bluuebunny/crossref_metadata_2025_split huggingface dataset:
Salivary biomarkers in SLE
Authors: Gotewal Sunny , Soomro Sanam , Akbar Umair , Saxena Ramesh , Petri Michelle , Mohan Chandra 
Published: January 2023

Abstract

Background
Lupus Nephritis (LN) affects close to half of all SLE patients and is currently diagnosed through kidney biopsy. In search for a noninvasive diagnostic method, four serum biomarkers of SLE (IGFBP2, sTNFRII, Axl, VCAM1) were valued for their diagnostic potential in the saliva of SLE patients.

Methods
IGFBP2, STNFRII, Axl, VCAM1 were ELISA assayed in the serum and saliva of SLE patients (16 inactive, 10 active non-renal, 10 active renal) and 14 healthy controls. Group wise analysis by Mann Whitney test and Spearman correlation analyses between serum and saliva were done.

Results
IGFBP2 was elevated in SLE serum compared to controls (FC=3.2 P=0.0002) while sTNFRII and VCAM1 showed elevation in active compared to inactive SLE (FC=2.2 P=0.002 and FC=2.8 P&lt;0.0001 respectively). Salivary IGFBP2 and sTNFRII were elevated in SLE compared to controls (FC=2.4 P=0.01, FC=2.8 P=0.04 respectively), but was not associated with disease activity or renal involvement. Saliva and serum biomarkers did not correlate in this sample cohort.

Conclusion
Although all four biomarkers (IGFBP2, sTNFRII, Axl, VCAM1) have shown diagnostic potential in SLE serum, only IGFBP2 and sTNFRII were elevated in SLE saliva. Further exploration into other salivary biomarkers through an unbiased aptamer based protein screening platform is in progress.
Human regulatory T cells suppress CD4+ T cells by rapidly altering the phosphoproteome
Authors: Joshi Rubin Narayan , Marabita Francesco , Binai Nadine , Sui Zhenhua , Altman Amnon , Heck Albert J. , Tegner Jesper , Schmidt Angelika 
Published: January 2023

Abstract
Regulatory T cells (Tregs) control key events of immunity primarily by suppression of effector T cells, and Treg dysfunction is involved in the pathogenesis of autoimmunity, allergy and cancer. We previously revealed that Tregs rapidly suppress T cell receptor (TCR)-induced calcium store depletion in conventional CD4+CD25− T cells (Tcons) independently of IP3 levels, consequently inhibiting NFAT signaling and effector cytokine expression.
Here, we study Treg suppression mechanisms through unbiased phosphoproteomics of primary human Tcons upon TCR stimulation and Treg-mediated suppression, respectively. We have demonstrated that Tregs suppress the signalling cascade in Tcons by inducing a state of overall decreased phosphorylation as opposed to TCR stimulation. Further we also discovered novel phosphosites (T595_S597) in the DEF6 (SLAT) protein that were phosphorylated upon TCR stimulation and conversely dephosphorylated upon coculture with Tregs. Mutation of these DEF6 phosphosites abrogated interaction of DEF6 with the IP3 receptor and affected NFAT activation and cytokine transcription in primary Tcons. Additionally, we also discovered a phosphatase inhibitor from our phosphoproteomic screen, the loss of which rendered the Tcons to be resistant to Treg-mediated suppression.
These novel mechanisms and phosphoproteomics data resource may aid in modifying sensitivity of Tcons to Treg-mediated suppression and contribute to improve treatment of autoimmunity and cancer, particularly considering the frequently observed resistance of target Tcons to Treg-mediated suppression in human autoimmune disease.
Conditional deletion of CD25 in Tregs abrogates their suppressive function independently of Foxp3
Authors: Toomer Kevin Henry , Malek Thomas R. 
Published: January 2023

