bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel mouse model of hypersensitivity to salt-soluble wheat protein: comparison of soft vs. durum wheat varieties
Authors: Gangur Venugopal , Jin Yining , Ebaugh Sarah , Secord James , Ng Perry KW , Olson Eric 
Published: January 2023

Abstract
Immune-mediated adverse reactions to wheat are rising at an alarming rate on a global scale for reasons that are not completely understood. Wheat is identified as a major red-flag allergenic food in many countries including the USA. Although mouse model of alcohol-soluble gluten hypersensitivity is available, a mouse model of hypersensitivity to salt-soluble wheat proteins (SWP)--the most common of the wheat allergens—is unavailable. Here we tested the hypothesis that SWP from both soft and durum wheat will elicit allergic response in BALB/c mice. High quality SWP from soft (Ambassador) and durum (Carpio) wheat were prepared, characterized and used in the study. Pups were weaned onto and maintained on a wheat-free diet. Group of mice (n=5/group) received three i.p. injections with SWPs plus alum. Blood was collected and used in the specific (S) IgE, IgG1/G2a antibody analysis. Upon i.p. challenge, mice were monitored for hypothermia shock response (HSR) and mast cell protease (mMCP)-1 response. Although both soft and durum wheat SWPs elicited robust SIgE Ab responses, durum wheat was superior (IgE titers: 905 vs. 2560). Both proteins elicited marked but comparable SIgG1/IgG2a Ab responses. Upon challenge, both proteins elicited HSR; however, durum-SWP elicited 6.7 times higher mMCP-1 response than soft-SWP. In summary, we report a novel mouse model of hypersensitivity to salt-soluble wheat proteins for the first time. These data also demonstrate that the durum (Carpio) wheat is more allergenic than the soft (Ambassador) wheat variety that we studied.
Efficacy of Curcuma longa in osteoarthritis: Association of IL-1β, IL-10 and MMP-9 with severity of disease
Authors: Saksena Anil Kumar , Srivastava Shobhit , Khattri Sanjay , Kumar Santosh 
Published: January 2023

Abstract
Osteoarthritis (OA) is a progressively debilitating immune mediated inflammatory disorder in which various biomarkers have been reportedly increased. This study was carried out to establish a correlation between IL-1β, IL-10 and MMP-9 in various grades of OA of knee and to observe the effect of Curcuma longa (CL-an indigenous drug) in such patients through a randomized, placebo controlled, double blind trial.
After obtaining clearance from Institutional Ethics Committee, 160 patients of either sex aged between 40 to 80 years, meeting the inclusion and exclusion criteria, were enrolled and randomly divided in two groups. The grading of the disease was done according to Kellgren-Lawrence (KL) grading scale. Placebo and extract of CL were given along with the standard treatment to the two groups in blind manner. The assessment of the patients was done after two and four months.
On day 0 the level of IL-1β, MMP-9 and IL-10 was found to be significantly higher in grade 3 and 4 patients as compared to grade 1 and 2 patients. After oral administration of CL extract there was significant clinical improvement (as compared to placebo) in all grades of patients as adjudged by WOMAC score and VAS. There was also significant decrease in levels of IL-1β and MMP-9 in parallel with the clinical improvement. Moreover, decline in the level of IL-10, after treatment with CL was not significant.
It is concluded that IL-1β, MMP-9 and IL-10 have strong parallel association with severity of OA. Further, CL produced significant relief in the patients of OA of knee, when given along with standard treatment.
High Monocyte Turnover Predicts Progression to AIDS in SIV Infected Aging Rhesus Macaques
Authors: Fahlberg Marissa , Walker Edith , Penney Toni , Cai Yanhui , Kuroda Marcelo J , Didier Elizabeth S 
Published: January 2023

