bluuebunny/crossref_metadata_2025_split huggingface dataset:
The blood—brain barrier is breached in murine neuropsychiatric Systemic Lupus Erythematosus (P4004)
Authors: Wen Jing , Wagshul Mark , Stock Ariel , Fleysher Roman , Branch Craig , Putterman Chaim 
Published: January 2023

Abstract
Neuropsychiatric systemic lupus erythematosus (NPSLE) is one of the earliest manifestations in human SLE, and a major cause of morbidity and mortality in this disease. While the pathways underlying NPSLE are not fully understood, blood brain barrier (BBB) disruption and altered brain perfusion have been postulated to contribute to the pathogenesis. The purpose of this study was to evaluate BBB integrity, macromolecule content, and other indicators of neurological damage in MRL-lpr/lpr mice which spontaneously develop NPSLE, compared to the background control strain MRL/+. Female MRL-lpr/lpr and MRL/+ mice were imaged by MRI at 9-10 weeks of age, at which time major neuropsychiatric symptoms including depression and cognitive dysfunction were already present. Dynamic contrast enhancement MRI indicated increased gadolinium uptake in MRL/lpr mice in all regions of the brain, with the largest differences visualized in the hypothalamus where these changes were significant. Furthemore, MRL/lpr mice displayed significantly higher concentrations of albumin, total immunoglobulin, and antibodies to double stranded DNA in their cerebrospinal fluid. In contrast, whole brain analysis of magnetic transfer contrast and quantitative T2 imaging indicated no significant differences between the MRL-lpr/lpr and MRL/+ mice. Thus, a compromised blood brain barrier (particularly in specific regions) in lupus prone MRL/lpr mice may allow for the passage of circulating autoantibodies from the serum into the brain, and induction of some of the neuropsychiatric abnormalities observed in this mouse strain. Preventing the regional breakdown in barrier integrity may be a novel approach to treatment of neuropsychiatric involvement in SLE.
Understanding lupus pathology in FcγRIIB-/-yaa mice: autoantibodies and autoantigens (P4008)
Authors: Kole Hemanta , Scott Bethany , Bolland Silvia 
Published: January 2023

Abstract
FcγRIIB knock-out mice in B6 background develop a lupus like autoimmune disease. With the addition of the yaa (Y-chromosome autoimmune accelerator) gene, pathogenecity in these male mice is significantly enhanced and autoantibodies switch from nuclear to nucleolar specificity. High titer of λ-light chains immunoglobulin, and anti-RNA antibodies were found in R2-/-yaa serum. Also, R2-/-yaa serum selectively bound 5 major nuclear proteins compared to R2-/- serum. To characterize the autoantibodies produced by R2-/-yaa mice and the nucleolar antigens that react with these antibodies, we have produced hybridomas. Hybridoma H526 produced anti-nucleolar IgG2c-λ antibodies. The antibody binds RNA, a synthetic polyribonucleotide poly (GC)20 and a RNA-associated nucleolar protein, nucleolin. R2-/-yaa serum also found to cross-react with poly (GC)20, nucleolin and also with poly ADP-ribose (PAR). Simultaneous presence of nucleolin and PAR autoantibodies has been found to be associated with lupus. Further characterization of nucleolin modification and lupus development is in progress.
Sex differences in the effect of vitamin D on inflammatory heart disease: protective in women but damaging in men (P3069)
Authors: Stafford Katelyn , Cooper Leslie , Douglass Erika , Brandt Jessica , Bucek Adriana , Coronado Michael , Kew Richard , Fairweather DeLisa 
Published: January 2023

Abstract
An estimated 1 billion people worldwide have deficient or insufficient levels of vitamin D (VitD), while roughly 25% of individuals in the US are reported to have inadequate VitD levels. Considerable evidence indicates that VitD deficiency is associated with an increased risk of cardiovascular disease (CVD), yet it remains unclear whether low VitD is simply a biomarker of CVD or has a true pathologic role. The role of VitD deficiency in the pathogenesis of inflammatory myocarditis is unknown- a disease that is higher in men. We found that only 20% of myocarditis patients had low VitD levels. When we examined VitD receptor (VDR) deficient mice in a model of viral myocarditis, we found that VDR decreased myocarditis in females (p=0.007) but increased inflammation in males (p=0.006). Examination of cytokines in the heart found that VDR-/- male mice had significantly reduced IFN-γ and IL-1β and increased IL-17A, but no significant differences were found in females. Comparison of microarray data during myocarditis to published VitD response element genes revealed around 200 genes associated with proinflammatory (e.g. caspase-1) and profibrotic (e.g. TGF-β1, MMP) responses were increased in WT male mice, which was confirmed by qRT-PCR in VDR-/- mice. Our data confirms that VitD through the VDR promotes myocardial inflammation in males, providing a mechanism for how low VitD levels in men increase myocarditis. This work was funded by NIH R01 HL087033 and HL111938.
CD36 expression in chondrocytes is involve in the clearance of apoptotic cells (P3096)
Authors: González Elena , Ortiz-Navarrete Vianney 
Published: January 2023

