bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted over-expression of S100B in the retina of transgenic mice induced exacerbated experimental autoimmune uveitis
Authors: Yu Cheng-Rong , Ogbonna Oluchi , Lee Hyunsu , Choi Jin Kyeong , Jittayasothorn Yingyos , Li Lichao , Egwuagu Charles E 
Published: January 2023

Abstract
S100B, originally found in glial cells (astrocyte and microglial cells), acts as an intracellular Ca++-sensor and an extracellular regulator protein. Its neuronal trophic or toxic effect on cells might be dependent on its cellular concentrations. Human uveitis is an intraocular inflammatory disease of infectious or autoimmune etiology and neuroinflammatory responses orchestrated by retinal microglia cells are implicated in exacerbation of uveitis. The S100B protein is predominantly secreted by glial cells in central nerve system (CNS). In this study we examined whether S100B protein plays a role in regulating inflammatory responses in the neuroretina. To this end we generated retinal S100B transgenic mice and investigated whether experimental autoimmune uveitis (EAU) would be exacerbated in these transgenic mice. We monitored EAU progression and severity by fundoscopy and ERG (Electroretinogram)and found that over-expression of S100B+ promoted retinal inflammatory responses and vision loss during EAU. Results of FACS and ELISA analysis did not indicate significant difference in the numbers of uveitogenic Th1 and Th17 cells in the draining lymph-nodes. However, significant amounts of pathogenic Th1 and Th17 cells were detected in the retina of S100B transgenic mice. Conversely, the numbers of IL-10-producing CD4+Foxp3+Treg cells in the retina was significantly decreased in the S100B transgenic mice. These results suggest that S100B can serve as a biomarker for ocular inflammatory diseases.
Antigen dose affects disease kinetics in a murine model of demyelinating disease
Authors: Gavile Catherine Ann M , Alexander Amanda , Adler Fred , Evavold Brian D 
Published: January 2023

Abstract
Multiple sclerosis is an autoimmune disorder caused by immune cell damage to the myelin sheath lining nerve cells, leading to neuronal damage and dysfunction. The murine model of the disease - experimental autoimmune encephalomyelitis (EAE) - is induced by inoculation with MOG (myelin oligodendrocyte glycoprotein) peptide and an adjuvant, leading to recapitulation of disease that is mediated primarily by CD4 T cells. In this study, we look at the effect of MOG dosage on demyelinating disease kinetics in WT and MOG-deficient animals, as MOG-deficient mice have different numbers of MOG specific CD4 Teff and Tregs. The T cells from MOG deficient animals have a higher affinity for MOG, expand faster, and cause exacerbated disease in an adoptive transfer model compared to CD4 T cells from wildtype mice. Our results indicate that the dose of MOG peptide used to induce disease can also modulate disease course. Using tenfold lower doses changes T cell and disease kinetics resulting in disease that resolves compared to controls. Taken together, we can use varying doses of MOG as a tool to probe CD8 and CD4 T cell expansion and monitor migration of immune cells to the CNS. Further understanding of the cellular tides during disease course enables us to gain insight on how cell ratios in different sites contribute to disease pathogenesis. Using this information, we are developing mathematical modeling tools that could be used to analyze and predict disease progression.
Matrix metalloproteinase -28 alters cellular energetics in macrophages, influencing polarization and activation
Authors: Tokmina-Roszyk Dorota , Onwuha-Ekpete Lillian C. , Refai Mohammed , Tokmina-Lukaszewska Monika , Bothner Brian , Fields Gregg B. 
Published: January 2023

Abstract
Matrix Metalloproteinase -28 (MMP-28) is the newest and least characterized member of the matrixins family of proteolytic enzymes. These enzymes are associated with the degradation of the extracellular matrix affiliated with both physiological and pathological processes, including immune responses. In similar fashion to the rest of MMP family, a vast amount of literature on MMP-28 addresses its’ extracellular role. This study highlights the intracellular role of MMP-28 in macrophages, specifically its ability to modulate cellular energetics and consequently influence M0, M1, and M2 phenotype polarization.
In our preliminary studies, we utilized shotgun proteomics profiling of WT and MMP-28 null mice under both healthy conditions and following experimental autoimmune encephalomyelitis (EAE) induction. We identified two mitochondrial protein complexes dysregulated in MMP-28 null mice. We then isolated bone marrow derived macrophages to further elucidate differences using the Seahorse mitochondrial and glycolytic stress assays. We found that MMP-28 alters mitochondrial respiration and glycolysis across all tested phenotypes (M0, M1, and M2). Moreover, our preliminary data emphasis a significant role for MMP-28 in the efficient utilization of various fuel sources during mitochondrial respiration. Our findings show, for the first time, that MMP-28 has a profound effect on cellular bioenergetics affecting both oxidative phosphorylation, glycolytic pathways, and efficient macrophage activation. This suggests the potential of MMP-28 as both an immunomodulatory agent to further study macrophage bioenergetics and a therapeutic agent for pathologies associated with macrophages.
Blood Monocyte Subsets are Dysregulated and Respond with High IL-6 Secretion in Patients with Systemic Sclerosis
Authors: Friedrich Kathleen , Bearwald Christoph , Pierer Matthias , Rossol Manuela 
Published: January 2023

