bluuebunny/crossref_metadata_2025_split huggingface dataset:
MHC-mismatched but not matched mixed chimerism can tolerize peripheral non-cross-reactive autoreactive T cells in type 1 diabetic NOD mice
Authors: Zhang Mingfeng , Racine Jeremy , Liu Yuqing , Lin Qing , Qi Tong , Wang Tiankun , Riggs Arthur D. , Zeng Defu 
Published: January 2023

Abstract
There are cross- and non-cross-reactive autoreactive T cells in type 1 diabetic (T1D) NOD mice. MHC-mismatched but not matched mixed chimerism reverses autoimmunity with deletion of cross-reactive thymocytes. However, how MHC-mismatched mixed chimerism tolerizes non-cross-reactive autoreactive T cells remains unclear. In the current studies, using Rag-1−/− BDC2.5 and BDC12-4.1 mice that have only non-cross-reactive transgenic autoreactive T cells, we found that MHC-mismatched but not matched mixed chimerism was able to induce anergy of host-type T cells as judged by surface markers (PD-1, CD80, Tim-3 and IL-7Rα), reduce Th1 and Th17 cells, and eliminate insulitis, but had no impact on the percentage of CD4+CD8+ thymocytes, indicating that MHC-mismatched mixed chimerism is required for tolerizing CD4 peripheral non-cross-reactive autoreactive T cells. Although both MHC-mismatched and matched mixed chimerism induced host-type DC upregulation of CD86, MHC-II, and PD-L1 and showed similar percentage of donor-type Foxp3+ Treg cells, only MHC-mismatched mixed chimerism increased the percentage of host-type Treg cells. In addition, although the MHC-mismatched mixed chimeras showed little insulitis, the host-type T cells proliferated vigorously in response to autoantigen stimulation in an in vitro culture, and neither donor- or host-type Treg cells inhibited the proliferation. Co-transfer of host- and donor-type T and Treg cells induced T1D in adoptive NOD-scid recipients but not in NOD-scid recipients with pre-engraftment of donor-type DCs. Therefore, induction of MHC-mismatched mixed chimerism can re-establish a tolerogenic DC and Treg network in the periphery and tolerize non-cross-reactive autoreactive T cells.
Characterizing the intracellular magnesium transporter MagT1 in murine lymphocyte function
Authors: Holmes Derek , Carroll Karen , Brodeur Scott , Pashine Achal 
Published: January 2023

Abstract
Free intracellular magnesium (Mg2+) plays a critical role in diverse immune cell functions. Human individuals with a genetic deficiency in the magnesium transporter MagT1 present with XMEN disease, a X-linked immunodeficiency characterized by uncontrolled Epstein-Barr virus infection and neoplasia, uncovering a critical role for Mg2+ in the regulation of NK and CD8T cell function. To interrogate the role of MagT1 in the immune response, we generated conditional knockout mice utilizing a tamoxifen inducible (Cre-ERT2) system to genetically delete Magt1. Here, we characterized the requirement for MagT1 in immune cell function following in vivo genetic deletion. MagT1 is not required for lymphocyte homeostasis following tamoxifen deletion, as T and B cell populations were unperturbed in the spleen, lymph node and thymus following short and long-term tamoxifan treatment. Magt1-deficient CD4+ T cells were defective in response to antigenic challenge following Ova immunization in vivo, as the numbers of BRDU+ CD4+ T cells were reduced. This observation was not due to a defect in proliferation, as the percentage of BRDU+ CD4+ T cells was similar between wild-type and Magt1-deficient mice. In support of this finding, Magt1-deficient CD4+ T proliferation is normal in multiple in vitro proliferation assays. While this observation is inconsistent with human findings from X-MEN patients, differences in human and mouse physiology might contribute to this discrepancy. Future interrogation of MagT1 function in NK and CD8+ T cells could provide mechanistic insight into the manifestations observed in X-MEN disease.
Absence of the Fyn tyrosine kinase ameliorates T cell induced colitis by inhibiting Th17 differentiation
Authors: Yin Catherine C , Fong Julie , Stein Paul L 
Published: January 2023

