bluuebunny/crossref_metadata_2025_split huggingface dataset:
IgG1 protects against IgG3 immune complex mediated renal disease. (176.21)
Authors: Strait Richard , Mahler Ashley , Barasa Nathaniel , Stringer Keith , Witte David , Herr Andrew , Finkelman Fred 
Published: January 2023

Abstract
Immunoglobulins (Ig) have been reported to inhibit or activate effector mechanisms with varying potency. In the mouse, IgG1 has less ability to activate complement (C), interact with stimulatory Fc receptors (FcRs) or form large immune complexes (IC) than other Ig isotypes. Therefore, we hypothesized that IgG1 might suppress IC immunopathology mediated by other isotypes. Consistent with this hypothesis, IgG1-deficient, but not IgG1-sufficient, mice developed renal failure at the time of the peak antibody response when immunized with a potent antigen. Renal disease was both C- and stimulatory FcR-independent, resulted from IgG3 IC cryoglobulin obstruction of glomerular capillaries and usually caused death within 2 weeks. Disease was prevented by administration of antigen-specific IgG1. A passive model of this obstructive glomerulopathy was induced by administration of a TNP-protein conjugate plus IgG3 anti-TNP mAb but not IgG1, IgG2a or IgG2b anti-TNP mAb. IgG3-dependent renal disease could be prevented by co-administration of IgG1, but not IgG2a or IgG2b anti-TNP mAb. These observations demonstrate the adaptive significance of Ig isotypes that poorly activate effector mechanisms and reveal an IC-dependent, complement- and stimulatory FcR-independent mechanism that can rapidly destroy renal structure and function. Our results suggest the possibility of using Ig isotypes that poorly activate effector mechanisms to inhibit IC-induced immunopathology.
Peripheral tolerance induction by PD-L1+ lymphatic endothelial cell is due to deficient costimulation that leads to rapid, high-level expression of PD-1 on CD8 T cells (176.24)
Authors: Tewalt Eric , Cohen Jarish , Rouhani Sherin , Guidi Cynthia , Qiao Hui , Fahl Shawn , Bender Timothy , Tung Kenneth , Vella Anthony , Adler Adam , Chen Lieping , Engelhard Victor 
Published: January 2023

Abstract
It has been shown that lymph node (LN) stromal cells directly present peripheral tissue antigens (PTA) leading to systemic peripheral tolerance. In particular, lymphatic endothelial cells (LEC) directly present an epitope from tyrosinase to CD8 T cells (TCD8). Here, we determined the roles of costimulatory and inhibitory pathways in the induction of LEC-mediated tolerance. LEC do not express costimulatory ligands but do express ligands for the PD-1, CD80, CD160, BTLA, and LAG-3 inhibitory pathways. Nonetheless, LEC-mediated deletion of tyrosinase-specific TCD8 is solely dependent on the PD-1:PD-L1 pathway. Based on radioresistance and the fact that LEC express the highest levels of any LN resident cell, we conclude that PD-L1 expressed by LEC is necessary and sufficient for tyrosinase-specific TCD8 deletion. Presentation of tyrosinase by LEC leads to deletion by inducing more rapid, high-level PD-1 expression on TCD8 than that induced by professional APC. This is due to lack of costimulation by LEC, and is correctable with agonistic anti-4-1BB and OX-40. Apoptosis of tyrosinase-specific TCD8 induced by PD-1 is a consequence of failure to upregulate the IL-2 receptor. Rescue of tyrosinase-specific TCD8 from LEC-mediated deletion by interference with PD-1:PD-L1 or provision of costimulatory signals leads to the induction of autoimmune vitiligo. As LEC express numerous PTA, this mechanism may be of general importance in the development of autoimmune diseases.
PGE2 promotes apoptosis induced by cytokine deprivation through EP3 receptor on mast cells (177.1)
Authors: Kovarova Martina , Koller Beverly 
Published: January 2023

