bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reactive Nitrogen species process a microbial carbohydrate presented by the MHCII Pathway (93.20)
Authors: Duan Jinyou , Avi Fikri Y , Kasper Dennis L 
Published: January 2023

Abstract
The class II major histocompatibility complex (MHCII) pathway in antigen-presenting cells (APCs) is the conduit by which extracellular proteins are processed by proteases, resulting in foreign peptides being presented to T cells. After depolymerization to a markedly decreased molecular size, zwitterionic polysaccharides (ZPSs) are also presented by this pathway. However, nothing is known about the chemistry of carbohydrate processing apart from its dependence on the presence of inducible nitric oxide synthase (iNOS).
By examining the ability of known nitric oxide-derived species, peroxynitrite, nitroxyl, and nitric oxide itself, to degrade polysaccharide A (PSA), a ZPS from Bacteroides fragilis, we determined that deamination was the predominant mechanism of PSA processing in APCs. Structural characterization of the nitric oxide-derived product PSA-NO indicated that the depolymerization didn¡t disturb PSA¡s repeat units with exception of the deamination cleavage of 4-amino groups of 3-linked 2-acetamido-4-amino-2,4,6-trideoxy galactopyranosyl (AATp) residues.
PSA-NO presented by APCs induced CD4+ T cell proliferation that was blocked by inhibitors of endosomal processing and by an antibody to HLA-DR. A novel mechanism (deaminative reaction) differentiates carbohydrate from protein processing during the oxidative burst.
Partial MHC Class II molecules preferentially bind to B cells (93.22)
Authors: Link Jason M , Meza-Romero Roberto , Afentoulis Michael , Agotsch Marisa , LaTocha Dorian , Burrows Gregory , Vandenbark Arthur A 
Published: January 2023

Abstract
Recombinant, two-domain MHC Class II proteins (α1β1MHCII) that lack sequence from the membrane proximal α2 and β2 domains of MHC Class II adhere preferentially to B cells in vivo and ex vivo; whereas, full length (four-domain) constructs do not bind. Because α1β1MHCII molecules that contain only native MHC Class II sequence have preferential affinity for B cells, we hypothesize that a natural, cell-free form of MHC Class II (similar to recombinant α1β1MHCII) exists and has affinity for a receptor expressed by B cells. Evidence that endogenous, natural MHC Class II molecules transfer to B cells and that α1β1MHCII has inter- and intra-species affinity for B cells suggest that this is a natural and evolutionarily conserved property. And evidence that α1β1MHCII can stimulate CD4+ T cells suggests that there is an immune function for partial, cell-free MHC Class II. Transfer of immunoreactive, cell-free α1β1MHCII/Ag complexes to B cells suggests a here-to-fore unrecognized pathway for T cell activation.
HLA-DQ dimer formation pattern and its possible contribution to the sleep disorder narcolepsy (93.23)
Authors: Miyadera Hiroko , Tokunaga Katsushi 
Published: January 2023

Abstract
Allelic polymorphisms of HLA class II are associated to the susceptibility/resistance to various diseases. In particular, the susceptibility to sleep disorder narcolepsy is strongly linked to DQB1*0602. In addition, some other DQB1 alleles also affect the susceptibility to the disease when present in addition to DQB1*0602. In order to understand how these alleles contribute to the susceptibility/resistance to narcolepsy, we have analyzed the abilities of these and other DQB1 alleles to form dimer with various DQA1 alleles. The residues which may contribute to the association of DQA1 and DQB1 were also identified and will be presented.
Nonsense Mediated Decay associated “Pioneer round of translation” peptides as source for MHC I mediated antigen presentation (93.3)
Authors: Schmidt Andreas , Shastri Nilabh 
Published: January 2023

Abstract
Nonsense mediated decay (NMD) plays a critical role in the mRNA quality control mechanism protecting cells from aberrant mRNAs containing premature termination codons (PTC). Recognition of these PTCs requires a “pioneer round of translation” prior to the bulk translation of mRNAs for cellular protein synthesis, therefore producing a pool of immediate early peptides.
Effectiveness of the immune surveillance system is insured by the timely and complete MHC I mediated presentation of a pool of precisely cleaved peptides representing all cellular proteins. So far sources of antigenic peptides are known to include regular degraded proteins, defective ribosomal products (Drips) and cryptic peptides starting with a non-AUG start codon. Here the contribution of peptides originating from the pioneer translation to the pool of peptides presented by MHC I molecules is described. In Hela cells RNAi mediated depletion of the essential NMD factor hUpf1 as well as the pioneer translation initiation complex factors CBP80 and PABP2 reveal impaired MHC I antigen presentation. In sharp contrast, targeted interference with conventional translation without effecting pioneer translation permits antigen presentation. Taken together these findings put products of the pioneer translation into an important position as novel resource for antigenic peptides and reveal a new relationship between NMD and immunosurveillance.
Identification and characterization of a novel splicing variant of the MHC class I-related neonatal Fc receptor (FcRn) for IgG (93.9)
Authors: Ye Lilin , Tuo Wenbin , Liu Xindong , Zhu Xiaoping 
Published: January 2023

