bluuebunny/crossref_metadata_2025_split huggingface dataset:
Autoantibodies targeting phosphatidylserine, cardiolipin, β2-glycoprotein I, annexin V and prothrombin in patients with recurrent spontaneous miscarriage (148.18)
Authors: Sater Mai , Almawi Wassim 
Published: January 2023

Abstract
An association between human reproductive failure and the presence of anti-phospholipid autoantibodies (APA) was suggested; both traditional and nontraditional APAs were associated with increased risk of recurrent spontaneous miscarriage (RSM). We measured levels of antibodies to phosphatidylserine (anti-PS), cardiolipin (ACA), β2-glycoprotein-I (anti-β2GPI), annexin V (anti-Anx V) and prothrombin (anti-PT) in 277 women with idiopathic RSM, and 288 control women by ELISA. Anti-PS IgG, ACA IgM/IgG, anti-Anx V IgM/IgG, and anti-PT IgM positivity were significantly associated with higher RSM risk, after controlling for age, BMI, menarche, and gravida. RSM was independently associated with high levels of ACA IgM (OR, 6.5; 95% CI, 2.5-17.1) and IgG (OR, 12.1; 95% CI, 6.6-22.2), anti-PS IgG (OR, 13.3; 95% CI, 6.4-27.4), anti-AnxV IgM (OR, 31.1; 95% CI, 15.7-56.6) and IgG (OR, 23.3; 95% CI, 8.8-51.7), and anti-PT IgM (OR, 2.8; 95% CI, 1.3-5.9). Levels of autoantibodies were categorized into 5 strata (percentiles 1-75, 76-99, 91-95, 96-99, &gt;99 among control patients) and analyzed in logistic regression models. The adjusted OR increased as the percentile value of ACA IgM/IgG ,anti-PS IgG and anti-Anx V IgM/IgG, and anti-PT IgM, increased. In conclusion, the presence of ACA IgM/IgG, anti-Anx IgM/IgG, anti-PS IgG, and anti-PT IgM antibodies are risk factors for RSM. The strongest association was seen for anti-Anx V IgM and IgG, followed by ACA IgG, and anti-PS IgG antibodies.
AMPK, a metabolic enzyme, negatively regulate EAE by modulating IL17 response (148.20)
Authors: Giri Shailendra , Mangalam Ashutosh , Rattan Ramandeep , Shridhar Viji , Rodriguez Moses 
Published: January 2023

Abstract
AMPK is an energy sensing metabolic switch in mammalian cells and regulates diverse metabolic pathway in cells. Recently, we observed that AMPK is lost in all immune cells of Experimental autoimmune encephalomyelitis (EAE), widely used animal model for MS. AMPK is lost at protein level in spleen macrophages, total T cells and their subsets (CD4, CD8 and regulatory T cells) isolated from EAE afflicted animals compared to control. To examine the role of AMPK, EAE was induced in Wt (+/+) and AMPKalpha1 null mice (-/-) and found that AMPKalpha1 (-/-) mice exhibited severe EAE disease. AMPKalpha2 is not involved in enhancing the severity of the disease. Moreover, AMPKalpha1 null mice significantly exhibited severe inflammation and demyelination in CNS. Loss of AMPKalpha1 leads to higher production of IL17 cytokine and reduced production of IFNgamma and IL4 under recall response with MOG35-55 as antigen. AMPKalpha1 KO mice exhibited higher number of infiltrated mononuclear cells in CNS and produced higher amount of IL17 significantly compared to Wt mice. Moreover, adoptive transfer of MOG35-55 specific T cells from AMPKalpha1 KO in Wt mice (KO to Wt) induced significantly higher degree of clinical disease compared to adoptive transfer of MOG specific T cells from Wt to Wt mice suggesting loss of AMPK negatively regulate clinical disease of EAE and identify AMPK as a novel therapeutic target for MS.
At-retinal differentially regulates Foxp3+ regulatory and IL-17+ pathogenic T cell in autoimmune arthritis (148.7)
Authors: Cho Mi-LA , Park Mi-Kyung , Oh Hye-Jwa , Park Eun-Mi , Lee Dong-Gun , Park Sung-Hwan 
Published: January 2023

