bluuebunny/crossref_metadata_2025_split huggingface dataset:
Symphony of Life: Genetics, Immunology, Cancer & Aging I. Genetic and immunological evaluation of mice with histocompatible tumors, virus induced breast cancer and survivors of metastatic breast cancer, HIV infection, and old people
Authors: Williams R Michael , Zuniga Joaquin , Williams R Michael , Granados Julio , Feris Edmond Tato , Yunis Edmond J. 
Published: January 2023

Abstract
Antigen altered idiotype induces immune suppression through the production of a "hole" in the antigenic/epitope specificity repertoire, the consequences of which can be a acquired immune deficiency SYNDROME called AIDS. There are measurable immunological consequences which include decreased CD4 cell numbers and low CD4/CD8 ratios and uncommon DISEASES like pneumocystis carinii pneumonia, virus induced cancers such as CMV mediated Kaposi's sarcoma or HPV mediated cancers (Kaposi's sarcoma, cervical cancer, tonsil cancer, etc.) and other DISEASES for which no viral etiology has been proven (breast cancer, lung cancer, melanoma, anal cancer, colorectal cancer, etc.). When there is the double whammy of immune deficiency AND virus infection, particularly one which preferentially infects and/or kills a distinct cell population (CD4+ lymphocytes in man, MTV induced mammary cancer in mice) the disease such as AIDS/HIV or metastatic breast cancer, are particularly severe. The measurable components of the immune system (CD4 counts, CD4/CD8 ratios, Tregs, CTLs, quantitative immunoglobulins, NK cell numbers and NK cell activity and cytokine levels are altered. We will present data including genetic (MHC class I, NK cell receptor ligands) and immunological (cell numbers in old mice or humans, metastatic breast cancer or HIV infected people, and those who are older than 90. Populations tested include centenarians Mexico City, mice surviving after a Sendai virus epidemic or injection of a histocompatible tumor, active homosexuals, and long term survivors of breast cancer or HIV infection. Data include MHC class I allele interaction with NKG2A receptors in Mexicans, survivors of breast cancer and long term non progressors with HIV infection.
Pulmonary Eosinophilic Granulomatosis with Polyangiitis (EGPA) has Allergic and Immunoregulatory Features
Authors: Lin Edwin , Dong Zack , Wechsler Michael , Yandell Mark , Clayton Frederic 
Published: January 2023

Abstract

Introduction
Eosinophilic granulomatosis with polyangiitis (EGPA) is a life-threatening vasculitis that can cause heart failure, neuropathy, and organ damage. EGPA is a rare cause of systemic vasculitis, and its prevalence is estimated at 1 in 2 million. The pathophysiology of EGPA is poorly understood. We aim to characterize EGPA lung immunopathologic findings.

Methods
We studied five open lung biopsies and one transbronchial biopsy of active, untreated EGPA patients and compared them to lung tissue controls. They were studied by histopathology, immunostaining, and RNA sequencing with confirmatory RT-PCR.

Results
The characteristic parenchymal interstitial infiltrate contains eosinophils, FoxP3+ regulatory T cells (Tregs), abundant macrophages, basophils, mast cells, and many IgG4 plasma cells. IgG4+ granular deposits resembling immune complexes are present focally, some coating macrophages. RNA studies confirm that EGPA lung has abundant IGHG4 (increased 1,885-fold relative to controls, p&lt;2E-15) and, to a lesser degree, other immunoglobulin transcripts. Statistically significant increases, each ≥8-fold greater in EGPA compared to controls, are also seen for SIGLEC8 (for eosinophils), FOXP3, IL13, CCL18, CCL13, B cell markers, CYP27B1 (which makes calcitriol, active vitamin D) and the alternatively activated macrophage marker CD209 (DC-SIGN).

Conclusions
EGPA has both type 2 and immunoregulatory features. We propose a novel mechanism involving these findings that induces the EGPA immune response.
A phase 1, randomized, controlled clinical study of CC-11050 in people living with HIV with suppressed plasma viremia on antiretroviral therapy (APHRODITE)
Authors: Boulougoura Afroditi , Gabriel Erin , Laidlaw Elizabeth , Khetani Vikram , Arakawa Ken , Higgins Jeanette , Rupert Adam , Gorelick Robert J. , Lumbard Keith , Pau Alice , Poole April , Kibiy Angela , Kumar Princy , Sereti Irini 
Published: January 2023

Abstract

Background
Phosphodiesterase 4 inhibitors (PDE4i) block the degradation of cyclic adenosine monophosphate and modulate both innate and adaptive immune responses. PDE4i have been approved for rheumatologic diseases and tested as host-directed therapy in TB. We examined the safety of CC-11050, a new potent PDE4i, in HIV+ people with suppressed viral load (VL). We hypothesized that CC-11050 could be used to modulate HIV-related inflammatory responses.