Abstract
IL-2R signaling is essential for thymic development and homeostasis of CD4+Foxp3+ Tregs, which are required to maintain self-tolerance. Although deletion of IL-2/IL-2R in mice leads to lethal autoimmunity, disease is delayed in comparison to mice lacking Foxp3. It is unclear whether this delay is due to redundant signaling in Tregs by other γc cytokines, or to loss of IL-2 activation of autoreactive T cells. To explore IL-2R function in Tregs, we evaluated the consequence of germline knockout (gKO) versus Treg-conditional knockout (cKO) of CD25. Both types of KO mice developed lethal systemic autoimmunity, but CD25 cKO mice exhibited a scurfy-like phenotype with a life span of 3–4 weeks, while death was delayed until 8–12 weeks in gKO mice. CD4+ and CD8+ T cells were more activated and produced higher levels of TNFα, IL-6, and IFNγ in CD25 cKO mice early in life when compared to CD25 gKO mice. This result in conjunction with normal thymic selection in both models indicates that the slower tempo of autoimmunity in CD25 gKO mice is due to impaired function of their autoreactive T cells, which does not occur in CD25 cKO mice. In addition, Foxp3 levels were only slightly reduced in thymocytes from both models, but they each showed diminished expression of Treg suppressive markers. This finding is consistent with the idea that IL-2R signaling is essential for functional programming of Tregs independent of Foxp3 expression. The effects noted above for nascent thymic Tregs in gKO mice were somewhat more striking than in cKO mice. This observation suggests another IL-2-dependent step in Treg development that is likely redundant. Overall, our data indicate that Tregs are completely non-functional without IL-2R signaling.
Treg-specific LAG3 deletion reveals a key role for LAG3 in regulatory T cells to inhibit CNS autoimmunity
Authors: Thaker Youg Raj , Andrews Lawrence P. , Workman Creg J. , Vignali Dario A. A. , Sharpe Arlene H. 
Published: January 2023

Abstract
The inhibitory receptor Lymphocyte activation gene 3 (LAG3; CD223) plays a key role in regulating T cell activation and tolerance. LAG3 can be expressed on CD4+ FoxP3+ regulatory T cells (Tregs) and conventional effector T cells (Tcons). We found that LAG3 is highly expressed by CD4+ FoxP3+ Tregs in the CNS of mice with experimental autoimmune encephalitis, a mouse model of multiple sclerosis, leading us to examine LAG3 function on CD4+ FoxP3+ Treg in EAE. To study LAG3 function on Tregs in EAE, we crossed mice in which LAG3 is absent on the cell surface of CD4+ FoxP3+ Tregs with 2D2 T cell receptor (TCR) transgenic specific for myelin oligodendrocyte glycoprotein (MOG35-55). Surprisingly, 100% of the 2D2 TCR transgenic mice lacking LAG3 on Tregs developed spontaneous EAE. In marked contrast, none of the 2D2 control mice developed EAE. Similarly, non-TCR transgenic mice lacking LAG3 on Tregs developed more severe induced EAE (by immunization with MOG35-55 in CFA) compared to controls (max clinical score 3.5±0.3 in LAG3 deficient vs. 2.8±0.1 in control SEM). Histological analysis revealed significantly more lesions in both brain and spinal cord of LAG3 deficient mice (mean number in spinal cord 226.5 ± 10.57 LAG3 deficient vs. 51.4 ± 40.81 in controls SEM). Ex vivo analysis at the peak of disease showed that disease severity was accompanied by an increase in the pathogenicity of Tcons producing high levels of IFN-γ and granzyme B. Although no significant differences were observed in CNS infiltration of Tregs, LAG3 deficient Tregs produced IFN-γ and granzyme B, suggesting that they are no longer protective, but instead contribute to CNS disease. These findings point to a key role for LAG3 in controlling Treg function and maintenance of tolerance in the CNS.
Early neutrophil depletion reduces inflammation-sensitized hypoxic-ischemic brain injury in mouse neonates.
Authors: Yao Hui-Wen , Kuan Chia-Yi 
Published: January 2023