Abstract
Retinoids can regulate immune responses. The aim of this study was to determine whether all-trans retinal (at-retinal) improves the inflammation responses and destruction of joints on collagen-induced arthritis (CIA). The arthritis score and incidence of arthritis were lower in the mice treated with at-retinal. Histopathologic evidence of joint damage was lower, and the infiltrations of immune cell were reduced in the mice treated with at-retinal. CII-stimulated proliferation of spleen cells, the expression of cytokines and oxidative stress proteins the serum levels of total IgG and IgG2a anti-CII antibodies, and the expression of osteoclast markers were significantly reduced in the mice treated with at-retinal. In vitro, at-retinal increased Foxp3 expression. At-retinal also inhibits inhibits Th17 development. The proportion of Foxp3+ Treg cells was increased in the spleen of mice treated with at-retinal, whereas the proportion of Th17 cells was reduced. In both mice and human culture system, TRAP positive mononuclear cells and multinucleated cells were significantly reduced in the presence of at-retinal. Taken together, these findings indicate that at-retinal has profound immunoregulatory functions and potential protective values for the treatment of autoimmune inflammatory disorders.
The CXCL13-CXCR5 axis contributes to atherosclerosis development in LDLr-/- mice by regulating myeloid development (149.1)
Authors: Daissormont Isabelle , Seijkens Tom , Halvorsen Bente , Hopken Uta , Lipp Martin , Aukrust Pal , Lutgens Esther , Biessen Erik 
Published: January 2023

Abstract
CXCL13 is a homeostatic chemokine instrumental in guided lymphocyte and dendritic cell trafficking towards lymphoid organs and stromal tissue. Evidence is culminating that in various chronic immune disorders extranodal CXCL13 expression at the site of inflammation contributes to the disease. Here we addressed the role of CXCL13 and its receptor CXCR5 in atherosclerosis. Bone marrow ablated LDLr-/- mice were repopulated with CXCL13 KO and CXCR5 KO bone marrow cells and after recovery fed a high-fat diet for 14 weeks. Carotid artery lesions were induced by perivascular collar placement. Both CXCL13 and CXCR5 deficiency resulted in significant attenuation of atherosclerosis, characterized by a decreased infiltration of granulocytes into the lesions. Haematopoietic deficiency of CXCR5 resulted in impaired homing of B cells and regulatory T cells towards peripheral lymph nodes. However, we didn’t observe this effect in the CXCL13 KO group. Surprisingly, FACS analysis showed a significant reduction in circulating CD11b+Ly6C+ pro-inflammatory monocytes and granulocytes both in the CXCR5 KO and CXCL13 KO group. In addition, plasma levels of M-CSF, G-CSF and RANK-L were strongly reduced. To conclude, haematopoietic deficiency of CXCL13/CXCR5 attenuates atherogenesis, probably attributable to the effects seen on Ly6Chighmonocyte and granulocyte levels in circulation. This study is the first to describe a critical role for the CXCL13/CXCR5 axis in myeloid development.
CCR4:CCL17 interaction supports clonal cell survival and complements BCR- and TLR-9- mediated cell proliferation in chronic lymphocytic leukemia (149.14)
Authors: Damle Rajendra , Temburni Sonal , Andersen Ryon , Kolitz Jonathan , Allen Steven , Rai Kanti , Chiorazzi Nicholas 
Published: January 2023

