bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heightened preclinical dysregulation of distinct adaptive and renal-associated mediators in patients who develop nephritis as they transition to systemic lupus erythematosus classification
Authors: Munroe Melissa , Anderson Jourdan R , Robertson Julie M , Niewold Timothy B , Tsokos George C , Keith Michael P , Merrill Joan T , Buyon Jill P , Harley John B , James Judith A 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease marked by immune dysregulation. Why some patients have only moderate symptoms and others develop organ-threatening manifestations is unclear. This study evaluates the temporal expression of autoantibodies and cytokines in sera from the Department of Defense Serum Repository during transition from preclinical lupus to SLE in patients (n=83) who do or do not present with nephritis. Patients who met renal criteria (n=30; 36%) did so within 5.2 (±5.5) months of SLE classification (range −5.2 to +12 months). Renal cases experienced earlier onset of autoantibody positivity vs. non-renal cases (mean −3.8 vs −2.6 years relative to SLE classification, p=0.0442). Prior to developing nephritis, renal cases exhibited elevated levels of distinct soluble mediators compared to matched non-renal cases and healthy controls, including adaptive mediators IL-4, IL-5, IL-12, and IFN-γ, chemokines IP-10 and MCP-3, and nephritis-associated mediators SCF and shed TNFRII (all p&lt;0.05), increasing again at the time of nephritis (all p&lt;0.02 compared to pre-nephritis levels). These same mediators were significantly increased at SLE classification in patients with nephritis vs. non-renal patients (all p&lt;0.0001). These data indicate that perturbations in distinct immune mediated inflammatory processes may help identify individuals at high risk of renal involvement for early and continued monitoring and intervention.
Searching for citrullinated autoantigen biomarkers for interstitial lung disease associated with Rheumatoid Arthritis
Authors: Ganesan Vinitha , Harlow Lisa , Kaku Barclay Machika , Gigilio Marisa , Ascherman Dana P , Minden Jonathan S 
Published: January 2023

Abstract
Interstitial lung disease (ILD) associated with Rheumatoid arthritis (RA) is the cause of death in ~13% of RA patients. Biomarkers are therefore urgently needed to predict ILD development in RA patients, so that appropriate treatment can be instituted. Citrullination occurs in the lungs of RA-ILD patients. We hypothesize that, this post-translational modification leads to the formation of neo-epitopes, triggering autoreactivity & inflammation of the lungs. Because the formation of citrullinated autoantigens and associated autoantibodies is likely linked to ILD in RA patients, we are using RA & RA-ILD patient sera to differentially immunoprecipitate (IP) in-vitro citrullinated HeLa protein extracts containing potential citrullinated autoantigens. When using mass spectrometry (MS) for protein identification, IP results are confounded by an overwhelming amount of antibody-derived peptides. To solve this, we developed a secondary purification step using Biotin-CDM, a novel reversible protein capture reagent that tags all proteins in a cell lysate. The captured biotinylated IP proteins are then separated from non-biotinylated antibodies and released in a un-biotinylated state in the appropriate buffer for proteomic analysis, free of contaminating antibodies. With this modified approach, we have detected several differences in citrullinated autoantigen recognition profiles between RA & RA-ILD patient sera. We are currently identifying these differential IP proteins using MS, with the goal of using target antigens as “bait” in co-IP to isolate other interacting proteins from lung tissue extracts. Once validated, these results will help us further our understanding of the complex networks involved in RA-ILD pathogenesis.
Immunobiology of antigen presenting cells during relapse vs. remission in multiple sclerosis
Authors: Sinha Sushmita , Cunnusamy Khrishen , Chaudhary Parul , Greenberg Benjamin M , Frohman Elliot M , Karandikar Nitin J 
Published: January 2023

