bluuebunny/crossref_metadata_2025_split huggingface dataset:
CPG potentiates the effects of cigarette smoke on releases of IL-8 in neutrophils (B55)
Authors: Mortaz Esmaeil , Adcock Ian , Ito Kazuhiro , Nijkamp Frans P 
Published: January 2023

Abstract
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. Smoking is considered the major cause of the disease. All smokers develop airway inflammation through oxidative stress with macrophages, neutrophiles and mediators (such as IL-8) involved. Previous studies have implicated a role of bacterial DNA(CpG, in the initiation of inflammation. In this study we investigated the capacity of cigarette smoke extracts (CSE) and CpG-DNA to trigger and modulate IL-8 responses in human neutrophils. A human isolated neutrophils, were exposed to the CSE, CpG, or in combination. Supernatants were isolated and analyzed for IL-8 by ELISA. The NF-B and AP-1/c-Fos activities were monitored by Western blot by using antibodies. CSE and CpG induced the release of IL-8. When co-administered release of IL-8 synergically increased which was correspondence with degradation of IB- in cytoplasm. CpG and CSE evoked concomitant increases in intracellular NO levels and consequently, nuclear accumulation of c-Fos and NF-B. Pharmacological inhibition of NF-B activity or using of N-acetylcysteine (NAC) attenuated IL-8 release. These results identify reactive oxygen dependent activation of NF-B and c-Fos as an important mechanism to CSE and CpG. In conclusion, this study show that the combination of CSE and CpG provide a substantial release of IL-8 which may accounts to exacerbation of lung in COPD patients when they are exposed to bacterium infections.
κκκακακκ
Intracellular signaling networks in the immune response: Interleukin-4 introduces competition and cooperation to interleukin-2-induced T cell proliferation (B57)
Authors: Comfort Kristen K , Haugh Jason 
Published: January 2023

Abstract
Cells sense and respond to stimuli through signal transduction pathways, which mediate proliferation, differentiation, and survival. The cytokines interleukin-2 (IL-2) and interleukin-4 (IL-4) are key regulators of the immune system, influencing the expansion and differentiation of T cells. Both synergistic and antagonistic effects of IL-2 and -4 co-stimulation have been shown; the antagonism may arise from the sharing of a common receptor subunit. We have sought to characterize IL-2 and IL-4 signaling at the level of intracellular pathways activated by these receptors. IL-2 receptors are known to activate the Ras/Erk and phosphoinositide (PI) 3-kinase pathways as well as the STAT5 transcription factor. IL-4 is able to activate PI 3-kinase/Akt as well as STAT6, though not Ras/Erk.
We found that IL-4 initially antagonizes, and later synergizes with, IL-2-stimulated HT-2 cell proliferation; a murine T cell line. At a signaling level, IL-4 abates IL-2-stimulated activation levels of Akt, Erk and STAT5 possibly through competition for limiting amounts of common receptor subunit. IL-2/IL-4 co-stimulation provokes prolonged activation only of STAT6. This extended STAT6 activation may be critical in the IL-2/IL-4 induced synergy in T cell growth. Currently, we are investigating the crosstalk between these pathways and their functional roles in IL-2 and IL-4-stimulated T cell responses.
Association of gender and IL-6R function and its role in alcoholic liver disease (B58)
Authors: Gallucci Randle M , Lee Eric G , Mickle Bethany M 
Published: January 2023

Abstract
Alcohol liver disease (ALD) is more severe in females than males. Proinflammatory cytokine release from Kupffer cells during inflammation is associated with the pathogenesis of ALD, and female chronically ethanol fed rats express cytokine mediators differently than male counterparts. Differences in IL-6 receptor function in females may play a role in the clinical observations of more severe ALD in females. In this study, the effects of sex steroid exposure on the expression and function of IL-6 receptor in ethanol fed rats were examined. Normal male and female or ovarectomized Wistar rats were fed liquid diet with and without ethanol for up to four weeks. Ovarectomized rats were additionally implanted with osmotic pumps containing either testosterone or estrogen. Ethanol consumption significantly increased in IL-6 receptor mRNA and protein expression and NFkB activation in female and estrogen treated rats. However C/EBPβ and IkB expression was higher in male and testosterone treated rats, indicating increased IL-6 signaling, and decreased NFkB signaling. Our data suggest that sex steroids play a role in IL-6R expression and function and that testosterone may be protective in ALD.
The Polycomb Group Member Bmi-1 Determines The Proliferative Potential Of CD8 T Cells (B6)
Authors: Heffner Maike , Fearon Douglas T. 
Published: January 2023