Methods
Thirty HIV+ participants, on antiretroviral therapy (ART) ≥ 1 year with HIV VL &lt;50 copies/mL were randomized 2:1 to 12 weeks of CC-11050 200mg BID or placebo with follow-up at weeks 2, 4, 8, 12 and 16. Primary endpoint was safety. We also assessed the effect of CC-11050 on CD4+, CD8+, NK, VL, plasma cytokines, monocyte and T-cell activation.

Results
At baseline, median age was 49.5 years and CD4+ 459 cells/μL. Most frequent adverse events (only grades 1–2) in CC-11050 group were headache, diarrhea, nausea, cough and nasal congestion. The CC-11050 group had lower IL-8 level after adjustment for baseline level, group and week (0.72 fold, p=0.02) and lower %NK cells compared to placebo (0.87 fold, p=0.02). At week 12, the CC-11050 group had higher %CD14++CD16+ monocytes than placebo (median 58.5% vs 50.7%, p=0.03). There was no significant effect on plasma HIV viremia, assessed by single copy assay and on cell-associated DNA and RNA in PBMC.

Conclusions
CC-11050 was well tolerated in HIV+ participants without affecting controlled viremia. CC-11050 had an effect on innate immune mechanisms, by decreasing NK cells and IL-8 level and increasing intermediate monocytes. Further study is needed to elucidate the efficacy of CC-11050 as potential anti-inflammatory adjuvant strategy in HIV.
TGF-beta in the UCB-MSCs inhibit TNF-alpha in human mast cells and atopic dermatitis
Authors: Park HwanHee , Yu Yeon-sil , Baek Song-Yi , Yoo Sae-Mi , Seo Kwang-Won , Kang Kyung-Sun 
Published: January 2023

Abstract
It is well known that umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) have been effective therapy in autoimmune inflammatory disease such as atopic dermatitis (AD), rheumatoid arthritis (RA) and psoriasis. Especially, UCB-MSC has a prominent therapeutic effect on AD. However, there is not much research on the mechanism of alleviation of AD by UCB-MSCs. In this study, we investigated the mechanism of AD therapy by UCB-MSCs, using human mast cells as the major pathogenic cells in AD. LAD2 cells were stimulated with IL- 33(30ng/ml) and Ionomycin (1uM) under IgE-XL condition and they secreted a significant amount of TNF-a. TNFa was significantly inhibited by co-culture with UCB-MSCs. UCB-MSCs secreted TGF-beta and PGE2, which play a crucial role in immune regulation. TNF-a of LAD2 was increased when co-cultured with UCB-MSCs after TGF-b siRNA transfection. Nevertheless, inhibition of PGE2 using indomethacin, NS398 and celecoxib did not restore secretion of TNF-a. At the protein level, we examined the ERK, JNK and AKT signaling pathways involved in TNF-α, and only the ERK signaling pathway was associated with TNF-α inhibition. Finally, we found that TNFa is regulated by TGFb induced by UCB-MSC in a DF-induced mouse model. Taken together, our findings suggest that TGF-b may play an important role in regulating mast cells in AD rather than PGE2 in UCB-MSCs.
Upregulation of endocannabinoids in fatty acid amide hydrolase (FAAH) knockout mice prevents staphylococcal enterotoxin B (SEB)-mediated acute lung injury through changes in the microbiome, immune and metabolic profiles
Authors: Sultan Muthanna Ali , Nagarkatti Prakash , Nagarkatti Mitzi 
Published: January 2023