Abstract
Multiple sclerosis (MS) is the most common cause of neurological disability in young adults. Approximately 80% of MS patients initially present with the relapsing-remitting disease. Although studies suggest immune hyperactivity during relapse, role of specific immune cells has been understudied. We investigated whether APCs might be the drivers of inflammation during an MS-relapse. Paired blood samples were obtained from patients during relapse (Rel) and remission (Rem) phase of MS. APCs were immunophenotyped for activation, inhibition and migration-associated markers. T cell-cytokine stimulatory potential of Rel vs. Rem-APCs was studied by co-culturing sorted APC-subtypes with healthy donor-CD3+ T cells. Rel-monocytes displayed a significantly higher expression of adhesion molecules while inhibitory receptor ILT4 was significantly increased on Rem-monocytes. Further, Rel-monocytes stimulated significantly more IFN-g and IL-17 from allogeneic CD4+ T-cells. Rel- B-cells had a significantly higher expression of adhesion molecules and displayed significantly increased potential of stimulating IFN-g from allogeneic CD8+ T-cells. Inhibitory receptor ILT3 was significantly increased on PDCs during Rem. Functionally, Rel-MDC stimulated significantly more IL-17 and IFN-g from allogeneic CD4+ and CD8+ T-cells, respectively. Overall, our study suggests that these key differences in APC subsets during Rel vs Rem phases could potentially modulate T cell responses by favoring more pro-inflammatory T-cell phenotype during MS relapse. Combined with our publications related to differential regulatory ability of CD4 and CD8 T-cells this study provides great insights into the underlying immunopathology of an MS relapse.
Emerging roles of IFNα, IL-10, IL-1 and IL-8 in central nervous inflammation and immune response imbalance in transgenic porcine model of neurodegenerative Huntington’s disease
Authors: Kovarova Hana , Jarkovska Karla , Valekova Ivona , Kotrcova Eva , Juhas Stefan , Motlik Jan , Bucci John , Gadher Suresh Jivan 
Published: January 2023

Abstract
Huntington’s disease (HD) is an inherited neurodegenerative disease with impairment of motor and cognitive functions. Studies in HD gene carriers expressing mutant huntingtin protein (mHTT) demonstrated altered immune response indicating that cytokines may have a significant role in disease development.
We utilized the novel transgenic HD model bearing N-fragment of human mHTT in minipig (Baxa M et al., J Huntington’s Dis. 2013, 2:47–68), to investigate central nervous and peripheral cytokine levels. Using Luminex® xMAP™ multiplexing technology and Thermo Fisher Scientific Inc., Swine Cytokine Magnetic 7-plex Panel (Invitrogen™ LSC0001M), the biological fluids were interrogated to identify cytokine alterations related to HD progression. The modelling of interaction networks between such cytokines and HTT facilitated study of intracellular signaling pathways associated with immune response dysregulation.
The most pronounced change was the decline of IFNα in cerebrospinal fluid and secretome of microglial cells (MG). In addition, IL-10 was also lower in the same biological fluids. Elevated levels of pro-inflammatory IL-1 and IL-8 were secreted by MG whilst IL-8 was also increased in serum of transgenic minipigs. The high proportion of mHTT in MG may have a causative impact on cytokine production. A novel role for CREB-binding protein in HD pathogenesis was highlighted.
These findings underlined the roles of IFNα, IL-10, IL-1 and IL-8 in central nervous system inflammation and immune response imbalance in HD progression warrants further investigation into their usefulness in human patients.
Acknowledgement
We thank CHDI, MESY Projects EXAM; CZ.1.05/2.1.00/03.0124, LO1609 and Thermo Fisher Scientific for expertise.
Fractalkine signaling during systemic endotoxemia inhibits perivascular microglial lesion formation in the diabetic retina
Authors: Mendiola Andrew S , Garza Rolando , Cardona Sandra M , Cardona Astrid E 
Published: January 2023

Abstract
It’s known that diabetics are more susceptible to infections and there is an association between diabetes and chronic inflammation, but whether systemic inflammation contributes to retinopathy remains unknown. Microglial-mediated inflammation has gained recognition as a key contributor to diabetic retinopathy (DR) pathogenesis. We have shown that signaling between the chemokine fractalkine (FKN) and CX3CR1 on microglia is important to maintain neuroprotection and that CX3CR1-deficiency directs microglial-mediated inflammation and neurotoxicity in the diabetic retina. To extend these studies, we tested the hypothesis that acute endotoxemia perpetuates microglial activation and that CX3CR1-deficent mice will be more susceptible to retinal pathology due to dysregulated microglial responses. Systemic endotoxemia was induced in nondiabetic and diabetic CX3CR1-HET and CX3CR1-KO mice by administration of four-daily injections of LPS (1 mg/kg/mouse; i.p.; n=12). Confocal analysis of retinal tissue revealed that in CX3CR1-KO mice, endotoxemia induced a robust-cellular activation represented by morphological changes, IL-1β, iNOS expression, and intense perivascular clusters of microglia. This phenotype was exacerbated in the diabetic CX3CR1-KO retina. These microglial lesions observed in CX3CR1-KO mice coincided with perivascular accumulation of the blood-protein fibrinogen. Lastly, fractalkine treatment (intraocular; 30 ng) into FKN-KO mice dampened microglial activation and astrogliosis during acute endotoxemia. These data suggest that systemic inflammation influences breakdown of the blood-retinal barrier, and may provide therapeutic advances by fractalkine treatment to mitigate DR pathogenesis.
Investigating the Role of IL-33 in the Pathogenesis of Familial Mediterranean Fever
Authors: Keskin Goksal , tutluer Seda , Inal Ali , Cerci Pamir , Olmez Umit 
Published: January 2023

