bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of CMV- and LCV-specific T cell responses and their sensitivity to immunosuppression in cynomolgus macaques (P6367)
Authors: Kamperschroer Cris , O'Donnell Lynn , Schneider Patricia , Li Dingzhou , Kawabata Thomas 
Published: January 2023

Abstract
Herpesviruses such as cytomegalovirus (CMV) and Epstein Barr virus (EBV) often cause disease under conditions of immunosuppression, such as transplant or AIDS. Loss of control of herpesvirus infections occurs at least in part due to loss or dysfunction of virus-specific T cells. An increasing array of immunosuppressive therapeutics are being developed that target different subsets of T cells or their functions. To better understand effects of therapeutics on antiviral T cells, we have used ELISPOT and ICS to measure T cell responses against CMV and lymphcryptovirus (LCV; analogous to EBV) in cynomolgus macaques. Our work has shown that nearly all monkeys respond against both viruses, although the numbers of T cells specific for CMV are larger than those against LCV. We have also characterized the variability in the magnitude of the T responses to both viruses over time. In addition, we have examined the effects of immunosuppressive agents on the numbers and function of antiviral T cells. Our work reveals remarkable stability of herpesvirus-specific T cells, even under conditions where drugs abolish T cell stimulation for a period of several weeks.
LAMP-2C regulation of MHC class II antigen presentation (P5020)
Authors: Pérez Liliana , Blum Janice 
Published: January 2023

Abstract
Chaperone-mediated autophagy (CMA) is a selective autophagy pathway, which relies on the lysosome-associated membrane protein (LAMP)-2A to translocate proteins from the cytoplasm into lysosomes. Alternative splicing of the LAMP-2 gene generates 3 highly conserved isoforms LAMP-2A, LAMP-2B and LAMP-2C. LAMP-2A overexpression increases MHC class II (MHCII) presentation of the cytoplasmic autoantigen, GAD, demonstrating a role for CMA in antigen presentation. Overexpression of LAMP-2B did not alter cytoplasmic GAD presentation, however, remarkably ectopic expression of LAMP-2C in B cells inhibited T cell responses to cytoplasmic GAD. Studies were undertaken here to understand the role of LAMP-2C in MHCII antigen presentation. The presentation of several exogenous proteins was not affected by LAMP-2C expression in B cells. Similar results were observed for the presentation of endogenous self and viral membrane proteins. These results suggest that LAMP-2C may be a specific inhibitor of antigen presentation via autophagy. Ectopic expression of LAMP-2C also failed to perturb MHCII presentation of the MP1-LC3 antigen via macroautophagy. Thus LAMP-2C appears to inhibit the presentation of cytoplasmic proteins that are processed through CMA and may not affect other autophagy pathways. Future studies are underway to determine mechanistically how LAMP-2C controls antigen presentation.
Cross-presentation to CD8+ T cells is critical to maintain protective immunity against chronic phagosomal bacteria (P5030)
Authors: Patel Rajen , Sad Subash 
Published: January 2023

Abstract
Salmonella Typhimurium (ST) is a virulent intracellular pathogen that resides within the phagosomes of infected cells. Dendritic cells (DCs) are capable of presenting phagosomal antigen to prime CD8+ T cells through the cross-presentation pathway. However, the role of CD8+ T cells and cross-presentation in immunity against ST has yet to be fully elucidated. We utilized recombinant ST expressing ovalbumin to study cross-presentation of cell-associated antigen during infection. Mice depleted of CD8+ T cells exhibit higher bacterial burden and increased mortality. DCs isolated from Ifnαr-/- mice, deficient in the cross-presentation pathway, exhibit attenuated antigen presentation against ST. However, our in-vivo data suggests that IFN-I mediated cross-presentation of ST is dependent on the route of infection, as Ifnαr-/- mice exhibit defects in DC trafficking to lymph nodes. Furthermore, we observed IFN-I mediated CD8+ T cell response to be pathogen specific, as antigen presentation of Listeria monocytogenes, an acute intracellular pathogen, was not attenuated in Ifnαr-/- mice. Interestingly, Batf3-/- mice deficient in CD8α DCs, a subset of DCs that specialize in cross-presentation, results in a significantly delayed CD8+ T cell response against ST and higher bacterial burden. Collectively, our data indicates that cross-presentation is an essential mechanism to mount a CD8+ T cell response against ST and is necessary for maintaining immune protection against the bacterium.
Serum from patients with SLE instructs monocytes to promote auto-antigen specific IgG and IgA responses (P4028)
Authors: Joo HyeMee , Xue Yaming , Upchurch Katherine , Zurawski Gerard , Pascual Virginia , Oh SangKon 
Published: January 2023