Abstract
Endogenous cannabinoids are considered key regulators of biological systems as they have been shown to exhibit anti-inflammatory properties, while the fatty acid amide hydrolase (FAAH) enzyme plays a role in degrading the endogenous cannabinoid, anandamide. Staphylococcus Enterotoxin B (SEB) is a superantigen that can cause acute lung injury (ALI) through inhalation. In this study, we found that FAAH knockout mice (FAAH−/−) were more resistant to developing SEB-induced ALI 48 hours after intranasal administration of 50 μg dose of SEB compared to wildtype (WT) mice. The SEB-treated FAAH −/− mice had similar clinical parameters and upregulation of endogenous anandamide as naïve FAAH−/− mice. The results from assessing the clinical profile by plethysmography showed unlike with WT groups, there were no significant changes in the functions of the lung in FAAH−/− exposed to SEB when compared to naive FAAH−/−. Immune profiling by flow cytometry revealed there were also no changes in T cells subsets or cytokine levels among naive or SEB-treated FAAH−/− mice. Furthermore, after MiSeq sequencing V3-V4 region of the 16S rRNA of colon/cecal flush and lung samples, both the bacterial phylogenetic and short chain fatty acid (SCFA) profiles showed no significant differences in naïve FAAH−/− mice compared to those treated with SEB, unlike WT groups that had significant differences in these profiles. Lastly, further investigation of the metabolic profile by glycolysis rate assay (GRA) of splenocytes from both experimental groups showed no significant differences in this metabolic pathway. Collectively, these data suggest that knockdown of the FAAH enzyme may lead to increase endogenous cannabinoid, anandamide, thereby preventing SEB-induced ALI.
Single-Step Purification of Sputum Extracellular vesicles from Cystic Fibrosis patients using aF4-MALS
Authors: Dobosh Brian , Liu Susan , Chen Michelle , Tirouvanziam Rabindra M 
Published: January 2023

Abstract

Rationale
Patients with cystic fibrosis (CF) present a large amount of respiratory damage caused in large part by chronic neutrophil influx into the lung. Neutrophils recruited to the lumen of the CF lung actively exocytose neutrophil elastase (NE) and other damaging molecules. Airway NE levels correlate strongly with disease severity in patients with CF. We previously showed that extracellular vesicles (EVs) from patients with other lung diseases carry NE and promote emphysema in a mouse model (Genschmer et al. 2019). Here, we hypothesized that airway NE also compartmentalizes within EVs in CF patients.

Methods
To avoid potential aggregation and purification biases, we gently sorted EVs from CF sputum samples using asymmetrical flow field flow fractionation (aF4). Sputum EV fractions were then subjected to analysis by multi-angle light scattering, nanoparticle tracking analysis and flow cytometry.

Results
Multi-angle light scattering and nanoparticle tracking analyses demonstrate the presence of EVs of different sizes ranging from 40–500 nm, with a concentration of ~5 × 107 EVs/mL. EVs were separated by size with aF4 and downstream flow cytometry analysis showed that discrete subfractions concentrate NE on their surface, but that NE burden was not proportional to size.

Conclusions
Our data show that there are discrete subtypes of EVs released by neutrophils carrying various amounts of NE on their surface. These findings provide evidence for a role of EVs in promoting inflammation in the lungs of patients with CF.
Anti-CD11b antibody treatment suppresses the disease conditions in rheumatoid arthritis (RA)-prone, FcγRIIB-deficient mice
Authors: Takahashi Kazuko , Ohtsuji Mareki , Lin Qingshun , Okazaki Hideki , Amano Hirofumi , Yagita Hideo , Nishimura Hiroyuki , Hirose Sachiko 
Published: January 2023

Abstract
Previously we established a RA-prone, FcγRIIB deficient mouse strain (KO1). Anti-mouse CD11b mAb (5C6) has been reported to inhibit the recruitment of CD11b+ myelomonocytic cells from the blood to the inflammatory site. The CD11b+ cells include neutrophils and monocytes, both of which are known to play important roles in the development of RA. In this study, we treated KO1 mice with 5C6 mAb to examine its effects on RA development.
Four-month-old preclinical KO1 mice were treated for 6 months; with 5C6, rat IgG as a control, or none. Among the 3 groups of mice, the severity of RA and immunological abnormalities were compared. RA-related factors in the ankle joints, spleens, and peripheral blood cells were examined.
The 5C6 treatment ameliorated the conditions of RA in KO1 mice, along with the decreases in inflammatory-cell infiltration and osteoclast formation. Transcriptional level analysis for the ankle joints showed that the 5C6 treatment down-regulated the expressions of RANK, RANKL, MCP-1, RANTES, TNFα, and IL-6; and up-regulated that of osteoprotegerin, the decoy receptor for RANKL. Suppression of RA was associated with the lower serum level of autoantibodies, and the decreased frequency of activated B cells. Expressions of B-cell stimulating cytokines were suppressed in the spleens and peripheral leukocytes of the 5C6-treated mice. While untreated KO1 mice spontaneously developed marked monocytosis, the frequency of monocytes was significantly downregulated in the 5C6-treated mice.
It is thought that the 5C6-mediated suppression of RA is caused by the decreased numbers of inflammatory cells and monocytes per se at the joints; also secondarily by the reduced amounts of B-cell stimulating cytokines, leading less autoantibodies.
Leukotriene B4 is required for inflammasome activation
Authors: Salina Ana , Brandt Stephanie , Medeiros Alexandra Ivo , Serezani Henrique 
Published: January 2023