Abstract
Hypoxia-ischemia to brain triggers immune responses consisting of activation and recruitment of leukocytes and expression of pro-inflammatory mediators. Inducing neutropenia confers protection against cerebral ischemia in adult and neonatal rats, but it remains unclear if neutrophils enhances neonatal brain damage in inflammation (LPS)-sensitized hypoxic-ischemic (HI) insults to mice. Herein, we demonstrated that following LPS/HI insult, the mRNA expression of C-X-C motif ligands 1 and 2, two potent neutrophil chemoattractants, granulocyte colony-stimulating factor that stimulates the bone marrow to produce and release granulocytes, and pro-inflammatory cytokines, including interleukins 1β and 6 and tumor necrosis factor α, were increased in mouse brains. As early as six hours after insult, neutrophil infiltration was readily detectable in mouse brains and increased with time, especially in those brains with severe damage. Neutrophils either resided within vessel like structures or accumulated within brain parenchyma. In addition, infiltrated neutrophils expressed interleukin 1β and tumor necrosis factor α, as well as citrullinated histones, a marker of neutrophil extracellular traps, in the damaged brains. Importantly, prophylactic depletion of neutrophils from the periphery reduced leukocyte infiltration, the expression of pro-inflammatory mediators in mouse brains, and brain atrophy, whereas post-insult depletion of neutrophils conferred marginal protection. Collectively, our data support the pathogenic roles of neutrophils in the acute phase of inflammation-sensitized hypoxia-ischemia brain injury.
Neutrophil elastase activates MMPs in macrophages and promotes adhesion and cytokine expression through the integrin – Srk pathway.
Authors: Krotova Karina , Khodayari Nazli , Oshins Regina , Aslanidi George , Brantly Mark 
Published: January 2023

Abstract
There are a number of diseases characterized by the presence of neutrophil elastase (NE) activity in tissues. It is generally accepted that presence of NE actively contributes to a pathological process, but the precise mechanism remains to be elucidated.
We hypothesize that one NE action is activation of an inflammatory response in macrophages (Mφ). First, we show that in response to free NE exposure, Mφ release profound proteolytic activity composed of several MMPs which could contribute to extracellular matrix (ECM) degradation. Second, NE treatment also upregulated inflammatory cytokine expression, such as that of TNFα, IL-6, IL-1b, and IL-8. Therefore, Mφ activated by NE can contribute to tissue destruction on several levels, including release of proteolytic activity and by supporting chronic inflammation through expression of chemokines and cytokines.
We also demonstrate that NE increases Mφ adhesion which can be attenuated by antibodies against integrin subunits. In support of our hypothesis of integrin involvement, we show an activation of the Srk kinase family in response to NE, which is a hallmark of integrin signaling pathway activation. Moreover, pretreatment of Mφ with specific Srk kinase inhibitor PP2 completely blocked cytokine production in response to NE.
In summary, these data propose the mechanism of macrophage activation by NE and also suggest the inhibition of Srk can be potential therapeutic target to reduce NE-induced inflammation in lungs.
CD11c+ cells are required for lymphocyte trafficking into previously infiltrated pancreatic islets during type 1 diabetes.
Authors: Sandor Adam , Lindsay Robin S. , Gebbert Matthew , Bradley Brenda , Haskins Kathryn , Jacobelli Jordan , Friedman Rachel Sharon 
Published: January 2023

