bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD6 modulation ameliorates immune complex-mediated glomerulonephritis
Authors: Chalmers Samantha A. , Garcia Sayra J , Herlitz Leal , Ampudia Jeanette , Ng Cherie , Connelly Stephen , Putterman Chaim 
Published: January 2023

Abstract
Lupus nephritis (LN) is a serious end organ complication of systemic lupus erythematosus (SLE) in which T cells are thought to play an essential role. CD6 is a co-stimulatory receptor on T cells, that binds to activated leukocyte cell adhesion molecule (ALCAM), a ligand expressed on antigen presentation cells and epithelial and endothelial tissues. The CD6-ALCAM pathway plays an integral role in modulating T cell activation and trafficking, and increased levels of CD6 are associated with pathogenic T cell responses. To assess the role of the CD6-ALCAM pathway in LN pathogenesis, we tested a monoclonal antibody against CD6 in a short-term, validated, inducible murine model of lupus nephritis known as nephrotoxic serum nephritis (NTN). NTN mice were treated 3× per week with an anti-CD6 mAb (10D12, 60ug/dose, n=23) or with vehicle control (n=23). Healthy mice were also included as a control (n=12). Mice treated with the anti-CD6 mAb displayed decreased levels of proteinuria (p&lt;0.001) and significantly improved BUN levels (p&lt;0.01) compared to vehicle control mice. Histology also significantly improved with anti-CD6 treatment (p&lt;0.05). RT-PCR revealed significantly decreased levels of VCAM and RANTES in the kidneys of treated mice, while anti-inflammatory IL-10 was increased, compared to vehicle control mice. Flow cytometry analysis indicated decreased accumulation of both renal-infiltrating activated T cells (CD4+CD25+CD69+, p &lt;0.01) inflammatory macrophages (p&lt;0.05). Overall, these results indicate that the CD6-ALCAM pathway is an important driver of inflammation and pathology in LN and, thus, a promising therapeutic option that is more selective than the immunosuppressive therapies currently offered.
Gata3 regulates the pathogenicity of Tbet-expressing Th17 cells in EAE
Authors: Butcher Matthew J , Gurram Rama Krishna , Chen Xi , Zhu Jinfang (Jeff) 
Published: January 2023

Abstract
Tbet+RORgt+ Th17 cells are thought to be key players in the pathology of experimental autoimmune encephalomyelitis (EAE) and GM-CSF production has been proposed to be one mechanism through which Th17 are encephalitic. However, the mechanisms through which Csf2 expression is regulated are unclear. Based on prior work highlighting a regulatory role for Gata3 in NKp46+ ILC3s, we hypothesized that Gata3 might play an analogous role in Tbet+ Th17 cells during EAE. Profiling Gata3 expression in MOG-immunized mice revealed that Th17 cells dynamically express Gata3 during their differentiation and maintain low levels thereafter. Therefore to determine how Gata3 might affect the pathogenicity of Tbet+ Th17 cells, we utilized tamoxifen inducible Gata3 knockout (Cre-ERT2 Gata3Fl/Fl) mice as donors in a transfer EAE model. In this model, a post-immunization deletion of Gata3 resulted in a failure to generate EAE symptoms due to a five-fold reduction in GM-CSF production, despite a normal Th17 and Tbet+ Th17 cell responses. To assess how Gata3 might affect the expression of Csf2 in a cell-intrinsic manner, we isolated Cd45.1/Cd45.2 and Cre-ERT2 Gata3Fl/Fl CD4+ effector T cells from the CNS of tamoxifen or vehicle treated co-transfer recipient mice for RNAseq. Interestingly, Gata3-deficient CD4+ T cells displayed stark reductions in Bhlhe40, Egr2, and Csf2 expression in a cell-intrinsic manner, which was confirmed in follow-up experiments. Taken together, our data suggests that Gata3 promotes the pathogenicity of Tbet+ Th17 cells in EAE, possibly via regulation of Bhlhe40 and GM-CSF expression.
This research was supported by the Intramural Research Program of NIAID, NIH.
The gut as a potential licensing site for central nervous system (CNS)-specific autoimmune lymphocytes
Authors: Salvador Ryan S. , Horai Reiko , Jittayasothorn Yingyos , Tang Jihong , Gery Igal , Caspi Rachel R 
Published: January 2023