Abstract
Existence and degree of somatic mutation of expressed Ig V genes stratify CLL cases into unmutated (U-CLL) and mutated (M-CLL), clinically distinct subgroups. CLL cells likely receive survival cues via interactions through their BCR, TLR, and cytokine/chemokine receptors. We reported ex vivo expression of CCR4 and its induction on CLL cells stimulated in vitro. In assays of chemotactic behavior in response to CCL17, migrated cells showed significantly higher percentages and densities of CD38 expression than the non-migrated cells suggesting a role for CD38 (a known marker of CLL prognosis) in the CCR4-mediated downstream pathway. Dendritic cell-derived CCL17 may exert an accessory role in BCR- and TLR-9-mediated immune responses in B cells in peripheral organs. CCL17 augmented BCR-mediated B-cell proliferation in 9/16 (56%) U-CLL cases, and in 3/15 (20%) M-CLL cases, and promoted TLR-9-mediated cell proliferation in 13/15(87%) M-CLL cases and 6/16 U-CLL cases. In addition, CCL17 promoted cell survival and down-regulated pro-apoptotic molecules Bid and PUMA in 6/16 cases studied. These pro-survival effects of CCL17 were partially abrogated by the blocking anti-CCR4 mAb (1G1). Taken together, these findings suggest that CCL17 plays a role in modulating BCR- and TLR-9-mediated signaling and migration in CLL. Inhibition of CCR4:CCL17 interaction in vivo could represent a novel therapy by preventing migration of CLL cells towards an environment that promotes their survival.
Lipid phosphate phosphatase 3 maintains low thymic sphingosine-1-phosphate and enables efficient thymic egress (149.8)
Authors: Schwab Susan , Bréart Béatrice , Ramos-Pérez Willy , Mendoza Alejandra , Huang Yong , Adams Ralf , Escalante-Alcalde Diana 
Published: January 2023

Abstract
The signaling lipid sphingosine-1-phosphate (S1P) stabilizes the vasculature, directs lymphocyte circulation, and shapes inflammatory responses. However, little is known about how S1P distribution is controlled in vivo, and it is not clear how a ubiquitously made lipid functions as a signal that requires precise spatial and temporal control. Here we have found that lipid phosphate phosphatase 3 (LPP3) maintains low thymic S1P and efficient egress of mature T cells from the thymus into circulation. Although five additional S1P-degrading enzymes are expressed in the thymus, they cannot compensate for the loss of LPP3. Moreover, conditional deletion of LPP3 in either epithelial cells or endothelial cells is sufficient to increase thymic S1P. These results suggest that S1P generation and destruction are tightly regulated, and LPP3 is essential to establish the balance.
Additional loss of Bim rescues viral-specific effector and memory T cells, but not endogenous memory T cells or NK cells in IL-15-deficient mice (150.10)
Authors: Kurtulus Sema , Sholl Allyson , Hildeman David 
Published: January 2023

Abstract
IL-15 is γc cytokine well appreciated for its role in the homeostasis of memory CD8+ T cells and survival of NK cells. IL-15 drives homeostatic proliferation of memory phenotype (CD44hi CD122hi) and antigen specific memory CD8+ T cells. We and others have recently shown that IL-15 regulates survival of a subset of effector CD8+ T cells (KLRG1hi CD127lo) and acts redundantly with IL-7 for the survival of KLRG1lo CD127hi effector CD8+ T cells. Mechanistically, IL-15 is thought to maintain T cells by elevating Bcl-2 expression. Further, enforced expression of Bcl-2 can prevent the loss of effector CD8+ T cells in IL-15-deficient mice. Here, we examined whether deficiency of the pro-apoptotic BH3-only molecule Bim could prevent the loss of NK cells and memory CD8+ T cells in IL-15-deficient mice. We found that lack of Bim did not prevent the loss of NK cells and endogenous memory (CD44hi CD122hi) CD8+ T cells in the absence of infection. However, when we analyzed antigen-specific responses following infection with lymphocytic choriomeningitis virus (LCMV), we found that deletion of Bim partially rescued the survival of KLRG1hi CD127lo effector CD8+ T cells in the absence of IL-15. In addition, deletion of Bim completely rescued the loss of functional LCMV-specific memory CD8+ T cells. Our results indicate that IL-15 exerts its homeostatic effects through different mechanisms for the maintenance of endogenous memory phenotype and antigen-specific CD8+ T cells.
Inflammatory chemokine receptors regulate CD8 T cell contraction and memory generation following infection (150.3)
Authors: Kohlmeier Jacob , Reiley William , Perona-Wright Georgia , Freeman Michael , Eric Yager , Connor Lisa , Brincks Erik , Cookenham Tres , Roberts Alan , Burkum Claire , Winslow Gary , Blackman Marcia , Mohrs Markus , Woodland David 
Published: January 2023

