bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phytohaemagglutinin plus anti-CD28 induce conversion of CD4+CD25- T cells into CD4+CD25+ regulatory T cells (47.17)
Authors: cao mengde , Cabrera Roniel , Xu Yiling , Liu Chen , Nelson David 
Published: January 2023

Abstract
CD4+CD25+ regulatory T cells (Tregs) play a key role in establishing and maintaining immune tolerance via their suppressive activities. The functional analysis, isolation methods, and clinical application of Tregs is impeded by their scarcity in peripheral blood. Large scale in vitro generation of Tregs with stable suppressive property represents an attractive strategy to set up cellular therapies that could prevent and cure T cells-mediated disorders. In this study, we present a novel in vitro approach to generate a large number of inducible Tregs from the conversion of conventional CD4+CD25- T cells by means of PHA and anti-CD28 mAb. The protocol described herein does not involve feeder cells, beads or other cellular compounds that would interfere with in vivo use. These CD4+CD25- - derived inducible Tregs not only have the similar phenotypes of natural Tregs, but also exhibit stronger suppression on in vitro CD4+CD25- T cell activation and proliferation in cell-to-cell contact way. Moreover, due to the limited number of naturally occurring Tregs in the peripheral CD4+ T cell compartment, our strategy might provide a novel basis for convenient therapeutic approaches designed to generate Tregs to known antigens in autoimmune diseases or graft-versus-host reactions for use as targeted immunotherapy. To date, this is the most efficient and reliable protocol for generating large numbers of suppressive CD4+ Tregs. These quickly induced in vitro Tregs can be used for further biological study and developed for antigen-specific cellular immunotherapy.
Involvement of SOCS Proteins in the Inhibitory Effect of IL-27 on Th17 Development (47.21)
Authors: Qin Hongwei , Reynolds Stephanie L. , Cong Yingzi , Elson Charles O. , Benveniste Etty N. 
Published: January 2023

Abstract
Suppressor Of Cytokine Signaling (SOCS) proteins are critical feedback inhibitors of the JAK/STAT signaling pathway and have neuroprotective effects. Recently, several reports have shown that the cytokine IL-27 functions as an inhibitory regulator, and represses the development of Th17 cells associated with autoimmune brain inflammation. Stimulation with IL-27 results in the activation of members of the STAT family, predominantly STAT-1 and STAT-3. In this study, we describe that IL-27 induces SOCS-1 and SOCS-3 gene expression, which is correlated with IL-27 induced STAT-1α and STAT-3 activation in anti-CD3 and anti-CD28 activated CD4+ T cells. Furthermore, we demonstrate that IL-27 induction of SOCS-1 and SOCS-3 gene expression in CD4+ T cells occurs at the transcriptional level as assessed by promoter assays. IL-27-induced SOCS-1 and SOCS-3 expression in CD4+ T cells from WT and STAT-1 deficient mice indicate that induction of SOCS-1 occurs in a STAT-1 dependent manner, and SOCS-3 induction partially depends on STAT-1. The inhibitory effects of IL-27 on Th17 development in CD4+ T cells with specific SOCS-3 deficiency and/or SOCS-1 knockdown will be investigated in the near future. These results indicate that IL-27 induces SOCS-1 and SOCS-3 expression in CD4+ T cells by activation of STAT-1α and/or STAT-3. We propose that SOCS-1 and SOCS-3 may participate in IL-27-mediated suppression of Th17 cell production and autoimmune brain inflammation.
SATB1 regulates expression of multiple genes involved in human T helper cell differentiation (47.23)
Authors: Ahlfors Helena , Limaye Amita , Tuomela Soile , Rasool Omid , Galande Sanjeev , Lahesmaa Riitta 
Published: January 2023

