bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantitative screening of active renal SLE patients’ urine for protein biomarkers using kiloplexed glass slide arrays
Authors: Soomro Sanam , Attia Maria , Petri Michelle , Mohan Chandra 
Published: January 2023

Abstract

Background
Systemic Lupus Erythematous (SLE) is a chronic inflammatory autoimmune disease marked by flares in multiple organ systems. Leading causes of morbidity and mortality in this disease include lupus nephritis and renal failure. Because the diagnosis of lupus nephritis is currently done using kidney biopsy, noninvasive diagnostic biomarkers are crucially needed to limit the use of this costly and invasive procedure. In this effort, active renal SLE patients’ urine was interrogated for potential biomarkers using a novel quantitative antibody array based protein screen of 1000 protein targets.

Methods
The urine of 9 active renal (AR), 6 active non-renal (ANR) patients, and 9 healthy controls (HC) were subjected to a quantitative antibody based protein screen of 1000 unique human proteins. After creatinine normalization, dysregulated proteins were selected for further validation using group wise fold change (FC) and Mann Whitney tests.

Results
The quantitative array based screen of 1000 targets showed 336 proteins to be elevated in the urine of active SLE patients compared to HC. Of these, 8 proteins were elevated in the urine of AR patients compared to ANR (FC&gt;2 P&lt;0.05). Array results correlated well ELISA results (Spearman r &gt; 0.6 in 60% of proteins validated thus far). Relationship of biomarkers to disease activity and renal pathology is under investigation.

Conclusions
We have successfully validated one of the largest targeted proteomic technologies currently available for biomarker identification. Although validation of hits as diagnostic biomarkers is still in progress, the identified proteins show promise in the noninvasive diagnosis of active renal disease in SLE patients.
The psoriasis therapeutic potential of a novel short laminin peptide C16
Authors: TSAO YEOU PING 
Published: January 2023

Abstract
Psoriasis is a chronic skin disorder characterized by cutaneous inflammation, keratinocyte hyperproliferation and desquamation formation. There are nearly 10 million patients around the world. Current remedies have potential serious side effects. There is an unmet need for new therapies with better efficacy and less adverse effects. Recently, we found that the C16 peptide derived from extracellular matrix component laminin 111 has the potential for psoriasis therapy. Topical treatment with C16 ameliorates imiquimod (IMQ)-induced psoriasis-like skin inflammation. BALB/c Mice (8-week-old) received a daily topical of IMQ cream (5%; Aldara; 3M Pharmaceuticals) on the shaved back for six consecutive days. The mice developed psoriasis-like skin inflammation and desquamation formation. Topical application of IMQ combining with C16 showed reduced skin inflammation and desquamation. Histology analysis confirmed obvious reduction of inflammatory cell infiltration and acanthosis. In cell culture, C16 also inhibited IMQ-induced keratiocyte proliferation. Since C16 peptide has been found that can bind to α5β1 and αvβ3 integrins, integrins α5β1 and αvβ3 may be involved in the mechanism of psoriasis therapy. Results of ongoing investigation will be presented in the meeting.
BTK inhibition ameliorates renal, skin, and brain disease in a spontaneous murine model of systemic lupus erythematosus
Authors: Chalmers Samantha A. , Wen Jing , Doerner Jessica L. , Stock Ariel D. , Webb Deborah , Herlitz Leal , Bosanac Todd , Nabozny Gerald H. , Fine Jay S. , Klein Elliott , Ramanujam Meera , Putterman Chaim 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) can affect multiple different organ systems, including the kidneys (lupus nephritis, LN), brain (neuropsychiatric SLE, NPSLE), and skin (cutaneous lupus, CLE). B cells and macrophages are implicated in the pathogenesis of these disease manifestations. We have previously shown the importance of Bruton’s tyrosine kinase (BTK), an enzyme important in B cell and macrophage signaling, in reversing disease in a model of immune nephritis induced by the passive transfer of nephrotoxic antibodies.
To extend our findings to a more severe type of nephritis more similar to human disease and examine the effects of BTK inhibition on extra-renal lupus manifestations, we treated a spontaneous model of lupus, MRL/lpr mice, with the novel BTK inhibitor, BI-BTK-1. Early treatment with BI-BTK-1 normalized proteinuria (p&lt;0.001) and BUN (p&lt;0.001) levels, and significantly improved renal histopathology. Importantly, in separate studies BTK inhibition also significantly reversed established proteinuria. Finally, BI-BTK-1 treated MRL/lpr mice had significantly improved survival as compared to control treated age, sex, and background matched mice (p &lt; 0.0001).
MRL/lpr mice develop brain and skin disease that model the pathology of NPSLE and CLE, respectively. Early BI-BTK-1 treatment significantly improved cognitive function and decreased inflammatory cell infiltration into the brain choroid plexus. Moreover, skin disease was also significantly improved as determined by attenuated macroscopic and histologic skin scores.
Our results further highlight the therapeutic potential of BI-BTK-1 in SLE, not only in treatment of LN, but potentially also for skin and brain disease as well.
Protein Kinase D1 deletion ameliorates collage-induced arthritis
Authors: Yoon Taewon , Cho Hongsik , Stuart John M. , Yi Ae-Kyung 
Published: January 2023

