bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of Antigen-Specific Immune Suppression Using Biodegradable Nanoparticles Containing Antigen and Dexamethasone
Authors: Kim Sang-Hyun , Moon Jun-Hyeok , Jeong Seong-Un , Lee Chong-Kil 
Published: January 2023

Abstract
Dexamethasone (Dex) is known to reduce inflammation and autoimmunity by modulating dendritic cell (DC) function, maturation, and differentiation. Nanoparticles (NPs) prepared using biodegradable and biocompatible poly(lactic-co-glycolic acid) (PLGA) can be used to target-delivery vehicles to DCs. In the present study, PLGA nanoparticles containing ovalbumin (OVA) and Dex (NP[OVA+Dex]) were prepared by W1/O/W2 double emulsion solvent evaporation method, and evaluated their antigen-specific immune tolerizing effects. DCs treated with NP[OVA+Dex] were decreased in the expression of MHC class II (I-Ab) and co-stimulatory molecules (CD80 and CD86), and increased in the proportion of CD86−PD-L1+ cell population. DCs treated with NP[OVA+Dex] were reduced in the production of pro-inflammatory cytokine, such as IL-1β, IL-6, IL-12p40 and TNF-α, whereas the production of immunosurpressive cytokine IL-10 was enhanced. Treatment of DCs with NP[OVA+Dex] were diminished in MHC class II-restricted OVA presentation and allogenic T cell stimulatory capacity. NP[OVA+Dex]-treated DCs induced CD4+CD25+FoxP3+ regulatory T cell differentiation from CD4+CD25− T cells isolated from normal, or OT-II mice. Mice injected i.v., or i.g. with NP[OVA+Dex] were suppressed in both inducing OVA-specific CTL responses and producing OVA-specific IgG. The present study demonstrates that NPs encapsulated with antigen and Dex are useful tools in inducing antigen-specific immune tolerance.
IL-17A control CNS inflammatory disease by regulating Treg cells through modulation of gut microbiota in HLA class-II transgenic mice model of multiple sclerosis (MS)
Authors: Shahi Shailesh K , Freedman Samantha N , Murra Alexandra C , Zarei Kasra , Guseva Natalya V , Corley Katherine Gibson , Bossler Aaron , Karandikar Nitin J , Mangalam Ashutosh K 
Published: January 2023

Abstract
Despite extensive studies on IL-17A in MS and its animal model EAE, the role of IL-17 in disease development and maintenance is unclear. We have previously established proteolipid protein-(PLP)91–110 induce EAE model in HLA-DR3 transgenic mice. In the present study, we investigated the role of IL-17A in disease development and severity utilizing HLA-DR3 transgenic mice lacking IL-17A (IL-17A−/−). We observed that HLA-DR3.IL17A−/− mice develop milder EAE than HLA-DR3 mice suggesting that IL17 is redundant for the development of EAE but might be required for the disease severity. Milder disease in HLA-DR3.IL17A−/− mice were due to an increase in CD4+CD25+FoxP3+ Treg frequency and suppressive function of Treg cells. Depletion of Tregs using anti-CD25 neutralizing antibody abrogated milder disease phenotype in HLA-DR3.IL17A−/− mice. As gut microbiota play an important role in the generation of Treg cells, we asked whether an absence of IL17A altered gut microbiota towards Treg promoting bacteria. Our 16s rRNA analysis of gut microbiota confirmed that IL-17 deficient mice had distinct gut microbiota than IL-17 sufficient mice with an increased abundance of Treg promoting bacteria such as Lactobacillus and Clostridia. Fecal transplantation studies are underway to confirm the role of Treg promoting gut bacteria. We next investigated whether IL-17F and GM-CSF can compensate for the absence of IL-17A. Interestingly blockage of both IL-17F and GM-CSF led to increased disease severity suggesting a protective role for IL-17F and GM-CSF. Thus our study suggests that there is a bidirectional link between the gut microbiota and IL-17A and the inverse relationship between IL-17A and Tregs might determine the susceptibility vs protection from EAE.
B cells, bugs, bowels, and bones: Bruton’s tyrosine kinase deficiency alters gut B lymphocyte populations and IgA recognition of commensal bacteria in autoimmune arthritis
Authors: Bonami Rachel , Thurman Christina , Nyhoff Lindsay , Barron Bridgette , Kendall Peggy L. 
Published: January 2023

