bluuebunny/crossref_metadata_2025_split huggingface dataset:
15-deoxy-Δ12,14-prostaglandin J2 enhances the interaction between Keap1 and p62/SQSTM1
Authors: Joo Myungsoo , Lee Ji Yeon , Kim Kyun Ha 
Published: January 2023

Abstract
15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) can suppress inflammation by activating Nrf2, an anti-inflammatory transcription factor. 15d-PGJ2 forms an adduct to Keap1 and disrupts Keap1 ubiquitinating Nrf2, resulting in the accumulation and activation of Nrf2 in the nucleus. Here, we investigated a fate of the Keap1 disabled by15d- PGJ2. Our results show that while suppressing the ubiquitination of Nrf2, 15d-P GJ2 did not affect the ubiquitination of Keap1. Unlike prostaglandin E2, 15d-PGJ2 increased the binding between Keap1 and p62/SQSTM1 and enhanced the degradation of Keap1 in a cycloheximide chase experiment. 15d-PGJ2 increased the amount of Keap1, when treated with lysosomal protease inhibitors, E-64d and pepstatin, but not with MG132, a proteasome inhibitor, suggesting that Keap1 is preferably removed via autophagosome. Together, these results suggest that 15d-PGJ2 increases the binding of Keap1 to p62/SQSTM1, facilitating the removal of the dysfunctional Keap1 via autophagy. Our findings suggest that 15d-PGJ2 regulates the anti-inflammatory activity of Nrf2 by not only inactivating the function of Keap1 but clearing the dysfunctional Keap1.
T Follicular Regulatory (TFR) Cells Regulate B Cell Responses By Targeting TF Helper (TFH) Cells
Authors: Lopez-Ocasio Maria D , Shevach Ethan M 
Published: January 2023

Abstract
Interaction of TFH cells with B cells not only helps TFH to fully commit to this lineage, but also provides B cells with survival and differentiation cues. A GC response is critical for the development of an immune response against pathogens, but a dysregulated response could lead to autoantibody production. TFR cells, a subset of Foxp3+ Tregs, localize into follicles to regulate GC responses. To elucidate the mechanism (s) and cellular target (s) utilized by TFR cells to suppress GC responses, we quantitated TFR function in vitro. In the absence of TFR cells, TFH from primed mice induce both naive B cell differentiation into GC B cells and class switching in the presence of anti-CD3 alone or anti-IgM/anti-CD3 in a contact dependent manner. Addition of TFR cells from primed mice efficiently suppressed GC B cell proliferation, differentiation and class switching in the anti-CD3 alone cultures, but only moderately suppressed BCR-stimulated B cells. Under anti-CD3 conditions, IL-4-deficient TFH cells did not promote B cell differentiation and class switching. In contrast, IL-21R-deficient B cells differentiated into GC B cells with a reduced number of IgG1+ cells. When IL-4 deficient TFH cells were co-cultured with IL-21R-deficient B cells, both GC differentiation and class switching were reduced. Under anti-IgM/anti-CD3 conditions, IL-4-deficient TFH cells promoted B cell differentiation, but class switching was reduced, while IL-21R-deficient B cells differentiated normally into GC B cells, but class switching was reduced. These studies suggest that at least in vitro, TFR cells regulate the GC responses by acting directly on TFH cells most likely by inhibiting cytokine production.
Remission induction of established nephritis by therapeutic administration of a novel BTK inhibitor in an inducible model of lupus nephritis
Authors: Chalmers Samantha A. , Doerner Jessica L , Bosanac Todd , Khalil Sara , Smith Dustin , Harcken Christian , Dimock Janice , Herlitz Leal , Webb Deborah , Seccareccia Elise , Feng Di , Fine Jay S , Ramanujam Meera , Klein Elliott , Putterman Chaim 
Published: January 2023