Abstract
Autoimmune diseases of the CNS, experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune uveoretinitis (EAU) can be induced by adoptive transfer (AT) of activated brain- or retina-specific T cells. The transferred T cells rest for several days in the recipient’s spleen or lungs, where they proliferate and differentiate to a migratory phenotype before invading the CNS, a process termed “licensing” for pathogenicity (PMID: 27986906). Our previous data in a spontaneous uveitis model in R161H mice bearing a retina-specific TCR indicated that the gut may serve as a priming site for uveitogenic T cells through molecular mimicry of gut flora (PMID: 26238373). We now asked if the gut might also serve as a licensing site for autopathogenic T cells.
Naive B10.RIII mice received AT of allotype-marked, activated R161H T cells and were monitored for EAU. Donor cells in tissues were detected by flow cytometry. Three days after AT, donor T cells could be detected in spleen, lung and gut, including the mesenteric lymph nodes and lamina propria of the large and small intestine. Similarly to lung and spleen, R161H T cells in the gut showed signs of proliferation by CFSE dilution. This was not altered by antibiotic treatment of recipients before AT to eliminate gut flora, suggesting that microbiota is not needed to retain effector T cells in the gut.
We hypothesize that primed retina-specific T cells can receive licensing signals in the gut. Since in spontaneous uveitis they may also be primed there, this could be of relevance to a disease situation. Further characterization of phenotypic and transcriptomic changes of “licensed” R161H cells retrieved from the gut may help to elucidate the local signals important for licensing at this site.
Sjögren’s syndrome minor salivary gland CD4+ T cells associate with glandular disease features and have a germinal center T follicular helper transcriptional profile
Authors: Farris A. Darise , Joachims Michelle L , Leehan Kerry M , Dozmorov Mikhail G , Georgescu Constantin , Pan Zijian , Rasmussen Astrid , Radfar Lida , Lewis David M , Stone Donald U , Grundahl Kiely , Scofield R. Hal , Lessard Christopher J , Wren Jonathan D , Thompson Linda F , Sivils Kathy L , Moore Jacen S 
Published: January 2023

Abstract

Objective
To assess the types of salivary gland (SG) T cells contributing to Sjögren’s syndrome (SS), we evaluated SG T cell subtypes for association with disease features and compared the SG CD4+ memory T cell transcriptomes of primary SS (pSS) and sicca subjects not meeting SS criteria (nSS).

Methods
SG biopsies of pSS and nSS subjects were evaluated for proportions (n=51 pSS, n=69 nSS) and absolute numbers (n=35 pSS, n=57 nSS) of CD4+ and CD8+ T cells. SG memory CD4+ T cells from focus score positive pSS (n=17) and focus score negative nSS subjects (n=15) were evaluated for gene expression by microarray. Differentially-expressed genes were identified and gene set enrichment and pathways analyses were performed.

Results
CD4+CD45RA− T cell frequencies were increased in pSS compared to nSS subjects (33.2 vs. 22.2%, p&lt;0.0001), while CD8+CD45RA− T cells were decreased (38.5 vs. 46.0%, p=0.0014). SG fibrosis positively correlated with numbers of memory T cells, regardless of phenotype. Proportions of SG CD4+CD45RA− T cells correlated with focus score (r=0.43, p&lt;0.0001), corneal damage (r=0.43, p&lt;0.0001), and serum Ro antibodies (r=0.40, p&lt;0.0001). Differentially expressed genes in CD4+CD45RA− cells of pSS versus nSS subjects indicated a T follicular helper (Tfh) profile, increased homing and increased cellular interactions. Predicted upstream drivers of the Tfh signature included TCR, TNF, TGF-β1, IL-4 and IL-21.