Abstract
Osteoarthritis (OA) is a chronic-degenerative arthropathy with high incidence and prevalence in which cartilage is destroyed due to extracellular matrix erosion (collagen and proteoglycan’s loss) and death of chondrocytes mainly by chondroptosis (program cell death) that could be clearance by neighboring chondrocytes. In order to confirm chondrocyte’s phagocytic capacity we performed a phagocytosis assay with Salmonella thyphimurium-GFP (moi 30) and we observed that after 30 min chondrocytes were able to phagocytose bacteria. We also found that 60% of chondrocytes, either from normal or OA tissue, were able to phagocyte 2 or more apoptotic chondrocytes. In addition, we found that less than the 5% of the chondrocytes express CD36 and the percentage of CD36 positive cells increases after the contact with apopotic cell. These data confirm that chondrocytes have the capacity to clearance apoptotic cells and that CD36 is involve in this process. Suggesting that chondrocytes could be able to eliminate apoptotic chondrocytes in the tissue in order to maintain homeostasis cartilage.
B lymphocytes regulate a pro-inflammatory T cell balance in human Type 2 diabetes (P3101)
Authors: DeFuria Jason , Jagannathan-Bogdan Madhu , Kuchibhatla Ramya , McDonnell Marie , Apovian Caroline , Nikolajczyk Barbara , Denis Gerald 
Published: January 2023

Abstract
Lymphocytes play key roles in the chronic inflammation critical for T2D pathogenesis. We have shown T2D patients have an elevated ratio of pro- to anti-inflammatory T cells, and B cells that produce a pro-inflammatory cytokine profile. Thus lymphocytes promote T2D-associated inflammation. Numerous studies implicate the pro-inflammatory CD4+ T cell balance in T2D pathogenesis, but mechanisms that underlie elevated CD4+ T cell inflammation are poorly understood. We explored the possibility that the T2D-associated changes we identified in B cell function regulate T cell inflammation. We show that B cells control the T2D-associated increase in Th17-mediated inflammation in T2D patients and in obese/insulin resistant mice. Surprisingly, the disease-associated ability of B cells to regulate T cell function is contact-dependent, despite evidence that B cell cytokines hyper-secreted in T2D patients activate T cells. In contrast, elevated activation of Th1 cytokines is B cell-independent. We conclude that both T cell-intrinsic and T cell-extrinsic (B cell-dependent) changes regulate T cell inflammation in T2D. These data indicate that B cell depletion may partially curb T2D-associated T cell inflammation, and thus disease pathogenesis; however, combinatorial treatments aimed at multiple inflammatory axes may be required for favorable clinical outcomes.
A2B adenosine receptors inhibit obesity-induced adipose tissue inflammation (P3109)
Authors: Csoka Balazs , Koscso Balazs , Toro Gabor , Kokai Endre , Nemeth Zoltan , Bai Peter , Hasko Gyorgy 
Published: January 2023

Abstract
Obesity promotes adipose tissue inflammation, which in turn causes insulin resistance in target organs by dysregulation of adipokine release and by increased classical and decreased alternative macrophage activation. Because A2B adenosine receptors are important regulators of macrophage activation, we examined the role of A2B adenosine receptors in diet-induced inflammation and insulin resistance. A2B receptor deletion impaired glucose metabolism in mice fed chow but not high fat diet. This impaired glucose homeostasis in A2B receptor deficient mice was paralleled by increased classical macrophage activation and inhibited alternative macrophage activation. The expression of alternative macrophage activation-specific transcriptions factors, including CCAAT/enhancer binding protein β, interferon regulatory factor 4, and peroxisome proliferator-activated receptor γ was decreased in A2B receptor deficient mice. Furthermore, in in vitro studies we found that activation of A2B receptors decreased free fatty acid-induced classical macrophage activation and increased IL-4-induced alternative macrophage activation. Therefore, therapeutic strategies targeting A2A and A2B receptors hold promise for preventing and/or treating obesity-related metabolic abnormalities.
The role of Ikaros in adipocyte differentiation of MDI-stimulated 3T3-L1 cells (P3111)
Authors: Park Bongkyun , Pyo Suhkneung 
Published: January 2023