Abstract
T helper (Th) 17 cells are a distinct proinflammatory CD4+ T cell subset that protects against fungal and extracellular bacterial infections. Excessive inflammation can be suppressed by Tregs. In autoimmune diseases, such as Crohn’s disease and ulcerative colitis, the Th17/Treg responses are unbalanced. Secretion of IL-17 attracts neutrophils and promotes the production of inflammatory mediators resulting in tissue damage. The Src family tyrosine kinase, Fyn, plays a critical role in regulating IL-17 production. In the absence of Fyn, CD4+ T cells skewed towards the Th17 lineage express RORγt but make little IL-17 and show ectopic expression of the Treg transcription factor FoxP3. We hypothesize that in a T cell transfer model of colitis, the absence of Fyn will decrease IL-17 induced inflammation and reduce disease severity. Rag KO recipients receiving WT CD45Rbhi (naïve) CD4 T cells showed characteristic weight loss associated with colitis. In contrast, recipients receiving Fyn−/− CD45Rbhi CD4 T cells maintained their body weight. Mice receiving either WT or Fyn deficient T cells had similar numbers of T cells in the lamina propria, suggesting that the reduced pathology is not due to proliferative defects. Both groups had similar numbers of IFNγ+ (Th1) and RORγt (Th17) positive cells but the Fyn mutant recipients showed a marked decrease in IL-17 secreting T cells. Neutrophil infiltration was highly reduced as well. Furthermore, IL-17 induced genes associated with neutrophil infiltration (S100A8, S100A9), neutrophil chemoattraction (CXCL1, CXCL2), neutrophil homeostasis (CXCL5) and tissue remodeling (MMP9) were all reduced. Together these data suggest Fyn may serve as a novel target for treating Th17 mediated diseases.
An in vivo functional screen identifies miR-148a as a critical regulator of B cell tolerance and autoimmunity
Authors: Gonzalez-Martin Alicia , Adams Brian D , Lai Maoyi , Shepherd Jovan , Salvador-Bernaldez Maria , Salvador Jesus M , Lu Jun , Nemazee David , Xiao Changchun 
Published: January 2023

Abstract
Autoreactive B cells are major contributors to autoimmune disease pathogenesis, but the molecular pathways responsible for the break of B cell tolerance in these patients remain largely unknown. In this study, we performed an in vivo functional screen of a lymphocyte-expressed miRNA library and identified miR-148a as a key regulator of this process. Elevated miR-148a expression impaired B cell tolerance by protecting immature B cells from BCR engagement-induced apoptosis, through downregulation of its targets Gadd45a, Bcl2l11, and Pten. Moreover, increased expression of miR-148a, which has been consistently found in lupus patients and lupus-prone mice, accelerated the development of lethal autoimmunity in a lupus mouse model. These results demonstrate that miR-148a functions as an important regulator of B cell tolerance and autoimmunity.
Evidence for citrullinated inhibitor of DNA binding 1 as a novel autoantigen in rheumatoid arthritis
Authors: Ohara Ray A , Edhayan Gautam , Remmer Henriette A , Morgan Rachel L , Amin M Asif , Stinson W Alexander , Graham Jerry , Kim Josh S , Campbell Phillip L , Arbab Ali S , Fox David A , Ruth Jeffrey H 
Published: January 2023

Abstract
Inhibitor of DNA binding 1 (Id1) is a nuclear transcription factor that is primarily fibroblast derived with elevated expression in rheumatoid arthritis (RA) synovial tissues (STs) and synovial fluids (SFs). Id1 is potently angiogenic in RA, and targeting Id1 or its signaling pathways may attenuate unwanted inflammatory outcomes. Cell signaling studies showed that Id1 can upregulate Jnk in FLS, human dermal microvascular endothelial cells, and endothelial progenitor cells and that Jnk could be targeted to reduce angiogenic responses in vivo. We also showed Id1 can be citrullinated and serve as an autoantigen by inducing anti-citrullinated protein antibodies (ACPAs) in RA peripheral blood (PB) sera and SFs. ELISA for Id1 was performed on exosomes isolated from RA, osteoarthritis, and normal (NL) FLS supernatants. RA FLS were transfected with a clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 plasmid targeting the Id1 gene. Lastly, immunodot blots (IDB) were performed on NL and RA PB sera and SFs to test the presence of ACPAs to citrullinated Id1 (citId1). Exosome analysis showed &gt;80% of Id1 detected in RA FLS supernatants was encapsulated within the exosomes. CRISPR-transfected (Id1 knockout) FLS showed a 75% decrease in cell proliferation compared to sham-transfected cells. Lastly, IDB analysis showed robust signals against citId1 from multiple RA PB sera and SFs. Our data show that Id1 is not only an important nuclear protein but is released from FLS, primarily in exosomes, expanding its role in the orchestration of inflammatory lesions through trans-cellular effects. We also show for the first time the presence of ACPAs with specificity to citId1 in RA PB sera and SFs and propose citId1 as a novel autoantigen in RA.
Deficiencies in myeloid cell populations lead to increased sensitivity of females compared with males to Francisella tularensis infection
Authors: Spencer Charles T , Ramos Muniz Mireya G , Olsen Darlene , Setzu Nicole , Martinez Danielle Y. 
Published: January 2023