Abstract
Incidence of newly-acquired HIV infections in persons over age 50 is increasing, from 13% in 2006 to 21% in 2013. Advanced age corresponds with lower 12-month survival and ART is contraindicated with the simultaneous use of many chronic disease medications. To address the need for age-specific interventions, we are studying aged rhesus macaques (RM) infected with SIV. In a pilot study, four young (6.27–7.37 years) and six older (17.71–23.82 years) RM were injected i.v. with SIVmac239. The older RM exhibited lower survival times compared to younger macaques (112.5 ± 76.8 days v. 353 ± 74.9 days, respectively). In young adult RM with SIV, we reported that increasing monocyte turnover (via BrdU uptake) as well as declining CD4+ cell counts, predicted disease progression. Among the aged RM, we observed that 3 animals developed increased or high monocyte turnover (HMT) after the first month of infection (35.2% ± 2.36) while the other 3 maintained steady state or low monocyte turnover (LMT) (5.74% ± 4.92) similar to that in the young animals (9.97% ± 2.34). Older RM with LMT survived longer (151 ± 85.6 days) than those with HMT (74 ± 54.5 days). The young adult and aged RM with LMT exhibited a dramatic decline of CD4+ T cells during peak viral load (−46% and −41%) 2 wks post infection compared to only a 22% decrease in aged RM with HMT. Also, the numbers of naïve T cells (CD4 and CD8) were lower in the HMT aged animals than in the LMT and young adults, at baseline and 2 wks post infection. These results suggest that there may be an additional or alternative preferential host cell target of SIV early in infection of older susceptible RM that we speculate to be macrophages. Work is continuing to examine the role of macrophages in pathogenesis of HIV infection in the elderly.
Role of TWEAK/Fn14 in chronic inflammatory disorders of the skin
Authors: Sidler Daniel , Herro Rana , Kawakami Yuko , Kawakami Toshi , Burkly Linda C , Croft Michael 
Published: January 2023

Abstract
Atopic dermatitis and Psoriasis are inflammatory disorders of the skin. Despite particular differences in respect of etiology, pathogenesis and clinical manifestations, these diseases share histological features such as epidermal hyperplasia and dermal fibrosis. Discovering molecules that contribute to the development of both diseases could provide opportunities for therapeutic intervention. It is accepted that keratinocytes and dermal fibroblasts play a pivotal role in both diseases by amplifying and maintaining inflammatory and fibrotic responses. TNF superfamily members, including TWEAK (TNFSF12), have been implicated in control of these cell types, but experimental insights are scarce. Employing TWEAK-deficient mice, we demonstrated that the TWEAK/Fn14 axis is indispensable for experimental atopic dermatitis and psoriasis. Furthermore, we found that subcutaneous injection of recombinant TWEAK into naïve mice is sufficient to induce robust inflammation with histological and molecular signatures of both atopic dermatitis and psoriasis. Moreover, in vitro experiments revealed that keratinocytes and dermal fibroblasts produced key chemokines and cytokines in response to TWEAK that are characteristic of both atopic dermatitis and psoriasis, and these molecules were amplified when TWEAK was combined with the signature cytokines IL-13 and IL-17. Similarly, subcutaneous injection of TWEAK with IL-13 or IL-17 synergized with respect to infiltration and intra cutaneous expression of proinflammatory molecules. These studies help to understand the network of factors active in the pathogenesis of skin inflammatory disorders, and highlight TWEAK as a central regulator of both atopic dermatitis and psoriasis.
The auto-reactive profile of B cells from early MS patients
Authors: Monson Nancy , Rivas Jacqueline , Ireland Sara , Rounds William , Ligocki Ann , Ma Lisha , Frohman Elliot , Greenberg Benjamin , Cowell Lindsay G , Stowe Ann Marie 
Published: January 2023

Abstract
My lab’s recent work has led to the discovery that antibodies expressed by memory B cells in the cerebrospinal fluid (CSF) of patients with Multiple Sclerosis recognize neurons and astrocytes in the brain. Genetic analysis further revealed that only certain heavy chain genes accommodate binding to these brain targets, and that memory B cells from control cohorts rarely express these antibody genes. In fact, in a recent clinical trial, we demonstrated that the prevalence of these antibody genes expressed by memory B cells in the CSF support identification of patients who either have MS or will develop MS in the future with 89–94% accuracy. This Antibody Gene Signature (AGS) is a novel biomarker that heralds the advent of antibody genetics as a means to support categorization of patients early in their disease course. Our goal for this project was to determine whether antibodies expressed by activated memory B cells that have initiated antibody production (called “plasmablasts”) in the peripheral blood of MS patients also recognize neurons and astrocytes. We cloned and expressed more than 50 antibodies expressed by peripheral plasmablasts of early MS patients and control cohorts. We found that antibodies expressed by peripheral plasmablasts from patients who develop MS bind to neurons and astrocytes in the brain. Those plasmablasts that did not express antibody heavy chains associated with the AGS did not bind to brain targets. Interestingly, only those patients in our cohort who have an elevated frequency of peripheral plasmablasts continue to accumulate brain MRI activity. It is possible that brain-reactive peripheral plasmablasts contribute to the brain damage associated with MS.
ER stress generates immunogenicity in human pancreatic β cells
Authors: Marre Meghan L. , James Eddie A , Piganelli Jon D 
Published: January 2023