Abstract
Adipogenesis is a tightly regulated cellular differentiation process, in which the preadipocytes are transformed into differentiated adipocyte cells. Ikaros has been known as a cell cycle regulator on lymphoid and myeloid cell differentiation. However, the precise role of Ikaros in adipogenesis is still unclear. We investigated the role of Ikaros in vitro in adipocyte differentiation of preadipocyte cell line, 3T3-L1. Western blot analysis showed that Ikaros expression was significantly increased by 2 days in MDI-treated 3T3-L1 cells, whereas the expression of c-Myc was markedly decreased after 2 days. Oil red O staining revealed that inhibition of Ikaros by siRNA suppressed lipid droplet accumulation. In addition, knockdown of Ikaros resulted in re-entry of cell cycle progression from G1 phase as well as inhibition of p21 and p27 expression, cell cycle arrest proteins. In contrast, c-Myc expression was increased. Immunoprecipitation analysis demonstrated that the interaction of Ikaros and c-Myc was significantly enhanced in MDI-treated 3T3-L1 cells, suggesting that the interaction between Ikaros and c-Myc is required for adipogenesis. Taken together, our data suggest that Ikaros may play a critical role in adipocyte differentiation by negatively regulating c-Myc expression.
Continuous immunosurveillance of oligodendrocyte antigens leads to the generation of effector T-cell pools that might contribute to CNS autoimmune disease (P3123)
Authors: Fabry Zsuzsanna , Harris Melissa , Hulseberg Paul , Ling Chagying , Karman Jozsef , Clarkson Benjamin , Sandor Adam , Nagy Andras , Sandor Matyas 
Published: January 2023

Abstract
Immunosurveillance of antigens from the CNS is tightly regulated in order to avoid autoimmune disease, such as multiple sclerosis. To test how CNS antigens are recognized by the peripheral immune system, we created transgenic mice having constitutive or inducible expression of EGFP-fused model neoantigens in myelinating glial cells. We examined the level of systemic priming to CNS neoantigens and compared it to priming from non-immune privileged gut tissue. We report here that the level of the EGFP-triple peptide in both the constitutive and inducible models is sufficiently high in the CNS to induce neoantigen-specific T cell priming in the periphery; however, there is no recruitment of these cells to the CNS. Immunosurveillance of CNS antigens in the peripheral immune tissues is enhanced during neuroinflammation, during which time activated neoantigen-specific T cells accumulate in the CNS. These data suggest that CNS antigens are surveilled in the periphery, leading to the generation of effector T cell pools. Additional inflammatory signals from the CNS induce the migration of effector T cells, which form microclusters with dendritic cells and autophagic oligodendrocytes that leads to the amplification of CNS inflammation. Increased immunosurveillance and inflammation might contribute to the chronic phase of CNS autoimmune disease. These new models can help us dissect the mechanisms of disease initiation and maintenance that is of clinical importance.
CD8+ T cell exhaustion in sarcoidosis contributes to disease severity (P3137)
Authors: Richter Kyra 
Published: January 2023

Abstract
Sarcoidosis is a multisystem granulomatous disease of unknown etiology. Though patients develop inflammation at active sites of involvement, an anergic phenotype dominates peripherally. Recent reports suggest that dysfunction in the CD4+ T cell compartment contributes to the anergic responses, yet little is known about the role of CD8+ T cells. Chronic inflammation studies demonstrate that persistent antigen stimulation leads to CD8+ T cell exhaustion. Furthermore, an increase in CD8+ exhausted T cells has been shown to correlate with disease severity in multiple chronic inflammatory diseases. Therefore we hypothesized that CD8+ T cell exhaustion contributes to sarcoidosis disease severity. We report that expression of inhibitory receptors including PD-1 are upregulated on CD8+ T cells in sarcoidosis subjects with active disease, whereas cytokine production, proliferation, and cytotoxicity are impaired. In addition, we assessed CD8+ T cell function during active disease and upon disease improvement. Improvement of disease correlated with reversal of the exhausted phenotype. These results demonstrate that CD8+ T cell exhaustion contributes to immune dysregulation in sarcoidosis. Importantly, restoration of CD8+ T cell function results in disease resolution indicating that CD8+ T cell exhaustion may correlate with disease severity and thus, exhausted CD8+ T cells may be a potential biomarker to predict disease outcome.
Lack of macrophage/monocyte derived β-endorphin contributes toward sensations of pain/discomfort in Irritable Bowel Syndrome (P3153)
Authors: Hughes Patrick , Moretta Melissa , Lim Amanda , Grasby Dallas , Bird Daniel , Bampton Peter , Andrews Jane , Zola Heddy , Krumbiegel Doreen 
Published: January 2023