Abstract
Although the etiology of Rheumatoid arthritis (RA) is unknown, it is thought that TLR signaling may be involved in the initiation and progression of the disease. Disruption of the TLR signaling at early stages of RA could be a possible therapeutic strategy. We have previously identified protein kinase D1 (PKD1) as an indispensable component in the MyD88-dependent TLR signaling pathway that plays a critical role in acute and chronic inflammation. Although it is currently not known whether PKD1 plays a pathogenic role in RA in humans, we have previously found that daily treatments of a PKC/PKD inhibitor Gö6976 significantly ameliorated arthritic symptoms in collagen-induced arthritis (CIA). Here, we further investigated the role of PKD1 in pathogenesis of CIA in humanized HLA-DR1 transgenic mice using a tamoxifen-inducible PKD1-gene deletion system. We have found that PKD1 deletion resulted in reduced incidence and severity of arthritis in HLA-DR1 mice immunized with type II collagen. In addition, Gr-1+ myeloid lineage cell infiltration into the joint space was significantly reduced and joint destruction (assessed by joint histopathology study and mCT scanning) was ameliorated in the PKD1-deleted mice compared to wild-type. Our results provide evidences that PKD1 might play an important pathogenic role in inflammatory arthritis and that PKD1 could be a new therapeutic molecular target for arthritis.
Nrf2 mediated metabolic reprogramming of tolerogenic dendritic cells is protective against aplastic anemia
Authors: Wei Hsi-Ju , Pareek Tej K. , Gupta Ashis , Kao Weiming , Almudallal Omar , Letterio John J. 
Published: January 2023

Abstract
Aplastic anemia (AA) is a rare autoimmunity characterized by suppression of bone marrow (BM) function resulting in progressive pancytopenia. BM transplants or immunosuppressive therapies remain the major treatment choices with limited benefit and significant side effects. Here we report for the first time the therapeutic utility of Nrf2 induced metabolically reprogrammed tolerogenic dendritic cells (TolDCs) in AA treatment. First, CDDO-DFPA-induced Nrf2 activation resulted in a TolDC phenotype as evidenced by induction of IL-4, IL-10, and TGF-b and suppression of TNFa, IFN-g, and IL-12 levels in Nrf2+/+but not in Nrf2−/− DCs. Cellular metabolism holds the key to determining DC immunogenic or tolerogenic cell fate. We observed the similar pattern of oxidative phosphorylation (OXPHOS) and glycolysis in immature and LPS-induced (matured) Nrf2+/+ and Nrf2−/− DCs. However, only Nrf2+/+DCs partially restored OXPHOS and reduced glycolysis during CDDO-DFPA-induced Nrf2 activation. We also observed significantly enhanced HO-1 and reduced iNOS/NO production in Nrf2+/+compared to Nrf2−/−DCs, suggesting Nrf2-dependent TolDC induction is linked to suppression of the inhibitory effect of NO on OXPHOS. Besides, Nrf2−/−DCs demonstrated higher antigen-specific CD4 T cell proliferation. Lastly, administration of TolDCs improved hematopoiesis and survival rate in AA murine model, with fewer Th17 and more Treg cells. Concomitantly, AA patient BM biopsies displayed higher DCs, T cells, and iNOS expression accompanied with lower Nrf2 and HO-1 expression compared to normal subjects. These results provide a new insight into therapeutic utility of metabolically reprogramed TolDCs by CDDO-DFPA induced Nrf2 signaling in treatment of AA.
Functional reprogramming of regulatory T cells in the absence of Foxp3
Authors: Charbonnier Louis-Marie , Lopez David , Bleesing Jacob , Garcia-Lloret Maria , Chen Karin , Ozen Ahmet , Li Ming , Pellegrini Matteo , Chatila Talal A. 
Published: January 2023