Abstract
Type 1 diabetes (T1D) results from the T cell mediated autoimmune attack of the insulin producing beta cells within the pancreatic islets. Although inhibition of T cell trafficking has been used therapeutically for other autoimmune diseases, the requirements for T cell trafficking to the islets are unclear. We show that short-term CD11c+ cell depletion in non-obese diabetic (NOD) mice with previously infiltrated islets reduced lymphocyte trafficking to the islets. Initial CD11c+ cell antigen presentation in the lymph node is known to be critical for initial T cell trafficking to the islets, but the role of CD11c+ cells in lymphocyte trafficking to infiltrated islets is unclear. CD11c+ cells include cells that are highly efficient antigen presenters; however, we show entry of both activated or naïve T cells into previously infiltrated islets were not reliant on cognate antigen. There were also no changes in vascular adhesion molecule expression or adhesion to the vasculature after CD11c depletion. We also show that chemokine receptor signaling is necessary for T cell trafficking to previously infiltrated islets. Based on these data, we hypothesize that CD11c+ cells facilitate the process of extravasation into infiltrated islets through chemokine production. CD11c+ cells in the islets express high levels of CXCL9 and CXCL16, chemoattractants for T lymphocytes. CXCR3 and CXCR6, the receptors for CXCL9 and CXCL16 respectively, are present on T cells in the islets. We therefore explored the importance of these myeloid expressed chemokines in T cell trafficking to the islets. Targeting CD11c+ cell chemokine production may be useful therapeutically for the treatment of T1D by preventing T cell entry into remaining or transplanted islets.
Gut pathobiont translocation induces lymphocyte migration to internal organs in autoimmunity
Authors: Fine Rebecca , Vieira Silvio Manfredo , Ruiz Daniel Fernando Zegarra , Kriegel Martin A. 
Published: January 2023

Abstract
Gut commensal translocation to distant sites can drive autoimmunity. We have evidence that a gut pathobiont, Enterococcus gallinarum, translocates spontaneously to internal organs in the lupus-prone (NZWxBXSB)F1 mouse model to induce systemic autoimmune disease. Lymphocyte migration during commensal translocation to secondary lymphoid organs is not well characterized but may contribute to understanding host-microbiota interactions in autoimmunity. We thus investigated if gut-imprinted lymphocytes migrate to non-gut organs that are progressively colonized by a pathobiont in the (NZWxBXSB)F1 model. We longitudinally characterized gut homing markers on lymphocytes isolated from various tissues of autoimmune-prone F1 mice and monocolonized C57BL/6 mice. In F1 males, circulating CD4+α4β7+ and CD4+CCR9+ cells were increased with age. These subpopulations were reduced after administration of oral antibiotics that deplete the microbiota including E. gallinarum. Next, we monocolonized non-autoimmune prone C57BL/6 mice with E. gallinarum to track lymphocyte migration specifically due to this pathobiont that we have shown to translocate to liver and spleen, induce Th17 responses and autoantibody production. Aged monocolonized C57BL/6 mice harbored greater Peyer’s patch and splenic CD4+ T cells as well as splenic CD4+α4β7+ T cells, supporting that gut-imprinted lymphocytes follow E. gallinarum to non-gut sites. In summary, we linked gut-imprinted lymphocyte migration to internal organs in the setting of systemic autoimmunity that is induced by a translocating pathobiont. Ongoing studies are aimed at determining if these T cells are commensal-reactive and if blockade of gut homing can abrogate autoimmunity.
Histone Demethylase Jmjd3 Controls T-Cell Trafficking and Persistence by Interacting with Klf2 for Expression of Pdlim4
Authors: Fu Chuntang , Li Qingtian , Zou Jia , Xing Changsheng , Zhu Motao , Tan Peng , Lin Meng , Wang Rongfu 
Published: January 2023

