bluuebunny/crossref_metadata_2025_split huggingface dataset:
Noncoding RNAs modify GATA3-driven transcription, leading to the immune profiles seen in psoriasis and atopic dermatitis
Authors: Mazahery Claire , Valadkhan Saba , Levine Alan D. 
Published: January 2023

Abstract
Atopic dermatitis (AD) and psoriasis are clinical manifestations of immune dysregulation in the skin. Psoriasis is generally classified as a T cell-mediated, IFN-γ dependent disease, while AD is skewed toward interleukin (IL)-4 dependence. Consistent with these classifications are clinical observations that IL-4 improves psoriasis disease score and an IL-4 receptor blocking antibody is approved for treatment of severe AD. However, the immunobiology is far more complex, as IL-13, often produced by IL-4 dependent T cells, can be elevated in psoriasis. Since GATA3 controls both IL-4 and IL-13 expression, we propose that regulation of GATA3 differs between the two diseases, resulting in overlapping yet distinct cytokine profiles. Our meta-analysis of two RNA sequencing profiles for each disease identified a noncoding RNA of unknown function (NRUF) in all four datasets (p&lt;1×10−10). Upon analyzing 48 datasets of immune responses to viral infection in epithelial cells and leukocytes, we found IL-13 and NRUF expression levels are most strongly correlated in lymphocytes. In T cell lines, we found elevated expression of the NRUF noncoding RNA associates with IL-4 and IL-13. However, IL-31, which is elevated in AD independently from the GATA3/IL-4/IL-13 axis, is not correlated to NRUF expression, supporting our hypothesis that NRUF drives disease pathology via the GATA3/IL-4/IL-13-dependent inflammatory response. Using overexpression or silencing approaches, we have characterized the ability of this NRUF to direct cytokine polarization of T cells from healthy control and donors with AD or psoriasis. We propose this NRUF modulates these two cutaneous diseases by regulating GATA3-based IL-4/IL-13 balance in T cells.
Delineating T cell autoreactivity in autoimmune diabetes by assessing the MHC-II-bound peptidome
Authors: Wan Xiaoxiao , Vomund Anthony N. , Peterson Orion J. , Lichti Cheryl , Unanue Emil R 
Published: January 2023

Abstract
Development of tissue-specific autoimmune diseases is tightly linked to major histocompatibility complex class II alleles (MHC-II). In humans, the HLA-DQ2/DQ8 variants contributes the highest genetic risk to type 1 diabetes (T1D). However, it remains unclear how the MHC-II-specific peptidome defines the outcomes of T cell self-reactivity. To address this question, we performed unbiased analyses of the MHC-II immunopeptidome of the pancreatic islets of non-obese diabetic (NOD) mice at the start of the autoimmune process. NOD mice spontaneously develop autoimmune diabetes due to the expression of the I-Ag7 MHC-II molecule, which is structurally homologous to HLA-DQ8. Combining mass spectrometry analysis and immunoassays, we identified the precise MHC-II-specific epitopes derived from diverse β-cell proteins and functionally characterized the corresponding T cell responses. The major peptides derived from insulin B chain and C-peptides and consisted of sets of varying length, usually around 14–16 residues. Their presence correlated with the initial T cell autoreactivity. Other minor epitopes elicited T cell responses at a more advanced stage, the phenomenon of epitope spreading. We also identified post translational change consisting of deamidation of C peptides- see abstract of Lichti et al. Importantly, most of the immunogenic epitopes were independently identified in the MHC-II peptidome of pancreatic lymph nodes and spleen, revealing a correlation of peripheral presentation with the tissue autoreactivity. In sum, these data demonstrate the landscape of the MHC-II epitopes being presented in a target autoimmune organ and delineate the characteristic features of a self-peptide that foster pathogenic responses.
Treg-restricted deletion of TRAIL (Tnfsf10) reduces autoimmune diabetes
Authors: Dadey Rebekah , Grebinoski Stephanie J , Zhang Qianxia , Gocher Angela , Brunazzi Erin , Andrews Lawrence Peter , Burton Amanda , Workman Creg , Vignali Dario 
Published: January 2023