Abstract
Lupus nephritis (LN) patients currently lack highly effective and safe treatment options. Bruton’s tyrosine kinase (BTK) is a tyrosine kinase which is important for B cell and macrophage function. Based on preliminary studies in an inducible model of nephritis that highlighted the importance of BTK dependent macrophage effector function in the pathogenesis of disease, we extended our studies to explore the effect of BTK inhibition on remission induction of established, proliferative nephritis.
Nephritis was induced in female 129 sv/J mice (10 weeks of age) via the passive transfer of nephrotoxic serum (NTS). Once a mouse developed severe nephritis (&gt;300 mg/dl proteinuria for two consecutive days, or a single measurement of &gt;2000 mg/dl), treatment begun via daily oral gavage with 3 mg/kg of BI-BTK-1, a novel, highly selective and potent BTK inhibitor. Each treated mouse was matched to a control mouse that received daily gavage of the vehicle alone.
Within two days of beginning treatment, mice treated with BI-BTK-1 had a significant reversal of the proteinuria compared to vehicle control treated mice (p&lt;0.05). Terminal urine revealed a significantly reduced A:C ratios (p &lt;0.001). Additionally, terminal serum revealed normalized BUN levels. Histological assessment revealed significant structural protection in the treated compared to control treated mice, including both glomerular (p&lt;0.001) and tubular compartments (p &lt; 0.001). Kidney RT-PCR and RNA-seq analysis are currently in progress.
Therapeutic treatment with BI-BTK-1 reversed severe, established nephritis induced by pathogenic antibodies. These exciting results indicate the novel therapeutic potential of BTK inhibition for treating LN patients with established disease.
Male microbiota-associated metabolite protects female BWF1 mice from lupus possibly by restoring tolerogenic CD103+ DC function.
Authors: Harder James W , Chhabra Anita Y. , Alard Pascale , Zhang Xiang , Hua Yuan , Ferrill Rachel , Kosiewicz Michele M 
Published: January 2023

Abstract
Alterations in microbiota composition are associated with autoimmune diseases. We have found previously that microbiota composition differs significantly between female and male BWF1 mice, and transfer of male microbiota to females suppresses disease and increases survival. Protection appears to be mediated, at least in part, through male microbiota action on CD103+ dendritic cells (CD103DC) that induce Tregs in the periphery (pTregs). Female BWF1 CD103DC appear to have a defect in their ability to synthesize retinoic acid (RA; critical for Treg conversion and synthesis requires retinaldehyde dehydrogenase, RALDH2, activity) that is restored by male microbiota transfer. How the male microbiota protects against disease is unknown, but may be mediated through differential production of metabolites. We have performed multiple metabolomic analyses on feces from female and male BWF1 mice and from female recipients of male microbiota. We have identified &gt;90 metabolites that are differentially produced, including those that can act as HDAC inhibitors, fatty acid synthesis inhibitors, and retinoid X receptor agonists (i.e., may enhance RALDH2 activity). We found that feeding the male microbial metabolite with RXR agonist activity to female BWF1 mice significantly increased CD103DC RALDH2 activity and the levels of pTregs in vivo, and delayed the onset of kidney disease. Taken together, these data suggest that at least one male microbiota-associated metabolite may be capable of suppressing disease directly, and may do so by enhancing tolerogenic CD103DC activity. Experiments are currently underway to test the effect of other male microbial metabolites on the immune mechanisms involved in lupus.
Selective HDAC6 inhibitor decreases lupus in mice
Authors: Ren Jingjing , Liao Xiaofeng , Vieson Miranda , Eden Kristin , Chen Miao , Scott Reilly , Kazmierczak Jillian , Luo Xin M , Reilly Christopher M 
Published: January 2023