Abstract
The development of T cell memory from naïve precursors is a complex process influenced by molecular cues received during T cell activation and differentiation. In the present study, we describe a novel role for the chemokine receptors CCR5 and CXCR3 in regulating effector CD8 T cell contraction and memory generation following influenza virus infection. Using mixed bone marrow chimeras, we find that Ccr5-/- Cxcr3-/- cells show markedly decreased contraction following viral clearance, leading to the establishment of massive numbers of memory CD8 T cells. Ccr5-/- Cxcr3-/- cells show preferential localization to the non-inflamed interstitial spaces of the infected lung, which coincides with reduced expression of the activation marker CD69 and the rapid appearance of CD127hi KLRG1lo memory precursor cells after viral clearance. Importantly, influenza-specific effector Ccr5-/- Cxcr3-/- CD8 T cells in the lung could be activated in vivo by the addition of exogenous antigen, which restored effector T cell contraction and significantly reduced memory T cell generation following viral clearance. Together, the data support a model of memory CD8 T cell generation where the chemokine-directed localization of T cells within infected tissues regulates antigen encounter and controls the extent of CD8 T cell activation and differentiation, which ultimately regulates effector versus memory cell-fate decisions.
The role of basophils in skin Th2 response using newly generated basophil-specific conditional depletion model (151.1)
Authors: Otsuka Atsushi , Kubo Masato , Miyachi Yoshiki , Kabashima Kenji 
Published: January 2023

Abstract
Basophils have been reported to promote Th2 skewing by antigen presentation in a certain condition without necessity of dendritic cells (DCs). On the other hand, recent studies also showed that DCs play a pivotal role of Th2 development. Therefore, it is controversial about the roles of basophils in induction of Th2-type immune responses. We have previously reported that HS4 region of IL-4 gene is essential for basophils. Taking advantage of this system, we have newly generated BaS TRECK transgenic (Tg) mice in which a diphtheria toxin (DT) receptor is knocked-in to the HS4 region to deplete basophils conditionally and specifically by injection of DT. We first evaluated the effect of basophils on repeated hapten application model as a representative of cutaneous Th2 skewing responses. Skin inflammation and serum IgE levels were significantly decreased by depletion of basophils. On the other hand, in ovalbumin patch induced-cutaneous Th2 skewing responses, skin reactions and the serum IgE level were not affected by basophil-deficiency.In addition, bone marrow derived-basophils induced IL-4 producing CD4+T cells only by OVA-peptide but not by OVA-proteins. Furthermore basophils did not uptake and process OVA-proteins. These data suggest that basophils elicited antigen presentation but did not uptake or process protein allergens themselves. Basophils seemed to induce Th2-type immune responses only to the exposure to haptens or protein peptides but not to protein allergens.
Stat5 is serine phosphorylated during IgE- and IgG-mediated mast cell activation (151.16)
Authors: Barnstein Brian , Falanga Yves , Ryan John 
Published: January 2023