Abstract

Background
Most of the blood monocytes are classical monocytes (CM), minor subpopulations are intermediate monocytes (IM) and non-classical monocytes (NCM). CD56+ monocytes are a subpopulation of CM. Aim of the study was to analyze monocyte subpopulations in Systemic Sclerosis (SSc) patients and to evaluate their cytokine production potential.

Methods
25 SSc patients and 16 age-matched healthy controls were included in the study. Monocyte subpopulations were analyzed by flow cytometry (antibody staining of CD14, CD16, CD56). Magnetic bead separation was used to isolate monocytes. The cells were stimulated with TLR4 ligand LPS and TLR8 ligand ssRNA40 and cytokines were measured by ELISA.

Results
The absolute number of circulating monocytes was significantly increased in SSc patients compared to healthy controls (684/μl ± 61 vs. 512/μl ± 38, p=0.033). Calculated absolute number of CM and CD56+ monocytes was not different between SSc patients and controls. In contrast, the calculated absolute numbers of IM (72/μl ± 13 vs. 32/μl ± 5, p=0.0003) and NCM was increased in SSc patients compared to controls (97/μl ± 12 vs. 45/μl ± 8, p=0.0011). The cytokine response of SSc monocytes to TLR4 ligand LPS was equal to control monocytes but SSc monocytes produced significantly more IL-6 in response to TLR8 ligand ssRNA40 than control monocytes. In addition, SSc monocytes already secrete IL-6 without further stimulation. IL-6 was also increased in the serum of SSc patients compared to healthy controls.

Conclusion
Total monocytes are expanded in the blood of SSc patients, and this increase is caused by an expansion of IM and NCM. The monocytes might contribute to the presence of IL-6 in SSc patients due to their increased potential to secrete this cytokine.
Defining the role of interferon signaling in mouse models of Down syndrome
Authors: Tuttle Kathryn , Waugh Katherine A. , Minter Ross , Sullivan Kelly D , Espinosa Joaquin M 
Published: January 2023

Abstract
Down syndrome (DS) is caused by triplication of chromosome 21 (chr21) and is the most common chromosomal abnormality (1/700 live births). Our lab recently identified interferons (IFNs) as a core signaling pathway hyperactivated among diverse lineages of primary immune cells from individuals with DS. Notably, four of the six IFN receptor (IFNR) subunits for Types I, II, and III IFNs are encoded on chr21. Heightened IFN signaling in the disomic population is associated with developmental defects, cognitive impairments, and autoimmunity, a clinical profile highly similar to individuals with DS. However, the relationship between IFN signaling and such phenotypes has not been investigated in DS. We stimulated three different mouse models of DS with toll-like receptor (TLR) agonists, which potently induce interferon production. Both chronic and acute administration of TLR agonists caused lethal hyperresponsiveness only in the DS strain that harbors three copies of the IFNR locus. The resulting inflammation impacts multiple organ systems. This observation has profound implications for understanding how people with DS may differentially experience inflammation in response to infection during their lifetime. These studies represent the first steps in establishing a causative relationship between IFN signaling and DS-associated immune dysfunction to identify potential therapeutic targets for improving health outcomes in DS.
Human bone marrow plasma cell survival is independent of APRIL
Authors: Nguyen Doan C , Saney Celia , Sanz Iñaki , Lee F. Eun-Hyung 
Published: January 2023