Abstract
Type 1 diabetes (T1D) is an autoimmune disease in which autoreactive T cells target and destroy pancreatic islet β cells. The key events that break peripheral tolerance in patients genetically predisposed to autoimmunity remain poorly understood. Many physiological and environmental triggers associated with T1D cause endoplasmic reticulum (ER) stress, which may increase abnormal protein post-translational modification (PTM). We hypothesized that β cell ER stress generates neo-antigens that can activate autoreactive T cells in T1D. Chemical (Thapsigargin) induction of ER stress in human islets or insulinomas increased their recognition (135–360 fold) by human T cells known to preferentially recognize deamidated GAD65, as measured by IFNγ secretion. This increased immunogenicity was accompanied by increased activation of the PTM enzyme tissue transglutaminase 2 (Tgase2; 2 fold). We will confirm the role of this enzyme in ER stress-induced human β cell immunogenicity with shRNA. We are also working to validate this pathway as a therapeutic target as follows: First, we are measuring calcium dynamics to determine if cytosolic calcium is crucial to ER stress-dependent immunogenicity. Second, we are assessing whether other triggers of ER stress, such as cytokines and glucose, also generate GAD65 PTM in human β cells. β cell ER stress generated through a variety of sources may be an opportunity for therapeutic intervention to prevent the destruction of β cells. Our on-going work will define the ER stress-induced pathways and PTM that contribute to recognition of GAD65. These findings will also have implications for the recognition of other autoantigens and for the development of T1D.
Immune regulatory receptors expressed on NK cells in type 1 diabetes.
Authors: Suwannasaen Duangchan , Thrope Jerill , Greenbaum Carla , Long Sarah Alice 
Published: January 2023

Abstract
Auto-reactive T cells specific to islet antigens contribute to the onset of type 1 diabetes (T1D), yet NK cells may also play a role in disease onset and progression. Mouse models suggest a dual role for NK cells in disease onset and progression while human studies have found deficiencies in NK number and function. However, human studies are confounded by variability in cohorts (pre-T1D, recent onset, long-standing T1D) and more phenotypic and functional analysis as has been performed in murine studies. In our initial studies, we characterized activation and inhibitory markers on NK cells of longstanding T1D (n=5) as compared to healthy controls (n=6). NK cells from the same sample were then compared to known T cell phenotypes. PBMC were analyzed by flow cytometry for markers of T and NK cells (CD45RA, CCR7, CD56, CD4 and CD8), immune regulation (PD1, KLRG1, TIGIT and CD57) and activation (CD69 and CD25). Results showed that there was a significant elevation of T cells but a decrease of NK subsets (CD56dim and bright) in T1D compared to healthy controls. Both CD57+ and CD57+TIGIT+ NK cells were significantly reduced in T1D, implying a more immature and less regulatory phenotype or more activated phenotype. In the same subjects, both CD4 and CD8 memory T cell populations expressing PD1 were significantly lower in T1D than in healthy controls. Moreover, the CD8 EMRA (CCR7− CD45RA+) T cells exhibited decreased KLRG1, TIGIT and CD57 expression. Taken together, these findings revealed a skewing of NK cell subsets in T1D. Further functional characterization of both NK and T cells in the same sample may lead to identification of biomarkers for T1D.
Increased expression of IRF-5 in the adipose tissue in obesity: Implication in metabolic inflammation
Authors: THOMAS REEBY SARA , Kochumon Shihab , Ahmad Rasheed , Sindhu Sardar 
Published: January 2023