Abstract
Stat5 ablation results in defective cytokine production as well as survival, supporting a critical role for this transcription factor in mast cell biology. We have reported the Stat5 tyrosine phosphorylation following IgE-mediated mast cell activation. We now find that Stat5 is also serine phosphorylated following activation by either IgE- or IgG-mediated signals. Both Stat5A and Stat5B were serine phosphorylated. The pathways leading to this event appear to differ based upon the initiating signal. While IgG-mediated activation appears to flow through the Fyn kinase and is strongly JNK-dependent, IgE-mediated Stat5 serine phosphorylation was Fyn-independent and showed a requirement for PI-3 kinase activation. These data demonstrate that Stat5 is activated by both tyrosine and serine modification through pathways that can be selectively regulated based on initiating signals.
T helper 9 cell development is dependent on the T cell maturation stage (152.13)
Authors: Ramming Andreas , Schulze-Koops Hendrik , Skapenko Alla 
Published: January 2023

Abstract
T helper 9 (Th9) cells, a novel CD4 T cell subset, seem to play a complex role in the outcome of specific immune responses. Whilst they may enhance a pro-inflammatory Th17 cell-driven immune response they are also able to prevent allograft rejection by intermediating T cell tolerance. Here, we have analyzed the Th9 cell differentiation requirements from human naive and memory CD4 T cells. Neonatal CD4 T cells required more stringent Th9 differentiation conditions when compared to adult CD4 T cells reflecting a different cytokine requirement for the expression of the Th9 cell master transcription factor PU.1. The requirements for Th9 cell differentiation weakened from neonatal through adult naive to memory T cells. Moreover, the phenotype of developing cells became gradually more heterogeneous even under stringent Th9-inducing conditions from neonatal through adult naive to memory CD4 T cells. Whereas neonatal CD4 T cells differentiated into “pure” Th9 cells producing exclusively IL-9, adult naive or memory CD4 T cells developed into effectors consisting of IL-9-producing cells as well as of cells capable of IL-4, IFN-γ, IL-5, or IL-17 co-production together with IL-9. The data suggest that the conditions for Th9 cell development and therefore for IL-9 production are continuously changing during life which may indicate a growing contributive role of IL-9 in specific immune responses with advancing age.
IL-27 mediated silencing of Foxp3 gene expression via enhanced DNA methylation (152.26)
Authors: Kim Gisen , Shinnakasu Ryo , Roh Sujin , Morris Venetia , Cheroutre Hilde , Kronenberg Mitchell 
Published: January 2023

Abstract
Foxp3 expression is regulated by multiple cytokine signals. While TGFβ and IL-2 are required for the induction and the maintenance of Foxp3 expression, others such as IL-4, IL-6 and IL-27 have been reported to inhibit Foxp3 induction. Despite the previous reports that demonstrated the indispensable role of the Stat3 signaling pathway for IL-6 and IL-27 mediated inhibition of Foxp3 expression, we have found that Stat3 was dispensable for the IL-27 mediated Foxp3 inhibition. Interestingly, while the IL-6 mediated inhibition was effectively reversed by retinoic acid (RA) in Stat3-/- T cells stimulated in the presence of TGFβ, RA failed to reverse IL-27 mediated Foxp3 inhibition. During Foxp3 induction, IL-27 significantly counteracted TGFβ-mediated acetylation of chromosomal histones in the Foxp3 regulatory elements, which was reversed by the addition of DNA methyltransferase inhibitor RG108. In addition to the increased expression of Dnmt1 and Dnmt3a, IL-27 potently enhanced the recruitment of at least Dnmt1 to the Foxp3 loci. Finally, the addition of inhibitors of DNA methyltransferase and histone deacetylases reversed the inhibitory effect by IL-27. These data indicate that IL-27 enhances DNA methylation and subsequent histone deacetylation in the Foxp3 loci, which results in silencing of Foxp3 gene expression. In addition, IL-27 may inhibit Foxp3 expression via a different mechanism from those mediated by IL-6.
B7-H1 (CD274) and sialoadhesin (CD169) on human dendritic cells induce IL-35 producing regulatory T cells (152.27)
Authors: Seyerl Maria , Kirchberger Stefanie , Majdic Otto , Seipelt Joachim , Jindra Christoph , Schrauf Catharina , Stöckl Johannes 
Published: January 2023