Abstract
In persistent viral infections certain virus-specific CD8+T cell clones demonstrate long term expansion despite evidence of cellular replicative senescence, indicating that within these clones are cells with stem cell properties to maintain continuous generation of effector cells. A candidate for maintaining the replicative function of these putative “stem cells”, is Bmi-1 which enables self renewal of haematopoietic and neural stem cells.
Stimulation of OT-I CD8+ T cells with 2.5nM SIINFEKL peptide upregulated Bmi-1 mRNA by 10 fold in 6 hours and protein by 24 hours. Expression was reversible upon removal of peptide, but was maintained by IL-2 and IL-15. Knockdown of Bmi-1 with a lentiviral vector expressing a specific shRNA impaired the proliferative capacity of IL-2 stimulated OT-I CD8+ T cells by 65% by day 4, and of CTLL-2 cells by 80% at day 12 after transduction. Ectopic expression of Bmi-1 in OT-I CD8+ T cells with a retroviral vector led to a 4.6 fold increase in cell number 10 days after transduction relative to cells with vector alone. OT-I CD8+ T cells adoptively transferred to Rag2−/−mice and expressing ectopic Bmi-1 expanded five-fold more than control OT-I CD8+ T cells after 80 days.
Thus, certain CD8+ T cells may resemble hematopoietic and neural stem cells in their expression of Bmi-1 to regulate replicative potential.
Resident Dendritic Cell (DC) Activation Initiates Early Innate Response to Kidney Ischemia-Reperfusion Injury (IRI) and Inflammation via IL-23/IL-17 and IL-12/IFN-γaxis (B72)
Authors: Li Li , Huang Liping , Ye Hong , Vergis Amy L , Sung Sun-Sang J , Lobo Peter I , Okusa Mark D 
Published: January 2023

Abstract
DCs contribute to innate immunity, autoimmunity and host defense through IL-12/IFN-γ and/or IL-23/IL-17 pathways. Although DC is the dominant kidney leukocyte subset, its role in the early IRI is unknown. We hypothesize that early kidney IRI is characterized by resident DC activation leading to IL-12/IFN-γ and IL-23 production. Depletion of DCs using lipsoomal clodronate prior to IRI led to kidney protection, which indicated the importance of DCs. DC triggered NKT cell IFN-γ production and its effect on kidney IRI was investigated by using αGalCer-primed BMDC. Adoptive transfer of BMDC-αGalCer or control BMDC into B6 mice was performed prior to kidney IRI. Plasma creatinine was 5-fold higher in DC-αGalCer treated IRI mice than those with BMDC (P&lt;0.001). Furthermore, DC-αGalCer treated CD1d−/− or IFN-γ−/− mice have the minimal injury and similar to the BMDC treated mice. Next we observed that as early as 4–6 hrs post kidney IRI there was a &gt;25-fold increase of IL-23p19 and IL-12p40 mRNA. Anti-IL-23p19 mAb protected kidneys from IRI and led to a reduction of PMNs and macrophages compared to control IgG. Lastly compared to WT mice, IL-12p35−/−, IL-12p40−/− mice kidney showed evidence of significant functional and histological protection (P&lt;0.001). These results demonstrate that DC activation and down stream mediators play a pivotal role in the early kidney IRI and could serve as targets for new therapies.
Macrophage migration inhibitory factor is involved in the pathogenesis of antigen-induced arthritis in mice (B78)
Authors: Rodriguez-Sosa Miriam , Juarez-Avelar Imelda , Rivera Irma , Verdin Leticia , Terrazas Luis Ignacio 
Published: January 2023

Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease caused mainly by pathogenic activation of T-cells recognizing cartilage antigens. Infiltration of these autoreactive T-cells and macrophages into the synovium results in the formation of pannus, eventually destructing bones and ligaments. MIF is a 12 kDa highly conserved trimeric protein which acts as an enzyme, hormone and cytokine. MIF is largely known for its role in macrophage effectors function and T cell activation, as well as a pro-inflammatory molecule. Using a murine antigen-induced arthritis model (AIA) in MIF−/− and MIF+/+ BALB/c mice we analyzed the role of endogenous MIF in rheumatoid arthritis. AIA was induced by intra-articular injection of heat aggregated OVA in presensitized (i.v. transferred CD4+ DO11.10 cells) mice. MIF −/− mice displayed low signs of disease, given that inflammation and eritema were reduced, these observations were associated with low levels of TNF-α, IFN-γ and nitric oxide in serum. Histological arthritic scores for synovial inflammation were also significantly decreased compared to MIF+/+ mice. Similarly, levels of MMP-2 and MMP-9 performed by inmmunohistochemistry, were lower. These results indicated that MIF plays a critical role in inflammation and joint destruction in AR.
Supported by DGAPA-PAPIIT IN208606-3.
Regulatory T cells selectively protect against experimental autoimmune encephalomyelitis induced with self but not foreign antigens (B79)
Authors: Akirav Eitan Moshe , Xu Yan , Bergman Cheryl M , Hill Myriam , Ruddle Nancy H 
Published: January 2023