Abstract
Naïve CD4+ Th progenitors (Thp) differentiate to functionally distinct effector T cell subsets including Th1, Th2 and Th17 cells which while being responsible for specific immune functions have also been implicated in pathological responses, such as autoimmunity, asthma and allergy. Special AT-rich binding protein 1 (SATB1) is a global chromatin organizer and a transcription factor induced by interleukin-4 (IL-4) during the early T helper 2 (Th2) cell differentiation. Having established that this upregulation of SATB1 is mediated by STAT6 transcription factor, we became interested in identifying SATB1 target genes to understand its role in human Th cell differentiation. Our results from genome wide transcriptomics analysis after SATB1 knockdown and ChIP-chip studies indicate that SATB1 regulates multiple genes important for Th cell polarization or function. Moreover, several genes are regulated by SATB1 in a Th cell subset specific fashion. Candidate genes of interest have been selected for further studies. The integration of these multiple datasets is in progress and aims at providing a basis for understanding SATB1 regulatory network during the early stages of human Th cell differentiation. This study was supported by grants from the Academy of Finland, the Sigrid Juselius Foundation and Turku University Hospital Fund.
Correlating the phenotype of in vitro-polarized Th17 cells with expression of IL-17A and IL-17F (47.6)
Authors: Schifano Matthew , Konrad Mark A. P. , Li Gangzhou , Araji Soha , Ruiz Natalie , Just Peggy 
Published: January 2023

Abstract
The T-helper 17 (Th17) lineage has surfaced as a topic of great interest in the fields of inflammation and autoimmunity. The secretion of interleukin (IL)-17A and IL-17F has implicated these cells in many autoimmune diseases including rheumatoid arthritis, Crohn's disease, asthma and multiple sclerosis. IL-17A and IL-17F have been shown to form both homodimers and heterodimeric complexes. Characterization of the expression of these Th17 effector molecules together with surface proteins such as CCR6, CD161 and RORγt will be useful for studying further the role of Th17 cells in human disease. In this study, in vitro-polarized Th17 cells were analyzed for surface expression, secretion or intracellular expression of Th17-related proteins. Using an ELISA with minimal cross-reactivity to IL-17A/A and IL-17F/F, IL-17A/F was found to be a major product of in vitro-polarized Th17 cells. Furthermore, IL-17A/A expression was less than or equal to IL-17A/F, while IL-17F/F expression was consistently lower than IL-17A/A or IL-17A/F.
Cytokine-neuroantigen fusion proteins represent a novel therapeutic approach for EAE (48.10)
Authors: Mannie Mark D. , Abbott Derek J. , Blanchfield Lori 
Published: January 2023

Abstract
Cytokine-neuroantigen (NAg) fusion proteins have promise as a new class of antigen-specific therapies for treatment of CNS autoimmune disease. The primary objective of this study was to assess therapeutic efficacy of selected cytokine-neuroantigen fusion proteins in the Lewis rat model of EAE. The neuroantigen domain of each fusion protein was comprised of the major encephalitogenic determinant of myelin basic protein. Three cytokine-NAg fusion proteins were potent inhibitors of EAE. These fusion proteins incorporated the IL-2 cytokine as the N-terminal domain (the IL2NAg fusion protein), the secreted IL-16 cytokine as the C-terminal domain (the NAgIL16 fusion protein), or the IFN-beta cytokine as the N-terminal domain (IFNbeta-NAg fusion protein). Compared to NAg alone, these fusion proteins strongly attenuated the subsequent active induction of EAE. These fusion proteins also inhibited EAE when administered after encephalitogenic challenge during onset of EAE. In conclusion, cytokine-NAg fusion proteins that incorporate IL-2, IL-16, or IFN-beta cytokine domains may comprise an effective tolerogenic therapy for CNS autoimmune disease.
Critical regulation of early Th17 cell differentiation by IL-1 signaling (48.24)
Authors: Chung Yeonseok , Chang Seon Hee , Martinez Gustavo J , Yang Xuexian O , Nurieva Roza , Kang Hong Soon , Watowich Stephanie S , Jetten Anton , Dong Chen 
Published: January 2023