Conclusions
The proportions and numbers of SG memory CD4+ T cells associate with key SS features, consistent with a central role in disease pathogenesis. SG memory CD4+ T cells express a germinal center Tfh profile.
Zfp36 family members redundantly protect against T cell-mediated autoinflammation and premature mortality
Authors: Cook Melissa Erin , Bradstreet Tara R , Santeford Andrea , Kim Jongshim , Webber Ashlee , Schwarzkopf Elizabeth A , Jarjour Nicholas N , Lin Chih-Chung , Stumpo Deborah J , Apte Rajendra S , Blackshear Perry J , Edelson Brian T 
Published: January 2023

Abstract
Cytokine production must be tightly regulated in order to prevent auto-inflammatory diseases. The zinc finger 36 (Zfp36) family of RNA-binding proteins, including Zfp36, Zfp36l1, and Zfp36l2, are known to negatively regulate mRNA stability or translation of many transcripts, including cytokines. Polymorphisms in ZFP36L1 and ZFP36L2 have been identified in GWAS studies of a variety of human autoimmune diseases, necessitating understanding the functions of these genes. While there are reports of all three family members controlling cytokine production from T cells, delineating the exact functions of these genes has been challenging due to spontaneous phenotypes or mortality upon global deletion of single genes and potential redundancy in their functions. To overcome this, we generated Cd4-Cre+ Zfp36fl/fl Zfp36l1fl/fl Zfp36l2fl/fl mice. Only upon triple deletion, but not individual or various paired deletions, do mice spontaneously develop an inflammatory disease characterized by early mortality and immune cell infiltration into various organs, including the central nervous system, kidneys, and liver. These mice have drastically elevated levels of many cytokines in their sera. Our findings demonstrate a novel redundancy of the Zfp36 family members in regulating T cell homeostasis and suppressing cytokine-driven inflammation. We are currently investigating the specific mechanisms and mRNA targets that contribute to this phenotype and whether disease is primarily driven by CD4+ or CD8+ T cells. Understanding the individual and redundant functions of the Zfp36 family members may lead to opportunities to target them for suppression of T cell-driven autoimmunity or for activating anti-tumor or anti-pathogen T cell responses.
Aged T cells shape neuronal autoimmune disease in a model of late-onset multiple sclerosis (Supported by NIH/NIAID R01AI121147)
Authors: Wang Weikan , Oh Jiyoung , Thomas Rachel , Su Dongming 
Published: January 2023

Abstract
Although multiple sclerosis (MS), a T cell-mediated autoimmune demyelinating disease, mainly develops in young people, late-onset has also been observed in aged people. The aged T cell immune system is different from the young. One of characteristics is disrupted thymocyte negative selection, and relatively enhanced thymic regulatory T (tTreg) cell generation and accumulated peripheral Treg (pTreg) cells. The relatively increased polyclonal Treg cells potentially shape the MS disease courses, and may even prevent remission stages of this disease. Using the mouse model experimental autoimmune encephalomyelitis (EAE) of human MS, we determined that a late-onset EAE has two types of disease courses. I: Onset of EAE in the aged group was later than the young group, but after onset, the disease became more severe than in their young counterparts; II: Alternatively, onset of EAE in the aged group never became severe until after a second antigen challenge was given, causing the symptoms to appear and progress to severe disease much faster than in their young counterparts. We also found that this late-onset of EAE was associated with a disparate distribution of Treg cells in lymph nodes versus in the central nervous system (CNS) during the disease. The aged mice had a high proportion of pTreg cells in the lymph nodes, but a low proportion in the CNS, compared to their young counterparts. We believe that accumulated pTreg cells in the elderly, which is one of hallmarks of aged T cell immune system, potentially results in their residing in the blood-brain barrier and/or choroid plexus, which hampers trafficking of monocytes and/or antigen-specific Treg cells into the CNS. Thus, it is detrimental for a CNS repairing processes in neuronal inflammation.
The Role of Aire in the selection of Regulatory T cells in Diabetes
Authors: Bridge Jennifer Anne , Balolong Jared , Dong Shen , Cramer Nathan , Mowery Cody , Crawford Frances , Ye Jimmie , Kappler John W , Bluestone Jeffrey A , Anderson Mark S 
Published: January 2023