Abstract
Familial mediterranean fever (FMF) is an autosomal recessive genetic disorder familial disease with inflammatory reactions of serosal membranes characterized by recurrent episodes of abdominal chest and joint pain, and fever. During the acute attacts, increased several proinflammatory cytokines have been described. IL-33 is a member of the IL-1 cytokine superfamily. It has been reported that IL-33 plays an important role in inflammation and homeostasis. Here, we analyzed serum IL-33 concentration in patients with FMF to assess its possible role in the pathophysiology of this disease.

Material and method
In this study, 58 patients with FMF (21 female, 37 male; mean age 27.8 ± 5.2 years, mean disease duration 8.2 ± 3,7 years) and 22 healthy controls (10 female, 12 male, mean age 26,5 ± 5,9 years) were included. Serum IL-33 levels were measured by ELISA.

Results
The mean serum IL-33 levels were 3,88 ± 2,25 pg/ml in patients with FMF and 2,89 ± 0.48 pg/ml in the healthy controls. The mean levels of serum IL-33 were 5,48 ± 2,13 pg/ml in active stage and 2,27 ± 0,36 pg/ml in inactive stage. According to these results; serum IL-33 levels were significantly higher in patients with FMF compared with healthy controls (p&lt;0.01). In addition, Serum IL-33 levels were significantly higher in active stage compared to in inactive stages and controls (p&lt;0.0001 and p&lt;0.0001). In the inactive patients with FMF, serum IL-33 concentrations were found to be lower compared to healthy controls (p&lt;0.05). In active FMF patients, the mean serum IL-33 level was correlated with arthritis (p&lt;0.05).

Conclusion
The high levels of serum IL-33, in active patients with FMF suggest that IL-33 may play a significant role of in the pathogenesis of FMF.
Expression of CCR5 and its ligand CCL5 in pancreatic cancer
Authors: Singh Santosh Kumar , Banerjee Saswati , Lillard James W. , Singh Rajesh 
Published: January 2023

Abstract
Despite recent advancements in understanding of pancreatic cancer (PC) molecular features and their impact on clinical behavior, PC systemic therapy decision-making is still guided by a constellation of clinico-pathological features, which are derived from histo-pathological analysis of primary PC tissues. Chemokines and their corresponding receptors play a crucial role in metastasis and organ specific homing of cancer cells in different cancers including PC. CCL5 is a homeostatic chemokine acts through its cognate receptor, CCR5. Here, we have provided the evidence that CCR5 and CCL5 are significantly elevated in both PC cell lines (BxPC-3, MIA PaCa-2 and AsPC-1) and clinical samples. Flow cytometric analysis of PC cell lines (BxPC-3, MIA PaCa-2 and AsPC-1) show significantly higher expression of CCR5. These findings were further confirmed at mRNA expression level by real-time PCR analysis. To determine the clinical significance of CCR5 expressed by PC cell lines, pancreatic cancer tissue microarray was stained for CCR5 and CCL5. Aperio scan scope scanning system was used to numerically analyze immuno-histochemical staining of CCR5 and CCL5. Our results show significantly (p &lt; 0.001) higher expression of CCR5 and CCL5 in cancerous tissues compared to normal pancreatic tissues. These data demonstrate both biological and clinical significance of CCR5 and CCL5 expression that may contribute to PC metastasis.
Human skin mast cells constitutively express gp130 and functional IL-6 receptor
Authors: McHale Cody C , Deppen Juline , Shirley Devon , Gomez Gregorio 
Published: January 2023

