bluuebunny/crossref_metadata_2025_split huggingface dataset:
A distinct pattern of mRNA expression by monocytes is found in a subset of children with autism spectrum disorders (ASD) who present with recurrent infection, repeated loss of cognitive skills, and persistent gastrointestinal (GI) symptoms. (51.16)
Authors: Jyonouchi Harumi , Geng Lee , Streck Deanna , Toruner Gokce 
Published: January 2023

Abstract
A subset of ASD children (ASD Test Group) characterized by repeated loss of cognitive skills triggered by infection and frequent persistent GI symptoms were studied. We evaluated mRNA expression by peripheral blood (PB) monocytes in ASD test group (N=20, median 8 y) , ASD controls(N=22, median 7.6 y) , and normal control children (N=10, median 5.5 y) as well as the mothers of the ASD test (N=19) and ASD control (N=22) groups. We found that 568 genes were up-regulated and 72 genes were down-regulated (&gt;2 fold) in the ASD test group versus 469 up-regulated and 57 down-regulated in the control groups. Only the ASD control group displayed up-regulation of CCL7 and CCL2 and down-regulation of IL-6 and CD86. The ASD test group mothers revealed up-regulation of 175 genes including CCL7 and down-regulation of 57 genes as compared to the ASD control mothers. The ASD test group also revealed decreased spontaneous production of IL-6 and IL-1β by PB mononuclear cells compared to controls. The 16/20 ASD test group children with persistent GI symptoms revealed up-regulation of CCL7 (&gt;5 fold) and CCL2 and down-regulation of inflammatory mediators (IL-6, IL-23, IL-1α/IL-1β, CD86, and other chemokines) as compared to ASD and normal controls. Our results indicate a distinct pattern of mRNA expression in PB monocytes in the ASD subset with characteristic clinical features. Interestingly, CCL7 and CCL2 are up-regulated in the brain in various neurodegenerative disorders.
Epitope-specificity and effector function analysis of T and B cell response elicited by a novel single-cycle West Nile virus vaccine candidate (52.8)
Authors: Winkelmann Evandro , Xu Fangling , Nelson Michelle , Bourne Nigel , Mason Peter , Milligan Gregg 
Published: January 2023

Abstract
We have previously reported the development and characterization of RepliVAX WN, a single-cycle flavivirus (SCFV) vaccine to prevent West Nile disease. RepliVAX inoculation elicits a strong, protective immune response in mice, hamsters, and non-human primates; however, the magnitude, epitope specificity, and functionality of the WNV-specific T and B cell responses elicited by immunization have not been characterized. Here we have begun to determine the ability of RepliVAX to elicit polyfunctional WNV-specific T cells. Vigorous WNV-specific CD8+ cytolytic T cell responses were detected in vivo in RepliVAX immunized mice at day 4 and 6 post inoculation. In addition to CTL activity, our initial results detected populations of CD8+ effector T cells secreting IFN-γ and/or TNF-α. Future studies will analyze the epitope-specificity and effector functions of both WNV epitope-specific CD4+ and CD8+ T cells from RepliVAX immunized mice by simultaneous measurement of IFN-γ, TNF-α, and IL-2 production. Importantly, RepliVAX vaccination resulted in development of vigorous CD8+ memory T cell responses. High numbers of NS4B epitope-specific CD8+ memory T cells were detected in spleens of immune C57BL/6J mice 30 days after inoculation with RepliVAX. We have also developed methods to quantify WNV E and NS1 protein-specific antibody secreting cell responses by ELISPOT. Together, these studies should provide an in depth analysis of immune effector function elicited by RepliVAX immunization.
The influence of prolactin on the inflammatory component of lupus nephritis. (83.11)
Authors: Dugan Amy , Morel Laurence 
Published: January 2023