Abstract
The neonatal Fc receptor for IgG (FcRn), a MHC class I-related molecule, functions to transport maternal IgG into the fetus or newborn and protects IgG from catabolism. The mRNAs of several MHC class I-related molecules have multiple splicing variants. By cloning porcine FcRn cDNA from the intestinal epithelial cell line IPEC, two cDNAs were found: a long form of 1071 bp (pFcRn-L) and a short form of 795 bp (pFcRn-S). These mRNAs were also detected in porcine kidney epithelial cell line LLC-PK1, peripheral blood mononuclear cells, as well as a variety of porcine tissues by RT-PCR and Northern blot. Sequence analysis showed that pFcRn-L cDNA encodes the full-length pFcRn, whereas pFcRn-S cDNA represents a splicing variant of pFcRn mRNA, coding for a truncated pFcRn with deletion of 92 amino acids matching to the alpha2 domain of pFcRn-L. Recombinant pFcRn-L bound IgG at pH 6.0, but not at pH7.5. However, recombinant pFcRn-S bound IgG at both pH 5.0–6.0 and pH 7.5. Furthermore, the intracellular trafficking patterns of pFcRn-L and pFcRn-S exhibited remarkable differences. The pFcRn-L was expressed on the cell surface and mainly localized in the early endosomal compartment, whereas pFcRn-S was primarily found in late endosome/lysosome. In contrast to pFcRn-L, pFcRn-S trafficking to the lysosomal compartment is independent of porcine beta2m expression as assessed in a beta2m-deficient cell line FO-1. Therefore, the pattern of FcRn gene expression which is characterized by the complexity of RNA splicing further implies the functional complication of FcRn.
Properties of a SOCS-1 small molecule antagonist (94.1)
Authors: Waiboci Lilian W , Johnson Howard M , Martin James P , Ahmed Chulbul M 
Published: January 2023

Abstract
Suppressor of cytokine signaling 1 (SOCS-1) is a member of a small family of protein molecules that are regulators of cytokines that signal through JAK2 tyrosine kinase and STAT transcription pathways. SOCS-1 binds to the autophosphorylation site of JAK2 tyrosine kinase and blocks its ability to activate substrates such as STAT1-alpha both directly and by initiation of proteosomal degradation. Thus, SOCS-1 is an attenuator of positive immune regulators such as gamma interferon. We reasoned that a peptide corresponding to the autophosphorylation site of JAK2 in the phosphorylated state, pJAK2(1001–1013), would bind to induced SOCS-1 in cells and block its inhibitory effects on mediators of the immune response. We therefore synthesized pJAK2(1001–1013) with an attached palmitate residue for cell penetration and showed that it enhanced suboptimal IFN-gamma, blocked SOCS-1 induced inhibition of STAT3 phosphorylation in IL-6 treated cells, enhanced IFN-gamma activation site (GAS) promoter activity, and enhanced antigen specific proliferation. In a mouse model of lethal vaccinia virus infection, pJAK2(1001–1013) completely protected mice against an overwhelming lethal dose (106 pfu intranasal) of vaccinia virus. The small molecule SOCS-1 antagonist should be quite useful in enhancing the immune response against infectious agents and cancer.
Supported by NIH grants AI 056152 and NS051245 to HMJ.
Glucocorticoids Augment CXCR4-Mediated Signaling and Function Via the Activation of the Src Kinase, Lck (94.10)
Authors: Ghosh Manik C. , Collins Gary , Carter Arnell , Taub Dennis D 
Published: January 2023