Abstract

BACKGROUND
The events that initiate inflammatory responses during infections are not well understood. The lipid mediator leukotriene B4 (LTB4) is produced within seconds to minutes after phagocyte challenge and emerging evidence shown that LTB4 increases antimicrobial effector functions and inflammatory mediators, such as IL1b. Inflammasomes are intracellular platforms required for the secretion of IL1B/IL18 and an inflammatory cell death termed pyroptosis. Whether LTB4 enhances inflammasome-dependent IL1b secretion remains to be fully understood. Here, we hypothesize that LTB4 enhances inflammasome assembly and release of IL1b in macrophages during infection and sterile inflammation.

METHODOLOGY AND RESULTS
To assess whether LTB4 is required for IL1b and pyroptosis in vivo, the skin of WT and LTB4R1−/− (BLT1) mice were infected with S. aureus for 24 h and biopsies were collected. To track inflammasome/IL1b production overtime, we treated IL1bDsRed mice as well as inflammasome reporter macrophages (ASC-cerulean) with a BLT1 antagonist. Using both genetic and pharmacological BLT1 blockage, we detected decreased IL1b production when compared to infected WT animals. A role for LTB4 in inflammasome activation was confirmed by detection of decreased caspase1 activation, ASC/NLRP3 assembly and gasdermin D (an initiator of pyroptosis) cleavage in vivo and in vitro in BLT1 deficient mice.

CONCLUSION
Our data show that LTB4 is necessary for inflammasome activation and blocking BLT1 actions might be a broad and practical approach to inhibit inflammatory diseases induced by exaggerated inflammasome activation.
The phosphorylation kinetics of the key regulators in T cell receptor signaling pathway
Authors: An Wei , Park Kyueon , Reyes Alfonso , Kwieraga Amanda , Sabri Nazila , Frey Avery , Chronopoulou Efthalia , Savas-Carstens Jan , Soper David , Elia Jeanne , Li Michael , Yang Xifeng 
Published: January 2023

Abstract
T cell receptor (TCR) signaling pathway regulates T cell homeostasis and adaptive immune responses. Clinically, the activation of TCR is indispensable to the success of T cell-based immunotherapy. The engagement of TCR phosphorylates immunoreceptor tyrosine-based activation motifs (ITAM) on CD3, which is followed by a protein phosphorylation cascade. Protein phosphorylation, regulated by kinases and phosphatases, changes protein conformation and determines protein function. A better understanding of TCR signaling phosphorylation events is crucial to both decipher the T cell regulation mechanism and boost the efficacy of T cell immunotherapy. Here, we developed a panel of monoclonal antibodies that target several of the TCR signaling regulators and are applicable for both intracellular flow cytometry (ICFC) and western blot (WB). Using these antibodies, we performed a kinetic analysis of the TCR signaling pathway. Jurkat T cells were cross-linked by soluble anti-CD3 and anti-CD28 antibodies, and the phosphorylation kinetics of the key TCR signaling regulators, such as phospho-ZAP-70 and phospho-PLCg1, were evaluated by ICFC and WB. We show that TCR signaling activation induced by cross-linking CD3 and CD28 is a relatively transient event and the optimal activation of the key TCR signaling regulators varies from 1 to 15 minutes. Our data profiled the phosphorylation kinetics of the key regulators in TCR signaling pathway.
The biological function of naturally occurring DOCK2 inhibitor in tissue-specific immune evasion
Authors: Sakurai Tetsuya , Uruno Takehito , Fukui Yoshinori 
Published: January 2023

Abstract

Study objection
DOCK2 is a Rac-specific guanine nucleotide exchange factor (GEF) predominantly expressed in hematopoietic cells. DOCK2 is essential for migration and activation of leukocytes, and its mutations in humans cause severe immunodeficiency, thereby indicating that DOCK2 plays a key role in immune surveillance. Interestingly, however, we found that a naturally occurring DOCK2 inhibitor exists in our body and named this molecule DOCK2 inhibitory metabolite (D2IM). In this study, we aimed to reveal biological functions of D2IM.

Method
The specificity of D2IM was examined with Rac GEF assay and binding assay. T cells and neutrophils from WT mouse were treated with D2IM and subjected to Rac activation assay and chemotaxis assay. D2IM production in various tissues was monitored with mass spectrometry. In addition, influence of the lack of CS on ultraviolet- and antigen-induced ocular inflammationwas analyzed using KO mice lacking D2IM synthase.