Abstract
A positive correlation between serum prolactin (PRL) and lupus disease activity such as IgG anti-DNA antibody deposition in the kidney has previously been shown. While the presence of immune complex deposition is required for the initiation of lupus nephritis (LN), renal MCP-1 expression and the subsequent infiltration and activation of macrophages ultimately results in inflammation and full-blown LN. The influence of PRL on the inflammatory component of LN has not been reported. Mice were 6-8 month-old males and were either C57Bl/6 wild-type (WT), C57Bl/6 PRL KO, or BcN (lupus strain). Renal proximal tubule cells were isolated and the PRL receptor expression was determined by RT-PCR and immunofluorescence microscopy. Renal proximal tubule cells from C57Bl/6 WT mice were stimulated with PRL and the amount of MCP-1 in the media was determined by ELISA. Cell surface expression and the mRNA expression of all 4 isoforms of the PRL receptor were comparable in the 3 genotypes. Proximal tubule cells produced significantly more MCP-1 when stimulated with 1000 ng/ml of PRL compared to 0 ng/ml (p&lt;0.01). Our results indicate that PRL has the potential to directly stimulate proximal tubule cell MCP-1 production/release. Whether lower doses of PRL would have a greater impact in the presence of immune complexes is unknown. Because the renal tubule cell isolation technique most likely removes immune complexes, an in vivo model of SLE to ascertain whether PRL .....
Delayed central tolerance of IGRP specific T cells is mediated by IGRP-expressing peripheral dendritic cells (83.28)
Authors: Krishnamurthy Balasubramanian , Fynch Stacey , Graham Kate , Thomas Helen , Santamaria Pere , Kay Thomas 
Published: January 2023

Abstract
Prevention of autoimmunity requires the elimination of self-reactive T cells during their development in the thymus and maturation in the periphery. Due to central and peripheral tolerance, transgenic NOD mice that overexpress islet specific glucose 6 phosphatase catalytic subunit related protein (IGRP) in antigen presenting cells, under the control of the class II MHC promoter, have no IGRP specific T cells. Peripheral tolerance of IGRP-specific T cells was mediated by both stromal cells and bone marrow derived APCs. However, central tolerance was mediated only by bone marrow-derived APCs. Moreover, central tolerance was age dependent, occurring only after 10 weeks and was not related to thymic involution, change in the absolute number of dendritic cells or the amount of IGRP expression. Age-dependent central tolerance was mediated by an increased proportion of thymus homing, signal regulatory protein alpha-positive CD8alpha negative dendritic cells. This provides in vivo data to indicate the potential feasibility of inducing central tolerance with DC therapy. They also raise the possibility that the efficiency of central tolerance might increase with age.
Intrinsic Interferon Signature in Dendritic Cells in lupus-prone mice. (83.9)
Authors: Gallucci Stefania , Bennett Heather , Shivers Debra , Ning Yue , Behrens Edward , Jog Neelakshi , Caricchio Roberto , Sriram Uma 
Published: January 2023

Abstract
Type I Interferons (IFNs) are pathogenic in Systemic Lupus Erythematosus. PBMCs from lupus patients over-express Type I IFN responsive genes. The cause and cellular source of this "Interferon Signature" are still unclear. Since we found that dendritic cells (DCs) from lupus-prone mice express the IFN Signature, we asked whether this IFN Signature was intrinsic to the DCs. We found that bone marrow-derived dendritic cells (BMDCs) from young pre-diseased Sle1,2,3 lupus-prone mice constitutively over-express Type I IFN responsive genes, analyzed by real-time RT-PCR (IFN-a, IFN-b, STAT1, STAT2, Mx1, IL-6, IL-15, IRF-7), as compared to autoimmune C57BL/6 BMDCs, as well as ELISA and flow cytometry. We also found that STAT1 is constitutively phosphorylated, suggesting an ongoing response to Type I IFN in the Sle1,2,3 DCs. Treatment with ligands for TLR7 and TLR9 showed that lupus BMDCs are hyper-sensitive to nucleic acids. To determine the mechanism of the constitutive hyper-activation of the IFN response in lupus DCs, we treated Sle1,2,3 BMDCs with inhibitors of TLR7 and TLR9 and found a partial role for chronic exposure to nucleic acids. We are now testing other mechanisms to explain the IFN Signature in lupus DCs. We have reported earlier that IL-4 suppresses Type I IFN responses in DCs of normal mice. We have now found that IL-4 inhibits the IFN Signature in Sle1,2,3 BMDCs, suggesting IL-4 as a potential therapeutic strategy for lupus by suppressing the Type I IFN effects.
Resident IL10-competent peritoneal B cells regulate colitis severity (84.18)
Authors: Maseda Damian , Smith Susan , Poe Jonathan , Tedder Thomas 
Published: January 2023