Abstract
The persistent development of autoantibodies is a hallmark of systemic lupus erythematosus (SLE). Previous work using SLE serum demonstrated that monocyte differentiation into dendritic cells (DCs) is a type I IFN-dependent manner and such SLE-DCs activate T cells. However, whether SLE-DCs promote B cell responses has not been elucidated. Here, we demonstrate that SLE-DCs can efficiently stimulate naïve and memory B cells to differentiate into polyclonal IgG- and IgA-plasmablasts (PBs) resembling those found in the blood of SLE patients. More importantly, when SLE-DCs were stimulated with SLE neutrophils, these SLE-DCs were able to induce ss-DNA specific IgG and IgA from naïve B cells. SLE-DC-mediated IgG-PB differentiation is dependent on BAFF and IL-10, whereas IgA-PB differentiation is mainly dependent on APRIL. Moreover, SLE-DCs as well as monocytes from SLE patients express CD138 and thus can trans-present CD138-bound APRIL to B cells, which is crucial for inducing IgA switching and PB differentiation. The expression of CD138-bound APRIL is not dependent of IFNα, explaining why DCs generated with IFNα (IFN-DCs) are less efficient at inducing IgA responses. Nonetheless, both SLE-DCs and IFN-DCs induce the expression of Bcl-XL in PBs and support their survival, thereby leading to increased Ig production. Taken together, our study suggests that a direct interplay between SLE-DCs and peripheral B cells contribute to SLE pathogenic autoantibody responses.
Role of costimulation in obesity-induced adipose inflammation and insulin resistance: pro- or anti-inflammatory? (P3105)
Authors: Zhong Jixin , Rao Xiaoquan , Braunstein Zachary , Sun Qinghua , Rajagopalan Sanjay 
Published: January 2023

Abstract
Activation of T cells is thought to play an increasingly important role in the pathogenesis of inflammation and insulin resistance in obesity and Type 2 diabetes. Costimulation is essential for amplification of the T cell response, with the co-stimulatory molecules CD80 and CD86 playing an important role in the pathogenesis of a variety of inflammatory diseases. In this study, we used CD80/CD86 double knockout (B7 KO) mice to investigate the involvement of these key molecules in diet-induced obesity (DIO) and insulin resistance. Wild-type (WT) and B7 KO mice were fed either high fat diet (HFD) or normal chow. After 12 weeks of HFD feeding, WT and B7 KO mice had similar weight gain. B7 KO mice had less epidydymal fat (1.31±0.04 g vs. 0.92±0.06 g for WT vs. B7 KO) which was confirmed by MRI measures. Despite less systemic T cell activation, insulin resistance was significantly worse in the B7 KO mice. B7 KO mice had decreased Treg content which was a result of both impaired development and proliferation. A defect in Treg cells conferred enhanced classical activation of macrophages in the adipose tissue. Adoptive transfer of Treg into B7 KO mice restored insulin sensitivity in B7 KO mice on HFD. Taken together, lack of B7-mediated costimulation results in impaired development and proliferation of Treg and enhanced adipose inflammation and insulin resistance. Our results suggest an essential role for B7 in maintaining Treg numbers in experimental DIO.
CXCR6/CXCL16 in liver disease (P3145)
Authors: Parker Richard , Weston Chris , Adams David 
Published: January 2023

Abstract
Chemokines primarily mediate lymphocyte migration. Steatohepatitis caused by metabolic syndrome or alcohol is a common cause of liver disease. We investigated the role of CXCL16/CXCR6 in the development of steatohepatitis. Expression of CXCL16 in liver and isolated cells was analysed with rt-PCR and immunohistochemistry. Serum and supernatant concentrations of CXCL16 were measured with ELISA. Expression of CXCR6 was investigated with flow cytometry. Lymphocyte adhesion was assessed using freshly isolated lymphocytes from liver or peripheral blood flowed over a confluent layer of isolated human hepatic sinusoidal endothelium (HSEC). Whole liver expression of CXCL16 was increased in disease with increasing expression with increasing severity of disease. Isolated HSEC, biliary epithelial cells (BEC) and hepatoma cell lines increased expression of CXCL16 and released soluble CXCR6 in response to proinflammatory cytokines, particularly the combination of TNFα and IFNγ. Liver infiltrating lymphocytes and monocytes were enriched for CXCR6 expression compared to peripheral blood. CD3+CD56+ NKT cells and CD56+ NK cells most commonly expressed CXCR6. Inhibition of CXCR6 or CXCL16 inhibited transmigration of lymphocytes across HSEC. Transmigration was increased by incubating lymphocytes with soluble CXCL16. CXCL16 is expressed in diseased liver where it plays a role in the transmigration of lymphocytes across endothelium. This may represent a new therapeutic target in liver disease.
The stenotic kidney of Rag1 mice subjected to 2K1C hypertension is protected from atrophy (P3078)
Authors: Hartono Stella , Grande Joseph 
Published: January 2023