Result
CS inhibited the Rac GEF activity of murine DOCK2 protein in vitro with a IC50 value of 2.0 mM. When leukocytes were treated with D2IM, chemoattractant-induced Rac activation was severely impaired, resulting in a marked reduction of migratory response of lymphocytes and neutrophils. D2IM most abundantly existed in the Harderian gland, which produces lipids to form the oily layer of the tear film, and its production was completely lost in mice lacking D2IM synthase. We found that the lack of D2IM augmented ultraviolet- and antigen-induced ocular inflammation in mice, which was suppressed by administration of eye drops containing D2IM.

Conclusion
D2IM is a naturally occurring DOCK2 inhibitor that contributes to create immune evasive microenvironment in the eye.
Functional Nrf2 restrains inflammatory and transcriptional phenotypes in microglia and its deficiency recapitulates the aging phenotype
Authors: Yu I-Chen Ivorine , Paraiso Hallel C , Kuo Ping-Chang , Scofield Barbara A. , Sweazey Robert D. , Chang Fen-Lei , Yen Jui-Hung 
Published: January 2023

Abstract
Microglia (MG) represent plastic myeloid cells resident in the brain that can dynamically respond to changes of local microenvironment and stimuli from the periphery. Dysfunctional microglial responses are thought to worsen the pathogenesis of neurodegeneration. The nuclear factor (erythroid-derived 2) - like 2 (Nrf2) protein is a transcription factor that regulates expressions of antioxidant and stress defense genes. Here, we reported that chronic Nrf2 deficiency in MG leads to neuroinflammation and Alzheimer’s disease-like cognitive impairment during aging. The Nrf2 transcript was downregulated in MG from the middle-aged (12 months-old) and aged (24 months-old) brain. Loss of Nrf2 primed MG towards inflammatory phenotype as revealed the significant increase of Clec7a and CD68 markers. Middle-aged Nrf2 knockout (Nrf2−/−) mice showed elevated reactive MG, proinflammatory cytokines, and infiltrating immune cells in the brain, and resembled Alzheimer’s disease like-cognitive impairment in aged mice. Nrf2−/− MG showed increased nuclear NF-κB p65 and CD86 at the resting state, whereas the reduced induction of CD206, Ym1, and Fizz1 after IL-4 stimulation. These results suggested that Nrf2-deficient MG are primed toward inflammatory phenotypes and resistant to the anti-inflammatory modulation. In addition, loss of Nrf2 resulted in downregulation of homeostatic signatures in MG, such as P2ry12, Tmem119, Gpr34, Tgfbr1, and Mafb, suggesting the importance of Nrf2 signaling to regulate microglial homeostasis. Overall, our results demonstrated that functional decline of Nrf2 results in dysregulated phenotypes in MG, which may lead to extravagant neuroinflammation and impaired cognition in aging and Alzheimer’s disease.
Lymphopenia and bone marrow T cell sequestration accompanying stroke are mediated by T cell S1P1 loss
Authors: Wilkinson Daniel S , Dechant Cosette , Chongsathidkiet Pakawat , Wang Haichen , Kemeny Hanna , Laskowitz Daniel , Fecci Peter 
Published: January 2023

Abstract
Sequestration of T cells in bone marrow is a phenomenon recently characterized by our group in the setting of intracranial tumors, regardless of histology. It is accompanied by lymphopenia and lymphoid organ regression and is mediated by loss of S1P1 receptor from the T cell surface. We now reveal that this phenomenon is not unique to tumors, but accompanies additional intracranial pathologies, most notably stroke. In this study, blood, bone marrow, and spleens were collected from mice at day 2, 5, 7 or 14 following stroke via middle cerebral artery occlusion (MCAO) or sham surgery and analyzed by flow cytometry. T cell S1P1 levels were assessed, as were T cell counts in each compartment. S1P1 receptor stabilization was achieved with a knock-in model in which receptor internalization is inhibited. Following stroke, T cells accumulated in the bone marrow of injured mice. T cell numbers peaked at day 7 post-stroke before returning to normal by day 14. Bone marrow accumulation was accompanied by transient lymphopenia and splenic involution following stroke. T cells in the bone marrow yielded decreased levels of S1P1 on their surface. Conversely, mice with genetically stabilized T cell S1P1 protected against sequestration, lymphopenia, and splenic regression following stroke. In conclusion, bone marrow T cell sequestration occurs transiently following stroke and is mediated by the S1P-S1P1 axis. This may be prove an adaptive mechanism to limit intracranial inflammation following an initial insult. Better understanding of this phenomenon may uncover a novel mechanism of immune privilege and allow for therapeutic modulation in the setting of stroke, brain tumor, and other types of intracranial injury.