Abstract
IgA is the most abundantly produced isotype, much of which is secreted into the gut lumen. IgA interacts with bacteria, but the dialogue between intestinal B lymphocytes, their antibody products, and commensals is incompletely understood. Elimination of bacteria prevents spontaneous arthritis in the K/BxN model of rheumatoid arthritis, as does disrupted B cell receptor signaling via Bruton’s tyrosine kinase (Btk) deficiency. We hypothesized that altered B cell signaling impacts commensal bacteria recognition. We find that germinal center B cells and IgA class-switched cells are dramatically reduced by Btk deficiency in the in Peyer’s patches of K/BxN mice. Plasmablast and plasma cell numbers are not reduced by Btk deficiency in the small intestine lamina propria; however, the frequency of IgA-coated bacteria is decreased, and the IgA-coated community is shifted. Parabacteroides distasonis is reduced in Btk−/y mice. P. distasonis infection enhances autoimmune arthritis development in antibiotic-treated mice that are otherwise protected, suggesting this commensal plays an inciting role in disease development. In contrast, P. distasonis was protective in prior studies of a multiple sclerosis model. These data show impaired B cell receptor signaling alters the dynamic interplay between B lymphocytes and commensal microbes to impact autoimmune arthritis development. BTK inhibitors are used to treat lymphoma and clinical trials investigating their efficacy in several autoimmune diseases, including rheumatoid arthritis, are ongoing. Our work suggests that the impact of such regimens on the delicate balance between commensal bacteria and adaptive immunity should be considered in the specific autoimmune context.
Discovery of Autoantibodies Associated with Psoriatic Arthritis
Authors: Wu Tianfu , Yuan Yulin , Tyring Stephen K 
Published: January 2023

Abstract

Objective
The autoimmune etiology in psoriasis is not very clear, we aim to identify autoantigens and autoantibodies in psoriasis, which may shed light on the molecular and cellular basis of the pathogenesis of psoriasis and psoriatic arthritis.

Methods
In this study, we developed an autoantigen array system harboring a variety of antigens including typical autoantigens in rheumatic diseases as well as skin antigens, inflammatory mediators and putative autoantigens in psoriasis. Sera from psoriasis patients (N = 73) were used to interrogate antigens on the array. Individual ELISA was also used in validation studies.

Results
We found several serum autoantibodies were elevated in psoriasis patients compared to healthy controls; particularly, IgG autoantibodies against two novel antigens, LL37 and ADAMTSL5, were significantly increased in the psoriasis patients compared to healthy controls. Importantly, serum levels of IgG autoantibodies against LL37 and ADAMTSL5 were correlated with Psoriasis Area and Severity Index (PASI), and reflected disease progression in longitudinally collected samples from psoriasis patients. Importantly, we found both anti-ADAMTSL5 and anti-LL-37 autoantibodies were significantly elevated in psoriatic arthritis (PsA) compared to Non-PsA, suggesting that these molecules may be involved in the pathogenesis of psoriatic arthritis.

Conclusion
Our findings suggest that these autoantibodies may be useful biomarkers and indicative of therapeutic targets of psoriasis and psoriatic arthritis.
Type I IFN and IL-4R define B cell checkpoint defects in systemic lupus erythematosus
Authors: Mountz John D , Liu Shanrun , Wu Qi , Yang PingAr , Essman W. Alex , Ojo Oluwagbemiga A , Luo Bao , Gao Min , Chen Jake Y , Sanz Ignacio , Chatham W. Winn , Hsu Hui-Chen 
Published: January 2023

Abstract
The development of pathogenic autoantibody producing B cells is normally limited at the early transitional (Tr) stage and a later T-dependent developmental checkpoint. The precise molecular mechanisms underlying defective autoreactive B cell deletion/anergy at each checkpoint have been difficult to define. We utilized a combined single-cell B cell transcriptome and high dimensional flow cytometry analysis approach for a parallel understanding of B-cell developmental checkpoint defects at multiple stages in SLE. We found that while high levels of B-cell endogenous interferon-β (IFNβ) is an important risk factor for autoantibody positive African American (AA) SLE patients, low expression of IL-4R was a risk factor of both AA and European-Americans (EA) patients for development of pathogenic autoantibodies. The molecular signature of autoreactive B cells that escape deletion at the Tr stage include type I IFN stimulated genes (ISGs), including IRF7, ISG15, ISG20, MX1, and STAT1. The molecular signature of autoreactive B cells that escape the second T-dependent checkpoint, include low expression of IL4R and the transcriptional repressor BACH2, and high levels of TBX21, ITGAX, FCRL5 and IFI30. Interestingly, in vitro culture stimulation confirmed that the presence of IL-4 signaling significantly suppressed the development of pathogenic CD21−CD27−IgD−CD11c+T-bet+ double negative 2 (DN2) B cells in SLE. These results suggest that B-cell checkpoint defects can be used to stratify SLE patients according to high type I IFN or low IL-4R and their response signatures. These immune phenotype and transcriptome signatures offer the potential to predict therapy responses to type I IFN blockade or other therapies.
Increased immune surveillance of neuron-restricted antigen during demyelination leads to axon loss perpetrated by CD8+ T cells
Authors: Clarkson Ben D.S. , Grund Ethan M , Mirchia Kanish , Standiford Miranda M , Howe Charles L 
Published: January 2023