Abstract
Naturally occurring CD4+CD25+ regulatory T cells (Treg) are selected in the thymus by self-antigens and can prevent the development of autoimmune diseases. Experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS), can be induced with myelin oligodendrocyte glycoprotein (MOG). Here we show that both MOG mRNA and protein are detected in the thymus. To test whether Tregs specific for mouse MOG protect against EAE, we examined the effects of Treg depletion on EAE induced with the Ig-like domain of mouse (self), rat or human (foreign) MOGs. Treg depletion resulted in increased EAE severity following immunization with mouse MOG, but surprisingly, did not affect EAE induced with either rat or human MOG. The increase in disease severity following Treg depletion of mouse MOG immunized mice was associated with increased T cell proliferation and IL17 production as well as an increase in T cell response to the immunodominant peptide MOG35-55. In the central nervous system, T cells from mouse MOG immunized mice showed increased infiltration as well as increased ratio of IFNγ to IL10 producing cells following depletion. These data demonstrate the high specificity of Tregs to self but not foreign MOG, thus, underlining their inability to “cross-protect” against autoimmunity induced with closely related antigens.
Supported by NMSS RG2394 and NIH CA16885.
Massive Changes in the TCR Repertoire of Regulatory T Cell-Deficient Mice: Multiple Vb spectratype alterations indicate strong responses by a large repertoire of autoimmune T cells (B88)
Authors: zheng lingjie , sharma Rahul , deshmukh umesh s , Jarjour Wael N , Kung John , Fu Shu Man , Ju Shyr-te 
Published: January 2023

Abstract
B6.Cg-Foxp3sf/J mice, a B6 strain lacking functional Foxp3 transcription factor and CD4+CD25+Foxp3+ regulatory T (Treg) cells, spontaneously develop multi-organ autoimmune responses and die at 4 weeks old. We hypothesize that the autoimmune reactions in scurfy mice will change their TCR repertoire as compared with normal B6 mice. We observed no significant changes in their Vb family expression levels by staining with fluorescent anti-Vb mAbs. However, their Vb family spectratypes were remarkably different from that of B6 mice and from each other, whereas Vb spectratypes of individual B6 mice were highly similar to each other. Significant differences were found for all 20 Vb families examined. Significant spectratype changes in many Vb families were also observed in Treg cell-deficient IL-2 knockout (KO) and IL-2Ra KO mice. These data demonstrate that Treg cell-deficiency allows a strong polyclonal expansion of a large autoimmune T cell repertoire, resulting in massive changes in the TCR repertoire in many or all Vb families.
MERCURY-INDUCED ACCELERATION OF SPONTANEOUS AUTOIMMUNITY IN PRE-NEPHRITIC (NZBxSWR)F1 (SNF1) FEMALE MICE (B90)
Authors: Pilones Karsten A , Gavalchin Jerrie 
Published: January 2023

Abstract
Mercury exposure in susceptible mice has been known to induce autoimmunity, including the proliferation of autoantibodies, Th2-dominated antibody responses and immune complex disease. We investigated whether the immunostimulating effects of mercury can accelerate the induction of autoimmunity in SNF1 mice, a model that closely resembles human SLE nephritis. Previous studies from our laboratory have shown that dysregulation of the idiotypic network is key in the development of renal immune complex deposits in SNF1 females. In this study, six week-old pre-nephritic SNF1 females were exposed to 10 mg/L of either mercuric chloride or methylmercury in drinking water and examined for modulations in pathogenic immunophenotypes, autoantibody titers and clinical evidence of disease. We found increased populations of splenic T-cells and B-cells reactive with a pathogenic idiotypic determinant (IdLNF1) in mice exposed to mercury which, interestingly, also showed reductions in the percentage and absolute numbers of regulatory phenotypes (CD4+CD25+GITR+). Splenic lymphocytes from exposed mice showed increased proliferative responses to IdLNF1. LPS-induced proliferation was also increased in exposed mice, regardless of mercurial species used. We found modulations in serum antibody levels, including increased titers of anti-double stranded DNA autoantibodies. Clinically, mice exposed to mercury showed increased proteinuria and are currently being evaluated for glomerular damage and nephritis. The results of this study support the hypothesis that low-level exposure to metal xenobiotics such as mercury may trigger or accelerate autoimmune disease especially in a background of genetic susceptibility.
The role of PD-1/PD-L and B7/CD28 pathways in modulating anti-islet immune responses (B94)
Authors: Yadav Deepak , Hill Natasha , Yagita Hideo , Azuma Miyuki , Sarvetnick Nora 
Published: January 2023