Abstract
Jmjd3, a histone H3K27 demethylase, plays a critical role in gene expression and T-cell differentiation, but its role and mechanisms in T cell trafficking remain poorly understood. Here we have shown that Jmjd3 deficiency in CD4+ T cells resulted in the accumulation of T cells in the thymus, but a reduced number in secondary lymphoid organs. To understand the molecular mechanisms of Jmjd3 action, we identified PDLIM4 as a significantly downregulated target gene in Jmjd3-deficient CD4+ T cells by gene profiling and ChIP-seq analyses. Further investigation shows that Jmjd3 bound to the promoter and gene body regions of PDLIM4 gene and regulated PDLIM4 expression by interacting with zinc finger transcription factor KLF2. Furthermore, we showed that PDLIM4 was involved in filamentous actin (F-actin) remodeling, thus functioning as a key regulator of T cell trafficking. Our findings have identified PDLIM4 as a novel Jmjd3 target gene that affects T-cell trafficking, and provided insights into the molecular mechanisms by which Jmjd3 regulates genes participate in T-cell trafficking.
Effect of insulin receptor expressing T cell infiltration in islets on beta cell functionality
Authors: Nandedkar Neha D. , Rhoades Emily L. , Gupta Nirdesh , Al-Dieri Ali G. , Bretz James , Hafner Hannah , Gregg Brigid , McInerney Marcia F. 
Published: January 2023

Abstract
T cells have a major role in the progression of type 1 diabetes (T1D) in human and the non-obese diabetic (NOD) mouse model. Activated T cells have increased insulin receptor (IR) expression on their surface. When T cells with high density of IR from NOD mice were transferred into young irradiated non-diabetic NOD mice, recipient mice developed insulitis and diabetes. Irradiated non-diabetic NOD mice that received T cells with low to negative density of IR had neither insulitis nor diabetes. In order to understand the effect of IR expressing T cells in T1D development, our lab has developed a novel transgenic mouse model, C57BL/6-CD3FLAGmIR/mfm, genetically modified to express FLAG tagged mouse insulin receptor (mIR) on T cells.
It was observed that FLAG-mIR expressing T cells can chemotax to the islet leading to insulitis. However, C57BL/6-CD3FLAGmIR/mfm mice were not hyperglycemic at any age. Metabolic studies were performed to evaluate if FLAG-mIR expressing T cell infiltration in the transgenic mice has effect on beta cell functionality. Impaired in vitro islet insulin secretion on treatment with non-glucose beta cells secretagogue and abnormal glucose tolerance in the transgenic mice resemble the pathological changes during prediabetes in human and NOD mice. Islet and Metabolic changes were also found in immunocompromised RAG mice that received transgenic mice splenocytes confirming that the transgenic phenotype can be passaged to immunocompromised RAG mice in a short time frame. This study provides a new perspective to understand the pathology of T1D and design a novel therapeutic approach targeting IR overexpressing T cells.
Inhibitor of MyoD Family A (I-mfa) regulates HSPC and myeloid differentiation
Authors: Houser Jeremy S. , Onopiuk Marta , Ratliff Michelle , Ngo Peter , Webb Carol , Tsiokas Leonidas , Humphrey Mary Beth 
Published: January 2023

Abstract
Hematopoietic stem and progenitor cell (HSPC) populations are capable of expanding in response to immunological insult or homeostatic turnover. Regulation of the fate decision between self-renewal and differentiation allows for both maintenance of blood cell populations and sustained hematopoiesis across the entire life-span. I-mfa, a small cytosolic protein, has been shown to inhibit lineage-specific transcription factors as well as regulate β-catenin/Wnt signaling. We have previously shown that I-mfa-null mice have increased myeloid cells resulting in increased osteoclasts and hypothesized that I-mfa regulates myeloid lineage differentiation and may affect HSPC populations.
In order to test this, bone marrow (BM) from I-mfa−/− mice was analyzed by flow cytometry, showing increases in both long-term and short-term hematopoietic stem cells compared to WT controls, an effect which increased with age. Additionally, both common myeloid precursors (CMP) and granulocyte-macrophage precursors (GMP) were increased in I-mfa−/− mice. Conditional knockout of I-mfa in all hematopoietic lineages using Vav1-Cre lead to similar findings, while conditional knockout in myeloid cells with LysM-Cre showed only increases in myeloid progenitors. These data indicate that I-mfa has separate roles in regulating HSPC expansion and myeloid cell differentiation. Mechanistically, M-CSF-stimulated I-mfa−/− BM had significantly increased transcription of β-catenin signaling target genes Ccnd1, Axin2, and Myc, as well as myelopoietic transcription factors Spi1, Irf8, and Klf4, compared to WT. Further studies are being conducted to determine the effect of I-mfa on quiescence, Wnt ligand sensitivity, and BM reconstitution capacity.
The pro-inflammatory microRNA-155 promotes FLT3-ITD-induced myeloproliferative disease through inhibition of interferon signaling
Authors: Wallace Jared A. , O’Connell Ryan 
Published: January 2023