Abstract
Regulatory T cells (Tregs) are a suppressive cell population that limit the anti-tumor response. One mechanism Tregs utilize is production of suppressive cytokines. We previously asked if deletion of the two main suppressive cytokines made by Tregs would have any overall effect on the suppressive ability of the Tregs. We found that Treg-restricted deletion of the cytokines IL-10 and IL-35 led to a compensatory upregulation of Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL; Tnfsf10). In these studies, upregulation of TRAIL was dependent on deletion of IL-10 and IL-35; however, we also wondered if TRAIL could also be upregulated in inflammatory environments and if deletion would affect Treg function in these environments.
We made a Tnfsf10L/L mouse, backcrossed onto both B6 and NOD backgrounds, and crossed each with respective Foxp3Cre lines. Surprisingly, we found little effect on tumor growth in B6 mice but found a substantive decrease in autoimmune diabetes incidence in the NOD mouse model. In the latter, we found that Treg-restricted deletion of TRAIL may extrinsically effect CD8+ and CD4+ T cell phenotype by increasing expression of suppressive molecules such as CD73 and LAP-TGFβ in these cells. Future studies are necessary to understand if this phenotypic change is responsible for the decrease in diabetes incidence.
A lifestyle-educational program improves depression levels of those with autoimmune disease
Authors: Ramirez Francisco E , Nedley Neil , Hunter Jennifer Michelle , Finlayson Lance Takeshi 
Published: January 2023

Abstract

Background
Patients with autoimmunity may have problems with depression. We explore the severity of depression among this population.

Methods
Participants that started and finished an 8 week depression educational program were studied. From n=5,861 participants from 5 continents, n=431 suffered from autoimmune disease and were used for the study. The program consisted of 2-hour long weekly meetings which occurred for a total of eight weeks. During each meeting, a 45-minute DVD presentation by a skilled physician was shown, a small group discussion was guided by trained facilitators. The focus of the program was to educate participants about healthy lifestyle behaviors such as exercise, nutrition, sleep hygiene, etc. The participants were assessed pre-post with the Depression and Anxiety Assessment Test that measured depression and demographics. Depression scores were classified into 4 categories: none (0–6), mild (7–10), moderate (11–19) or severe (20 or more).

Results
At baseline the average age was 54.9 (SD 13.3) and 85.4% were female. At baseline, mean group depression was 14.2 (SD 7.4), the depression levels were as follows: none (17.2%), mild (18.3%), moderate (34.3%), severe (30.1%). After the lifestyle-educational program, mean group depression decreased to 7.8 (SD 6.2). Post-program depression levels were as follows: none (51.97%), mild (17.6%), moderate (24.36%), severe (6.03%). The decrease in depression levels was significant with t(431) = −21.19 p &lt;.01.

Conclusions
The eight-week educational program was effective in improving depression levels for most of the participants with autoimmune disease. A follow up study is being planned to see if the results last long term.
Impact of age-associated decrease in thymic B cell expression of Aire and self-antigen genes on T cell tolerance
Authors: Cepeda Sergio , Xiao Yangming , Kraig Ellen , Griffith Ann 
Published: January 2023

Abstract
Susceptibility to many autoimmune diseases increases with age, however, mechanisms linking aging and susceptibility to autoimmunity remain incompletely understood. One hallmark of the aging immune system is atrophy of the thymus, the primary site of T lymphocyte generation and tolerance induction. Aging is also associated with declines in critical thymic functions, including expression of tissue restricted self-antigen (TRA) genes important in tolerance induction, many of which are regulated by the Autoimmune regulator (Aire). TRA expression in the thymus allows T cells to be tolerized to antigens typically expressed in peripheral tissues, and declining TRA expression is predicted to contribute to diminished T cell tolerance in aging. Until recently, medullary thymic epithelial cells (mTECs) were the only known source of thymic TRA expression, but it is now clear that a subset of thymic B (tB) cells also express Aire and mediate tolerance to Aire-dependent self-antigens. We found that expression of Aire and Aire-dependent self-antigens declines in tB from aged mice and humans, which is likewise predicted to diminish central T cell tolerance induction. To test these predictions, we used I-Ab MHCII tetramers to detect T cells recognizing a model TRA expressed in tB cells, Titin (Ttn, an auto-antigen associated with late-onset myasthenia gravis), in the thymus and secondary lymphoid organs (SLO) of young and aged mice. We find an increase in potentially auto-reactive Ttn-specific T cells in SLO of aged mice, concomitant with declining Ttn expression in tB cells. Ongoing experiments will compare the capacity of young and aged thymic B cells to tolerize T cells using the BDC2.5 TCR- and Aire-driven BDC peptide-transgenic mouse models.
Influenza infection exacerbates disease symptoms in relapsing models of multiple sclerosis
Authors: Diaz Katiria Soto , Kim Justin , Wetzel Lisa , McKim Daniel B. , Oelze Michael L. , Steelman Andrew J. 
Published: January 2023