Abstract
Clonally expanded CD8+ T cells outnumber their CD4+ counterparts in MS lesions yet their role in disease pathogenesis and the relevant target antigen(s) remain unknown. We posited that CNS CD8+ T cells are specific for neuronal antigen and may participate in axon or neuron injury in multiple sclerosis—thereby contributing to cumulative disability. Here we show using neuron-specific translational profiling that demyelination is sufficient to drive neuronal expression of MHC class I genes as well as antigen processing genes. We further demonstrate that neuron-targeted neoantigen (ovalbumin) is sampled by peripheral immune cells even in the absence of demyelination—as assessed by neuroantigen-specific (OTI) CD8+ T cell activation in cervical lymph nodes. However, OTI T cell retention in the healthy CNS was not observed. In contrast, cuprizone diet induced demyelination drives increased OTI T cell proliferation as well as accumulation of these cells to the CNS, leading to elimination of ovalbumin+ neurons. CNS recruited OT1 cells were found to be juxtaposed next to degenerating ovalbumin+ neurons and axons. These findings support a role for autoreactive CD8+ T cells in the axonal injury that underlies progression in multiple sclerosis. Future studies are aimed at identifying patients with pathogenic anti-axonal CD8+ T cells who may be responsive to targeted immunotherapy.
The role of CB1 in experimental autoimmune encephalomyelitis (EAE)
Authors: Nichols James Matthew , Kaplan Barbara 
Published: January 2023

Abstract
It is well known that cannabinoid receptors have critical roles in immune homeostasis. This includes the CB1 receptor, which is encoded on by the Cnr1 gene. Previous work by others using the EAE model in ABH Cnr1−/− mice showed that while disease severity and onset were similar between wild type (WT) and Cnr1−/− mice, recovery from a relapse was better in WT mice suggesting a level of neuroprotection mediated by the CB1 receptor. In this study, we used the active EAE model in Cnr1−/− and WT C57BL/6 littermates to determine the importance of the CB1 receptor in disease progression by examining both the peripheral and neural immune response. We found clinical disease to be more severe in Cnr1−/− mice as compared to WT mice, which corresponded with significant increases of IFNγ from supernatants of restimulated splenocytes as determined by ELISA. Our results also showed that IL17A was modestly higher in the serum and culture supernatants of the Cnr1−/− mice as compared to WT mice, and histologic analysis of spinal sections showed modestly higher levels of neuroinflammation in Cnr1−/− mice as compared to WT mice. This suggests that CB1 receptors may have an immunoregulatory effect in the peripheral immune response of EAE, which combined with the neuroprotective effect via CB1 found in the other study, ultimately leads to less severe clinical disease in WT mice.
Pulmonary involvement in a mouse model of Sjögren’s syndrome induced by activation of the STING pathway
Authors: Papinska Joanna Aleksandra , Gmyrek Grzegorz , Srinivasan R. Sathish , Deshmukh Umesh , Bagavant Harini 
Published: January 2023

Abstract
Sjögren’s Syndrome (SS) is a chronic autoimmune disorder characterized by an increased type 1 interferon gene signature, autoantibody production, and salivary gland inflammation. Engagement of Stimulator of interferon genes (STING) induces type 1 interferon production. Gain of function mutations in TMEM173, encoding STING, results in a severe vasculopathy affecting the skin and lungs. We have previously reported that activation of the STING pathway in mice, using a STING agonist DMXAA, causes an SS-like disease characterized by sialoadenitis and salivary gland dysfunction. Considering that lungs are affected in 9–20% of SS patients, this study was undertaken to investigate lung involvement in DMXAA treated mice.
Female C57BL/6 mice injected with DMXAA rapidly upregulated expression of IFNβ, IFNγ, and Mx1 in the lungs at 4 hours. This was followed by an increase in type 1 innate lymphoid cells on day 8. Histopathologic analysis showed the presence of peri-bronchial inflammatory infiltrates on day 35, which persisted until day 57. The lung inflammation was associated with an increased expression of multiple pro-inflammatory genes including CCl20, CXCl10, CXCl9, and IL17α. In addition, there was an increased frequency of lymphatic endothelial cells, suggestive of lymphangiogenesis. Although STING expression was seen in bronchial epithelium and alveolar cells in the lung, bone marrow chimeras between STING KO and wild type mice suggest that STING expression in myeloid cells was critical for lung inflammation.
Our results show that systemic activation of the STING pathway might play an essential role in lung inflammation in SS patients.
The metabolic modulator metformin affects the activation and survival of murine dendritic cell subsets
Authors: Gallucci Stefania , Chakhtoura Marita , Lee Michael H , Qiu Connie C 
Published: January 2023