Abstract
Renal artery stenosis is a common finding in patients with cardiovascular disease. Recent studies have provided evidence that innate immunity plays a critical role in the development of chronic renal disease in renovascular hypertension. We have previously demonstrated that interstitial infiltration of lymphocytes is an early event in the development of renal atrophy in the 2K1C model of renovascular hypertension. We therefore sought to test the hypothesis that lymphocytes play a role in the development of progressive atrophy/fibrosis in this model. We subjected mice to renal artery stenosis through placement of a polytetrafluoroethylene cuff on the right renal artery. In accordance with our previous observations, wild type mice subjected to RAS developed renal atrophy within 2 weeks following placement of the cuff (70.5 +/- 11.9%). Chemokine expression in renal cortex of the stenotic kidney reflected predominantly a Th1 response (STAT1, STAT4, TBX21); CCL2, CCL17, CCL12, and TNF mRNA expression were also upregulated, but not IL-6 and IL-10. In striking contrast to wild type mice, Rag1 mice developed significantly less atrophy (23.1 +/- 10.4, p&lt;0.0037 vs wild type). Unlike wild type mice, histologic evaluation of renal cortex of Rag1 mice showed no significant interstitial infiltration with CD3+ T cells or F4/80+ macrophages. We propose that T cell-mediated inflammation plays a critical role in the development of renal atrophy in 2K1C mice.
HMGB1 impairs erythropoiesis during sepsis (P3163)
Authors: Valdes-Ferrer Sergio , Blanc Lionel , Li Jian Hua , Sangeeta Chavan , Tracey Kevin 
Published: January 2023

Abstract
Severe sepsis is one of the leading causes of mortality and disability. Anemia is common in acute sepsis and related to decreased quality of life and increased mortality in sepsis survivors. Serum levels of HMGB1, a critical mediator of sepsis pathophysiology, remain elevated for weeks after onset of sepsis. We used a murine model of severe abdominal sepsis to study effect of HMGB1 on erythropoesis. Mice subjected to sepsis have significant decrease in hemoglobin (p=0.03 by day 3) and hematocrit (p=0.05 by day 7). Reticulocytosis, an indicator of bone marrow proliferation, was only transiently found on day 10. Administration of neutralizing anti-HMGB1 antibody to survivors beginning 9 days post- sepsis significantly improved hemoglobin and hematocrit levels. Exposure of erythropoetic stem cells, generated by culturing cord blood CD34+ cells with erythropoietin, stem cell factor and IL-3, to recombinant HMGB1 (rHMGB1) induced a decrease in hemoglobinization, and expression of GPA (CD235a) and transferrin receptor (CD71), indicating suppression of erythroid differentiation. rHMGB1 induced suppression of erythropoesis when added before day 8 and not later indicating that HMGB1 inhibits initial phases of differentiation. Together, these findings indicate that HMGB1 impairs erythropoiesis by altering differentiation of erythropoetic stem cells, and suggest that it may be possible to prevent or reverse anemia in sepsis survivors by administration of anti-HMGB1 antibodies.
Immune dysregulation in a major hematologic disease (P3167)
Authors: Joshi Sunil , Carey David , Chavez-Suarez Maria , Lang Mark , Broyles Robert , White Gary 
Published: January 2023