Abstract
In autoimmune diseases like T1D, it is proposed that failure in central tolerance mechanisms towards pancreatic islet self-antigens leads to the escape of pathogenic clones and loss of critical immunosuppressive antigen-specific Tregs. The importance of Aire in maintaining central tolerance against self-reactive antigens is evidenced by the multiorgan autoimmune disease seen in individuals with mutation the Aire gene. When Aire-expression is specifically ablated in mouse mTECs, there is a dramatic increase in the number of self-reactive T cells that escape negative selection, in addition, a dramatic loss of Tregs. Utilizing novel high-throughput platforms and single-cell DNA barcoding technology has allowed us to assess several thousand CD4+ T-cell clones. The use of FoxP3-GFP reporter mice permits us to identify individual Tregs that have undergone Aire-dependent selection in the thymus and compare the TCR repertoire to mice that have had Aire specifically ablated from the mTECs. Identification of unique clones and gene signatures within our large datasets has allowed us to start to qualitatively assess the functional role of the identified TCRs within the model of T1D. We have begun comparisons of our extensive datasets to insulin-specific TCRs and TCRs that we have previously identified from diabetic animals. In addition, the peptide specificities of the identified TCRs are being evaluated using Baculovirus MHC-II peptide libraries. Our proposed study aims to expand our knowledge on TCR repertoire of Aire-dependent Tregs and the antigen-specificity in T1D, improving our understanding of the respective function of thymic-derived antigen-specific Treg suppression in peripheral tissues associated with autoimmune T1D.
Inflammation associated weight cycling contributes to an obesogenic memory phenotype in adipose tissue
Authors: McDonald Sierra J , Sougiannis Alexander T , Vanderveen Brandon , Cranford Taryn , Enos Reilly T , Velazquez Kandy , Chatzistamou Ioulia , Fan Daping , Murphy Angela E 
Published: January 2023

Abstract
Energy expenditure through physical activity and dieting promotes weight loss. However, sustaining a healthy weight can be challenging and often a pattern known as weight cycling emerges. We evaluated the inflammatory status of mice undergoing weight cycling. Male C57BL/6 mice were randomized into four groups (n=10/group): low fat diet (LFD) for 32 weeks (LFD), high fat diet (HFD) for 32 weeks (HFD), LFD for 28 weeks then changed to HFD for 4 weeks (LFD-&gt;H), HFD for 21 weeks then changed to LFD for 7 weeks and then changed to HFD for 4 weeks (HFD-&gt;L-&gt;H). LFD-&gt;H and HFD-&gt;L-&gt;H mice did not significantly differ in body weight, body fat weight, or body fat percentage, but were significantly higher than LFD mice while remaining lower than HFD mice (p&lt;0.05). In addition, HFD-&gt;L-&gt;H mice had smaller adipocytes of the epididymal fat pad compared to HFD and LFD-&gt;H mice which both had larger adipocytes (p&lt;0.05) compared to LFD. TNFα and IFNγ were higher (p&lt;0.05) in the epididymal fat pad of HFD-&gt;L-&gt;H mice compared to LFD and LFD-&gt;H mice. This was consistent with more M1-type macrophages (p&lt;0.05) and cytotoxic T-cells (p&lt;0.05) as indicated by ITGAX and CD8a gene expression, respectively. However, MCP1 was significantly lower (p&lt;0.05) in HFD-&gt;L-&gt;H mice compared to LFD-&gt;H. Liver histopathological and protein analysis revealed HFD-&gt;L-&gt;H mice had greater NASH and NAS (p&lt;0.05) scores, increased total STAT3 and NF-kB (p&lt;0.05) compared to LFD controls. Taken together, weight cycling can lead to aberrations in the storage of triglycerides when challenged with an increased caloric intake. This is further supported by an increase in adipose tissue inflammation in weight cycling mice which is likely contributing to the observed obesogenic memory phenotype.
Imaging neuroinflammation in murine endotoxemia: a dual-tracer microPET evaluation
Authors: Turecki Lauren , Palandira Santhoshi P , Liu Hui , Addorisio Meghan , Tsaava Tea , Chang Eric , Ma Yilong , Carrion Joseph , Tracey Kevin J , Pavlov Valentin A 
Published: January 2023