Abstract
Preliminary data demonstrated that a greater percentage of female mice infected with F. tularensis succumbed to disease and developed symptoms faster than male mice. Increases in the serum inflammatory cytokine levels corresponded to this enhanced sensitivity in females consistent with a stronger inflammatory. Herein, we sought to understand the cellular basis for this sex difference in the inflammatory response between males and females. We used a combination of in vivo and ex vivo cellular analysis to determine differences in the cellular response to F. tularensis. Multiparametric cytokine analysis was used to quantify changes in serum and supernatant cytokines, real-time RT-PCR was used to measure cytokine mRNA expression in tissues, and multiparametric flow cytometry was used to discriminate cell populations responsive to infection. Despite a tendency for fewer T regulatory (Treg) cells, males had fewer inflammatory macrophage and an increase in regulatory macrophages. This corresponded with an overall decrease in the transcripts of IL-10, IL-5, and IL-4 in the tissues of mice succumbing to disease and an increase in IL-6 transcripts, a marker for the level of inflammation. The functional deficiency of regulatory macrophages and increase of M1 macrophages may enhance the inflammatory response to F. tularensis ultimately leading to decreased survival. Further investigations will focus on understanding the interactions between these myeloid populations with F. tularensis and other cells of the immune system. Development of therapeutics that activate or induce expansion of regulatory macrophages or that suppress the activity/activation of M1 macrophages may prevent death from this disease.
Reprogramming of myeloid compartments supporting tissue repair during DSS-induced colitis recovery
Authors: Tremblay Alexandra V , Bian Zhen , Niu Shuo , Culpepper Courtney , Liu Yuan 
Published: January 2023

Abstract
Myeloid-derived suppressor cells (MDSC) emerging during tumor growth or chronic inflammation play a critical role in regulating T cell function. However, mechanisms governing the generation of these cells remain unclear and need to be further defined. Using a DSS-induced colitis and recovery model, we characterized the dynamic changes within the myeloid compartments and the emerging of MDSC during active and resolution phases of inflammation. We show that the immature myeloid cell population expands and undergoes a functional reprogramming event in bone marrow (BM) and the spleen to form suppressive MDSC not at the active inflammation phase, but specifically at the resolution phase during colitis transition to recovery. In particular, two major functional changes occur when colitic mice were allowed to recover: 1) CD11b+Gr-1+myeloid cells in bone marrow and spleen acquire T cell suppressive functions, and 2) immature granulocytic myeloid cells increase the expression of chemokine receptor CXCR2, which enables their entry into circulation from BM. Additionally we determined enhanced activation of STAT3 and subsequent transcriptional enhancement of Arg1, iNOS, and gp91 in the MDSC isolated from resolution time points. We found that IL-17, the major cytokine associated with active colitis, remains elevated in the serum throughout the wound healing/resolution process. IL-17, together with the enhanced production of tissue repair cytokines, including IL-10, an activator of STAT3, produce a unique cytokine profile, resulting in a switch to induce reprograming and mobilization of the immature myeloid cells to suppress the inflammatory reaction in favor of tissue repair.
IL-7 receptor polymorphisms is related to signaling strength which is associated with autoimmune T cells activation in multiple sclerosis
Authors: Li Wenqing , Hixon Julie A. , Tritapoe Julia , Barata Joao T. , Durum Scott K. 
Published: January 2023