Abstract
B cells mediate multiple functions that influence immune and inflammatory responses. A rare subset of splenic CD1dhiCD5+ B cells has been found to modulate T cell responses, contact hypersensitivity and experimental autoimmune encephalitis by secreting IL10. However, equal numbers of B cells producing IL10 are found in the peritoneal cavity (PC). In this study, the phenotypic and functional characteristics of PC IL10-competent B cells were characterized. PC IL10-competent B cells share several phenotypic markers with their splenic IL10-competent counterparts, and were found within the B1a (47%), B1b (28%), and B2 (5%) subsets. Stimuli that promote in-vitro IL10 production differ between the spleen and PC populations, with PC B1 cells spontaneously producing IL10 without exogenous stimulation, while splenic B cell IL10 production is increased upon TLR stimulation. In a Rag-/- colitis model, the transfer of IL10-competent PC B cells dramatically reduced disease progression, reduced the number of activated and memory CD4+ T cells in the PC and total CD8+ T cells in the mesenteric lymph nodes. Together, these data reveal that IL-10 competent B cells in the peritoneal cavity significantly modulate T cell pathogenicity.
TCR and Fas-mediated apoptosis targets Effector Memory T cells (85.14)
Authors: Ramaswamy Madhu , Cruz Anthony , Price Susan , Rao V Koneti , Siegel Richard 
Published: January 2023

Abstract
The death receptor Fas plays an essential role in TCR-induced apoptosis of activated CD4+ T cells, in a process termed restimulation-induced cell death (RICD). However, within a heterogeneous population of human CD4+ T cells, we have found that cells with an effector memory phenotype (CCR7-CD27-) are specifically programmed for sensitivity to Fas-induced apoptosis and RICD. Similary, mouse effector memory T cells (CD44hiCD62Llo) are the most sensitive to cells are very sensitive to RICD and direct killing by Fas receptor ligation. Fas resistant ‘central memory’ as well as Fas-sensitive ‘effector’ cells had similar levels of induced FasL, surface Fas, as well as pro-survival Bcl2/BCLxL levels. In ALPS patients with Fas mutations, resistance to Fas apoptosis was found predominantly in the effector memory subsets. Biochemical studies show a preponderance of lipid raft localized Fas and highly efficient formation of the death-inducing signaling complex (DISC) in memory and effector T cells. Thus sensitivity to TCR and Fas-mediated apoptoisis is mediated at the level of early signaling events in the Fas pathway. These observations may explain the specificity of the Fas/FasL system in T cell homeostasis toward chronically expressed and endogenous antigens to check autoreactivity and responses to chronic infections.
A programmed gene expression initiated by clearance of infection turns CD4 memory T cells dormant (85.18)
Authors: Sadegh-Nasseri Scheherazade , Khoruzhenko Stanislav , Dalai Sarat 
Published: January 2023