Abstract
A fraction of the circulating antibody (Ab)-secreting cells (ASC) matures into long-lived plasma cells (LLPC) in the bone marrow (BM) microniches. Previous studies showed that ASC survival and longevity require APRIL, which upon binding its receptors, BCMA or TACI, activates PI3K/Akt (and its downstream mTOR) pathways and upregulates the expression of antiapoptotic proteins Mcl-1 and Bcl-2. Later work revealed that APRIL binding to SDC-1 (CD138), a cell-surface heparin sulfate proteoglycan (HSPG), also enables delivery of survival signals. Recently, we showed that APRIL is crucial in the ex vivo survival of early-minted human blood ASC. Here, using an in vitro cell-free BM microniche system, we demonstrate the differential roles of APRIL in the survival of human blood ASC and BM plasma cells (PC) and LLPC. APRIL substantially enhanced the survival of both CD138+ and CD138− ASC populations in the blood, which highly expressed BCMA. In contrast, it had no survival advantage on BM PC or LLPC, despite their high BCMA expression. Additionally, anti-CD138 Ab inhibited the survival of both blood ASC and BM PC and LLPC, including CD138− cell subsets, suggesting inhibiting the later CD138 upregulation also affects blood ASC survival. These data suggest that APRIL is important for the survival of early-minted blood ASC but not BM PC or LLPC. In conclusion, APRIL is an important survival and imprinting factor of blood ASC but is not required for LLPC maintenance.
TNF-α induces a pro-inflammatory phenotypic shift in monocytes through ACSL1: Relevance to metabolic inflammation
Authors: Alrashed Fatema , Ahmad Zunair , Iskandar Mina Amin , Tuomilehto Jaakko , Ahmad Rasheed 
Published: January 2023

Abstract

Background
TNF-α mediated proinflammatory phenotypic change in monocytes is known to be implicated in the pathogenesis of metabolic inflammation and insulin resistance. However, the mechanism by which TNF-α induces inflammatory phenotypic shift in monocytes is poorly understood. Since long-chain acyl-CoA synthetase 1 (ACSL1) is associated with inflammatory monocytes/macrophages, we investigated the role of ACSL1 in the TNF- α driven inflammatory phenotypic shift in the monocytes.

Methods
Monocytes (Human monocytic THP-1 cells) were stimulated with TNF-α. Inflammatory phenotypic markers (CD16, CD11b, CD11c and HLA-DR) expression was determined with real time RT-PCR and flow cytometry. IL-1b and MCP-1 were determined by ELISA. Signaling pathways were identified by using ACSL1 inhibitor, ACSL1 siRNA and NF-kB reporter monocytic cells. Phosphorylation of NF-kB was analyzed by western blotting and flow cytometry.

Results
Our data show that TNF-α induced significant increase in the expression of CD16, CD11b, CD11c and HLA-DR. Inhibition of ACSL1 activity in the cells with triacsin C significantly suppressed the expression of these inflammatory markers. Using ACSL-1 siRNA, we further demonstrate that TNF-α induced inflammatory markers expression in monocytic cells requires ACSL1. In addition, IL-1b and MCP-1 production by TNF-α activated monocytic cells was significantly blocked by the inhibition of ACSL-1 activity. Interestingly, elevated NF-κB activity resulting from TNF-α stimulation was attenuated in ACSL1 deficient cells.

Conclusion
Our findings provide an evidence that TNF-α associated inflammatory polarization in monocytes is an ACSL1 dependent, which indicates its central role in metabolic inflammation.
Defining the Phenotype and Function of Granzyme A Expressing T-Helper Cells
Authors: Hayes Tristan A , Kaplan Mark H 
Published: January 2023

Abstract
Granzymes have been implicated in numerous diseases including arthritis, viral and bacterial infections, hypersensitivity, autoimmune diabetes, and some cancers. In a STAT6 transgenic mouse model of atopic dermatitis, we identified a population of Granzyme A expressing CD4-T- cells. The role that these cells play in disease is unclear. To define their phenotype, we generated granzyme A (GrA)-expressing T helper cells in vitro using a combination of IL-4/IL-6 and IL-21. GrA-expressing TH cells did not express other TH subsetassociated cytokines, and other TH subsets did not appreciably express GrA. To further examine the development and function of GrA+ TH cells, we developed a Granzyme A-GFP reporter allele termed Grama (GrA Monitoring Allele) mouse. Grama+ cells were identified in the spleen and intestine. Using RNA-seq analysis of in vitro derived cells, we additionally identified several genes, including Arg1, Zpbp2, and Rpl39, that were enriched in GrA-expressing T cells. Thus, GrA-expressing CD4 T cells may represent a novel TH subset and it will be interesting to define the function of this subset in inflammatory diseases.
Complement activation causes oncogene expression in Gaucher disease
Authors: Pandey Manoj K , Magnusen Albert F , McKay Mary A , Nyamajenjere Tsitsi C , DiPasquale Betsy Ann , Magnusen Daniel N , Rani Reena , Witte David , Grabowski Gregory A , Köhl Jörg 
Published: January 2023