Abstract
Increased mast cells numbers are observed at sites of allergic inflammation. Although a critical factor in the resolution of these inflammatory responses is the restoration of normal mast cell numbers. Early studies showed that cytokines protect mast cells from programmed cells death, suggesting a simple model in which diminished cytokines levels during resolution leads to cell death. The report that prostaglandins (PGs) can contribute to the resolution of inflammation together with the demonstration that mast cells express all four PGE2 receptors raises the possibility that PGE2 act in part by augmenting mast cell apoptosis. We report here that, while exposure of mast cells to PGE2 alone does not lead to apoptosis, PGE2 through the EP3 receptor promotes cell death initiated by cytokine withdrawal. Apoptosis is accompanied by higher dissipation of mitochondrial potential (ΔΨm), increased caspase-3 activation, and chromatin condensation with low molecular weight cleavage. PGE2 augmented cell death is dependent on increase in intracellular calcium release, calmodulin dependent kinase II and MAPK activation. Synergy between the EP3 pathway and the intrinsic mitochondrial apoptotic pathway results in increased Bim expression and higher sensitivity of mast cells to cytokine deprivation. This supports a model in which PGE2 contributes to the resolution of inflammatory response in part by augmenting the removal of inflammatory cells particularly mast cells.
Modulation of mast cell function by TIM-1 signaling (177.4)
Authors: Phong Binh , Kane Lawrence 
Published: January 2023

Abstract
Transmembrane, immunoglobulin and mucin domain (TIM)-1 belongs to a family of transmembrane proteins with emerging roles in immune modulation. As a putative atopy susceptibility gene, polymorphisms in human and mouse TIM-1 are associated with atopic diseases, including asthma and atopic dermatitis. Antibodies targeting different extracellular domains of Tim-1 either attenuated or exacerbated airway inflammation in a mouse model of asthma. Recent studies found that Tim-1 is expressed on mast cells. Tim-1 crosslinking by its ligand Tim-4 enhanced secretion of pro-inflammatory cytokines in IgE and Ag-activated bone marrow-derived mast cells (BMMCs). However, the mechanism(s) by which Tim-1 modulates mast cell function and how Tim-1 activity may be altered by antibody treatment is unknown. We hypothesize that Tim-1 engagement provides a co-stimulatory signal to enhance mast cell degranulation and mediator release in allergic inflammation. We found that Tim-1 requires a tyrosine phosphorylation motif in its cytoplasmic tail to co-stimulate NF-AT/ AP1, NF-κB, and IL-6 promoter transcriptional activation as well as IL-6 cytokine secretion. Furthermore, IgE-Ag and Tim-1 costimulation of BMMCs using a panel of Tim-1 antibodies and its ligand Tim-4 demonstrate that IL-6 and TNF-alpha secretion can be modulated by activity of agonistic and blocking Tim-1 antibodies. These studies suggest that Tim-1 may serve as an important modulator of mast cell effector functions in atopic diseases.
Exploring airway smooth muscle-mediated mast cell function at the single cell level using carbon-fiber microelectrode amperometry (177.6)
Authors: Manning Benjamin , Haynes Christy 
Published: January 2023

Abstract
An important distinguishing feature of asthma pathology is the migration of mast cells (MCs) into the airway smooth muscle (ASM). MCs are known to influence the immune response in a variety of capacities, including the release of many stored immunoactive mediators from secretory vesicles via exocytosis. Conversely, ASM is known to produce several mediators that potentially influence MC activity including the chemoattractant CXCL10. However, the specific consequences of interaction between MCs and ASM on asthma pathophysiology have yet to be fully explored. Carbon-fiber microelectrode amperometry (CFMA) is a unique analytical tool that allows the direct and label free detection of secreted serotonin as it is released from a single MC. Individual packets of serotonin corresponding to single vesicle fusion events are manifested as discrete current spikes in the collected amperometric trace. Individual spike analysis of each trace provides information such as vesicular content and delivery capacity, vesicle fusion efficiency and other kinetic information pertaining to exocytosis regulation. To explore the relationship between MCs and ASM in asthma, CFMA was used to monitor the effects of ASM and asthma-related factors, such as the cytokines CXCL10 and RANTES, on MC function in vitro. Analysis of CFMA data has shown significant modulation of MC secretory function in response to these factors, demonstrating the value of CFMA for the study of MC-related inflammatory processes.
Long-term oral delivery of encapsulated rapamycin is not detrimental to immunity in old mice (178.11)
Authors: Benavides Adriana , Fernandez Elizabeth , Sharp Z. , Strong Randy , Stacy Sue , Infante Anthony , Javors Martin , Richardson Arlan , Kraig Ellen 
Published: January 2023