Abstract
Brain dysfunction, including neuroinflammation, metabolic changes, and cognitive impairment has been reported in sepsis and other disorders “traditionally” characterized by peripheral immune and metabolic dysregulation (Annu Rev Immunol, 2018, 36:783–812). In this context, non-invasive evaluation of neuroinflammation is important for strategizing new diagnostic and therapeutic approaches targeting the brain. We utilized Micro Positron Emission Tomography (microPET) with [18F]Fluoro-2-deoxy-2-D-glucose (18FDG) and 11C-Peripheral Benzodiazepine Receptor ([11C]PBR) to evaluate brain metabolic alterations and microglia activation (indicating neuroinflammation) during murine endotoxemia. Lipopolysaccharide (LPS, endotoxin) (2 mg/kg) or saline was injected (i.p.) in male C57Bl/6 mice 6 hrs prior to microPET imaging. [11C] PBR28 (~0.5 mCi) was injected via the tail vein followed by 60 mins dynamic imaging. Subsequently, 18FDG (0.5 mCi) was injected i.p. with a 10 mins static scan acquired following 40 mins uptake. Brain images were analyzed in a standard anatomical space using Statistical Parametric Mapping. Significantly (P&lt;0.01) increased glucose metabolism in endotoxemic mice (vs controls) was observed in the hippocampal CA2/CA3 region and other brain areas. Increased [11C]PBR28 binding (P&lt;0.05) was also determined in the hippocampal CA2/CA3 region. These results indicate brain hypermetabolic activity and neuroinflammation during endotoxemia specifically affecting the hippocampus – an area with a primary role in memory and cognition. These findings support further development of PET-based evaluation of neuroinflammation in preclinical and clinical settings of inflammatory and metabolic disorders.
How safe is the application of nanotitania when it can induce inflammatory response, affect liver function or body weight in animal models?
Authors: Sharma Nilesh , Leibman Hannah , Sadrinia Cyrus 
Published: January 2023

Abstract
Consumer products containing significant amounts of Ti-nanoparticles include paints, toothpaste, colorants, cosmetics, sunscreens, medicine, and beverages. Ti is generally considered biologically inert, but Ti-nanoparticles were observed to cause significant toxicity in recent studies. In this study, lab mice were administered intraperitoneally TiO2 rutile crystals (30–50 nm) at the rate of 333 and 1332 mg/kg (body weight) at 0, 5 and 10 day during a 15-d period. After termination of the experiment, spleen extract and circulating blood were assayed for cytokines using ELISA. Elevated levels (p&lt;0.05) of inflammatory cytokines (TNF-α, IFN-γ, IL-1-α, IL-1β and IL-6) were detected in spleen extracts, whereas significantly reduced levels of VEGF and Rantes were obtained from both spleen extract and blood, relative to control. Liver functions and organ weights were also significantly affected under both doses. Toxicity model based on C. elegans also demonstrated significant toxicity in respect of mortality and behavior response under the dose of 25–100 ppm. Further, gene expression studies related to immune responses are continuing to determine the toxicity effects in C. elegans and mouse models.
The kinase activity of IRAK4 controls sterile autoinflammation and manifestations of Murine Lupus
Authors: Agliano Federica , Ménoret Antoine , Karlinsey Keaton S. , Ragazzi Michael , Karginov Timofey , Vella Anthony T. 
Published: January 2023