Abstract
GBA1 mutations lead to defective lysosomal glucocerebrosidase resulting in accumulation of glucosylceramide (GC) in Gaucher disease (GD). Patients with GD have an increased risk to develop B cell lymphomas. The exact mechanistic bases for this propensity remain elusive. Recently, we uncovered formation of GC-specific IgG autoantibodies in Gba1 D409V/knockout (Gba19V/−) mice, which recapitulate features of human GD, and in humans with untreated GD. In vivo formation of IgG-GC immune complexes induced massive complement activation and C5a generation. Importantly, C5a-mediated activation of its cognate C5a receptor 1 (C5aR1) on immune cells enhanced GC synthesis, thereby fueling GC accumulation and excess tissue recruitment and activation of inflammatory myeloid and lymphoid immune cells, leading to visceral tissue damage in GD. Here, the expression of Runt-related transcription factor 1 (RUNX-1) was determined in Gba19V/− mice, to evaluate if C5a/C5aR1 axis activation may control the development of lymphomas in GD. RUNX-1 is a member of the Runt oncogene family linked to hematologic malignancies. We determined RUNX-1 expression in tissue from C5aR1 sufficient (+/+) and deficient (−/−) Gba19V/− mice as well as strain-matched control WT and C5aR1−/− mice. Compared to WT, Gba19V/− mice had increased RUNX-1 expression. Strikingly, RUNX-1 expression was markedly downregulated in C5aR−/−Gba19V/− vs. C5aR1+/+Gba19V/− mice. Our findings suggest that the C5a-C5aR1 axis activation in GD drives RUNX1 expression as a novel mechanism to control the development of hematologic malignancies in GD that may be diminished by targeting the C5aR1 axis in GD.
Functional characterization of an activating anti-TLR4 monoclonal antibody (UT18) with a demonstrated role in reversal of new-onset type I diabetes in NOD mice
Authors: LOCKER KATHRYN CS , Hoebe Kasper , Ridgway William M , Herr Andrew B 
Published: January 2023

Abstract
Type I diabetes (T1D) is an autoimmune disorder characterized by inflammation and cellular infiltration of the pancreatic islets, resulting in insulitis and damage to islet beta-cells. T1D pathogenesis involves soluble and cellular mediators of both the innate and adaptive arms of the immune system; thus, finding therapeutic targets for reversal of acute disease has proved challenging. We have shown that an activating monoclonal antibody (UT18) targeting mouse TLR4/MD2 reverses acute T1D in non-obese diabetic (NOD) mice. UT18 preserves insulin-producing islet beta-cells and decreases insulitis; however, the molecular mechanisms underlying disease reversal remain unclear. Using AMNIS imaging flow cytometry, we observed an atypical internalization event in which UT18-bound TLR4 persists in EEA1-enriched endosomes rather than recycling back to the cell surface as seen with the TLR4 ligand LPS. Because the subcellular localization of TLR4 alters its proximity to adaptor proteins, we performed immunoblots of downstream signaling mediators. UT18 activates both MyD88 and TRIF pathways; however, the magnitude of MAPK activation is dampened and the kinetics of signaling differ from the rapid, robust activation characteristic of pro-inflammatory LPS. Our data suggest that UT18 functions as a mild TLR4 agonist, eliciting an intermediate signaling profile hypothesized to contribute to tolerance of antigen presenting cells. Knowledge of how UT18 manipulates the TLR4 signaling axis may be applicable for the development of novel immunotherapies for T1D and other autoimmune or inflammatory diseases in which innate immune receptors contribute to pathogenesis.
Age associated insulin resistance is controlled by microbiota through a monocyte-B1a cell pathway
Authors: Bodogai Monica , O'Connell Jennifer , Kim Yoo , Egan Josephine , Biragyn Arya 
Published: January 2023

