNS of T-bet-/- recipients. Ongoing studies will seek to identify the role of T-bet expression in non-Th cell populations and their interactions with 2D2 Th17 cells in EAE induction.
VAV1 adaptor functions regulate both T cell polarization and susceptibility to immune mediated diseases (BA14P.211)
Authors: Kassem Sahar , Gaud Guillaume , Dejean Anne , Bernard Isabelle , Fournié Gilbert , Malissen Bernard , Colacios Céline , Saoudi Abdelhadi 
Published: January 2023

Abstract
Vav1 is a guanine nucleotide exchange factor (GEF) that is essential for signal transduction of the T cell receptor (TCR) and plays an important role in the development and activation of T cells. Our previous results identified a polymorphism in the Vav1 gene that impacts on its adaptor functions without notable effect on its enzymatic activity. To analyze the impact of this polymorphism on the susceptibility to immune diseases, we generated a knock-in (KI) mouse bearing an arginine (R) to tryptophan (W) substitution in the Vav1 protein (Vav1R63W KI). Using this model, we confirmed that Vav1R63W mutation had no impact on Vav1 enzymatic activity in CD4 T cells but decreased its adaptor function, as revealed by the reduction of TCR induced calcium flux and ERK/AKT activation. Moreover, we showed that Vav1R63W favors Th2 cytokine production by CD4 T cells. We next analyzed the susceptibility of these mice to immune-mediated diseases and showed that KI mice were less susceptible to MOG-induced central nervous system inflammation. This finding likely resulted from a reduced production of effector cytokines (IFN-γ, IL-17 and GM-CSF) by autoreactive CD4 T cells. Finally, we found an increased susceptibility of the KI mice to asthma features, consistent with enhanced Th2 polarization. Together, these data highlight the importance of Vav1 adaptor functions in T cell polarization and susceptibility to immune mediated diseases, with opposite effects on autoimmune and allergic diseases.
Epithelial lymphotoxin beta receptor regulates embryonic medullary thymic epithelial cell development for central tolerance (BA14P.212)
Authors: Wu Weiwei , Shi Yaoyao , Fu Yang-Xin , Zhu Mingzhao 
Published: January 2023

Abstract
Medullary thymic epithelial cells (mTEC) play critical roles in central tolerance. Given multiple cell types involved and complex cellular and molecular crosstalk, the mechanisms underlying mTEC development remain intriguing. Previous studies showed reduced mTEC number in lymphotoxin beta receptor (LTβR) knockout (KO) mice, but exactly how LTβR functions is still unclear. Here, by using conditional knockout (cKO) mice, in which LTβR is specifically depleted from thymic epithelial cells, we found dramatically reduced number of mTECs in LTβR cKO adult mice. Unexpectedly, further experiments did not find any homeostatic proliferation or apoptosis defect of mTEC in postnatal cKO mice at any stages. Further analysis of embryonic thymi interestingly found mTEC number is reduced while the number of progenitor of mTEC (mTECp) is comparable between WT and cKO mice, suggesting differentiation and/or expansion defects of mTEC in cKO mice. To further investigate the biological impact of epithelial LTβR deficiency, thymic expression of peripheral tissue restricted antigens and self-reactivity at periphery were determined in adult mice. Thymic negative selection was also directly addressed using TRAMP and SV40-TCR tg mice. Current data suggest significant impairment of thymic tolerance and autoimmune phenotype at periphery. Collectively, our study has revealed that thymic epithelial LTβR is essential for embryonic mTEC development and establishment of central tolerance in adult mice.
Indirect presentation of antigen-coupled cells mediates specific CD4+ T cell tolerance by PD-L1 for the prevention of type 1 diabetes (BA14P.207)
Authors: Fife Brian , Spanier Justin , Pauken Kristen , Heffernan James , Sahli Nathanael , Mitchell Jason 
Published: January 2023

Abstract
Antigen coupled to the surface of cells using ethylene carbodiimide is a potent inducer of tolerance in multiple models of autoimmunity including Type 1 Diabetes (T1D). Yet, the mechanisms contributing to the induction of T cell tolerance in vivo during T1D are unclear. We used the BDC2.5 T cell receptor transgenic T cell transfer model to study how p31-coupled cells inhibit T cell function in vivo. Antigen-coupled cells that were either deficient in MHC class II or MHC-mismatched induced tolerance similarly to MHC class II-sufficient matched cells, suggesting that indirect presentation of coupled cell antigens is required for tolerance induction in vivo. We also show that BDC2.5 T cells predominantly encounter coupled cell antigen that has been ingested by host antigen presenting cells, and that the inhibitory receptor PD-L1 is required on the host but not the coupled cells to induce tolerance, further highlighting an indirect mechanism of tolerance induction. These data add to our current understanding of how antigen-coupled cells induce tolerance and aid in the translation of this therapeutic into the clinic.
Bacillus infantis NRRL B-14911-induced myocarditis: a novel disease model to study the autoimmune mechanisms of myocardial injuries in the myocarditis-susceptible, A/J mice (BA15P.221)
Authors: Krishnan Bharathi , Massilamany Chandirasegaran , Smith Tim , Loy John , Barletta Raul , Reddy Jay 
Published: January 2023