Abstract
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Most patients present with a relapsing-remitting form (RRMS), wherein they experience new or exacerbated neurologic symptoms known as relapses followed by periods of partial or complete recovery (remissions). Previous evidence suggest that upper-respiratory infection increases the risk of relapse, but the mechanisms are ill-defined. The aim of this study was to elucidate the effects of upper-respiratory viral infection on disease progression in three models of relapsing experimental autoimmune encephalomyelitis (REAE). Relapsing EAE was induced in SJL/J, C57BL/6J and NOD/SHILtJ mice. At the peak of disease, mice were randomized into treatment groups, then inoculated with saline or mouse-adapted human influenza A virus (strain A/Puerto Rico/8/1934 H1N1; 0.7 HAU) two days later. Weights and scores were recorded daily. At day 42 post induction mice were euthanized and antigen recall responses measured from lymphocytes isolated from the spleen and cervical lymph nodes. Infection exacerbated symptoms of disease in both SJL/J and NOD/SHILtJ and tended to exacerbate disease in C57BL/6 mice. Following antigen stimulation, splenocytes and cervical lymph node lymphocytes from infected mice had increased production of IFNγ compared to cells isolated from saline inoculated controls. There was no effect of infection on IL-17A or GM-CSF production. These data indicate that infection may function to expand myelin-specific Th1 cell clones by an undefined mechanism. Together, these findings indicate influenza infection can exacerbate symptoms of REAE in SJL/J and NOD/SHILtJ mice.
STAT3 modulates metabolic programming of inflammation-induced macrophages
Authors: Patel Bhakti , Zhang Huiyuan , Zal Malgorzata A. , Wan Xianxiu , Zal Tomasz , Watowich Stephanie S. 
Published: January 2023

Abstract
Redox homeostasis in an inflammatory environment is crucial to ensure a balanced immune response. Several inflammatory disorders are associated with impairment of redox homeostasis, leading to DNA damage and subsequent immune dysregulation. The transcription factor STAT3 has anti-inflammatory activity in myeloid cells, mediated by inhibition of Ubc13, a key Toll-like receptor (TLR) signaling component. STAT3 anti-inflammatory activity is crucial in protection from systemic inflammation, maintenance of lineage-balanced hematopoiesis, and inhibition of DNA damage accumulation in hematopoietic progenitors. The molecular cues by which STAT3 mitigates DNA damage in an inflammatory environment, however, are poorly understood. Recently, we found that STAT3-deficient bone marrow derived-macrophages (BMDMs) exhibited increased oxidative stress upon TLR4 stimulation, including reduced antioxidant amounts and elevated production of reactive oxygen species (ROS). These responses were accompanied by increased gH2AX foci formation, suggesting accumulation of DNA damage. By contrast, BMDMs lacking Ubc13 exhibited increased expression of antioxidants and reduced DNA damage. RNA-sequencing analysis identified transcriptional targets of STAT3 and Ubc13 in steady state and TLR-stimulated BMDMs. Collectively, our findings suggest STAT3-mediated control of Ubc13 is important in regulating inflammation-induced oxidative stress and DNA damage by modulating antioxidant signaling and DNA damage repair pathways. Thus, STAT3 plays a crucial role in metabolic reprogramming of macrophages during inflammation to preserve redox homeostasis.
Validation of a chronic imiquimod-induced psoriasiform dermatitis model in Balb/c mice
Authors: Kemeny Agnes , Horvath Szabina , Perkecz Aniko , Pinter Erika , Gyulai Rolland 
Published: January 2023