Abstract
Histone deacetylase 6 (HDAC6) is a Class IIb HDACs enzyme primarily residing in the cytoplasm. HDAC6 alters gene transcription by removing acetyl groups from lysine residues on transcription factors. We, and others, have previously demonstrated that HDAC6 expression is increased in systemic lupus erythematosus (SLE) patients and animal models of lupus and that inhibition of HDAC6 decreased disease. In our current studies, we tested if an orally active selective HDAC6 inhibitor would decrease disease pathogenesis in a lupus mouse model with established early disease. Importantly, we sought to delineate the cellular and molecular mechanism(s) of action for the HDAC6 inhibitor. We treated 20-week-old early-diseased NZB/W F1 (lupus) female mice with two different doses of the selective HDAC6 inhibitor (ACY-738) for five weeks. At the termination of the study, our results showed a reduced germinal center B cell response, decreased T follicular helper cells and diminished IFN-g production from T helper cells in splenic tissue. Additionally, we found the IFNa-producing ability of plasmacytoid dendritic cells was decreased along with immunoglobulin isotype switching and the generation of pathogenic autoantibodies. Renal tissue showed decreased immunoglobulin deposition and reduced inflammation as judged by glomerular and interstitial inflammation. Taking together, these studies show selective HDAC inhibition decreased several parameters of disease pathogenesis in lupus prone mice. The decrease was in part due to inhibition of autoreactive B cell differentiation. Studies are currently underway to define further the mechanism of how HDAC6 inhibits auto-reactive B cell differentiation.
R428 as a novel therapeutic agent for the treatment of experimental immune-mediated nephritis
Authors: Shao Wenhai , Zhen Yuxuan 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease. Glomerulonephritis is a major cause of morbidity in SLE. Glomerular proliferation is essential for the pathogenesis and progression of glomerular diseases. Nephrotoxic serum-mediated anti-glomerular basement membrane (anti-GBM) disease is a well-studied mouse model of immune-mediated glomerulonephritis. Axl receptor tyrosine kinase mediates glomerular cell survival signaling, resulting in proliferative responses. We previously showed that Axl-KO mice developed significantly reduced nephritis with improved kidney function and survival rate compared to the WT mice under the same treatment. In this study, we explore the therapeutic effect of Axl-specific small molecular inhibitor, R428, in anti-GBM nephritis. Our results show that R428 effectively prevents disease progression and exacerbation. Mesangial cell proliferation was greatly reduced in the R428-treatment mice. Mechanistic studies revealed that R428 suppresses the expression of pro-inflammatory cytokines and reduces Akt phosphorylation in the kidney. In summary, these results indicate that R428, currently under clinical trial in cancer patients, may have clinical therapeutic application in lupus nephritis patients.
A double-blind, placebo-controlled, crossover study of magnesium supplementation in patients with XMEN syndrome: preliminary results.
Authors: Ravell Juan C , Price Susan , Kanellopoulou Chrysi , Matthews Helen F , Cohen Jeffrey , Lenardo Michael 
Published: January 2023

Abstract

Introduction
X-linked immunodeficiency magnesium defect, Epstein-Barr virus (EBV) infection and neoplasia (XMEN) syndrome is a primary immunodeficiency caused by the loss of expression of the magnesium transporter 1 (MAGT1). This syndrome is associated with CD4 lymphopenia, chronic EBV infection in most patients, and EBV related lympho proliferative disorders. The loss of MAGT1 leads to impaired T cell activation and decreased expression of the activator receptor, NKG2D on natural killer (NK) cells and CD8 T cells, leading to decreased EBV-specific cytolytic function of these cells. Results of previous studies suggest that magnesium supplementation may be a viable therapeutic option for patients with XMEN.

Methods
Patients ≥6 years of age with XMEN syndrome and persistent EBV viral load of ≥5,000 copies/mL by whole blood PCR are randomized to receive escalating doses of either placebo or oral magnesium L-threonate for 12 weeks. This is followed by crossover treatment for an additional 12 weeks. For patients who experience a 0.5-log decrease in the number of EBV-infected B cells by FISH with oral magnesium as compared to placebo, the study is complete. Patients who do not meet this outcome then undergo a 2-week washout period and proceed to Part II, an open-label, non-randomized evaluation of intravenous magnesium sulfate (MgSO4) followed by oral magnesium L-threonate.

Results
here we report the preliminary results for the first patient enrolled in the clinical trial, including changes in the number of EBV infected B cells and NKG2D expression with magnesium treatment.
Detection of naive B cells expressing potentially protective antibodies
Authors: Bancroft Tara A , McGuire Andrew , Gray Matthew , Feng Junli , Pancera Marie , Steach Holly , Debuysscher Blair , Stamatatos Leonidas , Taylor Justin 
Published: January 2023