Abstract
Recently, encapsulated rapamycin (e-rapa) was shown to extend lifespan in mice when given at an old age (Harrison Nature 2009), so it has been suggested that this mTOR inhibitor may be efficacious in slowing the aging process. However, use of rapa in the elderly might further compromise immune competence. Therefore, we sought to test the effects of e-rapa on immunity in older individuals by looking at T cell and B cell responses. Because rapa has been shown to be protective against some bacteria and viruses, effects on humoral immunity to a viable microbe were tested. Adult (4 months) and old (20 months) mice on e-rapa or control diets were challenged with the periodontal bacteria Aggregatibacter actinomycetemcomitans; e-rapa did not negatively impact the antibody titers seen in either age group. E-rapa effects on responses to a protein antigen, TAChRα, were also tested. No significant e-rapa effect was seen on antibody titers following primary or boost immunizations. Moreover, pilot data show that T cell proliferation to p146-162, the immunodominant epitope of TAChRα, was not significantly affected by the encapsulated drug. Since TAChR is the autoantigen in Myasthenia Gravis, we also immunized TAChRα transgenic mice (JI 169:6570) and showed that tolerance was maintained and the levels of TREGS were unaffected by e-rapa treatment. To-date, our data suggest that encapsulated rapamycin will not negatively impact immune regulation in old individuals.
Interaction of TNF and TNFR2 stabilizes the phenotype and function of CD4+FoxP3+ regulatory T cells in the inflammatory environment (179.16)
Authors: Chen Xin , Wu Xueqiang , Howard O.M.Zack , Oppenheim Joost 
Published: January 2023

Abstract
Our previous results showed that TNF-TNFR2 signaling promotes activation and expansion of Tregs. Thus we hypothesize that TNF-TNFR2 signaling may play a critical role in maintaining phenotypic and functional stability of Tregs during an inflammatory response. We were able to confirm that, in colitis model induced by transfer of naïve CD4 cells into Rag KO mice, the disease could be inhibited by co-transfer of WT Tregs, but not by co-transfer of TNFR2-deficient Tregs. Furthermore, in the colon lamina propria of the colitis model, the majority of WT Tregs maintained FoxP3 expression. In contrast, increased number of TNFR2-deficient Tregs lost FoxP3 expression. In vitro, FoxP3 expression by highly purified Tregs was reduced to almost undetectable levels after potent TCR-stimulation, which was partially abrogated by TNF. This effect of TNF was blocked by anti-TNFR2 Ab, but not by anti-TNFR1 Ab. In addition, TNF was not able to increase FoxP3 expression by TNFR2-deficient Tregs undergoing TCR-stimulation. A full mouse genome array study revealed that, as compared with TNFR2- Tregs, TNFR2+ Tregs from normal mice expressed 4-fold lower levels of a gene encoding SATB1, in line with a recent study show that the repression of this genome organizer play a crucial role in maintenance of Treg phenotype and function. Thus, our data clearly show that the TNF-TNFR2 signaling is critical for the phenotypic and functional stability of Treg in the inflammatory environment.
Two histone/protein acetyltransferases (HATs), p300 and CBP, promote Foxp3+ T regulatory (Treg) cell production and function (179.18)
Authors: Liu Yujie , Wang Liqing , Han Rongxiang , Beier Ulf , Brindle Paul , Hancock Wayne 
Published: January 2023

Abstract
The master Treg transcription factor, Foxp3, is pivotal to the development and function of Treg cells. Foxp3 stability and function are regulated by acetylation, and we now identify p300 and CBP as controlling Treg production and function in vivo and in vitro. We found both p300 and CBP bind and acetylate Foxp3, and increase Foxp3 expression, DNA binding, and transactivation. We investigated their roles in Tregs by conditional deletion of p300, CBP, or both. While p300flflFoxp3cre and CBPflfl/Foxp3cre mice were born at the expected Mendelian ratios, p300flfl/Foxp3cre mice developed autoimmunity by several weeks of age, whereas CBPflfl/Foxp3cre mice showed long-term survival. However, p300flfl/CBPflfl/Foxp3cre mice developed severe autoimmunity and survived for only 3-4 weeks. Compared to littermate controls, both p300flflFoxp3cre and CBPflfl/Foxp3cre mice had decreased Foxp3 expression and impaired Treg suppressive function, whereas p300flfl/CBPflfl/Foxp3cre mice had even lower Foxp3 level and their Tregs essentially lacked suppression function. Additional studies showed p300 and CBP affect Foxp3 expression by regulating the Foxp3 promoter or CNS2 region, respectively. Our findings provide genetic evidence for central roles of these HATs in Treg biology, and provide a rationale for development of pharmacologic inhibitors to modulate Treg function in the context of oncology and other settings where it may be desirable to dampen but not eliminate Treg suppressive functions.
Constitutive nuclear localization of NFAT in FoxP3+ regulatory T cells independent of calcineurin activity (179.4)
Authors: Li Qiuxia , Shakya Arvind , Guo Xiaohua , Zhang Hongbo , Tantin Dean , Jesen Peter , Chen Xinjian 
Published: January 2023