Abstract
Foxp3-deficient regulatory T (Treg) cells lack suppressor function and manifest a T effector (Teff) cell-like phenotype. We demonstrate that Foxp3 deficiency dysregulates mTORC2 signaling and gives rise to augmented aerobic glycolysis and oxidative phosphorylation. Mutant Treg cell-specific deletion of the mTORC2 adaptor gene Rictor or expression of a Foxo1 transgene improved regulatory function and ameliorated disease. Rictor deficiency reestablished a subset of Treg cell genetic circuits and suppressed the Teff cell-like metabolic program. Treatment of mutant Treg cells of patients with FOXP3 deficiency with mTOR inhibitors similarly antagonized their Teff cell-like program and restored suppressive function. Thus, regulatory function can be reestablished in Foxp3-deficient Treg cells by targeting their metabolic pathways, providing opportunities to restore tolerance in Treg cell disorders.
Induction rate of regulatory T cells from conventional T cells is affected by substrate rigidity
Authors: Lee Jounghyun Helen , Nataraj Neha , Dang Alex , Kam Lance C. 
Published: January 2023

Abstract
The immune system maintains a balance between protection and tolerance. Regulatory T cells (Tregs) act as a tolerance mechanism to suppress effector immune cells. Recent studies suggest that the induction of Tregs from conventional T cells (Tconvs) has many practical and therapeutic advantages. Previously, both human and mouse T cells were reported to exhibit different responses to activating substrates of different rigidities as indicated in IL-2 secretion levels. In this work, we explore the previously unknown effect of substrate rigidity on the induction of Tregs from Tconvs. We used Sylgard 184 poly(dimethylsiloxane) (PDMS) to obtain rigidity ranging a few hundred kilopascals to megapascals. Mouse CD4+ T cells (Foxp3-GFP linked B6 mouse) were obtained from spleen and further isolated to CD25+ and CD25− cells using magnetic bead-based isolation kits. CD4+CD25− T cells (&gt;99% Foxp3−) were then seeded onto the surfaces coated with antibodies to CD3 and CD28 in IL-2 and TGF-b-enriched media. Surprisingly, there was a significant increase in Treg induction rate at lower substrate rigidities (i.e., Young’s modulus, E ~ 100 kPa) compared to high rigidity (i.e., E ~ 3 MPa). To confirm that this significant difference in induction rate is truly related to T cell mechanosensing, we administered compound Y-27632 (cY) to inhibit myosin contractility. In the presence of cY, the difference in induction rate at varying rigidities was significantly reduced. This study furthers our understanding of mechanosensing properties of immune cells and raises questions about the underlying molecular mechanisms involved in this process of T cells choosing to proliferate or differentiate.
PD-L1-engineered pancreatic islet grafts overcome rejection in allogeneic recipients
Authors: Batra Lalit , Shrestha Pradeep , Yolcu Esma S. , Zhao Hong , Bowen William S. , Woodward Kyle B. , Coronel María M. , Tan Min , García Andrés J. , Shirwan Haval 
Published: January 2023

Abstract
The use of chronic immunosuppression is a major hurdle for clinical islet transplantation as a curative modality for the treatment of type 1 diabetes. T effector cells (Teffs) are a main culprit of allograft rejection, and their pathogenic response is kept in check by CD4+CD25+FoxP3+ T regulatory cells (Tregs). The PD-1/PD-L1 immune checkpoint pathway plays an important role in the Teff/Treg balance with demonstrated clinical efficacy in cancer immunotherapy. This study was designed to assess the immunoregulatory function of PD-L1 in preventing allogeneic islet graft rejection. A chimeric protein (SA-PD-L1) containing the extracellular portion of PD-L1 fused to a modified form of core streptavidin was generated. SA-PD-L1 protein was expressed in insect cells and purified. The protein was functional as it enhanced TGF-beta-induced conversion of Teffs into Tregs and suppressed the proliferation of Teffs in response to alloantigens. Importantly, SA-PD-L1 was transiently displayed on the surface of biotinylated islets, and such engineered islets survived for over 100 days in allogeneic recipients treated with a short course (15 days) of low dose rapamycin. In marked contrast, unmodified islets under the same rapamycin regimen were rejected within 20 days. SA-PD-L1-engineered islets without rapamycin, although showing prolonged survival, were eventually rejected within 40 days. These results provide strong proof-of-efficacy and feasibility for the use of SA-PD-L1 protein as an immunomodulator to promote allogeneic islet graft survival in the absence of continued immunosuppression.
Treatment with benign IgE reduces asthma symptomology in a mast cell dependent manner
Authors: Martin Rebecca , Zellner Matthew P , Lownik Joseph Cornelius , Luker Andrea J 
Published: January 2023