Abstract
Sickle cell disease is the most prevalent genetic disease on the planet, and is a major cause of morbidity and death. Much of the morbidity in sickle cell disease is due to frequent, severe infections due to immune dysregulation associated with progression of disease. Both innate and adaptive immunity are impaired. It is well established that T and B cell responses are required for host defense. The CD4+ Th cells express TCR that recognize antigen bound to MHC II molecules expressed on APCs such as DCs, B cells and macrophages. Thus the cognate interaction between receptor-ligand clusters on Th and APCs led to the activation of naïve CD4+ Th cells causes them to release cytokines, which influence the activity of many cell types, including the NKT, CD8+ CTLs and the APCs that activated them. Using a “humanized” sickle mouse model of sickle cell disease, we recently found that the transition from SPF to ‘dirty’ (conventional) housing significantly dysregulated the immune-system. These changes are characterized by a hyper-inflammatory state with the activation of innate-immune response (upregulation of TLR4) and loss of antigen-presentation machinery (loss of MHC class II expression) as the disease progresses. Specifically, our results indicate the loss of MHC II expression on APCs from various tissue of sickle mouse with the disease progression.
Resveratrol blunts unwanted platelet activation that occurs during platelet storage and as a consequence of red blood cell transfusion (P3171)
Authors: Lannan Katie , Spinelli Sherry , Casey Ann , Blumberg Neil , Phipps Richard 
Published: January 2023

Abstract
Blood transfusions are a common medical treatment dating back to the early 19th century and are now widely accepted as a life saving practice. However, red blood cell and platelet transfusions are associated with alterations in hemostasis and can lead to platelet-mediated adverse outcomes, such as thrombosis, immune dysregulation and inflammation. Platelets are intimately involved in hemostasis and inflammation, and can cause severe problems when excessively or insufficiently activated. A major unmet medical need in the field of transfusion medicine is to develop new agents that safely prevent unwanted platelet activation in transfused patients and in patients with underlying cardiovascular complications. Here, we investigate the potential of naturally occurring compounds to be used as novel anti-platelet agents, which could be used to mitigate transfusion complications. Naturally occuring compounds, such as resveratrol, have been suggested to lower the risk of cardiovascular complications. We demonstrate the ability of resveratrol to dampen unwanted platelet activation, which can occur after RBC transfusion. Additionally, we demonstrate that resveratrol can be used to effectively dampen platelet activation during the storage of platelet concentrates for transfusion. Resveratrol, as well as other natural compounds, could be used to mitigate platelet-mediated adverse transfusion reactions and could be used to improve the safety and efficacy of stored platelet concentrates.
Moyamoya syndrome is associated with production of autoantibodies to a broad spectrum of self-antigens and correlated with disease phenotype (P3175)
Authors: Li Quanzhen , Wang Ling , Zhang Zhengshan , Duan Lian 
Published: January 2023

Abstract
Moyamoya syndrome (MMS) is a chronic cerebrovascular disorder characterized by a slowly progressive occlusion of the internal carotid artery. Previous study suggested that immune disorder and autoantibody production may involve in the pathogenesis of this disease. In order to elucidate the correlation of the autoAbs with the disease phenotype and to identify possible biomarkers, we utilized an autoantigen microarray bearing 83 specificities to characterize IgG and IgM autoantibodies expressed in the sera of MMS patients (n=56) and healthy controls (HC, n=31). 13 IgG autoantibodies and 35 IgM autoantibodies were significantly increased in MMS patients compared with HC (p&lt;0.05). The increased expression of anti-MPO, anti-MBP and anti-PR3 in MMS sera were further confirmed by ELISA. Cluster analysis identified 4 autoAb patterns including chromosome related (anti-centromere and histone), ECM related (anti-matrigel, laminin), RNA related (anti-Ro60 and SSA/SSB) and thyroid related (anti-thyroglobulin and TPO) antibodies which were increased in MMS and correlated with different clinical manifestations including course of disease, number of involved brain vessels and thyroid activity, etc. Furthermore, MMS sera exhibited positive reaction with the patient brain vessels by IHC staining. The above findings indicate that IgG and IgM autoAbs may play an important role in the pathogenesis of MMS and could be useful biomarkers for the prediction of the disease
The role of syndecan-4 in the development of rheumatoid arthritis (P4052)
Authors: Endo Tsutomu , Morimoto Junko , Ito Koyu , Iwasaki Norimasa , Uede Toshimitsu 
Published: January 2023