Abstract
Aging is associated with increased hyperglycemia, insulin resistance and dysregulation of the immune system, but the causative factors underlying their association remain unknown. We show that IR is induced by activated innate 4-1BBL+ B1a (4BL) cells that accumulate as a response to age induced changes in gut microbial composition and subsequent decrease in beneficial microbial metabolites. The loss of the commensal bacterium Akkermansia muciniphila impairs intestinal integrity, causing leakage of bacterial products such as endotoxin, which activate CCR2+ monocytes in an environment with reduced butyrate concentration. These CCR2+ monocytes infiltrate in the omentum where they induce 4-1BBL expression on B1a cells. The cascade continues with 4BL cells inducing IR, presumably by triggering 4-1BB receptor signaling as in obesity-induced metabolic disorders. This pathway and IR are reversible, as manipulation of gut microbiota can restore normal insulin response in aged mice and macaques. In addition, treatments that target monocytes or 4BL cells had the same effect on IR. These results underscore the pathological function of B1a cells and suggest that the microbiome-monocyte- B cell axis could potentially be targeted to reverse age-associated IR.
Peripheral Blood Th40 cells Reflect Disease Progression and Are Controlled by Rituximab in Human Multiple Sclerosis
Authors: Wagner David H , Vaitaitis Gisela , Waid Dan 
Published: January 2023

Abstract
Multiple Sclerosis (MS) is a neuro-degenerative autoimmune disease, progressive in nature, that lacks biomarkers for diagnosis or progression. We described a population of CD4+ T cells that express the CD40 receptor, Th40 cells, which proved causal in murine models of autoimmunity.

Hypothesis
Peripheral blood Th40 numbers reflect MS progression and their control correlates with improvement. Peripheral blood and cerebral spinal fluid from MS patients and disease controls were examined for HLA haplotype and PBMC were characterized by flow cytometry. Random sampling of CIS, RRMS, SPMS and PPMS patients demonstrated diverse HLA haplotypes; DR2 / DQ6 were highly represented but surprisingly DR4, DR3 and DQ2 were prominent. In antigen recall, each HLA haplotype preferred unique myelin-based antigens when presenting to Th40 cells. Percentages of Th40 cells in peripheral blood of CIS and RRMS had a wide range while the range in PPMS and SPMS was tight yet significantly elevated. CSF from RRMS patients had Th40 cell percentages mirroring peripheral blood. RRMS subjects had elevated B cells that surprisingly were the major source of IL-17. Rituximab treated subjects demonstrated a significant but temporal reduction in Th40 cell numbers; FoxP3+ cells were elevated while Th40 inflammatory-cytokine production was reduced.

Conclusions
The wide range of Th40 cell numbers in CIS and RRMS but universally high numbers in SPMS suggest that Th40 cell number expansions in MS reflect progression. Th40 cells in CSF demonstrate access to the CNS and an important correlation between peripheral blood and CNS. Antigen recall to myelin demonstrates Th40 pathogenicity. Rituximab treatment ablates B cells that then affect pathogenic effector Th40 cells.
Long-range cis-regulatory architecture of the human IL2 gene
Authors: Sharma Prabhat K , Thomas Rajan M , Johnson Matthew , Wells Andrew 
Published: January 2023

Abstract
Interleukin-2 is a potent T cell growth factor with crucial roles in both immunity and tolerance. The IL2 gene is regulated by multiple signaling pathways, transcription factors, and epigenetic processes operating at the 500 bp upstream regulatory region (URR). Genome-wide association studies (GWAS) in humans have shown that genetic variation in the IL2 region is associated with susceptibility to autoimmune diseases. This region harbors several conserved noncoding sequences. We are performing a comprehensive epigenomic and functional interrogation of the human IL2-IL21 multi-locus region, using a combination of open chromatin mapping (ATAC-seq), recombinant promoter-reporter assays, 3-dimensional chromosome conformation capture (Capture-C), and CRISPR/CAS9 genome editing. ATAC-seq analysis identified TCR/CD28 activation-dependent chromatin remodeling at −46, −51, −80, −83, −-85, −121, and −128 kb upstream of IL2 in human T cells. Chromatin conformation capture indicates that several of these distal regions physically interact with IL2, and are capable of enhancing transcription from the IL2-URR in recombinant reporter assays. The −128 kb element showed autoimmune disease-associated allelic variation in enhancer activity, and CRISPR/CAS9-mediated deletion of this element in human T cells resulted in a 2–3 fold reduction in activation-induced IL-2 production. These results suggest that the IL2 locus has evolved an extensive regulatory architecture that allows for variable production of IL-2, and provide insight into why most autoimmune IL2 polymorphisms are located far away from the gene.