Abstract
Th17 cells have been recently discovered in both mouse and human. Although IL-1 has been shown to be important in human Th17 cell differentiation with little knowledge of the underlying mechanism, its function in mouse is less clear. Here we show that IL-1R1 expression in T cells, which was induced by IL-6, was necessary for Th17-mediated autoimmunity and for early Th17 differentiation in vivo. Moreover, IL-1 signaling in T cells was required in dendritic cell-mediated Th17 differentiation from naïve or regulatory precursors and IL-1 synergized with IL-6 and IL-23 to regulate Th17 differentiation and maintain cytokine expression in effector Th17 cells. Importantly, IL-1 regulated the expression of IRF4 and RORγt during Th17 differentiation; over-expression of these two factors resulted in IL-1-independent Th17 polarization. Our data thus indicate a critical role of IL-1 in Th17 differentiation and this pathway may serve as a novel target for Th17-mediated immunopathology.
The work is supported by research grants from NIH (to CD), an Intramural Research Program of the NIEHS, NIH (to AMJ), Leukemia and Lymphoma Society (to CD) and MD Anderson Cancer Center (to CD and SSW) and the Gillson Longenbaugh Foundation (to SSW). RN is a recipient of a Scientist Development Grant from the American Heart Association. CD is a Trust Fellow of the MD Anderson Cancer Center, a Cancer Research Institute Investigator, a Leukemia and Lymphoma Society Scholar and an American Lung Association Career Investigator.
Physical and Chemical stress induce Changes in the Expression of Ro60, p53, PCNA, Fas-L, Fas-R, Caspase 8, Caspase 3 in skin of Newborn Balb/c mice (48.27)
Authors: Sanchez Rodriguez Sergio  Hugo , Macías-Pérez1 Martha Edith , Reveles Espinoza Alicia Maria , Aguilera Galaviz Luís Alejandro , López-Luna Maria Argelia 
Published: January 2023

Abstract
Systemic Lupus Erythematosus is an autoimmune disease, whose skin lesions are exacerbated by environmental stressors such a UV light and heat. These physical factors modified the expression and localization of Ro60 protein and the homeostasis in the cell cycle. Objective: To better understand the molecular expression profile of Ro60, p53 and PCNA expression, and the possible activation of apoptosis through the Fas-L, FasR, caspase 8, and caspase 3 pathway, we developed an animal model under physical and chemical stress. Methods: Balb/c mice were exposed to UV radiation, heat, HgCl2, H2O2, ethanol, camptothecine and cicloheximide, in absence or presence of caspase 3 inhibitors. Afterwards, a skin extract was made it, proteins were characterized by SDS-PAGE and Western blot, and p53, PCNA, FasL, FasR, caspase 8, and caspase 3 were immunodetected by ECL and densytometric analysis. Results: The Ro60 expression is modified under the influence of physical and chemical stressors, also it is increased mainly with UV light and heat in sharp contrast decreased with caspase 3 inhibitor. It was observed that p53 expression is increased by all the stressors except UV light, using the caspase 3 inhibitor the expression is abolished. In other hand PCNA, is down regulated under the influence of all the stressors but is considerable expressed with caspase 3 inhibitor. The induction of apoptotic pathway using stressors, was monitoring by changes of proteins like FasL, FasR, caspase 8, caspase 3, it was observed an increased levels of this proteins with HgCl2, camptothecine and cicloheximide, however in presence of caspase 3 the expression was decreased.
Chlorpromazine, procainamide and hydralazine produced a murine autoimmune disease resembling human lupus (48.31)
Authors: Wong-Baeza Carlos , España Luis , Tescucano Alonso , Wong Ramírez Carlos , Baeza Isabel 
Published: January 2023