Abstract
Dexamethasone is a synthetic member of the glucocorticoid (GC) class of hormones that possesses anti-inflammatory and immunosuppressant activity and is commonly utilized to treat chronic inflammatory disorders, severe allergies and other disease states. While glucocorticoids are known to mediate well-defined transcriptional effects via GC receptors, there is increasing evidence that GCs also initiate rapid non-genomic signaling events in a variety of cell types. Here, we report that dexamethasone appears to induce the phosphorylation of Lck and the activation of other down stream mediators in resting human T cells including p59Fyn, Zap70, Rac1, Cdc42 and Vav1. DM treatment also appeared to augment CXCL12-mediated signaling in resting T cells through its cell surface receptor, CXCR4, resulting in the enhanced actin polymerization and cell migration upon ligand exposure. Lck was found to be a critical intermediate in these DM-induced signaling activities. Moreover, DM-mediated Lck phosphorylation in T cells was dependent on the presence of both the glucocorticoid receptor and the CD45 molecule. Overall, these results elucidate additional non-genomic effects of DM on resting human T cells, inducing Lck activation and augmenting chemokine signaling and function.
Glucocorticoids Suppress Activation of Mast Cells through induction of Inhibitory Regulators of Signaling Pathways (94.13)
Authors: Peng Ze , Hiragun Takaaki , Qiao Huihong , Beaven Michael A 
Published: January 2023

Abstract
Glucocorticoids suppress production of inflammatory cytokines via the glucocorticoid receptor (GR) by inhibiting activity of relevant transcription factors, a process known as transrepression. Here we provide evidence that dexamethasone and other glucocorticoids also suppress activation of mast cells through induction of synthesis of inhibitory regulators of signaling pathways by a process referred to as transactivation. The glucocorticoid-inducible regulators identified so far include Src-like adaptor protein (SLAP), downstream of tyrosine kinase (Dok)-1, MAP kinase phosphatase-1 (MPK-1) (Mol. Pharmacol. 67:598, 2005; J. Immunology 177:2047, 2006),. Suppressor of cytokine signaling 1 (Socs1), and cytokine inducible SH2-containing protein (Cish) (unpublished data). We have found that the induction of these inhibitory regulators account for the inhibition of key antigen-mediated signaling events such as the activation of the tyrosine kinase Syk, MAP kinase pathways, and downstream transcription factors. The effects of overexpressed wild type GR, and a dimerization-negative mutant GR with minimal transactivation activity, further suggest that the inhibitory actions of glucocorticoids are dependent on gene transactivation as well as cytokine-gene transrepression. These findings have important implications in the design and use of glucocorticoids that exhibit selectivity towards transrepression.
Signaling motifs in the IL-17 receptor (94.2)
Authors: Gaffen Sarah L , Shen Fang , Maitra Amarnath , Hanel Walter , Mossman Karen 
Published: January 2023

Abstract
IL-17 and its receptor IL-17RA have received much attention as the defining cytokine of a new class of T helper cells termed Th17. Mounting evidence suggests that IL-17 causes pathology in autoimmunity, but surprisingly little is known about mechanisms of IL-17 signal transduction. Although produced by T cells, IL-17 activates genes typical of innate immune cytokines such as TNFα and IL-1β, despite little sequence similarity in their respective receptors. A prior bioinformatics study predicted a subdomain in IL-17-family receptors with homology to a Toll/IL-1R (TIR) domain, termed “SEFIR.” However, the SEFIR domain lacks motifs critical for bona fide TIR domains, and its functionality has never been verified. Here, we used a reconstitution system in IL-17RA-null fibroblasts to map functional domains within IL-17RA. We demonstrate for the first time that the SEFIR domain mediates signaling, independently of TIR adaptors such as MyD88 and TRIF. Moreover, we identified a novel “TIR-like loop” (TILL) also required for activation of NF-κB, NF-κB-dependent genes and upregulation of C/EBPβ and C/EBPδ. We further identified a distinct domain required for activation of C/EBPβ and induction of a subset IL-17 target genes. This is the first structure-function analysis of any IL-17R superfamily receptor, and reveals unique structural and functional properties in IL-17 signaling.
Regulation of p53 expression in PBMC by beta Interferon in Multiple Sclerosis (94.21)
Authors: Zhang Fanglin , Sriram Subramaniam 
Published: January 2023

Abstract
Background: Beta Interferon (IFN) is a first line treatment in Multiple Sclerosis (MS); however its mechanism of action remains unclear. P53 is a key player in regulating apoptosis through the transcriptional activation of target genes. Previous studies showed an integration of beta IFN signaling with stabilization of p53 in murine cells. We examined the activation and stabilization of p53 in PBMC following in vitro culture with beta IFN, and in patients receiving beta IFN treatment.
Methods: PBMC were isolated from 6 heath controls (HC) and 6 MS patients and then cultured with beta IFN. We also examined p53 expression in 7 MS patients receiving beta IFN-1b treatment. P53 expression in vitro and in vivo experiments was determined by real time RT-PCR, Western blotting and flow cytometry.
Results: P53 expression increased in a dose and time dependant manner following culture with beta IFN. Flow cytometry studies showed increased stabilization of p53 in CD3+ T cells and monocytes. PBMC isolated from MS patients receiving beta IFN in vivo also showed the increase in p53 stabilization. However, the stabilization varied between patients receiving beta IFN: two patients showed no increase in p53; in the remaining five patients, the kinetics of p53 induction varied.
Conclusion: Our studies show that p53 is vigorously induced in PBMC in vitro and following injection of drug in vivo. P53 expression induced was variable between patients receiving beta IFN. We suggest that p53 can potentially regulate the expansion of autoreactive cells that might contribute to the development and progression of MS.
The study was supported by funds from Serono Inc
Nuclear Factor of Activated T Cells (NFAT) is Suppressed by the Plant-Derived Cannabinoid, Cannabidiol. (94.23)
Authors: Kaplan Barbara L. F. , Kaminski Norbert E. 
Published: January 2023