Abstract
We developed a modified imiquimod (IMQ)-induced dermatitis protocol (Horvath et al, Scientific Reports 2019) using Finn chambers to minimize the unwanted systemic side effects of this widely used psoriasis animal model. It enables to perform prolonged imiquimod treatment in a self-control way as well. In the present study we investigate the long-term application of IMQ in this localized model.
20 mg Aldara cream (5% IMQ) or 20 mg vaseline were applied in two Finn chambers on the dorsal skin of Balb/c mice during the first 4 days of the experiment and every second or third day from day 5 to day 15, in separate groups. Vaseline or corticosteroid cream were applied on the intermediate days. Skin thickness, blood perfusion, body weight and skin scaling were measured daily. Histopathological alterations were evaluated on H&E stained sections, inflammatory cytokine concentrations (IL-1β, TNF-α, IL-17, IL-22, IL-23) were measured with Luminex technology.
Skin edema increased to 80–120% in the every 2nd or 3rd days treated group. Blood perfusion reached maximal response on day 4 and then gradually decreased until the end of the experiment. Moderate body weight loss was observed on the first 5 days of the experiment. Inflammatory cytokine concentrations in the skin were elevated during the onset of the symptoms (1–5 days) but dropped in the chronic phase (day 10 or 15). Topical corticosteroid treatment significantly reduced skin edema from day 8, but it had no effect on blood perfusion.
Our results proved that long-term Aldara application in Finn chambers enables the study of chronic psoriatic skin inflammation. Furthermore, our chronic model may be used to investigate topically applied anti-inflammatory drug candidates in psoriasiform dermatitis.
Inhibition of thrombin signalling on the surface of monocytes reduces inflammation in oxazolone-induced delayed type hypersensitivity
Authors: Wilkinson Hannah , Chen Daxin , Dorling Anthony 
Published: January 2023

Abstract
Thrombin can directly signal to innate immune cells via protease activating receptor-1 (PAR-1) but the functional consequence of receptor activation has yet to be fully defined. This study aims to assess the outcome of signalling through PAR-1 on monocytes in vivo. In a model of oxazolone-induced delayed type hypersensitivity (DTH)-contact dermatitis; inhibiting thrombin signalling via transgenic expression of hirudin on murine CD31 cells (Hir-Tg) significantly reduced ear swelling (ES) vs. wild type (WT) at 24 and 48 hours. The Hir-Tg mice had reduced CD68 cell recruitment and the recruited cells had a phenotype more polarised towards anti-inflammatory M2, with reduced iNOS, IFNγ & CCR2 expression, and increased expression of IL-10 and ABCA1. This phenotype was shown to be due to inhibition of thrombin signalling on the monocytes, as WT recipients of Hir-Tg bone marrow had a reduced ES, CD68 infiltration, granuloma and iNOS expression. Whereas Hir-Tg recipients (who would still express hirudin on the surface of endothelial cells) of WT bone marrow did not show a reduction in ES and behaved phenotypically akin to WT mice. Mice receiving IP-PAR1 antagonist prior to re-challenge had a similar reduction in ES and similar CD68 infiltration. This data shows that inhibiting thrombin signalling on the surface of innate immune cells both reduces recruitment in models of DTH and alters the behaviour of the cells to a more anti-inflammatory phenotype.
Single dose of anti-high mobility group box 1 protein (HMGB-1) neutralizing antibody ameliorates dysregulated inflammation and restores fracture healing in a polytrauma rat (Rattus norvegicus) model
Authors: Muire Preeti Judith , Mangum Lauren H , Avila Joshua J , Lofgren Alicia L , Wenke Joseph C 
Published: January 2023

Abstract
Polytrauma (PT) is associated with dysregulated inflammation (DI) and complicated/delayed fracture healing. We recently reported delayed fracture healing and increased circulating levels of HMGB-1 in a rat model of PT compared to osteotomy (OST). Since HMGB-1 binds to and activates TLR2, TLR4 and RAGE surface receptors to induce pro-inflammation, we investigated this protein’s role in delayed healing. We hypothesized that neutralization of cell-free HMGB-1 immediately after PT would resolve DI and restore fracture healing in PT. Anti-HMGB-1 polyclonal antibody (2mg/kg) was administered via IP injection following PT (PT-Ab) and bone/tissue volume (BV/TV) of fractures was evaluated by micro-CT imaging at 5 weeks post PT. As hypothesized, by neutralizing HMGB-1, fracture healing was improved with significantly higher BV/TV ratio in PT-Ab compared to PT rats. Changes to circulating CD68+ CD86+ (M1) and CD68+CD163+ (M2) monocyte/macrophage populations, as well as alterations to CD4+ and CD8+ T cells and their RAGE and TLR4 surface expression, were assessed on 1 and 3 days post-injury (d). While circulating M1 and M2 populations are scarce in naïve rats, these populations elevated post trauma. M1 was significantly higher in PT than in OST and PT-Ab at 1d but not at 3d. M2 was significantly high in only OST at 1d. In contrast to OST, we observed decreased RAGE and TLR4 expression on circulating T cells at 1d in PT and PT-Ab and at 3d in PT but not in OST and PT-Ab. Our observations suggest that elevated levels of HMGB-1 following severe trauma initiate immune dysregulation causing delayed fracture repair and the data presented herein indicates that HMGB-1 may be a therapeutic target to restore normal immune response and normal fracture healing in PT.
Epigenetic Regulation of Notch1/2 Signaling Modulates CD4+ T cell Phenotype and Impairs Diabetic Wound Healing
Authors: Davis Frank M , Wolfe Sonya , Dendekker Aaron , Joshi Amrita , Audu Christopher , Moore Bethany B , Lukacs Nicholas W , Kunkel Steven L , Gallagher Katherine 
Published: January 2023