Abstract
Memory T cells survive throughout the lifetime of an individual and are protective upon recall. We have demonstrated that low levels of antigen present at the resolution of infection and upon presentation by B cells induce a state of unresponsiveness in specific CD4+ memory T cells. We have shown that this process occurs naturally during the fall of antigen. The quiescent memory T cells become activated by stimulatory signals generated by a subsequent infection. Here we show that the quiescent memory T cells survive for over a year in the absence of homeostatic proliferation. Microarray gene expression assay of long-term memory CD4 T cells revealed downregulation of proliferation, immune activation and apoptosis prevention genes in unresponsive memory CD4 T cells, compared to the responsive group. Upregulated genes in quiescent memory T cells appear to work synergistically with the downregulated genes in that group. Data from these experiments suggest that memory CD4 T cells survive in the absence of antigen for extended period of time by becoming quiescent naturally as the infection fades and resume their activity once they encounter antigen simultaneously with danger signal, providing quick and efficient immune response.
Age-associated alteration in naive and memory Th17 cell response in humans (85.8)
Authors: Lee Jin Soo , Lee Won-Woo , Kim Sang-Hyun , Kang Seong Wook , Kang Insoo 
Published: January 2023

Abstract
Th17 cells play an important role in clearing extracellular microorganisms and developing autoimmune diseases. T cell immunity changes with aging, likely contributing to the increased risk of infection and malignancy in elderly people. However, it is not known whether aging affects Th17 cell response in humans. Thus, we investigated this issue. The healthy elderly (age ≥ 65) had a decreased frequency of IL-17-producing CD4+ T cells in peripheral blood after 4 hour PMA/ionomycin stimulation compared to the healthy young (age ≤ 40). In contrast, the frequency of IFN-γ-producing CD4+ T cells was not different between the two groups. We next purified naive and memory CD4+ T cell subsets from the peripheral blood of both groups and stimulated them for 7 days with T cell receptor triggering in the presence or absence of Th17-polarizing cytokines. The frequency of IL-17-producing cells in the memory subset was still lower in the elderly than in the young. However, the frequency of naive CD4+ T cells producing IL-17 was higher in the elderly than in the young. ELISA measuring IL-17 and IFN-γ levels in tissue culture supernatants showed similar results. These findings indicate that the elderly have a defect in maintaining Th17 memory cells but not in differentiating these cells from naive CD4+ T cells. Such a defect could potentially contribute to the increased risk of infection with aging.
Circadian clock gene expression in bone marrow derived mast cells and effects on FcϵRI expression (86.12)
Authors: Wang Xiaojia , Van Scott Michael , Brown Jared 
Published: January 2023

Abstract
Many functions in the immune system are associated with time-of-day. For instance, blood histamine levels in mastocytosis patients display a diurnal variation. In addition, pulmonary function and inflammation in patients with nocturnal asthma is more severe during the night. However, it is largely unknown if local circadian clocks in immune cells directly control physiological outcomes. We hypothesized that a circadian clock in murine bone marrow derived mast cells (BMMCs) modulates their activation in vitro. Mature BMMCs were synchronized with serum rich media (50% horse serum). Total RNA was harvested at 4 hour intervals for 72 hours following synchronization and expression of circadian genes (mPer1, mPer2, Bmal1, Rev-erbα, and Dbp) and fcer1a were amplified by qPCR. The surface expression of FcϵRIα was analyzed by flow cytometry every 4 hours for 72 hours following synchronization. Serum shock induced rhythmic expression of circadian genes (mPer2, Bmal1, Rev-erbα, and Dbp) with a mean period of 25.9 hours in BMMCs. The expression of fcer1a gene and FcϵRIα protein displayed expression changes following serum shock with mean periods of 26.3 and 28.6 hours respectively as calculated by Single Cosinor Time Series Analysis. These findings demonstrate that BMMCs express circadian clock genes and FcϵRI expression is modulated by synchronization with serum rich media. Serum shock of BMMCs may provide an in vitro model to study the circadian biology of allergic disease.
CCR3-mediated degranulation and eosinophil-associated RNases secretion from murine eosinophils; capacity of intact cells and free granules (86.21)
Authors: Shamri Revital , Melo Rossana , Weller Peter 
Published: January 2023