Abstract
Introduction: Neuroimmune interactions are increasingly implicated in Irritable Bowel Syndrome (IBS). Immune derived β-endorphin (β-end) inhibits colonic sensory afferents in health (Hughes et. al. Gut 2012), but little is known of the immunocyte responsible for β-end secretion in humans and whether this is altered in IBS patients. Methods: β-end and TNF-α staining was assessed by flow cytometry analysis of CD4, CD8, CD19, CD14 or CD33 labelled PBMC that were unstimulated or stimulated with PMA/ionomycin or LPS and compared between 9 healthy and 21 IBS patients. β-end immunoreactivity was assessed in CD3 or CD68 labelled colonic biopsies from 7 healthy and 10 IBS patients. Results: In PBMC β-end was observed in unstimulated monocytes and LPS stimulated macrophages, but not unstimulated or PMA/ionomycin stimulated T or B cells, and was decreased in IBS patients relative to healthy subjects. Most β-end stained cells in colonic biopsies were CD68 positive, while only a low proportion were CD3 positive, and IBS patients had decreased numbers of CD68+ve cells. Intracellular levels of β-end negatively correlated with TNF-α in monocytes, and positively correlated with macrophage numbers in colonic biopsies. Discussion: Monocyte / macrophages are the predominant immune derived source of β-end in human subjects, and this is lower in IBS patients. The loss of immune derived β-end potentially contributes toward the sensations of pain / discomfort in IBS.
Human mast cells secrete mitochondrial DNA that has inflammatory actions, is increased in the serum of children with autism, and is inhibited by luteolin (P3155)
Authors: Theoharides Theoharis , Zhang Bodi , Asadi Shahrzad , Weng Zuyi 
Published: January 2023

Abstract
Mast cells participate through cytokine release in acquired and innate immunity, as well as inflammation involved in the pathogenesis of autism, atopic dermatitis and psoriasis, but the trigger is unknown. The peptide neurotensin (NT), found in the brain, gut and skin, is significantly increased in the serum of autistic children (n=20; 3 years old) along with significantly more mitochondrial (mt)DNA for Cytochrome B (p=0.0002), as compared to normally developing controls (n=12); these findings may characterize an autistic endophenotype since over 50% of patients have “allergic-like” symptoms and brain inflammation. Here we report that human LAD2 cells stimulated by NT and other triggers secrete mt components, including mtDNA, extracelluarly without cell death. Purified LAD2 mt components further trigger release of histamine, IL-1β, IL-8, PGD2 and TNF from mast cells, as well as vascular endothelial growth factor (VEGF) from human keratinocytes and human microvascular endothelial cells, and IL-6 from human microglial cells. When mtDNA from LAD2 cells was injected ip in rats, it was detected in rat serum within 4 hrs indicating that extravascular mtDNA could enter the systemic circulation. Pretreatment with the natural flavonoid luteolin inhibited mediator secretion in vitro. Such mt components secreted from stimulated live mast cells may act as “innate pathogens” contributing to the pathogenesis of inflammatory diseases and may serve as targets for novel treatments.
Type III hereditary angioedema: diagnostic and management challenges (P3173)
Authors: Issa-El-Khoury Karine , McCusker Christine , Alizadehfar Reza , Lejtenyi Christine , Ben-Shoshan Moshe 
Published: January 2023

Abstract
INTRODUCTION: Type III hereditary angioedema (HAE-III) is a heterogeneous entity presenting with normal C1-INH levels and is often difficult to diagnose. CASE PRESENTATION:A 13-year-old previously healthy girl presented to our emergency department with facial angiodema. Medications included Naproxen for tooth pain and oral combined contraceptives for menometrorrhagia that she had been taking for 6 months. She initially developed pruritic plaques on her legs that resolved within 5 days. On the day of presentation, she developed progressively painful lips’ swelling. There were no systemic symptoms. Angioedema resolved within 24 hours and did not recur over a three-month follow-up period. Family history was notable for recurrent angioedema in her mother and two maternal aunts. RESULTS:Investigations revealed normal tryptase level, C3 and C4 levels, C1 esterase inhibitor level and functional protein assay. DISCUSSION:Given the family history and clinical presentation, the diagnosis is consistent with HAE-III. In contrast to other forms of HAE, normal C4 levels do not rule out this entity. NSAIDs have also been implicated in its pathogenesis and could have contributed to her symptoms. Recent studies suggest that HAE-III may be associated with urticaria. In this case, prophylactic medication such as tranexamic acid or bradykinin inhibitors will be determined according to attacks’ frequency and severity. Clinicians should maintain high level of awareness of this rare disease.
The micro-RNA signature of Lupus Nephritis: a new view on the disease pathogenesis (P3084)
Authors: Costa-Reis Patricia , Russo Pierre , Sullivan Kathleen 
Published: January 2023