Abstract
FoxP3 plays an essential role in conferring suppressive functionality to CD4+/FoxP3+ regulatory T (Treg) cells. While studies have shown that FoxP3 has to form cooperative complexes with NFAT to bind to target genes, it remains unclear whether NFAT is available in the nucleus of primary Treg cells for FoxP3 access. It is generally believed that NFAT in resting cells resides in the cytoplasm and its nuclear translocation depends on calcineurin activation. We report that a fraction NFAT protein constitutively localizes in the nucleus of primary Treg cells, where it selectively binds to FoxP3 target genes. Treating Treg cells with calcineurin (CN) inhibitor does not induce export of NFAT from the nucleus, indicating that its nuclear translocation is independent of CN activity. Consistently, Treg cells are resistant to CN-inhibitors in the presence of IL-2 and continue to proliferate in response to anti-CD3 stimulation, while proliferation of non-Treg cells is abrogated by CN-inhibitors. In addition, PMA, which activates other transcription factors required for T cell activation but not NFAT, selectively induces Treg cell proliferation in the absence of ionomycin. TCR-interaction with self-MHC class II is not required for PMA-induced Treg cell proliferation. Treg cells expanded by PMA or in the presence of CN-inhibitors maintain Treg cell phenotype and functionality. These findings shed light on Treg cell biology, paving the way for strategies to selectively activate Treg cells.
Sphingosine analog AAL-R enhances TLR7-mediated dendritic cell activation via p38 MAPK and type I IFN signaling pathways (180.12)
Authors: Seo Young-Jin , Pritzl Curtis , Vijayan Madhuvanthi , McClain Mariah , Hahm Bumsuk 
Published: January 2023

Abstract
Sphingosine analogs display immunosuppressive activities and are therapeutically used for the treatment of autoimmune diseases. Here, we investigated the effects of the sphingosine analog AAL-R (FTY720 derivative) on dendritic cell (DC) response to toll-like receptor (TLR) stimulation. AAL-R inhibited DC maturation in response to TLR3 or TLR4 activation, representing its previously known immunosuppressive action. In contrast, AAL-R increased TLR7-mediated DC responses by increasing the expression of MHC-I and co-stimulatory molecules and type I interferon (IFN), and by enhancing the capacity of DCs to induce CD8+ T cell proliferation. Importantly, the stimulatory activity of AAL-R was dependent on type I IFN signaling, since type I IFN receptor-deficient DCs failed to respond to AAL-R. Further, AAL-R activated p38 MAPK signaling to increase type I IFN synthesis and TLR7-mediated DC maturation. Thus, our results indicate that AAL-R’s regulatory action is strongly affected by the form of pathogenic molecular patterns and is stimulatory when DCs are treated with a TLR7 agonist. These findings enhance our understanding of sphingosine regulation of host immune responses particularly in pathogenic infections.
Roles of TRAF5 in TLR signaling (180.4)
Authors: Buchta Claire , Bishop Gail 
Published: January 2023

Abstract
Dysregulation in Toll-like receptor (TLR) signaling has been implicated in many disease states, including chronic inflammatory conditions such as atherosclerosis. The cytoplasmic adaptor proteins TNF receptor associated factor (TRAF)3 and TRAF6 are known to mediate TLR signaling. Recent data from our lab demonstrate for the first time that TRAF5 also plays a significant role in immune cell TLR functions. B lymphocytes, macrophages, and dendritic cells from TRAF5-/- mice show increased cytokine production and enhanced early signaling pathways after stimulation through various TLRs. Interestingly, B cell TLR responses are the most greatly affected by TRAF5 deficiency. Our data show that TRAF5 is a negative regulator of TLR signaling and restrains proinflammatory cytokine production. It has been reported that TRAF5 deficiency accelerates the development of atherosclerosis in mice, while human patients with coronary heart disease express lower levels of TRAF5 mRNA in blood compared with healthy controls. Elucidating the role of TRAF5 in TLR signaling may provide a new target for therapies against a variety of inflammatory conditions, including those predisposing to atherogenesis. Our current studies focus on identifying the key molecular interactions by which TRAF5 mediates its effects on TLR pathways.
TLR2 molecular recognition of PorB from commensal Neisseria lactamica (180.6)
Authors: Massari Paola , Toussi Deana , Liu Xiuping , Carraway Margareta 
Published: January 2023