Abstract
Marijuana is derived from the Cannabis Sativa plant. Although there are over 60 cannabinoid compounds in the plant, Δ9-tetrahydrocannabinol (THC) is the primary psychoactive congener of marijuana and binds to the two known cannabinoid receptors, CB1 and CB2. THC has exhibited immunosuppressive actions both in vivo and in vitro. Interestingly, another predominant cannabinoid from the plant, cannabidiol (CBD), possesses low affinity for both cannabinoid receptors, yet also exhibits immunosuppressive actions. A major target of immune suppression by CBD is interleukin-2 (IL-2) as demonstrated in PMA/Io-stimulated mouse splenocytes. The focus of these studies was to determine the mechanism by which CBD suppressed IL-2. Using purified T cells from mouse splenocytes, CBD suppressed PMA/Io-stimulated IL-2 production, similar to the transplant drug cyclosporin A. Consistent with the observation that CBD does not possess high affinity for CB1 or CB2, CBD also suppressed PMA/Io-stimulated IL-2 from purified T cells derived from CB1/CB2 null mice. IL-2 transcription is regulated by several transcription factors, including NFAT, activator protein-1 (AP-1), and nuclear factor κB (NF-κB). Using the human Jurkat T cell line, in which CBD suppressed PMA/Io-stimulated IL-2 production, NFAT- and AP-1-luciferase reporter constructs were transiently transfected and induced with PMA/Io in order to examine the effect of CBD on transcriptional activation. CBD suppressed both PMA/Io-induced NFAT- and AP-1-luciferase in a concentration-dependent manner. These results are consistent with the mechanism by which other plant-derived, synthetic and endogenous cannabinoids suppress IL-2 and other functional immune endpoints.
(Supported in part by NIH DA007908).
Protein Phosphatase 2A destabilizes TNF alpha mRNA by dephosphorylating Tristetraprolin (94.8)
Authors: Sun Lei , Stoecklin Georg , Van Way Susan , Hinkovska-Galcheva Vania , Guo Ren-Feng , Anderson Paul , Shanley Thomas 
Published: January 2023

Abstract
Tumor necrosis factor (TNF)-α is a major cytokine produced by alveolar macrophages in response to pathogen associated molecular patterns such as LPS. TNF-α secretion is regulated at both transcriptional and post-transcriptional levels. Post-transcriptional regulation occurs by modulation of TNF-α mRNA stability via the binding of tristetraprolin (TTP) to the AU (adenosine/uridine)-rich elements (AREs) found in the 3’-untranslated region (3’-UTR) of TNF-α transcript. Phosphorylation plays important roles in modulating mRNA stability. Our results show that inhibition of PP2A by okadaic acid or siRNA significantly enhanced the stability of TNF-α mRNA. This result was associated with increased phosphorylation of p38 MAPK and MK-2. PP2A inhibition increased TTP phosphorylation and enhanced complex formation with chaperone protein 14-3-3. A functional consequence of TTP/14-3-3 complex formation appeared to be protection of TTP from dephosphorylation by inhibition of the binding of the catalytic unit of PP2A to phosphorylated TTP. Our data indicates that PP2A regulates TNF-α mRNA stability by modulating the phosphorylation state of members of the p38/MK-2/TTP pathway.
This work was supported by grants from the National Institute of Health (7R01GM066839-03, to TPS).
Herpes Simplex Virus I Obstucts the Type II Interferon Pathway in Keratinocytes by Induction of Suppressor of Cytokine Synthesis-1 (94.9)
Authors: Frey Kenneth Gene , Johnson Howard M , Bigley Nancy J 
Published: January 2023