Abstract
Most effective vaccines work through the induction of protective antibodies able to neutralize or eradicate infection. Unfortunately, the induction of protective antibodies has proved difficult for a number of infections, such as HIV/AIDS, or the protective antibodies that are elicited through vaccination do not bind all strains of the virus, such as with influenza. Broadly neutralizing antibodies against these viruses, displaying protective potentials in experimental animal models, have been isolated from infected individuals. The detailed characterization of these antibodies revealed that they are derived from specific, but infrequent, VH/VL gene pairing. To better characterize the rare naïve B cells that express the germline (gl) forms of these antibodies (gl B cell receptors, glBCRs) we developed unique anti-idiotype antibodies, that specifically recognize the gl form of HIV-1 and influenza broadly neutralizing antibodies, b12 and FI6, respectively. The abilities of anti-idiotypic antibodies against gl-b12 and -FI6 IgG to specifically identify the rare naïve human B cells that express gl-b12 or -FI6 were evaluated. In the case of FI6, we generated an anti-idiotype that bound to 5 closely related alleles within the VH3 family. Using this anti-idiotype in conjugation with a Flu protein that can bind to gl-FI6, we have begun to characterize a family of gl-FI6-like antibodies. For b12, one anti-idiotype displayed superior ability to target naïve B cells expressing gl-b12-like BCRs. The availability of this novel reagent allows for the high-throughput, in-depth, characterization of the rare B cells that are the precursors of broadly neutralizing antibodies, and will assist efforts to elicit such antibodies through vaccination
CTL-based vaccine-induced control is associated with induction of high follicular to extra-follicular ratios of virus-specific CD8+ T cells.
Authors: Mohammad Hadia Mohammad Abdelaal , Li Shengbin , Sawahata Ryoko , Mwakalundwa Gwantwa , Fraser Kathryn , Mylvaganam Geetha , Martins Mauricio , Masopust David , Amara Rama Rao , Watkins David , Connick Elizabeth , Skinner Pamela J 
Published: January 2023

Abstract
There is a need to develop an effective HIV vaccine. We earlier showed that during chronic HIV-1/SIV infections, HIV/SIV replication is concentrated within B cell follicles, whereas HIV/SIV-specific CD8 T cells are largely excluded from these sites suggesting that the inability of HIV/SIV-specific CD8 T cells to fully suppress virus replication may be due to their deficiency in B cell follicles. We hypothesize that a successful HIV vaccine will either prevent HIV seeding B cell follicles or induce high levels of virus-specific CD8 T cells in B cell follicles. Here we investigated whether control associated with three CTL inducing SIV vaccines was associated with levels of SIV-specific CD8T cells in follicular (F) and extrafollicular (EF) areas in lymph nodes of vaccinated animals after challenge with pathogenic SIV relative to a cohort of unvaccinated chronically infected animals using in situ tetramer staining combined with immunohistochemistry. We defined control as a set point pVL of ≤104. We found lower levels of tet+ SIV-specific CD8 T cells in F compared to EF areas of non-controller animals (P&lt;0.0001), but not in controller animals (P=0.1). Although we found similar levels of tet+ SIV-specific CD8T cells in F and EF areas between the controller and non-controller animals (P=0.6) and (p=0.5) respectively, the controller animals had significantly higher F: EF ratios of tet+ SIV-specific CD8T cells (P=0.028). Also, we found a significant inverse correlation between F: EF ratio of tet+ SIV-specific CD8 T cells and pVL in the controller (r=− 0.75, P=0.0046) but not in non-controller animals (r=0.01, P=0.97). These results support developing CTL-based HIV vaccines that augment relative levels of virus-specific CTL within B cell follicles.
SIV-specific CD8 T cells with perforin granules located exclusively within cell membranes correlate with the maturation of SIVmac239Δnef vaccine induced protection
Authors: Mwakalundwa Gwantwa L , Wagstaff Reece , Mohamed Hadia , Johnson Paul R , Skinner Pamela J 
Published: January 2023

Abstract
Vaccination with live-attenuated SIVmac239Δnef protects most animals challenged with a pathogenic SIV. In this model, there is a maturation of protection which occurs between 5 and 20 weeks post-vaccination. We previously showed that this maturation of protection did not correlate with distribution or density of SIV-specific CD8 T cells in lymphoid or genital tissues. In this study, we investigated whether the maturation of protection correlated with levels of the effector protein perforin in SIV-specific CD8 T cells in lymphoid or vaginal tissues. Using in situ tetramer staining with MHC tetramers combined with immunohistochemistry, and quantitative image analysis, we quantified perforin levels in SIV-specific CD8 T cells; Perforin negative cells are characterized as central memory T cells (TCM), perforin low cells are effector memory (TEM), and perforin high/med are effector T cells (TEFF). We also quantified a unique population of SIV-specific CD8 T cells with perforin localized exclusively within the cell membrane, which are likely to be a subset of TEM. From 5 to 20 weeks post-infection, we found increase in perforin negative and decrease in perforin high tetramer binding CD8 T cells. We also found an increase in SIV-specific CD8 T cells expressing low levels of perforin located exclusively in the cell membrane that correlated with the maturation of protection. These findings indicate that the maturation of protection induced by SIVmac239Δnef vaccine correlates with a shift from a primary response dominated by effector CD8 T cells, to a memory response, which includes an increase in SIV-specific CD8 T cells with perforin located exclusively in the cell membrane. These findings help inform the development of a successful HIV vaccine.
Rubella/SIV vectors for immunotherapy of SIV infection in rhesus macaques
Authors: Berkower Ira , Virnik Konstantin 
Published: January 2023