Abstract
Notoriously known for its involvement in type I hypersensitivities, Antigen (Ag)-specific IgE mediates a variety of mild to severe responses, including asthma. Ag-specific IgE is additionally important for immunity against gastrointestinal helminths, but these helminths also elicit production of low-affinity, poly-specific IgE. Helminth infection has been shown by several groups to be protective against asthma. The mechanisms behind these findings have included the induction of regulatory pathways, but the role of poly-specific or “benign” IgE has not been fully assessed. To test this in the absence of helminth infection, we utilized a four week model of murine asthma and injected IgE anti-DNP as our “benign” IgE twice a week. We found that treatment significantly reverses the eosinophil accumulation, airway hyperresponsiveness, and lung pathology seen with this model. Further analysis shows that the “benign” IgE treatment is only needed during the antigen challenge phase and not during sensitization phase. Using in vitro assays we were able to show that non-specific IgE can block Ag-specific IgE degranulation even after Ag-specific IgE pre-incubation. Overall, these data demonstrate a novel avenue for blockage of mast cell degranulation and a potential regulatory role for IgE.
Poly(ADP)Ribose Polymerase inhibition by gene knockout or pharmacologically by olaparib restores steroid sensitivity in murine model of steroid-resistant Asthma
Authors: Ghonim Mohamed Ahmed , Wang Jeffrey , Ibba Salome Valentina , Luu Hanh , Boulares Hamid 
Published: January 2023

Abstract

Background
Asthma is a serious health issue worldwide and a common treatment for the disease is a combination of steroids with β2-agonist; however, many patients are refractory to steroid treatment. Individuals with steroid-resistant asthma have limited therapeutic options; some can die by status asthmaticus. steroid-resistant asthma is intimately associated with neutrophilic inflammation. Our laboratory has established a critical role for PARP-1 in asthma and neutrophile-based inflammation. Thus we hypothesize that PARP-1 may restores steroid sensitivity in murine model of steroid-resistant asthma.

Objective
To investigate whether PARP-1 inhibition could restore steroid sensitivity in steroid-resistant asthma model.

Methods
Murine model of steroid-resistant asthma and cell culture system were used.

Results
OVA challenge promotes eosinophilic-Th2 mediated response that is blocked by dexamethasone treatment. OVA priming with LPS/IFNγ results in class switching into neutrophile with developing resistance to the treatment with dexamethasone. PARP inhibition by gene knockout or by olaparib reversed the established steroid-resistant asthma manifestation in mice. This is attributed to marked reduction in the inflammatory cells infiltrating the airways and the significant reduction in the Th2 cytokines production, AHR, and the OVA-specific IgE secretion in both BALF and serum of the mice. The reversal of steroid resistance is explained by marked increase in the expression of Glucocorticoid Receptors (GR).

Conclusion
Our findings demonstrate a critical role for PARP-1 in steroid resistance and support the potential of PARP inhibition as a viable therapeutic strategy for treatment of steroid-resistant asthma.
Suppressive role on bacterial resistance of CD10+Pax5+cells in alcohol use disorder patients
Authors: Tsuchimoto Yusuke , Asai Akira , OHAMA Hideko , Fukunishi Shinya , Higuchi Kazuhide 
Published: January 2023