Abstract
Obesity is marked by a state of chronic low-grade inflammation called metabolic inflammation which plays a role in the development of insulin resistance and type-2 diabetes (T2D). We and others have shown that the innate immune toll-like receptors (TLRs) are involved in metabolic inflammation/insulin resistance. The transcription factor called interferon regulatory factor (IRF)-5 is a major regulator of proinflammatory macrophage polarization; however, its role in obesity/T2D remains unclear. Therefore, we determined modulations in the IRF-5 expression and analyzed their relationship with signature metabolic inflammatory markers in the subcutaneous adipose tissues (AT) obtained from adult persons classified as lean, overweight, and obese on the basis of BMI. The data show that IRF-5 expression was upregulated (P&lt;0.05) in obese as compared with lean individuals at both mRNA and protein levels; and these changes correlated with BMI (r=0.3; P= 0.03) and body fat percentage (r=0.48; P=0.0005). The elevated IRF-5 expression also correlated positively (P&lt;0.05) with various inflammatory markers including TNF-α (r=0.47), IL-6 (r=0.31), IL-1β (0.36), IL-18 (r=0.27), CXCL-10 (r=0.30); IL-8 (r= 0.33), CCL-5 (r=0.41); CCR-5 (r=0.42); CCR-2 (0.54) as well as TLR adapter proteins MyD88 (r=0.61) and IRAK-1 (r=0.50). Interestingly, IRF-5 expression was found to associate with fasting blood glucose (r=0.40, P = 0.008) and glycated hemoglobin (r=0.45, P=0.009). As expected, IRF-5 expression correlated negatively with plasma adiponectin levels (r= −0.43; P=0.009). Collectively, our data show that increased AT- IRF-5 expression is concordant with signature inflammatory markers which may have significance in metabolic inflammation.
The role of monoclonal paraproteins in Systemic Capillary Leak Syndrome (SCLS)
Authors: Hakeem Reem M , Druey Kirk , Zhihui Xie 
Published: January 2023

Abstract
The Systemic Capillary Leak Syndrome (SCLS) is a rare, orphan disease characterized by bouts of acute, reversible plasma extravasation into tissues, which leads to hemoconcentration, hypoalbuminemia, hypotension, and vascular collapse. Although the cause of SCLS is unknown, 80–95 % of SCLS patients have a monoclonal gammopathy of unknown significance (MGUS), in which clonal plasma cells secretes large amounts of monoclonal immunoglobulins or “paraproteins”. MGUS is a premalignant precursor to multiple myeloma (MM) and is notably detected in most SCLS patient sera. Another marked distinction is that acute, but not basal SCLS sera contain elevated concentrations of inflammatory mediators known to promote endothelial permeability, notably Vascular Endothelial Growth Factor (VEGF) and Angiopoietin 2 (Angpt2). To address these findings experimentally, we purified whole IgG from patient and control sera to examine whether these immunoglobulins have an impact on endothelial cell barrier function and performed functional assays to characterize the observed changes in morphology. Preliminary data suggest that patient IgG binds to endothelial cells and elicits significant F-actin stress fiber formation and VE-cadherin internalization. SCLS IgG seems to be critical in triggering endothelial dysfunction and dissecting the underlying signaling mechanisms involved will help us better understand disease pathogenesis and potentially pave the way for therapeutic target development.
SMAC mimetic in combination with HDACi effectively release brakes on cell death of chronic myeloid leukemia K562 cells accelerating ligand-mediated apoptosis.
Authors: Hontz Adrianne E , Vrazo Alexandra C , Figueira Sarah K , Kieser Pearce C , Risma Kimberly A 
Published: January 2023