Abstract
Mast cells, the effector cell type of allergic reactions, have been implicated in numerous traditionally non-allergic diseases including cancer, diabetes, and obesity. Interleukin-6 (IL-6) is a pleiotropic cytokine involved in many of these pathologies suggesting that IL-6 could be the link that connects mast cells to these disease states. However, it had not been formally demonstrated that human primary mast cells express a functional IL-6 surface receptor. In this study, we show that human skin mast cells (hSMCs) constitutively express IL-6Ra and gp130, a common signal transducing chain shared by members of the IL-6 cytokine family that includes leukemia inhibitory factor, oncostatin M, ciliary neurotrophic factor, IL-11, cardiotrophin 1, IL-35 and IL-27. Whereas previous studies with mouse bone marrow-derived mast cells showed that IL-10 was required for surface expression of gp130, we found that IL-10 did not enhance expression on hSMCs although gp130 mRNA was increased. IL-6R functionality is demonstrated by the IL-6-induced phosphorylation of STAT3, and increased expression of SOCS3 mRNA. Interestingly, IL-6 gene expression was enhanced with IL-6 itself suggesting a positive feedback mechanism. Similar results were obtained with IL-27, which also utilizes gp130 together with WSX-1 for signaling. Mast cell degranulation was not induced with IL-6 or IL-27 alone, and neither cytokine affected FcɛRI-induced release of β-hexoaminidase. However, IgE-dependent TNF production was enhanced with IL-27. These data demonstrate that human mast cells can be directly activated by IL-6 or other gp130-utilizing cytokines, and support the notion that IL-6 could be a link that connects mast cells to non-allergic disease.
Differential Expression of the Transcription Factor SPI1 (PU.1) in Dendritic Cell Subsets
Authors: Soper David M , Madeux Danny , Yang Xifeng 
Published: January 2023

Abstract
SPI1 belongs to the E26-transformation-specific (Ets) family of transcription factors and is exclusively expressed in hematopoietic cells. Originally identified as an oncogene that blocks erythroblast differentiation, SPI1 plays a critical role in the development and lineage commitment of both myeloid and lymphoid cells. Gene knockout studies show that spi1−/− mice exhibit a multi-lineage defect in the generation of monocytes, granulocytes, B, T, and dendritic cells. While SPI1 expression is required for normal hematopoietic cell development, the level of SPI1 expression influences specific lineage commitment. Using in-house generated species-specific clones, human peripheral blood mononuclear cells (PMBCs) and mouse splenocytes were evaluated for SPI1 expression by flow cytometric analysis. In human PMBCs, Lin− HLA-DR+ CD11c+ CD303− monocyte-derived dendritic cells (mDCs) exhibit high levels of expression while Lin− HLA-DR+ CD11cint CD303+ plasmacytoid dendritic cells (pDCs) do not express SPI1 protein. These data suggest SPI1 expression is required for the development and function of human mDCs, while SPI1 expression is not necessary for terminally differentiated human pDCs. Interestingly, SPI1 expression is detected in both murine DC subsets: Lin− I-A/I-E+ CD11c+ CD317− mDCs and Lin− I-A/I-E+ CD11cint CD317+ pDCs, although the expression level in pDCs is significantly lower than in mDCs. These observations indicate expression patterns differ between mouse and human cells, and demonstrate that DC subsets exhibit differential expression of SPI1 protein.
Zeb2 is required for development of plasmacytoid dendritic cells
Authors: Wu Xiaodi , Briseño Carlos G. , Grajales-Reyes Gary E. , Wumesh KC , Kretzer Nicole M. , Murphy Theresa L. , Murphy Kenneth M. 
Published: January 2023

Abstract
Recent work has shown that the transcription factor Zeb2 is regulated by and cooperates with T-bet to promote terminal differentiation of NK cells and cytotoxic T cells. In the mouse, Zeb2 is expressed throughout dendritic cell (DC) development and in mature plasmacytoid DCs (pDCs) and CD11b+ classical DCs (cDCs), but not in CD8+/CD103+ cDCs. We hypothesized that downregulation of Zeb2 expression would be essential for the development of CD8+/CD103+ cDCs. Upon conditional deletion of Zeb2, we observed a substantial decrease in pDC frequency and an increased ratio of CD8+:CD11b+ cDCs; meanwhile, Zeb2 haploinsufficiency yielded a partial defect in pDC development. Additional experiments demonstrated that this defect was cell-intrinsic and durable, and that it could not be rescued by administration of type I interferon, which increased pDC frequency in cultures of wild-type DC progenitors but directed Zeb2-deficient DC progenitors almost entirely to the CD8+/CD103+ cDC lineage. Deletion of Zeb2 induced by poly(I:C) treatment in an Mx1-Cre-driven model also resulted in perturbations in other myeloid lineages. Although poly(I:C) treatment led to an acute loss of Ly-6Chi monocytes both in Zeb2fl/fl;Mx1-Cre(tg) mice and in control mice, those monocytes were replenished to baseline frequencies in control mice but not in Zeb2-deficient mice. Similar decreases in monocyte frequency were observed in other organs, and further experiments suggested that this defect was also cell-intrinsic, gene dosage-dependent, durable, and observable in model systems that do not require use of poly(I:C). Thus, we have identified an essential regulator of development in multiple myeloid lineages.
IRF4 and IRF8 act in CD11c+ cells to regulate terminal differentiation of lung tissue dendritic cells
Authors: Kovats Susan , Turner Sean , Paul Jinny , Ainsua-Enrich Erola , Bajana Sandra 
Published: January 2023