Abstract
Chlorpromazine, procainamide and hydralazine have indeed been implicated in producing a human lupus-like disorder. These drugs induce the formation of a phospholipid arrangement different to the lipid bilayer called non-bilayer phospholipid arrangement (NPA). Since these drugs form NPA in liposomes and cultured cells, it is possible that these drugs can stabilize NPA structures in cell membranes producing an abnormal NPA exposure, perhaps facilitating the subsequent production of specific antibodies. To evaluate this potential role of NPA inductors, the drugs alone or drug-induced NPA were administered to BALB/c mice. We observed that 30-45% of mice treated with NPA inductors and 55-60% treated with drug-induced NPA, produced anti-NPA antibodies. These antibodies appeared 4 weeks prior to anti-cardiolipin, anticoagulant, anti-histone and anti-nuclear antibodies. Mice presented some areas of the face with alopecia, the histopathology of these areas showed similar changes to those found in human lupus skin lesions. Dense inflammatory infiltrate in dermis with deposition of immune complexes in dermal-epidermal junction and also along the basement membrane of glomerular capillaries were observed. This model of lupus might contribute to a better understanding of the immunological basis of human lupus and probably toward the development of better human therapeutic strategies.
IRF5 Genetic Risk Haplotype Influences Host B Cell Gene Responses to Epstein-Barr Virus (EBV) (49.14)
Authors: Templeton Amanda K , Dominguez N , Lu R , Vidal G , Levin J , Sestak A , Kelly J , Kaufman K , Bruner G , Gaffney P , Harley J , James J , Guthridge J , Poole B 
Published: January 2023

Abstract
Both gene and environment interactions play keyroles in the development of systemic lupus erythematosus (SLE). We examined effects of the IRF5 lupus risk haplotype upon the host's B cell response to the binding or infection with EBV, a suspected environmental trigger for SLE. Whole genome microarray expression profile data was collected from cells exposed to EBV for 16 hours. Analysis of gene expression by gene set enrichment analysis revealed that key differences in expression between SLE patients and controls (or individuals carrying the IRF5 risk and non-risk haplotype) were in a subset of interferon response genes. Patients with the IRF5 risk haplotype have a heightened interferon signature under all experimental conditions; whereas, the patients with the IRF5 protective haplotype have a B cell interferon signature similar to that of unrelated, matched controls. Overexpression of interferon pathway genes in B cells following viral exposure in control individuals carrying the IRF5 risk haplotype suggests that the IRF5 risk alleles alone can modulate ones biological response to the environmental insult. Patients carrying either the IRF5 risk or non-risk alleles appear to already be predisposed to having a higher interferon signature even without exposure to virus, suggesting that other genetic factors are also influencing the interferon response, independent of virus. Support by NIH (AI007633 and AI31584).
The Sle2c1 murine susceptibility locus controls T cell homeostasis through defective IL-2 production (49.15)
Authors: Xu Zhiwei , Morel Laurence 
Published: January 2023

Abstract
The function of the Sle2 mouse lupus susceptibility locus and its derived Sle2c1sublocus have been previously shown to be associated with a lower threshold of activation of the BCR leading to an accumulation of B1a cells in NZM2410 model. To explore whether these loci had any effects on other immune components, we introduced lpr as an amplifier into B6.Sle2 and its subcongenic strains, and analyzed systemically their cellular and functional phenotypes. Consequently it was found that the co-expression of Sle2 and lpr on a C57BL/6 background significantly increased lymphadenopathy primarily targeting T cells, as well as induced renal pathology which included heavy lymphoid infiltrates. Comparison of the 3 Sle2 subloci mapped the synergistic interaction with lpr to Sle2c. Further examination of both Fas-deficient and Fas-intact mice showed that Sle2c1 resulted in increased T cell proliferation, a reduced IL-2 production, and a reduced Foxp3+ regulatory T cell compartment in spleen and lymph nodes, phenotypes which are characteristic of lupus in human patients and mouse models. Our results demonstrate that the Sle2c1 locus contains a candidate gene which, in addition to regulate BRC activation threshold, also affects T cells homeostasis through altering IL-2 production and Treg cell balance.
PTPN22 deficiency cooperates with the CD45 E613R wedge allele to break tolerance on a non-autoimmune background (49.18)
Authors: Zikherman Julie , Hermiston Michelle , Steiner David , Hasegawa Kiminori , Chan Andrew 
Published: January 2023