Abstract
Unique immunometabolic pathways control the ability of dendritic cell subsets to activate, and metabolic modulators are proposed as therapeutic candidates in cancer and autoimmunity, although their effects on specific immune cells are not fully known. The metabolic inhibitor metformin, the first-choice oral treatment for type II diabetes, has many effects on immunometabolism, including the inhibition of complex I of oxidative phosphorylation. Metformin was shown to decrease the severity of autoimmunity in murine models by inhibiting the activation of T cells. Moreover, it can diminish tumor growth through affecting the polarization of tumor-infiltrating macrophages. Here, we determined the effects of metformin on three subsets of dendritic cells that are proposed to have different energy requirements for activation. Upon TLR stimulation, we found that metformin does not affect the activation of the inflammatory GM-CSF-dependent dendritic cells (iDCs) or the Flt3-L-dependent conventional dendritic cells (cDCs), which rely on an immuno-metabolic shift to glycolysis to fully activate and express costimulatory molecules and pro-inflammatory cytokines, but it decreased cDC survival at resting state. In contrast, we found that metformin inhibited the activation of plasmacytoid dendritic cells (pDCs), which requires both an increase in oxidative phosphorylation and glycolysis for activation. Our studies provide a new layer of complexity in the potential of metformin as treatment in autoimmunity and cancer by showing that this drug can inhibit the activation of pDCs and also eliminate resting cDCs, therefore altering in opposite directions the impact of these innate cell subsets on the immune response.
Beta cells activate islet resident macrophages in a culture bioassay
Authors: Zaman Mohammad Mahabub-Uz , Zakharov Pavel 
Published: January 2023

Abstract
The pancreatic islets of all species contain a small number of resident macrophages. Transcriptional profiles of such islet macrophages indicate that they are in an activated state in steady state conditions expressing high MHC-II, TNFα, and IL-1β. However the reason for this activation is still unknown. To understand the molecular mechanism how the islet environment affects the biology of its resident macrophages we have developed a culture system that reproduces the beta cell: macrophage interaction taking place in islets. Our protocol involves culturing beta cells or insulinomas with bone marrow precursors in CSF-1 conditioned media for seven days. During the period of co-culture the insulinoma cells begin to bud off the plate and cluster with the developing macrophages forming a pseudo-islet structure. Two photon microscopic analysis of the organoids showed the presence of macrophages in the cluster closely attached to beta cells. Macrophages in the organoid capture insulin granules and express high level of MHC-II and PDL1. Microarray analysis shows upregulation of inflammatory genes of the NFκB pathway and a tight correlation with gene signature of bone marrow macrophages stimulated with LPS. The macrophage differentiation and activation is specific for insulinomas and does not take place with other immortalized cell lines; it requires cell contact between β cells and macrophage precursors: it does not take place with already differentiated macrophages. In sum, the beta cell:macrophage symbiosis can be generated in vitro by co-culturing beta cells and bone marrow precursors. We are currently investigating the mechanism how beta cells modulate the activation profile of macrophages using this in vitro co-culture system.
Pancreatic beta cells are constantly interacting with the immune system
Authors: Wan Xiaoxiao , Zinselmeyer Bernd , Zakharov Pavel , Vomund Anthony N , Lichti Cheryl F , Unanue Emil R 
Published: January 2023