Abstract
Piecemeal degranulation (PMD), in which intact eosinophils completely or partially empty granules and selectively secrete performed mediators, is the principal mechanism for human eosinophil degranulation. Unlike extensively studied human eosinophils, both the capacity and mechanisms underlying eosinophil degranulation responses of murine eosinophils have been poorly investigated and remain controversial. We applied a new methodology to detect degranulation by measuring secretion of eosinophil-associated RNases (mEARs) and found that murine eosinophils “degranulated” following stimulation with CCL11 and CCL24, as detected by an increase in RNase A and EPO activities in cell supernatants. TEM revealed signs of PMD including significant increase in the number of emptying granules. CCL11 and CCL24-mediated mouse eosinophil degranulation was Gαi and PI3K-dependent. Moreover, intact beta 1 and 2 integrins as well as dynamic cytoskeleton are required for this PMD. Unexpectedly, we found that inhibition of Rho-GTPase kinase increases PMD. Moreover, cell-free granules purified from mouse eosinophils were found to express functional CCR3 and secreted mEARs as well as EPO in response to CCL11, suggesting a unique mechanism of degranulation in cell-free context. Collectively, these data demonstrate that murine eosinophils undergo PMD in response to physiological stimulation with CCL11 and CCL24, findings that are pertinent to murine models of eosinophil-associated diseases.
Phenotypic features and differentiation of human interleukin 9-producing CD8+ T cells (86.25)
Authors: Wang Shengjun , Yang Xianzhi , Shi Ye , Tong Jia , Su Zhaoliang , Tian Jie , Liu Qingling , Liu Yan , Lu Liwei , Xu Huaxi 
Published: January 2023

Abstract
Cross-talk between TGF-β and IL-4 can direct the differentiation of CD4+ T cells into interleukin 9-producing cells, which are termed Th9 cells. In this study, we show that CD8+ T cells also express IL-9. TGF-β and IL-4 could stimulate CD8+ T cells to differentiate into IL-9 producing cells in plate bound-anti-CD3 mAb (pbCD3) activated peripheral blood mononuclear cells (PBMCs). Soluble-anti-CD28 mAb (sCD28) decreased the expression of IL-9 which induced by IL-4 and TGF-β with pbCD3. Interleukin 9-producing CD8+ T cells display greatly suppressed cytotoxic function and low expression IFN-γ. The mRNA of Th1/Tc1 transcription factors T-bet is decreased in CD8+ cells from IL-4 and TGF-β with pbCD3 activated PBMCs. However, the expression of Th2/Tc2 transcription factors GATA3 is increased in human IL-9+ CD8+ T cells. Additionally, the proportion of IL-9 producing CD8+ T cells was higher in the allergic rhinitis as compared with the health controls. Taken together these data show that the existence of a human IL-9 producing CD8+ subset and can be categorized as a T cytotoxic 9 (Tc9) subset.
Sepsis-induced immunosuppression is mediated by TRAIL-expressing CD8+ regulatory T cells (87.13)
Authors: Griffith Thomas , Unsinger Jacqueline , Kazama Hirotaka , McDonough Jacqueline , Hotchkiss Richard , Ferguson Thomas 
Published: January 2023