Abstract
IL-35 is a heterodimer of EBV-induced gene 3 and of the p35 subunit of IL-12, and was identified as an inhibitory cytokine produced by natural regulatory T cells in mice, but not in humans. Here we demonstrate that DC activated by human rhinoviruses (R-DC) induce IL-35 production and release, as well as a suppressor function in CD4+ and CD8+ T cells derived from human peripheral blood but not in naïve T cells from cord blood. The induction of IL-35-producing T cells by R-DC was FOXP3-independent. We observed that, when we blocked B7-H1 and sialoadhesin on the R-DC side with specific mAb against both receptors, the induction of IL-35 was prevented. Thus, the combinatorial signal delivered by R-DC to T cells via B7-H1 and sialoadhesin is crucial for the induction of human IL-35 producing regulatory T cells. These results demonstrate a novel pathway and its components for the induction of immune-inhibitory T cells.
The next step in the analysis of lymphocyte proliferation (152.7)
Authors: Langsdorf Chris , Bradford Jolene , Zhang Yu-Zhong 
Published: January 2023

Abstract
The mixed lymphocyte reaction (MLR), in which lymphocytes from two donors are combined and co-cultured, has significantly contributed to our understanding of immune function. Initially, the proliferation of responder cells was evaluated by measuring the uptake of radioactive 3H-thymidine. As technology improved, this method gave way to a technique measuring the incorporation of 5'-bromo-2'-deoxyuridine. Further advances led to assays for detection of incorporated 5'-ethynyl-2'-deoxyuridine and dye-dilution assays using carboxyfluorescein-diacetate succinimidyl ester (CFSE). Here we evaluate another advance in the measurement of lymphocyte proliferation kinetics using CFSE in combination with immunophenotyping and a novel fluorescent cell proliferation tracing dye. In the current study mononuclear cells were isolated from the peripheral blood of healthy human donors using a density gradient and labeled with CFSE or a novel violet cell proliferation dye. One-way MLRs were performed by inhibiting proliferation of antigen-presenting cells with Mitomycin-C. Two-way MLRs were also performed by co-culturing lymphocytes from allogeneic donors. The phenotype, viability, and proliferative index of stimulator and responder cells were evaluated using multicolor flow cytometry.
Effect of age related changes in the bone marrow stroma on B lymphopoiesis (153.19)
Authors: Bilwani Fareena , Knight Katherine 
Published: January 2023

Abstract
B lymphopoiesis arrests in rabbits by 16 wk-of-age, and we hypothesize that the arrest is due to age-related changes in the BM stroma. We determined the number of BM stromal cell progenitors (BMSCPs) using limiting dilution analysis and found a nearly 90% decrease in the number of BMSCPs by 6 wk-of-age. This decrease in BMSCPs is reflective of the age-related decline in proB and preB cell progenitors in BM. We tested the capability of BMSCPs to differentiate into adipocytes or osteoblasts in vitro, and found that BMSCPs from 4-8 wk-old rabbits displayed a propensity to form osteoblastic colonies while BMSCPs of rabbits over 8 wk-of-age readily formed adipocytic colonies. Histology of frozen BM tissue sections revealed trabecular bone in rabbits less than 8 wk-of-age. In contrast, BM from rabbits 8 wk-of- age or older showed large amounts of adipose tissue and almost no trabecular bone formation. Using a transwell co-culture system we found that adipocytes secrete a soluble factor that inhibits production of proB cells. We conclude that the decline in B lymphopoiesis of rabbits with age is due both to a decrease in the number of BMSCPs and also to the preferential differentiation of BMSCPs into adipocytes which in turn, secrete a molecule that inhibits B lymphopoiesis.