Abstract
Introduction: MicroRNAs (miRNAS) are responsible for post-transcriptional gene silencing. Our hypothesis is that dysregulated miRNAs modify gene expression programs in lupus nephritis (LN), leading to sustained pathology. Methods: RNA was extracted from 18 kidney specimens of LN patients and 6 controls, human kidney cell lines and primary monocytes. Direct digital detection of over 700 miRNAs was performed and confirmed by qRT-PCR. Results: A LN-specific miRNA signature was identified, reflecting cell proliferation and inflammation, according to pathway analysis. When compared to normal tissue, a significant decrease in miR-26a and miR-30b was found in LN (p=0.002; p=0.005, respectively). The results were confirmed by qRT-PCR. miR-26a was associated with crescents in kidney specimens, a classic proliferative sign (p=0.04). Human kidney tubular, mesangial and endothelial cells expressed miR-26a and miR-30b. These miRNAs were increased in primary monocytes from lupus patients and in monocytes exposed to immune complexes, a stimulus for terminal differentiation. Conclusions: We identified, for the first time, decreased miR-26a and miR-30b expression in LN. These miRNAs have been implicated in the regulation of proliferation and our finding of an association with crescents and increased expression in monocytes from lupus patients, which are known to be more differentiated and more prone to apoptosis, is consistent with a role in the regulation of pathologic proliferation in LN.
A small shared epitope-mimetic compound potently accelerates osteoclast-mediated bone damage in autoimmune arthritis (P3090)
Authors: Fu Jiaqi , Ling Song , Liu Ying , Hannah Margaret , Gilon Chaim , Holoshitz Joseph 
Published: January 2023

Abstract
We have recently proposed that the shared epitope (SE) may contribute to rheumatoid arthritis (RA) pathogenesis by acting as a ligand that activates pro-arthritogenic signal transduction events. In order to examine this hypothesis, here we determined the arthritogenic effect of a novel small SE-mimetic compound, c(HS4-4). In this study, we show that c(HS4-4), containing the SE primary sequence motif QKRAA, interacted with the SE receptor calreticulin, potently activated reactive oxygen species (ROS) and nitric oxide (NO) production and markedly facilitated OC differentiation and function in vitro. The pro-osteoclastogenic potency of c(HS4-4) was 100,000 to 1,000,000-fold higher than the potency of a recently described linear SE peptidic ligand. When administered at low-nanogram doses to collagen-induced arthritis (CIA) mice, c(HS4-4) significantly facilitated arthritis onset, increased disease incidence and severity, augmented bone destruction, and increased OC abundance in synovial tissues and osteoclastogenic propensities of bone marrow-derived cells. In conclusion, c(HS4-4), a small SE-mimetic compound with drug-like properties, potently activates OC-mediated bone damage and disease severity in inflammatory arthritis. These findings support the hypothesis that the SE acts as signal transduction ligand that activates an arthritogenic pathway, and attest to the druggability of this pathway.
Akt activation by CD40 controls plasma cell and memory B cell differentiation but not germinal center formation by autoreactive B cells (P4032)
Authors: Lee Sang-Ryul , McCray Suzanne , Clarke Stephen 
Published: January 2023

Abstract
A hallmark of adaptive immunity is the formation of germinal centers that generate long-lived plasma cells and memory B cells. These events are undesirable by autoreactive B cells since they would lead the production of pathogenic autoantibodies and memory B cells that would accrue over a lifetime, but is unknown at a molecular level how this is achieved. To address this question we examined the ability of B cells specific for the SLE-specific self-antigen Sm to respond to antigen in vivo in the presence of functional T cells. Sheep red blood cells (SRBC) have an antigen that binds anti-Sm B cells and therefore immunization of anti-Sm mice with SRBCs provides antigen for anti-Sm B cell activation and activation of functional cognate T cells. We find that anti-Sm B cells from germinal centers in response to SRBC immunization, but fail to generate splenic or bone marrow plasma cells. Secondary, immunization shows the absence of memory B cell formation. BCR and CD40 signaling appears normal in anti-Sm B cells with the exception of an Akt signal by CD40. Our data suggest that Akt activation by CD40 signaling controls the formation of plasma cells and memory B cells by autoreactive B cells of the type activated in murine and human SLE. Experiments are underway to test this possibility.