Abstract
Herpesviruses are masters at evading the immune system. HSV-1 employs a variety of strategies to blunt the immune response, for example, downregulation of expression of class I MHC molecules. Studies using mouse L929 fibroblasts and HEL-30 keratinocytes revealed a differential response to treatment with interferon-γ (IFN-γ). L929 cells were protected from HSV-1-induced lysis by pretreatment with IFN-γ while HEL-30 cells were not. Interestingly, treatment of HEL-30 cell with IFN-γ followed by HSV-1 infection led to a 14-fold increase in SOCS-1 transcripts while treatment with IFN-γ alone increased SOCS-1 by 7-fold, while in comparison L929 cells showed much less increase in SOCS-1. Recent evidence indicates that HSV-1 inhibits the interferon pathway. SOCS-1 is the primary negative regulator of signaling by IFN-γ via the JAK/STAT pathway. Here we establish that infection of HEL-30 cells with HSV-1 (syn 17+) leads to a rapid induction of SOCS-1 at both transcript and protein levels. This induction is evident as early as 2 hours p.i., and is stable up to 8 hours p.i. Use of siRNA against SOCS-1 indicates that knockdown of SOCS-1 prior to treatment with IFN-γ results in inhibition of HSV-1 replication. These results suggest a possible therapeutic strategy to herpes infection by treatment with SOCS-1 siRNA and IFN-γ.
Follicular CD4+ T helper cells induce human B cells to undergo Ig isotype switching and differentiation to Ig-secreting cells through the production of IL-21 (95.1)
Authors: Tangye Stuart Graham , Avery Danielle T , Bryant Vanessa L , Ma Cindy S 
Published: January 2023

Abstract
The primary function of B cells is to produce high-affinity Ag-specific Ig by differentiating into plasma cells. Naïve B cells can also alter the effector function of their Ig molecule by class switch recombination (CSR). CSR and plasma cell differentiation occur within germinal centres (GC) and are believed to be largely regulated by signals delivered by T follicular helper (TFH) cells. TFH cells reside within the GC and can be resolved from other T-cell populations by the expression of elevated levels of CXCR5. The mechanism by which TFH cells induce B-cell differentiation is unknown. We examined the effects of IL-21, a product of TFH cells, as well as these cells themselves, on the fate of human naïve B cells. IL-21 induced CD40L-stimulated naïve B cells to undergo CSR to acquire expression of IgG and IgA, and secrete large amounts of IgG, IgA and IgE. Isotype switching induced in CD40L-stimulated naïve B cells by IL-21 was linked to cell division, as revealed by analysis of CFSE-labelled B cells. The addition of IL-4 to cultures of CD40L/IL-21-stimulated naïve B cells had divergent and isotype-specific effects with IL-4 enhancing IL-21-induced switching to IgG and IgE whilst inhibiting switching to IgA. When naïve B cells were co-cultured with autologous tonsillar TFH cells, but not CD4+CXCR5− T cells, they produced high levels of IgM, IgG and IgA. Strikingly, differentiation of autologous naïve B cells by TFH cells was abrogated by neutralising endogenous IL-21. These findings demonstrate the critical role of IL-21 in TFH-cell dependent B-cell differentiation and suggest that diminished or excessive production of IL-21 may contribute to the development of immunodeficiencies or autoimmune diseases, respectively.
Neuroalternative Enhancement of Development of Th17 Cells by Signals from the Type 1 Receptor for Vasoactive Intestinal Peptide (VPAC1) (95.11)
Authors: Yadav Mahesh , Goetzl Edward 
Published: January 2023

Abstract
VIP (vasoactive intestinal peptide) has diverse immunological effects transduced by class II G-protein-coupled receptors VIP receptor type 1 (VPAC1) and type 2 (VPAC2). The VIP-VPAC1/2 axes in T cells promote hypersensitivity and inflammation in many settings, but also may be anti-inflammatory at high VIP concentrations. The Th17 subset of CD4 T cells, that mediates local tissue and systemic inflammation through IL-17, develops under the control of several cytokines of which IL-23 has a distinctive role. To determine if the immuno-inflammatory effects of VIP are attributable to recruitment of Th17 cells, mouse splenic CD4 T cells from VPAC2 knockout mice that express only VPAC1 were cultured with anti-CD3 + anti-CD28 Ab, without and with IL-23 or VIP. Over 5 days, 0.1 μM and 1 μM VIP enhanced the development of Th17 cells significantly and with the same time-course as IL-23. VIP also augmented IL-17 production by human T lymphocytes of the HUT102 line, which expresses only VPAC1. Our results suggest that the VIP-VPAC1 axis is an alternative to IL-23 in enhancing Th17 cells development normally and in autoimmunity. Drugs that increase or inhibit VPAC1 signals may be therapeutic in infectious and autoimmune diseases.
This work was funded through NIH grant AI029912