Abstract
microRNA-155 (miR-155) is a pro-inflammatory microRNA that functions within a variety of immune cell types to direct proper immune responses. However, miR-155 has also emerged as an oncogene in a number of cancers, and overexpression of miR-155 in the bone marrow is sufficient to induce a lethal myeloproliferative disease in mice. This suggests that miR-155 could be a critical link between inflammation and cancer. Activating mutations in the FMS-like tyrosine kinase 3 (FLT3) receptor known as FLT3-ITD are common in human myeloid malignancies and confer a poor prognosis. Interestingly, FLT3-ITD aberrantly activates well known inflammatory pathways, including NF-kB and STAT5, and drives increased expression of miR-155. We utilized a mouse model of FLT3-ITD-induced myeloproliferative neoplasm to examine the role of miR-155 in promoting disease outcomes in this setting.
We found that miR-155-deficient FLT3-ITD mice exhibit decreased myeloid expansion in the bone marrow, blood, and spleen resulting in a less severe myeloproliferative disease. Furthermore, our data indicate that miR-155 is needed to maintain a robust hematopoietic stem and progenitor cell (HSPC) and myeloid progenitor pool in FLT3-ITD mice by promoting proliferation of these stem cell compartments. Further analysis of the HSPCs and myeloid progenitor cells revealed that FLT3-ITD mice lacking miR-155 had an increased response to interferon, known to have a growth-suppressive effect on hematopoietic cells. These findings demonstrate an interesting link between inflammatory pathways and hematopoietic malignancy, and suggest that miR-155 inhibition could have therapeutic efficacy in FLT3-ITD induced myeloproliferative diseases and/or myeloid leukemia.
A novel approach to enhance T cell recovery after bone marrow transplant
Authors: Wimberly Kymberly L. , Semwal Manpreet , Xiao Yangming , Griffith Ann 
Published: January 2023

Abstract
Cytoablative treatments such as chemotherapy and radiation are commonly used during allogeneic hematopoietic stem cell (HSC) transplants. After cytoablation, T cells must be replaced to generate effective immune responses. Cytoablative therapies damage the thymic stromal cells (TSC) comprising the lymphopoietic microenvironment necessary for T cell development. Damage to TSCs causes delayed thymic recovery, and corresponding delays in T cell recovery in HSC transplant patients, which directly contribute to increased susceptibility to infection and malignant relapses. However, the mechanisms that cause TSCs to be particularly sensitive to cytoablative therapies are not completely understood. Substantial cellular damage is caused by reactive oxygen species (ROS) generated during radiation and chemotherapy treatments. Our recent work identified a deficiency in the antioxidant enzyme catalase in TSCs, indicating that this population may be particularly sensitive to ROS. We hypothesize that oxidative damage to TSCs during cytoablative therapy is exacerbated by catalase insufficiency, and that this is an important contributor to delayed thymus recovery after treatment. If so, an optimized regimen of antioxidant supplementation during cytoablative therapy may represent a novel approach to enhance immunity after HSC transplant. We have tested this hypothesis using dietary and genetic supplementation of catalase activity in mice receiving bone marrow transplants after irradiation. Our preliminary data support the notions that catalase deficiency increases TSC sensitivity to radiation, and that thymus recovery after bone marrow transplant can be improved by supplementing catalase activity in mice.