Abstract
Enthusiasm for immunotherapy has reached an all-time high within the last year due to remarkable clinical outcomes using strategies directed at activating T cells. The mechanisms by which newly activated T cells execute tumor target cells have not been described; it is assumed that CD4 and CD8 T cells may utilize ligation of TNF receptor family members, Fas, TNF, and TRAIL. However, not all tumors are susceptible to T cell killing by death receptor ligands. Chronic myeloid leukemia K562 cells are notably resistant to pro-apoptotic, ligand-induced cell death; whereas, T cell leukemia Jurkat cells undergo rapid caspase 3/7 activation and cell death (within 4–6 hours) in response to pro-apoptotic death ligands Fas and TRAIL. We hypothesized that K562 cells may be sensitized to respond similarly by targeting the regulatory proteins controlling activation of executioner and/or initiator caspases, thus accelerating cell death. SMAC mimetic compounds (SMC) are a novel class of drugs that target pro-survival signaling molecules. Single agent treatment with SMC enhanced TRAIL- and TNF-induced caspase activation, but had only modest effects on cell death after 24 hours. Addition of histone deacetylase inhibitors (HDACi) in combination with SMC, accelerated TNF- and TRAIL- mediated caspase activation and led to rapid cell death in K562 cells. By relieving multiple levels of inhibition in the tumor targets, we achieved rapid and efficient killing of previously resistant tumor cells using recombinant death receptor ligands. Combination therapy with SMC and HDACi may enhance current immunotherapy approaches designed to 1) activate tumor specific T cells expressing death receptor ligands or 2) administer recombinant ligands such as TRAIL.
Mouse models for immunology research available from The Jackson Laboratory Repository.
Authors: Valenzuela Alicia , Lutz Cathleen M , Rockwood Stephen , Sasner Michael 
Published: January 2023

Abstract
The Jackson Laboratory Repository serves as a centralized facility for the development, distribution and cryopreservation of mouse models of human biology and disease. Hundreds of new strains are added annually to one of the largest collections of characterized mouse strains available.
This poster presents our newest strains involving genes associated with adaptive immunity. The Pdcdl (programmed cell death 1 - PD1) knockout (KO) mice allow increased infiltration of inflammatory cells in several disease models. CC10-OVA transgenic mice direct OVA expression to lung epithelium; and a KO/KI mouse expresses tamoxifen-inducible cre under the control of the Cd19 promoter in B lymphocytes.
New mouse models with mutations in genes involved in the innate immune response include: Dectin-1 (Clec7a) KO mice, which exhibit increased sensitivity to fungal infection and a dysregulated chemokine response; GM-CSF (Csf2) KO mice with impaired phagocytosis, a lupus-like disorder and glomerulonephritis; mice with a KO in MPYS (Tmem173), a pattern recognition receptor that activates type 1 interferon; Ccr2gfp KI/KO mice used in tracking monocyte chemotaxis; a transgenic mouse model of hyperimmunoglobulin E syndrome that expresses modified Stat3; and a new addition to our extensive collection of interleukin mutants, Il1a, a new conditional KO/reporter allele that is produced by monocytes and macrophages.
Additionally, several Cas9-expressing lines, requiring only a specific single guide RNA to generate single or multiple simultaneous mutations, are available. These lines overcome the burden of packaging size limits.
Researchers are encouraged to deposit mice to the Repository: www.jax.org/donate-a-mouse.
Helios expression defines two distinct populations of Foxp3+ regulatory T cells
Authors: Thornton Angela M , Kilaru Gokhul , Burr Patrick , Rieder Sadiye , Muljo Stefan Adi , Shevach Ethan M 
Published: January 2023

Abstract
The transcription factor Helios is expressed in a subset of Foxp3+ Tregs and we have proposed that Helios is a marker of thymic derived Treg (tTreg). Other studies have suggested that Helios is primarily a marker of T cell activation. In order to study the two Treg subpopulations, we have generated Helios-GFP reporter mice and crossed them to Foxp3-RFP reporter mice. The expression pattern of Helios in the reporter mice is similar to that detected by intracellular staining. When Foxp3+ Helios+ and Foxp3+ Helios− were isolated by FACS and transferred to normal mice, both phenotypes were stable. Both populations expressed a highly demethylated TSDR. A comparison of the two populations using RNA-Seq demonstrated 600 differentially expressed genes (500 higher in Helios+, 100 higher in Helios−). The Helios+ population expressed a more activated (Ly-6C−) phenotype and had slightly higher suppressive capability in vitro. Both subsets were equivalent in their ability to suppress IBD in vivo, but the Helios+ subset was more effective in the protection of RAG−/− mice from disease induced by transfer of splenocytes from scurfy mice. Thus, Helios expression can differentiate two distinct populations of Treg and may differentiate peripherally derived Treg (pTreg) from tTreg.
This research was supported by the Intramural Research Program of the NIH, NIAID.