Abstract
Interleukin-1 receptor-associated kinase (IRAK) 4 is a serine/threonine kinase involved in TLR/IL-1R responses. Upon TLR/IL-1R activation, autophosphorylation of IRAK4 induces proinflammatory gene transcription. In this study we hypothesize that the kinase activity of IRAK4 may be a druggable target in the treatment of sterile autoinflammation and Lupus. C57BL/6 female mice injected with the hydrocarbon oil Pristane, exhibited a significant Pristane-dependent induction of splenomegaly; whereas treatment with the IRAK4 kinase inhibitor reduced this inflammatory symptom. Conversely, no significant difference was observed in males. Using mass spectrometry, we found that the urine of Pristane-injected mice contained increased levels of putative markers for several inflammatory diseases, which were reduced by IRAK4 kinase inhibition. We showed that Pristane-injected mice had increased cell free DNA in serum, which was not impacted by kinase inhibitor treatment. However, chemokine release was significantly reduced in IRAK4 kinase inhibitor-treated mice. We further analyzed the kinase activity of IRAK4 in MRL-lpr mice, which were compared with MRL-lpr/IRAK4 kinase-inactive (KDKI) mice (where IRAK4 is expressed but its kinase activity is lost). Although MRL-lpr/IRAK4KDKI and MRL-lpr mice did not show differences in CD4+ and CD8+ cells activation, we found a significantly reduced splenomegaly in MRL-lpr/IRAK4KDKI mice compared to controls, also exhibiting a gender bias. Thus, IRAK4 kinase activity might represent a new therapeutic and druggable target in the recruitment of immune cells during sterile inflammatory diseases in humans, including Systemic Lupus Erythematous (SLE).
Lymphangiogenesis near the Cribriform Plate after Cerebral Ischemia
Authors: Choi Yun Hwa , Hsu Martin , Laaker Collin , Sandor Matyas , Fabry Zsuzsanna 
Published: January 2023

Abstract
Recently, it has been hypothesized that antigens, antigen-presenting cells (APC), and cerebrospinal fluid (CSF) may drain from the central nervous system (CNS) into lymphatics near the cribriform plate or dura to provide fluid homeostasis and antigen drainage. However, the role of lymphatic vessels during neuroinflammation is not well understood yet. Our lab has previously shown that lymphatic vessels near cribriform plate undergo lymphangiogenesis during experimental autoimmune encephalomyelitis (EAE), a mouse model of Multiple Sclerosis. Here, we looked to see whether lymphangiogenesis also occurs in a stroke mouse model of neuroinflammation. We established the transient middle cerebral artery occlusion (tMCAO) model of stroke by placing a filament for 60 minutes into the middle cerebral artery, that was followed by reperfusion after removing the filament. We show that lymphangiogenesis occurs near the cribriform plate, peaks at day 7 and decreases after 14 days following tMCAO. To confirm that the newly formed lymphoid vessels at the cribriform plate could connect with the CSF, we injected Evans Blue dye through the cisterna magna and confirmed the presence of the dye in these lymphoid vessels. Flow cytometry analysis showed that robust leukocyte infiltration such as microglia (CD45int, CD11b+), macrophage (CD45hi, CD11b+), dendritic cells (CD45hi, CD11b+, CD11c+), CD8 T cells (CD45hi, CD8+), CD4 T cells (CD45hi, CD4+), and B cells (CD45hi, B220+) near the cribriform plate after 7 days of tMCAO correlates with lymphangiogenesis (CD45−, Podoplanin+, CD31+). The manipulation of inflammation-induced lymphangiogenesis may lead to therapeutics for neuroinflammatory diseases.