Abstract
IL-7 is required for survival of most T cell subsets and generally promotes T cell immune responses. Loss of functions of IL-7R in human has been known to cause severe combined immunodeficiency. Somatic gain of function mutations of IL-7R have been found in childhood T-cell acute lymphoblastic leukemia (T-ALL), these mutations usually occur in region of residue 244 in the exon 6 and lead to insertion of multiple amino acids. More recently, polymorphisms in IL-7R have been shown be a risk factor for multiple sclerosis (MS) and some autoimmune diseases. The polymorphysims that affects risk to most of these immunopathologies is T244/I, the same region harboring gain-of-function mutations in T-ALL. To investigate the mechanism of IL-7R variants association with MS and seek new therapeutic approaches directed to IL-7R pathway, we hypothesize that the functional significance of the T244/I polymorphism in IL-7R is related to increased signaling. To test our hypothesis, the T244 and I244 alleles of IL7R are transfected into BaF3 cells. The high risk allele T244 induces stronger Stat5 activation and promotes better survival of BaF3 cells. We further examine the strength of signaling in vivo in mice. IL-7R deficient bone marrow hematopoietic progenitors are transduced by retroviral infection with T244 or I244 allele and transferred to Rag1 deficient mice. Human IL-7R rescues T cell development in mice. Consistent with the in vitro study, the CD8 cells harboring the high risk allele T244 display stronger Stat5 activation compared with cells with I244. Our preliminary study suggests that high risk allele T244 of IL-7R signals stronger than allele I244, and this may promote activation of autoimmune T calls in MS and other autoimmune diseases.
PGE2 and IL-27: novel pro-inflammatory mechanisms involving dendritic cells and Tr1 cells
Authors: Hooper Kirsten M , Yen Jui-Hung , Kong Weimin , Ganea Doina 
Published: January 2023

Abstract
Interleukin-27 (p28/EBI3) is an immunomodulatory cytokine expressed by activated antigen presenting cells. Although first discovered to be involved in Th1 cell differentiation, further studies demonstrated the immunosuppressive functions of IL-27 including the inhibition of Th17 cell development and the induction of type 1 regulatory T cells (Tr1) and exhausted CD4+ T cells. The anti-inflammatory effects of IL-27 have been demonstrated in vivo in murine models of parasitic infections and autoimmune disease models such as experimental autoimmune encephalomyelitis and inflammatory bowel disease (IBD). We previously detailed the pro-inflammatory effects of PGE2 in collagen-induced arthritis and IBD through stimulation of IL-23 production leading to development of Th17 cells. Here we describe novel pro-inflammatory functions of PGE2, i.e. inhibition of IL-27 production by murine bone marrow-derived dendritic cells (DC), inhibition of Tr1 differentiation and of IL-10 production by Tr1 cells. We determined that the effect of PGE2 on IL-27 production in LPS-stimulated DC is mediated through EP2/EP4 receptors, induction of cAMP, and partial inhibition of both IRF1 and IRF3. Furthermore, we found that PGE2 treatment of LPS-stimulated DC reduces IRF1 binding to an essential ISRE site within the p28 promoter. In addition to the effects of IL-27 in DC, we also found that PGE2 directly inhibits IL-27-induced differentiation of Tr1 cells through EP4, and inhibits production of IL-10 by Tr1 cells through EP2/EP4. These studies further describe the pro-inflammatory effects of PGE2 and identify possible new targets for treatment of inflammatory diseases.
DCIR is an Important Regulatory Molecule in Allergic Inflammation
Authors: Dembele Marieme , Kaufman Gabriel N. , Xue Di , Beland Marianne , Mazer Bruce D. 
Published: January 2023