Abstract
Pep and CD45 are tyrosine phosphatases whose targets include the Src-family kinases, critical mediators of antigen receptor signaling. A polymorphism in PTPN22, the gene that encodes the human Pep ortholog Lyp, confers susceptibility to multiple human autoimmune diseases. However, the significance of the R620W risk allele is not clear. We report that misexpression of wild type or R620W Lyp/Pep in Jurkat cells, in the context of their binding partner Csk, unmasks the risk allele as a hypomorph.
Although Pep deficient mice on the B6 background have hyper-responsive memory T cells, they fail to develop autoimmune disease. Mice containing a point mutation in CD45 (E613R) develop a B cell-driven lupus-like disease on the mixed 129/B6, but not on the B6 background. To model in mice how human susceptibility loci such as PTPN22 cooperate to provoke autoimmune disease, we studied the ability of Pep deficiency to act as a genetic modifier of the CD45 E613R mutation on the non-autoimmune B6 background.
Double mutant mice develop a lupus-like disease as well as a lymphoproliferative syndrome. Following antigen receptor stimulation, peripheral B cells in the double mutant mice phenocopy hyper-responsive CD45 E613R B cells, whereas peripheral T cells respond like Pep-/- T cells. These studies suggest that Pep-/- T cells in the context of a susceptible microenvironment can drive hyper-responsive CD45 E613R B cells to break tolerance.
A B cell intrinsic defect initiates autoimmunity in New Zealand Black chromosome 13 congenic mice (49.21)
Authors: Loh Christina , Pau Evelyn , Chang Nan-Hua , Wither Joan 
Published: January 2023

Abstract
Introgression of a New Zealand Black (NZB) chromosome 13 (c13) interval onto a lupus-resistant C57BL/6 (B6) background (denoted, B6.NZBc13) is sufficient to produce many of the hallmarks of lupus. To characterize the immune defects leading to these abnormalities observed in B6.NZBc13 mice, bone marrow (BM) chimeras and BCR transgenic mice were produced. In BM chimeras, transfer of B6.NZBc13 BM cells was sufficient to transfer autoimmunity. Interestingly, in mixed BM chimeras the abnormal T and B cell activation as well as DC expansion was observed in both B6 and B6.NZBc13 derived cells; but with greater B cell activation in B6.NZBc13 derived cells. When an anti-HEL Ig transgene was crossed onto the congenic background disease was abrogated and the abnormal cellular phenotypes normalized. Although tolerance was retained in anti-HEL Ig/soluble HEL double transgenic mice, increased numbers of 'edited' cells were seen in the periphery. B cell function studies revealed altered phosphorylation of signaling molecules downstream of the BCR. These findings indicate the presence of a BM-cell intrinsic defect on NZB c13 that can be localized to a B cell defect, which is necessary to initiate the autoimmune phenotype in B6.NZBc13 mice.
The PTPN22 allelic variant associated with autoimmunity impairs B cell signaling (49.28)
Authors: Habib Tania , Arechiga Adrian F , Funk Andrew J , He Yantao , Zhang Xian , Zhang Zhong-Yin , Buckner Jane H 
Published: January 2023