Abstract
Patients who survive severe sepsis often display severely compromised immune function. One hallmark of such immune suppression in septic patients is an impaired delayed-type hypersensitivity (DTH) response, manifested by a loss of skin testing to recall antigens. Since sepsis induces significant apoptosis in lymphoid and myeloid cells and apoptotic cells are themselves tolerogenic, we tested the hypothesis that suppression of DTH is mediated by tolerogenic properties of the apoptotic cells generated during sepsis. Mice subjected to cecal ligation and puncture (CLP) demonstrated a loss of DTH for the 7 days following CLP; however, the immune response returned to normal by day 10. Blocking sepsis-induced apoptosis via Bcl-2 overexpression or Bim deficiency prevented the loss of DTH. Importantly, injection of apoptotic cells into Bim-/- mice prevented an effective DTH response, thereby suggesting a causal link between apoptotic cells and immune suppression. Surprisingly, when Trail-/- mice were examined, we found that these animals had significant apoptosis but retained their DTH responses. Further studies revealed that apoptotic cells generated during sepsis induced a CD8+ regulatory T cell (Treg) that mediated suppressed DTH by TRAIL production. These results establish a link between apoptotic cells and immune suppression during sepsis, and suggest TRAIL may be a viable therapeutic target for boosting the adaptive immune response following sepsis.
Oxidized phospholopids induce a tolerogenic response that is protective in a Streptozotocin-induced model of type 1 diabetes (T1D) (87.19)
Authors: Sharma Rahul , Sharma Poonam , Du Zhongmin , Leitinger Norbert 
Published: January 2023

Abstract
Oxidized phospholipids (OxPL) derived from oxidized lipoproteins or from membranes of apoptotic cells accumulate in damaged tissue. We hypothesized that OxPL generated during apoptosis may protect from inflammation through inducing a tolerogenic response. Our data shows that i.v. injection of C57BL/6 (B6) mice with OxPAPC (oxidation product of the membrane phospholipid 1-palmitoyl-2-arachidonoyl-sn-3-glycero-phosphoryl-choline) results in a reduced proportion of the CD11b-Hi CD11c+ dendritic cells (DC) in the spleen with much lower expression of MHC II and co-stimulatory molecules CD80 and CD86 as compared to saline injected controls. Furthermore, the number of CD4+Foxp3+ regulatory T cells (Tregs) was significantly higher in the spleens of mice treated with OxPAPC. Mechanistically, both the splenic CD11c+ DC purified from OxPAPC-treated mice and the OxPAPC-treated bone marrow-derived DC induced a more potent in vitro differentiation of naïve T cells to inducible Tregs as compared to the untreated controls. In a multiple low dose streptozotocin (MLD-STZ)-induced model of T1D, the B6 mice pre-treated with OxPAPC had a higher proportion of Tregs and were protected against MLD-STZ induced hyperglycemia as compared to saline injected controls. The data suggests that OxPAPC has therapeutic potential for treatment of T1D and other autoimmune diseases by inducing a DC-mediated increase of Treg differentiation.
Resistance training and aerobic exercise alters immune function (87.25)
Authors: Kumaraguru Uday , Nandakumar Subhadra , Chi David , Stone Michael , Krishnaswamy Guha 
Published: January 2023

Abstract
Exercise affects various components of the immune system that could be clinically beneficial or deleterious. Accordingly, moderate exercise stimulates the immune system, while intense exercise suppresses certain immune cell activities. Some of the immune-regulation observed may be due to the regulatory T cells. This could also explain the difference between moderate and strenuous exercisers and the probable reason for lower incidence of autoimmunity in active individuals. Intense exercisers (Trained -regular) and Moderate exercisers (untrained- occasional) were recruited as volunteers from of our university community after IRB approval. Blood samples were collected. PBMCs were used for immune cell profile analysis and the plasma was used for cytokine estimation. Results suggest recruitment of all lymphocyte subpopulations to the vascular compartment: CD4, CD8, B, and Natural killer (NK) cells. Depending on intensity of exercise, the CD4-to-CD8 ratio decreased, reflecting the greater increase in CD8s than CD4s. Both memory and naive phenotype were found, while memory type prevailed. The number of Tregs was increased in all subjects and inversely correlated with IL-6 concentration. Resistant training associated initiation of inflammatory cytokine suggest metabolic link between skeletal muscles and the lymphoid system. It is therefore to be expected that moderate exercise protects against malignancy or infection whereas exhaustive exercise is linked to increased pathology.