Abstract
Costimulation via the PD-1/PD-L and B7/CD28 pathways modulates immune response towards self/non-self. We investigated whether the PD-1/PD-L pathway is impaired in autoimmune diabetes. Secondly, we hypothesized that B7-2 affects antigen presenting cell (APC) function. A progressive increase in the proportion of PD-1, B7-H1 and B7-DC positive T cells and APCs was observed in female non-obese diabetic (NOD) mice with age. However, NOD mice not only exhibited reduced availability of PD-1, B7-H1 and B7-DC signals as compared to non-diabetic C57BL/6 mice, but the capacity to induce B7-H1 expression was also reduced in NOD islets. In vivo blocking studies revealed that B7-H1 and B7-DC co-operate with B7-2 in augmenting priming and expansion of naïve anti-islet CD4 T cells. Lack of B7-2 significantly reduced the phagocytic ability and survival of dendritic cells. Interestingly B7-2 deficiency caused impaired PKC-epsilon response in APCs upon CD28-Ig stimulation. Thus, our data suggest that susceptibility to diabetes in NOD mice is associated with a defect in the availability of PD-1/PD-L mediated costimulation. On the other hand, B7-2 promotes APC function and survival.
D.Y. is recipient of JDRFI postdoctoral fellowship.
This work is supported by grants from NIH (# DK054063 and # AI51973) to N.S.
Mature B cells from healthy people which are permanently class switched to the IgD isotype are autoreactive (B95)
Authors: Koelsch Kristi A , Zheng Nai-Ying , Zhang Qingzhao , Duty Andrew , Abraham Leni A. , Helms Christina , Mathias Melissa D. , Jared Mathew , Smith Kenneth , Wilson Patrick C. 
Published: January 2023

Abstract
Determining the origin and fate of autoreactive B cells is critical to understanding and treating autoimmune diseases. We report that compared to antibodies from naïve and IgG memory B cells those from cells that have class switched to IgD via genetic recombination (Cδ-CS) are highly reactive with self-antigens, despite being derived from healthy people. Half of the antibodies from Cδ-CS B cells bind various autoantigens, and they are frequently polyreactive. Many also bind HEp-2 antigens. Intriguingly, some Cδ-CS B cells have accumulated residues in the variable regions that mediate anti-DNA reactivity via somatic hypermutation and selection, suggesting an immunological origin for anti-DNA antibodies in healthy people, while other Cδ-CS B cells are naturally autoreactive. We interpret these findings to indicate that autoreactive B cells can either be induced to class switch to IgD or autoreactive B cell clones that use IgD as the B cell receptor are not effectively deleted. Determining the mechanism by which the majority of Cδ-CS B cells are autoreactive may be important in understanding peripheral tolerance mechanisms and may provide insight to the enigmatic function of the secreted IgD antibody.
Physical forces can trigger T cell receptor signaling (35.10)
Authors: Roffler Steve R , Li Ya-Chen , Chen Bing-Mae , Wu Pei-Chun , Cheng Tian-Lu , Liao Yuan-Chun , Kao Lung-Sen , Tao Mi-Hua , Lieber Andre 
Published: January 2023

Abstract
Engagement of the T cell receptor (TCR) by antigenic peptides presented by the major histocompatibility complex (pMHC) activates specific T cells to control infections. The mechanism of TCR triggering, however, has remained obscure. Here, using micromanipulation of individual T cells, we show that physical forces acting on the TCR can induce calcium mobilization in a Lck-dependent manner. Investigation of artificial antigen-presenting cells (APCs) expressing engineered TCR ligands supports a model in which intercellular tension on the TCR generated during ligand engagement can initiate signaling in T cells. Furthermore, specific interactions between intercellular adhesion molecule-1 (ICAM-1) on APCs and the integrin LFA-1 on T cells may regulate tension to set the threshold for TCR triggering during ligand engagement.
Role of CD4 and CD8 coreceptors in the membrane proximal signaling and signal enhancement by self-peptide (35.15)
Authors: Artomov Maksym , Chakraborty Arup K 
Published: January 2023