Abstract
Syndecan-4 (Syn4), a cell-surface heparan sulfate proteoglycan (HSPGs) expressed by several types of cells, has been implicated as a critical mediator for inflammatory responses. Recent report suggested that HSPGs including Syn4 expressed by B lymphocytes regulate B cell development and survival. Here, we have investigated the role of Syn4 in the development of murine models of Rheumatoid Arthritis. In type-II collagen-induced arthritis (CIA) model, which is both T and B cell-dependent model, we found that Syn4-deficiency showed attenuated clinical severity and pathological features, although Syn4-deficient (Syn4-KO) mice generated unimpaired numbers of Th1 and Th17 cells in the draining inguinal LN (dLN). Because Syn4 expression was highly detectable on B cells, we analyzed type-II collagen-specific antibody (Ab) production, and found that Syn4-KO mice generated comparable levels of IgM, but significantly reduced levels of total IgG, IgG2a and IgG2b compared with WT mice. Reduction of collagen-specific IgG Abs in Syn4-KO mice was also evident by defective formation of germinal center (GC) in the dLN. In addition, we found that Syn4-KO mice showed reduced numbers of B cell subsets (total B cells, follicular B cells and GC B cells) in the dLN following immunization, although the numbers of follicular helper T cells were comparable between both groups. These results suggest that Syn4 modulates CIA development through enhancing the generation of GC formation and Ab production.
Role of the TAM receptor Axl in differentiation and activation of B cells (P4058)
Authors: Nundel Kerstin , Rothlin Carla , Marshak-Rothstein Ann 
Published: January 2023

Abstract
In dendritic cells (DCs), TLR activation upregulates TAM receptor expression and these TAM receptors initiated pathways subsequently shut down cytokine production. Moreover, TAM receptor deficient mice develop a severe SLE-like disease. TLR9 and TLR7 play a key role in the detection of autoantigens by both DCs and B cells in the context of systemic autoimmunity. To better understand the direct effects of TAM receptors on B cells, we have used BCR Tg mice (AM14) that recognize autologous IgG2a. AM14 B cells are activated by immune complexes (ICs) that incorporate either DNA or RNA through pathways dependent on TLR9 and TLR7, respectively. Contrary to DCs, expression of the TAM receptor Axl is not induced by TLR ligands but is dependent on crosslinking of the BCR per se. However, BCR/TLR9, but not BCR/TLR7, co-engagement inhibits Axl upregulation, pointing to a role for TLR9 in the regulation of Axl expression. Activation of AM14 B cells by RNA-containing ICs induces TLR7-dependent differentiation into plasma cells and these plasma cells express high levels of Axl. In contrast, BCR/TLR9-dependent activation of AM14 B cells by DNA-containing ICs blocks Axl expression and does not lead to plasma cell differentiation. These data identify unique outcomes of BCR/TLR7 and BCR/TLR9 co-engagement on B cell differentiation and Axl expression. Furthermore, these B cell intrinsic responses may account for the opposing roles of TLR7 and TLR9 in the regulation of systemic autoimmunity.
FLEx-autoAb transgenic mice, a novel mouse model for studying peripheral tolerance to B cells that acquire self-reactivity following somatic hypermutation. (P4034)
Authors: Koh Yi , Nemazee David , Rickert Robert , Radic Marko , Cascalho Marilia , Casellas Rafael , Theofilopoulos Argyrios , Kono Dwight 
Published: January 2023

Abstract
Uptake of nucleic acid-containing antigens by antigen receptors (BCRs) on B cells leading to endosomal TLR activation is thought to be critical for antinuclear autoantibody (ANA) production in lupus. However, it has been difficult to study this in peripheral B cells that acquire ANA specificity because current ANA BCR models are subjected to central tolerance mechanisms. To overcome this, we generated a FLEx-autoantibody (autoAb) transgenic model in which VH specificity can be changed from a non-self-reactive anti-nitrophenyl (NP) to anti-chromatin (3H9-56R) reactivity following Cre recombinase expression induced by tamoxifen (all B cells) or the activation induced cytidine deaminase promoter (during class-switch recombination/somatic hypermutation). In nonautoimmune C57BL/6 mice, B cells that acquire self-reactivity to chromatin were completely deleted after several days at all stages of development, although numbers of plasma cells were too low to analyze. Faslpr mutation enabled the development of only low levels of anti-id positive (56R+) plasma cells but did not rescue B cells at any other stages of development after tamoxifen. The provision of excess T cell help, through induction of chronic graft-versus-host disease in B6-Faslpr mice resulted in a marked increase in 56R+ plasma cells. These findings suggest that ANA-specificity and engagement of endogenous TLR is not sufficient to rescue autoreactive B cells even in mice with Fas deficiency.