Abstract
The dendritic cell immunoreceptor (DCIR) is an inhibitory C-type lection receptor possessing immunoregulatory properties. We have shown that DCIR serves as a receptor for IVIg. In this study, we sought to determine its requirement in modulating IVIg mechanism of action by using a murine model of allergic of airways disease.
Wild type (WT) and DCIR−/− mice were sensitized and challenged with ovalbumin (OVA), and lung histopathology, bronchoalveolar lavage and phenotyping of inflammatory cells were performed. We further studied the effect of IVIg on allergen uptake and processing of CD11c+ cells in vitro. Briefly, bone marrow-derived dendritic cells from WT, DCIR−/− and Fcr2b−/− mice were treated with IVIg prior to exposure to OVA-ALEXA-647 or DQ-OVA.
DCIR−/− mice exhibit exacerbated pulmonary inflammation and eosinophilia compared to WT mice; this phenotype is rescued by IVIg treatment as in WT mice. Furthermore, IVIg significantly impairs the antigen uptake and processing machinery of dendritic cells from WT and DCIR−/− derived BMDCs but not that of Fcr2b−/−-derived BMDCs. In conclusion, DCIR is important in regulating allergic airway inflammation and its presence is not essential for IVIg to function. DCIR appears to be required for normal regulation of pulmonary inflammation.
PLAG (1-Palmitoyl-2-Linoleoyl-3-Acetyl-rac-Glycerol) modulates eosinophil chemotaxis by regulating CCL26 expression from epithelial cells
Authors: Jeong Jinseon , Kim Young-Jun , Yoon Sun Young , Kim Young-Jae , Kim Joo Heon , Kim Myung-Hwan , Sohn Ki-Young , Kim Heung-Jae , Han Yong_Hae , Chong Saeho , Kim Jae Wha 
Published: January 2023

Abstract
Increased number of eosinophils in the circulation and sputum is associated with the severity of asthma. The respiratory epithelium produces chemokine (C-C motif) ligands (CCL) which recruits and activates eosinophils. A chemically synthesized monoacetyl-diglyceride, PLAG (1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol) is a major constituent in the antlers of Sika deer (Cervus nippon Temminck) which has been used in oriental medicine. This study was aimed to investigate the molecular mechanism of PLAG effect on the alleviation of asthma phenotypes. A549, a human alveolar basal epithelial cell, and HaCaT, a human keratinocyte, were activated by the treatment of interleukin-4 (IL-4), and the expression of chemokines, known to be effective on the induction of eosinophil migration was analyzed by RT-PCR. The expression of IL-4 induced genes was modulated by the co-treatment of PLAG. Especially, CCL26 expression from the stimulated epithelial cells was significantly blocked by PLAG, which was confirmed by ELISA. The transcriptional activity of signal transducer and activator of transcription 6 (STAT6), activated by IL-4 mediated phosphorylation and nuclear translocation, was down-regulated by PLAG in a concentration-dependent manner. In ovalbumin-induced mouse model, the infiltration of immune cells into the respiratory tract was decreased by PLAG administration. Cytological analysis of the isolated bronchoalveolar lavage fluid (BALF) cells proved the infiltration of eosinophils was significantly reduced by PLAG. In addition, PLAG inhibited the migration of murine bone marrow-derived eosinophils, and human eosinophil cell line, EoL-1, which was induced by the addition of A549 culture medium.
Dermal exposure to the antimicrobial triclosan affects the gut microbiome and augments Th2 allergic responses mediated through Toll-like receptor 4
Authors: Marshall Nikki B , Lukomska Ewa , Long Carrie Mae , Anderson Stacey 
Published: January 2023

Abstract
Antimicrobial compounds like triclosan are ubiquitous in our environment; the CDC finds that75% of the general U.S. population has detectable levels in their urine. Curiously, recent epidemiological studies report positive associations between allergic disease and triclosan exposure. Our laboratory recently reported augmented allergic responses to ovalbumin in BALB/c mice with dermal triclosan exposure although triclosan itself was not immunogenic. Here we show that repeated application of triclosan to the skin alters expression of toll-like receptors including adramatic increase in TLR4 expression. In-vivo antibody-blockade of TLR4/MD2 significantly decreased responses in the skin tissue with triclosan exposure including expression of IL-6, TSLP, CXCL2, TLR2 and TLR4. The draining lymph nodes were also significantly affected by TLR4 blockade, including decreased cellularity and production of IL-4 and IL-13 by CD4 T cells. Proposed endogenous ligands of TLR4, S100A8 and S100A9, were also found to be highly expressed in the skin tissue and infiltrating neutrophils thus identifying a possible mechanism of TLR4 activation. Changes in gut microbiome have also been linked to changes in Th2 allergic responses. Here we found that after 28 days of topical application of triclosan, the relative abundance of Lactobacillus was increased in the gut. A specific mechanism of action of triclosan is inhibition of the enoyl-ACP reductase FabI gene involved in bacterial fatty acid synthesis which is not expressed by Lactobacillus. Together these data suggest that triclosan could augment allergic responses in part through activation of the TLR4 pathway and modulating the host microbiome.