Abstract
Current biophysical measurements of the coreceptor/MHC binding kinetics present a puzzle when trying to reconcile conventional understanding of coreceptor as a recruiter of the Lck to engaged TCR with the unusually low stability of MHC-coreceptor interaction (koff &gt;20 s-1). Moreover, the fast kinetics of MHC-coreceptor interactions is in direct contradictions with the assumptions of the currently available models of signal enhancement by non-cognate peptides when presented in mixture with small amounts of stimulating peptides. In our study we describe how competition between the diffusion of proteins in the membrane and their mutual interactions creates the spatial organization of membrane proteins (T-cell receptor, coreceptor, MHC protein) leading to successful signaling. Using spatially resolved computer simulations, we find, indeed, that fast kinetics of coreceptor-MHC interaction is of critical importance for the maintenance of the proper balance between diffusion and protein interactions.
The mechanisms unveiled in this study provide possible resolution to the important debate regarding the effect of coreceptor on the enhancement by self-peptides originated through the contradicting results obtained in CD4 and CD8 T-cells. We provide the signaling model explaining the difference in CD4 and CD8 T-cell in a single framework.
LFA-1 regulates CD8+ T cell activation through both TCR-mediated and LFA-1-mediated Erk1/2 signal pathways (35.16)
Authors: Ma Qing , Li Dan , Molldrem Jeffrey J 
Published: January 2023

Abstract
LFA-1 regulates T cell activation and signal transduction through the immunological synapse. TCR stimulation rapidly activates LFA-1, which provides unique LFA-1-dependent signals to promote T cell activation. However, the detailed molecular pathway and the precise mechanism by which LFA-1 contributes to TCR activation remain unclear. Herein, we report that LFA-1 directly participates in Erk1/2 signaling upon TCR stimulation in CD8+ T cells. The presence of LFA-1, not ligand binding, is required for the TCR-mediated Erk1/2 signal pathway. LFA-1-deficient CD8+ T cells have defects in sustained Erk1/2 signaling and TCR/CD3 clustering, which subsequently prevents MTOC re-orientation, cell-cycle progression and mitosis. LFA-1 regulates the TCR-mediated Erk1/2 signal pathway in the context of immunological synapse for recruitment and amplification of Erk1/2 signal. Furthermore, LFA-1 ligation with ICAM-1 generates an additional Erk1/2 signal, which synergizes with the existing TCR-mediated Erk1/2 signal to enhance T cell activation. The LFA-1-mediated Erk1/2 signal pathway is independent of ZAP-70 and PI3K but partially depends on Lck. Thus, LFA-1 contributes to CD8+ T cell activation through two distinct signal pathways. The function of LFA-1 is to enhance TCR signaling through the immunological synapse and deliver distinct signal in CD8+ T cell activation.
Cytolytic synapses control effectiveness of target cell destruction by CTL (35.17)
Authors: Sykulev Yuri , Beal Allison M , Anikeeva Nadia , Varma Rajat , Cameron Thomas O , Norris Philip , Dustin Michael L 
Published: January 2023

Abstract
We have investigated the stability of cytolytic synapses as well as patterns of cytolytic granule polarization and kinetics of their release by CTL with different potency to kill target cells. Less potent CTL form unstable cytolytic synapses, accounting for a third of the difference in potency providing the best evidence that stable synapse is important for cytotoxicity. To determine what other unknown mechanistic components may account for the distinct potency of target cell killing, we evaluated differences related to various pathways of granule delivery to the secretory domain of these CTL. Visualization of lytic granule delivery shows that the granules can take long or short paths to the secretory domain. The difference in path is dictated by the kinetics of early TCR signaling. Rapid and robust early signaling causes swift granule concentration near the MTOC and subsequent delivery directly to the secretory domain - the shortest and fastest path. Indolent signaling leads to late recruitment of the granules that move first to the periphery of the synapse and then move tangentially to fuse at the outer edge of the secretory domain - a longer path. The short pathway of granule delivery is associated with more efficient killing. Thus, rapid granule delivery to the secretory domain and containment of released granules within a stable synapse determines the potency of CTL to destroy target cells.