Abstract
T cell plasticity, allowing for transition of CD4+ T cells from an inflammatory to a reparative phenotype, is critical for normal wound healing. In pathologic conditions, such as type 2 diabetes (T2D), wounds fail to heal due to persistent inflammation. Notch activation has been associated with CD4+ TH17/T regulatory (Treg) polarization, in several inflammatory diseases; however, it has not been examined in diabetic wounds. Recently, there is increasing evidence that epigenetic mechanisms control T cell plasticity in tissue. Using FoxP3GFP+ reporter mice we find that FoxP3+CD4+ Tregs were markedly upregulated in normal wounds at late time points. In contrast, wounds from a murine T2D model (DIO) displayed decreased FoxP3+CD4+ Tregs and an overabundance of RORγt+CD4+ TH17 cells with elevated IL17A production. We find that Notch 1 and 2 expression were markedly upregulated in DIO CD4+ T cells. Our prior work has demonstrated that MLL1, a histone methyltransferase, increases gene expression via H3K4 trimethylation (H3K4me3). DIO CD4+ T cells displayed increased Mll1 resulting in elevated H3K4me3 on the Notch 1 and 2 gene promoters increasing receptor expression and activation. Mice with a CD4+ T cell specific depletion of MLL1 (Mll1f/fCD4Cre+) had decreased H3K4me3 on the Notch 1 and 2 promoters with decreased Notch expression. Further, genetic depletion of Notch signaling in CD4+ T cells (DNMAMLf/fCD4Cre+) reduced IL17A production and TH17 cells in diabetic wound tissue. In conclusion, MLL1-mediated activation of Notch 1 and 2 in diabetic wound CD4+ T cells contributes to a persistent TH17 inflammatory response and results in impaired diabetic tissue repair.
A potential association of an interferon gene signature with RBC alloimmunization in sickle cell disease
Authors: Madany Emaan , Kadi Najwa El , Pandya Sumaarg , Hendrickson Jeanne , Gibb David R 
Published: January 2023

Abstract
RBC transfusion can lead to the production of alloantibodies against RBC antigens. RBC alloimmunization can result in hemolytic events and severely limit the availability of compatible RBCs. Patients with sickle cell disease (SCD) have the highest rate of alloimmunization, compared to any other disease population. However, mechanisms underlying this increased frequency are poorly understood. Inflammation in the recipient has been shown to promote alloimmunization in mice and humans. In mouse transfusion models, type 1 interferons (IFNα/β) and interferon-stimulated genes (ISGs) have been shown to promote alloimmunization. Given the chronic inflammatory state in patients with SCD, we hypothesized that SCD patients may also have an IFNα/β gene signature that may contribute to the increased frequency of alloimmunization. To test this hypothesis, we measured the expression of multiple ISGs, including myxovirus resistance protein 1 (MxA) and Siglec-1 by whole blood immunoassay and flow cytometry, respectively. MxA and Siglec-1 levels were significantly elevated in SCD patients, compared to transfused controls. We then determined the degree to which ISG expression correlated with alloimmunization frequency by linear regression. There was a trend toward elevated MxA expression in patients with 1 or more alloantibodies. Patients with 2 or more alloantibodies had significantly elevated MxA compared to non-alloimmunized transfused patients. These findings suggest the presence of an IFNα/β gene signature in patients with SCD and warrant further investigation of the contribution of IFNα/β pathways toward the profoundly elevated frequency of RBC alloimmunization in patients with SCD.