Abstract
Toll-like receptors recognize diverse conserved pathogen-associated molecular patterns (PAMPs). TLR2 has the broadest ligands repertoire, including bacterial lipidated and non-lipidated proteins such as porins. TLR2/porins interaction is possibly based on electrostatic attraction. PorB porin, expressed by all Neisseriae, has significant strain-specific sequence variability within the putative TLR2-binding regions. PorB from commensal N.lactamica (NL) and pathogenic N.meningitidis (NM) bind to TLR2 in vitro with different specificity and induce inflammatory responses of different magnitude. Whole NM is also more potent than NL in inducing cell activation. A TLR2-binding signature sequence in the PorB surface exposed loops might influence specific interaction with TLR2 and activation of signaling pathways. Exchange of NM PorB for NL PorB in NM induces attenuated inflammatory responses. To identify PorB/TLR2 interactive domains (and possibly TLR1) and to provide a mechanistic explanation for their different activity, we have expressed PorB mutants with altered loops sequences and show a gradient of cell activation. However, hybrid PorB mutants bind to TLR2 in vitro. This possibly suggests that the reduced activity of PorB mutant could be due to non-functional TLR2 heterodimerization with TLR1.
Differential roles of DNA-PKcs in the innate response to CpG-DNA (180.9)
Authors: Chu Wen-Ming , Ma Chi , Muranyi Marianna , Chu Catherine 
Published: January 2023

Abstract
CpG-DNA and its analog CpG-ODN powerfully activate dendritic cells (DCs) to produce pro-inflammatory cytokines, which are critical for vaccine strategies for allergy, infectious disease and cancer. There are two major types of CpG-DNAs, CpG-A and CpG-B. CpG-A activates the IFNa/b pathway, which requires IRF1 and 7, while CpG-B triggers the pro-inflammatory pathway, which requires AP-1 and NF-kB. Primarily, CpG-A triggers the IFNa/b response in pDCs in a complete TLR9- dependent manner. Yet, CpG-A together with DOTAP clearly activates DCs to produce IFNa/b in both TLR9 dependent and independent manners. Also, CpG-B induces IFNb production in DCs. To further understand how CpG-DNA activates innate immunity, we investigated a role of DNA-PKcs in this activation. Our results showed that loss of DNA-PKcs reduced pro-inflammatory cytokine response to CpG-B in DCs in a time and dose dependent manner. Interestingly, the IFNa/b response to CpG-A was defective in DNA-PKcs-deficient DCs, whereas the IFNb response to CpG-B was enhanced in the same cells. Also, Stat1 phosphorylation was diminished in either DNA-PKcs or TLR9 deficient DCs, and was further reduced in DNA-PKcs/TLR9 double deficient DCs. Additionally, our data showed that DNA-PKcs associated with TRAF6, which is critical for the IFNa/b and the pro-inflammatory cytokine responses to CpG-DNA. Together, our results suggest DNA-PKcs plays a differential role in regulating the innate immune response to CpG-DNA.
Rapid evolution of the binding specificities and expression patterns of CD33-related Siglecs in primates (181.4)
Authors: Padler-Karavani Vered , Hurtado-Ziola Nancy , Verhagen Andrea , Sonnenburg Justin , Chen Xi , Varki Ajit , Angata Takashi 
Published: January 2023

Abstract
Siglecs (Sialic acid-binding Immunoglobulin-like Lectins) are vertebrate sialic acid (Sia) binding proteins mostly expressed in hematopoietic and immune cells. They are type-I proteins with an extracellular N-terminal Sia-binding Ig-like V-set domain, one or more C2-set Ig-like domains, a transmembrane domain and a C-terminal cytoplasmic tail. CD33-related Siglecs (CD33rSiglecs) are a genetically clustered subgroup. Prior comparative genomic analysis indicated accelerated evolution of CD33rSiglecs selectively occurring in the Sia-binding V-set domain, suggesting that this domain is under the greatest selection pressure. To gain further insight into this rapid evolution of CD33rSiglecs, we prepared recombinant form of the N-terminal domains of CD33rSiglecs from human, chimpanzee, and baboon, and compared their sialoglycan binding-specificities. Using ELISA on a panel of gangliosides or analysis on a sialoglycan microarray we show that binding patterns are widely divergent between the three species. Some show preference to Neu5Gc over Neu5Ac, especially in chimpanzees and baboons, indicating an evolutionary adjustment to the loss of Neu5Gc expression in humans. Expression patterns of CD33rSiglecs on circulating blood cells of humans and related great apes also show evidence for rapid evolution, and overall expression is greater in apes compared to human. The selection mechanisms driving this rapid evolution will be discussed.