Abstract
PTPN22 is a gene encoding the protein tyrosine phosphatase (PTPase) Lyp. A single-nucleotide polymorphism (SNP) changing residue 1858 from cytosine to thymidine (1858C/T), encoding the variant Lyp620W, is associated with multiple autoimmune disorders. Studies have demonstrated that Lyp has an inhibitory effect on T cell receptor signaling, and that Lyp620W expression results in a dominant gain of inhibitory function. However, the presence of autoantibodies in all of the diseases associated with the 1858T variant, and recent evidence that Ca2+ flux is altered in B cells of 1858T carriers, strongly suggest that Lyp620W may play a role in B cell signaling and homeostasis. In this study we examined the B cell activation profiles following BCR ligation of healthy subjects who express Lyp620W. We found that B cells from these subjects display impaired B cell signal transduction, characterized by impaired proliferation and a decrease in phosphorylation of key signaling proteins including Syk and PLCγ2. Inhibition of Lyp PTPase activity reversed the signaling defect in B cells expressing Lyp620W, resulting in enhanced BCR activation to the level of LypR620 controls. These findings demonstrate that Lyp620W alters BCR signaling and implicates B cells in the mechanism by which the PTPN22 1858T allelic variant contributes to autoimmunity. This work was supported by funds from the Juvenile Diabetes Research Foundation.
A functional single nucleotide polymorphism in PTPN22 contributes to diabetes susceptibility in the BioBreeding Rat (49.4)
Authors: Sarmiento Janice D. , Wallis Robert , Marandi Leili , Poussier Philippe 
Published: January 2023

Abstract
The C1858T polymorphism in the Ptpn22 gene is associated with increased susceptibility to several autoimmune disorders including Type 1 Diabetes (T1D). This produces a gain-of-function R620W variant with diminished binding affinity to Csk, which, like PTPN22 is an inhibitor of antigen receptor signaling. In the T1D-prone BioBreeding (BB) rat, this gene is located in the Iddm3 locus on chromosome 2, making it a likely candidate gene. Sequencing revealed a non-synonymous SNP causing an A629T substitution C-terminal to the PTPN22 P1 domain that binds to Csk. Co-immunoprecipitations examining the PTPN22-Csk interaction have shown a 2-fold reduction in binding affinity of the BB compared to the ACI variant. Importantly, a genome-wide segregation analysis of an F2(BBxACI.1u.lyp) cohort revealed the dominant effect of the BB allele to confer a 3-fold increased T1D risk compared to the allele carried by the T1D-resistant ACI strain. Homozygosity for the BB allele is also associated with phenotypes indicative of immune dysregulation including increased proportions of activated CD4 T cells in the periphery. Reminiscent of the phenotypes observed in T1D patients carrying the R620W variant, BB-derived T and B cells exhibit hyporesponsiveness to antigen receptor engagement, with a concomitant decrease in IL-2 production by CD4 T cells.
Banting and Best Diabetes Centre, Genome Canada, Ontario Research Foundation and CIHR
A hypomorphic allele of ZAP-70 reveals a distinct thymic threshold for autoimmune disease versus autoimmune reactivity (49.6)
Authors: Hsu Lih-Yun , Tan Ying-Xim , Weiss Arthur 
Published: January 2023

Abstract
ZAP-70, a Syk family protein tyrosine kinase, is critical for efficient signaling downstream of the TCR. Our lab and others have previously shown that tyrosine 315 and 319 in the interdomain B positively regulate ZAP-70 function by recruiting Vav1 and Lck, respectively. Surprisingly, in addition to their scaffolding function, we recently discovered that Y315 and Y319 play an important role in the autoinhibition ZAP-70 kinase activity. To address the relative importance of the scaffolding function of these residues versus their autoinhibition function, we generated a knock-in ZAP-70 mutant mouse (YYAA mouse) with Y315 and Y319 both mutated to ananine residues. These YYAA mice showed many similarities to a previously identified ZAP-70 mutant mouse, SKG, which harbors a distinct hypomorphic mutation. Both YYAA and SKG mice have impaired T cell development, hyporesponsiveness to TCR stimulation, and defective positive and negative selection. YYAA mice, like SKG mice, develop rheumatoid factor antibodies, but fail to develop autoimmune arthritis. Analysis of TCR repertoire revealed that qualitative difference in TCR signaling may skew the TCR repertoire in ways that differentially influence propensity to autoimmunity versus autoimmune disease susceptibility.