Abstract
Dendritic cells (DCs) initiate immune responses in barrier tissues including lung and skin. Conventional DC subsets, CD11b−(cDC1s) or CD11b+(cDC2s), arise via distinct networks of transcription factors involving IRF4 and IRF8 and are specialized for unique functional responses. Using mice in which a conditional Irf4 or Irf8 allele is deleted in CD11c+ cells, we determined if IRF4 or IRF8 deficiency beginning in CD11c+ cDC precursors (pre-cDCs) changed the homeostasis of mature DCs or pre-DCs in the lung, dermis and spleen. CD11c-cre-Irf4−/− mice selectively lacked a lung-resident CD11chiCD11b+SIRPa+CD24+ DC subset, but not other lung CD11b+DCs or alveolar macrophages. Numbers of CD11b+CD4+ splenic DCs, but not CD11b+ dermal DCs, were reduced, indicating cDC2s in the lung and dermis develop via different pathways. Irf4 deficiency did not alter numbers of cDC1s. CD11c-cre-Irf8−/− mice lacked lung-resident CD103+ DCs and splenic CD8a+ DCs, yet harbored increased IRF4-dependent DCs. This correlated with a reduced number of Irf8−/− pre-cDCs, which contained elevated IRF4, suggesting that Irf8 deficiency diverts pre-cDC fate. Analyses of Irf4 and Irf8 haploinsufficient mice showed that while one Irf4 allele was sufficient for lung cDC2 development, two functional Irf8 alleles were required for differentiation of lung cDC1s. Thus, IRF8 and IRF4 act in pre-cDCs to direct the terminal differentiation of cDC1 and cDC2 subsets in the lung and spleen. These data suggest that variation in IRF4 or IRF8 levels resulting from genetic polymorphisms or environmental cues will govern tissue DC numbers and therefore regulate the magnitude of DC functional responses.
IL-17A is rapidly triggered by staphylococcal superantigens and is pathogenic in toxic shock syndrome
Authors: Szabo Peter Anthony , Goswami Ankur , Welch Ian , McCormick John , Haeryfar S.M. Mansour 
Published: January 2023

Abstract
Toxic shock syndrome (TSS) is a life-threatening illness characterized by high-grade fever, erythematous rash, hypotensive shock, and multi-organ dysfunction within hours of onset. It is caused by exposure to bacterial exotoxins known as superantigens (SAgs), which are produced by the common bacterium Staphylococcus aureus. During infection, SAgs activate up to 20% of T cells inducing a severe systemic inflammatory response that can lead to vascular leakage, multiple organ damage and death. However, the role of IL-17A, a potent inflammatory cytokine, in this potentially fatal reaction remains virtually unexplored. We have found that human peripheral blood mononuclear cells (PBMCs) stimulated with SAgs in vitro immediately up-regulate IL-17A mRNA (up to 12,000-fold) and produce substantial amounts of IL-17A protein within hours. Utilizing the cutting-edge RNA-Flow Cytometry technique, we identified a subset of memory T cells that was responsible for the rapid IL-17A response. We also investigated the effect of IL-17A signaling on downstream inflammatory cytokine and chemokine gene expression via IL-17A receptor blockade. Lastly, we used HLA-DR4 transgenic mice to demonstrate rapid IL-17A production in response to SAgs, similar to human PBMCs. Neutralizing IL-17A in this model greatly reduced tissue damage, morbidity and mortality. Taken together, our results reveal a novel role for memory T cells in TSS and define a previously unrecognized contribution by IL-17A to the initiation and pathogenesis of the syndrome.
An antagonistic role for Fyn and Lyn kinases in autoimmune arthritis
Authors: Paranjape Anuya R , Ryan John J 
Published: January 2023

Abstract
Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder characterized by infiltration of innate immune cells into the synovial joints, whose etiology is unclear. While the Fcγ receptor (FcγR) aggregation on innate inflammatory cells by auto-antibodies is a critical stimulus, much of FcγR signaling remains unknown. Previous research from our lab has shown that FcγR-mediated innate immune cell activation is antagonistically controlled by the Src family kinases, Fyn and Lyn. Our current study investigates the Fyn/Lyn dichotomy in controlling the severity of the inflammatory arthritis using K/BxN model or RA. Our preliminary studies show that Lyn deletion exacerbates joint swelling and clinical arthritis scores, while Fyn deletion reduces plasma inflammatory cytokine levels. These data indicate an antagonistic role for Fyn and Lyn kinases in autoimmune arthritis and support further study of the mechanisms by which these Src family kinases regulate inflammation.