Abstract
We have been examining how beta cells communicate their antigens to the innate immune system, in the context of the diabetic autoimmunity. Beta cells release peptides derived from the insulin granules intermittently into the blood following challenges with glucose. Most of the peptides derive from crinosomes, degradative vesicles that result from the fusion of insulin granules with lysosomes. Such a process is required in order to maintain homeostasis in the beta cells. A vast majority of the peptides in crinosomes derive from insulin and contain many epitopes responsible for activation of CD4 T cells. This process of the release of the peptides takes place normally in all mouse strains as well as in human beta cells; it is independent of the autoimmune status. In the NOD strain with its diabetic propensity genetic background the peptides released from crinosomes can be found bound to antigen presenting cells in all lymph nodes, resulting in interactions with T cells. We have documented that CD4 T cells to insulin peptides interact with the released peptides leading to their partial activation. Aside from peptide release, beta cells also communicate locally in the islets with the resident macrophages. We find that beta cells intimately interact with the macrophages, resulting in direct passage of the vesicles and their antigenic products. These resident macrophages are therefore strong presenting cells and are responsible for the entrance of the insulin-reactive CD4 T cells into islets. In brief, an endocrine organ like the pancreatic islet is constantly challenging the immune system by making autoantigens available.
Weighted Gene Correlation Network Analysis of Ovarian Cancer Driven by CXCL13- CXCR5 Interactions
Authors: Carey Kaylin , Griffen Tiara L , Young Corey D , Dill Courtney D. , Lillard James W 
Published: January 2023

Abstract
Ovarian Cancer (OvCa) is a disease that affects postmenopausal women, with high-grade serous ovarian carcinoma being the most common and lethal type. Many patients are asymptomatic in the early stages of OvCa, thus going undetected, leading to higher patient mortality rates. Identifying biomarkers involved in ovarian cancer progression could enhance current therapeutic outcomes. Our laboratory was the first to show that CXCL13- CXCR5 signaling mediates prostate, breast and lung cancer cell growth, migration, invasion, and survival. We provided evidence that these chemokines are highly elevated in OvCa cell lines and clinical samples. These previous findings provided the rationale to support the hypothesis CXCL13-CXCR5 signaling promotes OvCa progression, metastasis and survival. In this study, we analyzed transcriptome data to determine possible molecular mechanisms and CXCL13-CXCR5 signaling pathways controlling OvCa progression. Weighted Gene Network Co-expression (WGCNA) analysis and Ingenuity Pathway Analysis were used to identify gene coexpression networks correlated with aggressive OvCa clinical phenotypes. CXCR5 was found to be co-expressed with several genes such as RB1, PIK3C3, GNAI1, LTB TNFRSF11B which are known to facilitate OvCa progression and tertiary lymphoid structure formation. Upon further analysis, we found that these gene expressions closely correlated with age at diagnosis and patient relapse. Our study suggests an important role of CXCL13-CXCR5 signaling and reveals an important set of co-expressed epigengenes involved in OvCa relapse.
IL-27-dependent STAT1 activation is enhanced in CD4 T cells from HIV infected patients
Authors: Cheng Jie , Kumar Jai , Kumar Princy , Catalfamo Marta 
Published: January 2023

Abstract
In patients with HIV infection, reconstitution of the CD4 T cell pool after initiation of combination antiretroviral therapy (cART) is a slow process and depends on CD4 T cell counts prior to therapy. This suggests that the CD4 T cell pool is under homeostatic pressure compared to the CD8 T cell pool which is expanded. We have previously shown that lymphopenia and IL-7 increase expression of the Signal Transducer and Activator of Transcriptions 1, 2 and 3 (STAT1, 2 and 3) leading to an enhanced response to Type I IFNs and contributing to the immune activation of CD4 T cells. A recent report has shown that IL-27, a member of the IL-12 family of cytokines, inhibits HIV replication in monocytes and monocyte-derived dendritic cells. IL-27 signals through the JAK/STAT and MAPK pathways. Since IL-27 activates STAT1 and STAT3, we hypothesized that IL-7-dependent modulation of STATs expression can influence the response to IL-27 in T cells from HIV patients. We tested whether the γc-cytokines IL-2, IL-7, IL-15 have an effect on STATs expression and their impact on IL-27 signaling in T cells from healthy controls. We found that in addition to IL-7, IL-2 and IL-15 significantly increased expression of STAT1 and STAT3 in CD4 and CD8 T cells and led to an enhanced STAT1 and STAT3 activation upon IL-27 in vitro stimulation. We also found that compared to healthy controls, CD4 T cells from HIV infected patients had a significantly increased STAT1 expression and showed enhanced STAT1 activation upon in vitro stimulation with IL-27. This effect was not observed in CD8 T cells. These data suggest that IL-2, IL-7 and IL-15 modulate IL-27 signaling. In the context of HIV infection, the enhanced IL-27-dependent STAT1 activation may impact CD4 T cell activation and function.