Abstract
We recently discovered that Bacillus spp., NRRL B-14911, a marine microbe, has the ability to induce myocarditis through molecular mimicry. The bacterium contains a mimicry epitope designated, BAC 25-40, and it induces autoimmune myocarditis by generating cross-reactive T cells for cardiac myosin heavy chain-alpha 334-352 (Myhc). We have analysed the complete genome sequence leading us to identify this microorganism as Bacillus infantis NRRL B-14911, a close relative of the strain that has been isolated in sepsis of newborn infants. Conditions have been optimized for the bacterium to grow in a Zobell marine medium at 37oC in an aerobic environment. Our preliminary studies indicate that A/J mice infected with Bacillus infantis NRRL B-14911 show the generation of CD4 T cells that can react with both BAC 25-40 and Myhc, as determined by major histocompatibility complex class II/IAk tetramer staining. We propose that Bacillus infantis NRRL B-14911-induced myocarditis can serve as a useful disease model to study the immune-mediated mechanisms of bacterial myocarditis as they relate to molecular mimicry and/or epitope spreading.
Gender differences in the development of autoimmune myocarditis induced with cardiac myosin heavy chain-alpha, 334-352 in C57Bl/6 mice (BA15P.222)
Authors: Gangaplara Arunakumar , Massilamany Chandirasegaran , Steffen David , Reddy Jay 
Published: January 2023

Abstract
Various animal models of experimental autoimmune myocarditis (EAM) have been developed to understand the immune pathogenesis of myocardial injuries. Although, genetic susceptibility is one major predisposing factor in the causation of myocarditis, other factors like gender-bias can also influence the disease outcome. For example, A/J mice carrying IAk allele on ‘A’ background are highly susceptible to EAM induced with cardiac myosin heavy chain-alpha (Myhc); whereas C57Bl/6 mice on ‘B’ background possessing IAb allele are resistant. Whether these phenotypic differences are due to inherent variations in the presentation of immunodominant epitopes of cardiac antigens are not known. We addressed this question using Myhc 334-352 as a putative cardiac antigen that induces EAM in A/J mice. Unexpectedly, we discovered that C57Bl/6 mice immunized with Myhc 334-352 showed antigen-specific proliferative responses regardless of gender as determined by T cell proliferation assay and major histocompatibility complex (MHC) class II/IAb dextramer staining. However, in contrast to females, only male mice developed myocarditis which showed higher frequencies of CD4 T cells producing T helper 17 family cytokines namely, interleukin (IL)-17A and IL-22 but not IL-17F. The observation that both IAb and IAk alleles can present single peptide but with varied disease outcomes provides opportunities to dissect the influence of non-MHC genes and also sexual dimorphism on myocarditis-susceptibility.
Pyranopyran-1, 8-dione, an active compound from Viticis Fructus ameliorates cigarette smoke induced lung inflammatory response in a murine model (CAM5P.239)
Authors: Bae Hyunsu , Jung Kyung-Hwa , Kang Geun-Hyung , Kim Won Seob , Kim Hyun Seong , Hong Moochang , Kim Sun Kwang 
Published: January 2023

Abstract
Chronic obstructive pulmonary disease (COPD) is defined as poorly irreversible airflow obstruction due to the inhalation of noxious chemicals and gases, most commonly cigarette smoke (CS). The extract of Viticis Fructus (VF), is widely used as a traditional herbal medicine in various Asian countries for the treatment of migraine pain and allergic diseases. Therefore, we attempt to isolate active compound from VF. After several rounds of activity-guided fractionations, 1H, 8H-Pyrano [3, 4-c] pyran-1, 8-dione (PPY) was isolated. In this study, we hypothesized that PPY, constituent of VF, could suppress CS exposure lung inflammation in mice model. The mice were exposed to 3R4F reference cigarettes for 2 weeks with 6 cigarettes a day. The mice were administered various dose of PPY (1, 2, 10 mg/kg body wt) via an oral administration 2 hr prior to CS exposure. The results of this study indicate cellular profiles and histopathologic analysis demonstrated that peribronchial and perivascular inflammatory cell infiltrates were significantly decreased in the PPY treated groups when compared to the CS exposure group. In summary, the results of this study indicate that PPY has significantly inhibited CS induced lung inflammation. The remarkable anti-inflammatory effects of PPY suggest its therapeutic potential in COPD treatment. Keywords: COPD, 1H, 8H-Pyrano [3, 4-c] pyran-1, 8-dione (PPY), cigarette smoke, IL-6, TNF-α