Abstract
Currently available anti-retroviral therapy (ART) can fully suppress viremia after SIV infection in macaques, but the drugs do not cure infection. When ART drugs are withdrawn, the virus rebounds vigorously. Apparently, ART cannot control or eliminate viral reservoirs. We postulate that early ART, combined with induction of strong T-cell immunity via live viral vectors, can achieve a functional cure by reducing or eliminating long-lived viral reservoirs. This could be detected as lack of viral rebound when ART is stopped.
We have developed the rubella vaccine strain (RA27/3)as a live attenuated viral vector that was safe and highly immunogenic in rhesus macaques. Rubella vectors-expressing SIV Gag replicated vigorously in vivo while eliciting potent T cellimmunity to gag. The vectors alsoelicited anti-Gag antibodies that were equal to SIV infection, durable for &gt;1 year, and were boosted by re-exposure to the vector. We are testing immunotherapy in a three stage experiment: 1st stage, SIV infection followed by starting ART on day 3; 2nd, Immunizing with SIV/Gag vectors while on ART; 3rd Stopping ART and measuring viral rebound. So far, we have shown complete viral suppression while on ART and a good immune response to the rubella vector and to the gag insert.
Pending viral loads will indicate whether all control animals were infected by SIV, and any reduction or delay in viral rebound due to immunotherapy effects on the viral reservoir. The results in primate models may predict the effect of immune therapy on recent HIV infection of humans. This approach could be ideal for treating HIV infection in infants, since the viral reservoir is small, and the immune system is still intact and capable of responding to the rubella/gagvector.
The effects of direct-fed microbial supplementation, as an alternative to antibiotics, on growth performance, intestinal immune status and epithelial barrier protein expression in broiler chickens
Authors: Oh Sungtaek , Gadde Ujvala Deepthi , Lee Youngsub , Davis Ellen , Zimmerman Noah , Rehberger Tom , Lillehoj Hyun S. 
Published: January 2023

Abstract
This study was conducted to investigate the effects of Bacillus subtilis supplementation in broiler chicken diets on growth performance, feed efficiency, intestinal cytokine and tight junction (TJ) protein mRNA expression. Day-old broiler chicks (n = 140) were to one of five dietary treatments: basal diet (CON), basal diet supplemented with antibiotic (BMD) or probiotics, namely B. subtilis strain 1781 (PB1), a combination of B. subtilis strain 1104+strain 747 (PB2) or B. subtilis strain 1781+strain 747 (PB3). At 14 days of age, ileal samples were collected and used for intestinal cytokine, TJ protein and mucin gene expression analysis using qRT-PCR. The chickens fed with antibiotic (BMD) and B. subtilis strain 1781 alone (PB1) had significantly higher body weights compared to controls of the same age. Dietary supplementation with antibiotic (BMD) or probiotics (PB1, PB2, PB3) significantly improved the feed efficiency as evidenced by decreased FCR compared to controls. No differences were observed in the expression of IL1β, IL17F, IFNγ and MUC2 gene among the different treatment groups. However, elevated expression of IL6 (BMD, PB1, PB2), IL8 (PB2) and TNFSF15 (PB1, PB2, PB3) compared to controls was observed in the ileum. IL2 and IL10 expression was upregulated in chicks in the PB2 and PB3 groups, and IL4 was elevated in the PB1 group. IL13 was elevated in all probiotic-fed groups. Probiotic supplementation was also shown to significantly increase the expression of TJ proteins JAM2, ZO1 (PB2, PB3) and occludin (PB1, PB2). Taken together, B. subtilis supplementation altered intestinal immune activity and influenced gut barrier integrity through increased expression of TJ proteins.