Abstract
Alcohol use disorder (AUD) patients are the immunocompromised hosts and these patients have an increased risk of several opportunistic infections. CD10+Pax5+cells are included in lineage negative cells which have been described as suppressor cells for host antibacterial defenses. In this study, we examined the immunological role of CD10+Pax5+cells in AUD patients. CD10+Pax5+cells were isolated from peripheral blood of AUD patients and healthy donors (HD) and analyzed for retinoic acid receptor (RAR) expression by flow cytometry. These cells (1 x 106cells/ml) were cultured with 10 μg/ml of retinoic acid (RA) for 24 hours. After washing, culture fluids of these cells for 24 hours were harvested. Monocytes (1 x 106cells/ml) isolated from HD, were stimulated with culture fluids from CD10+Pax5+cells after the RA stimulation and the bactericidal activity against Enterococcus faecalis was assayed by colony counting methods. In the results, the number of CD10+Pax5+cells was same between AUD patients and HD. CD10+Pax5+cells from HD were expressed RAR (63.7 ± 2.19%), but those of AUD patients were not (12.4 ± 3.31%). When monocytes were stimulated with culture fluids of CD10+Pax5+cells after the RA stimulation from HD, the bactericidal activity of these cells was 62.75 ± 3.78%. However, the bactericidal activity of same monocytes which were stimulated with culture fluids of CD10+Pax5+cells after the RA stimulation from AUD patients, was suppressed(5.5 ± 3.15%). In conclusions, through the production of some soluble factors active against killing functions of monocytes, CD10+Pax5+cells increase the susceptibility of AUD patients to opportunistic infections.
Evaluation of T regulatory cells responses in acute and chronic phases of Chikungunya patients
Authors: Gois Bruna Macedo , Guerra-Gomes Isabel Cristina , Peixoto Rephany Fonseca , Dias Cinthia Sousa Nobrega , Palmeira Pedro Henrique Sousa , Araújo Josélio Maria Galvão , Keesen Tatjana 
Published: January 2023

Abstract
The aim of this work was to characterize T regulatory cells (Treg) from patients presenting both acute and chronic forms of Chikungunya disease. To reach this aim, peripheral blood samples from controls (n = 7), acute (n = 7) and chronic (n = 6) patients were collected and evaluated by flow cytometry regarding Treg markers such as CD39, CD73, Granzyme B, Perforin, PD-1, CTLA-4, INF-γ, IL-10 and TGF-β. It was observed: 1) Decrease in Treg cells frequency of acute and chronic patients compared to controls; 2) Decreased expression of extracellular ATP cleavage enzymes (CD39 / CD73) in Treg cells from both patients groups; 3) Treg cells from acute and chronic patients presented a decreased production of Granzyme B and Perforin compared to control group; 4) Treg cells of acute patients showed a decrease of 50% in CTLA-4 expression, which is reestablished in patients presenting the chronic form of the disease; 5) In addition, PD-1 receptor was decreased on the Treg cell surface of acute and chronic patients compared to healthy group; 6) Production of INF-γ by patientsTreg was similar to controlsTreg; 7) IL-10 Treg producing cells did not change compared to control group, however the chronic patients showed higher frequencies of IL-10 Treg producing cells compared to acute patients; 8) Treg cells from patients in both forms of Chikungunya disease decreased the production of the TGF-β, compared to controls. Thus, our results suggest that the decrease of regulatory T cells and markers may contribute to the favoring of viral clearance, however, the maintenance of inflammation can promote cellular damages that are related to severe clinical characteristics of the disease, suggesting that Treg cells play a key role in the development Chikungunya pathogenesis.
Interleukin-27 enhances the function of regulatory T cells to prevent Graft-versus-host diseases
Authors: Le Thi Hong Nga , Hamilton Betty K. , Min Booki 
Published: January 2023

Abstract
Graft-versus-host diseases (GvHD) remain life-threatening complications after allogeneic stem cell transplantation. Foxp3+Tregs can inhibit GvHD, while preserving graft-versus-tumor activity, making Tregs a promising candidate for GvHD treatment. Yet, the clinical application is hampered by the limited numbers and ineffective functions during treatment. Conventional CD4 T cells acquire Foxp3 expression and regulatory functions by stimulating them with IL-2 and TGFb (iTregs). Unlike thymus-derived Tregs (tTreg), ineffective regulatory functions and phenotypic instability of iTregs remain areas of improvement. We reported that IL-27 is able to enhance Treg functions to reduce autoimmune and allergic inflammation. Herein, we sought to test if IL-27-stimulation in Tregs improves therapeutic efficacy of Tregs in a murine model of MHC-mismatched allogeneic GvHD. IL-27-pretreated tTregs efficiently reduced acute GvHD-associated mortality, whereas the efficacy of IL-27-pretreated polyclonal iTregs to prevent GvHD was marginal. We hypothesized that elevating antigen specificity in iTregs would increase the therapeutic functions of iTregs. Indeed, IL-27-pretreated allogeneic iTregs exhibited highly improved therapeutic function, equivalent to that of tTregs. IL-27-induced iTreg functions were also tested using human cells. IL-27 prestimulated third party human iTregs partially rescued mice from xenogeneic GvHD. Our data suggest that IL-27 stimulation in Tregs may play an important role in regulating Treg functions during GvHD, raising the hypothesis that defects in Treg functions (possibly via IL-27) may underlie different susceptibility of allogeneic bone marrow transplant patients who develop GvHD or not.