bluuebunny/crossref_metadata_2025_split huggingface dataset:
Higher PIK3C2B gene expression of H1N1+ specific B-cells is associated with lower H1N1 immunogenicity after trivalent influenza vaccination in perinatally HIV infected children
Authors: Cotugno Nicola , Zicari Sonia , Morrocchi Elena , De Armas Lesley R , Pallikkuth Suresh , Rinaldi Stefano , Rocca Salvatore , Manno Emma Concetta , Zangari Paola , Andrews Sarah F , Cagigi Alberto , Rossi Paolo , McDermott Adrian B , Pahwa Savita , Palma Paolo 
Published: January 2023

Abstract
Perinatally HIV-infected children (PHIV), despite effective antiretroviral treatment (ART), present chronic immune activation and suboptimal memory B-cell response to vaccinations compared to healthy controls (HC). Here we aimed at identifying frequency and transcriptional profiles of H1N1-specific B-cells (H1N1-Sp) in PHIV differentially responding to Trivalent Influenza Vaccination (TIV) and HC. H1N1-Sp were FACS-sorted from PBMCs collected 21 days after TIV, and analysed by multiplexed RT-PCR (Fluidigm). Differentially induced genes after H1N1 in vitro stimulation were further assessed on sorted memory B cells. H1N1 response was measured by hemagglutination inhibition assay (HIA) and B-cell ELISpot. 10 out of 19 PHIV were non-responders (NR) while all HC (n=8) correctly responded to TIV (≥4 fold change HIA and &gt;80 ELISpot/106PBMCs). Our results showed no differences in H1N1-Sp frequencies and absolute counts between the groups. H1N1-Sp of PHIV showed higher expression of genes related to apoptosis susceptibility (PPP1R13B (logFC=12.77, p=0.01) and immune activation (CD28 (logFC=10.64, p=0.02) compared to HC. Among PHIV, lower PIK3C2B (logFC=−6.67, p=0.02) expression was found in vaccine responders (R) vs NR. In addition, only R showed a reduction in PIK3C2B expression after in vitro H1N1 stimulation in resting memory B cells (CD19+IgD-CD27+CD21+) (FC=−2.6, p&lt;0.05). In conclusion, a gene expression perturbation, underlying immune activation, persists in H1N1-Sp from PHIV despite ART. Also, a higher expression of PIK3C2B may lead to a lower H1N1 immunogenicity after TIV. These preliminary data may inform future vaccination-adjuvants aiming at modulating PIK3C2B in order to improve vaccination outcomes in PHIV.
CD4 cell-derived IL-2 synergizes with influenza infection to exacerbate lung inflammation
Authors: Strutt Tara M , Gilchrist Ashley 
Published: January 2023

Abstract
Defining the most penetrating correlates of protective memory T cells is key for designing improved vaccines and T cell therapies. Here, we evaluate how interleukin (IL-2) production by CD4 memory cells, a widely held indicator of their protective potential, impacts recall responses against murine influenza A virus (IAV). Unexpectedly, we show that IL-2-deficient memory cells are more effective on a per cell basis at combating IAV than wild-type memory cells marked by strong IL-2 production. Improved outcomes orchestrated by IL-2-deficient cells include reduced weight loss and improved respiratory function that correlate with reduced levels of a broad array of inflammatory factors in the infected lung. Blocking CD70-CD27 signals that reduce T cell IL-2 production tempers the inflammation induced by wild-type memory CD4 cells and improves the outcome of IAV infection in vaccinated mice. Using a reductionist model, we show that IL-2 drives rapid and extremely potent lung inflammation involving NK cells and neutrophils, which can synergize with sublethal IAV infection to promote acute morbidity and mortality. These results suggest that IL-2 production is dispensable for optimal protective CD4 T cell recall responses and that the lung environment is particularly sensitive to IL-2-induced inflammation.
IFN-I blockade improves the immunogenicity of viral vector vaccines
Authors: Palacio Nicole M , Dangui Tanushree , Wang Yidan , Penaloza-MacMaster Pablo A 
Published: January 2023

Abstract
Type I interferons (IFN-I) are critical for antiviral immunity. Studies in the lymphocytic choriomeningitis virus (LCMV) model show that IFN-I signaling improves the control of acute infection, but IFN-I signaling can be immunosuppressive and impair the control of chronic infection. The role of IFN-I after vaccination, however, remains understudied. Vaccination is biologically distinct from natural infection, as immune responses with the former are elicited after in situ challenge with a low dose of an attenuated pathogen, resulting in a benign localized infection that induces immunological memory. To evaluate the role of IFN-I in this setting, we immunized C57BL/6 mice intramuscularly with LCMV-based vaccines expressing model antigens, including SIV Gag, co-administered with IFN-I receptor blocking antibodies. IFN-I blockade resulted in significant improvement of CD8 T cell and B cell responses. Furthermore, IFN-I blockade also improved the immunogenicity of other viral vectors, including rhabdovirus- and poxvirus-based vectors. Improvement of vaccine-elicited immunity was also observed in BALB/c mice using alternative immunization routes. Importantly, transient IFN-I blockade did not affect vaccine clearance, but it abrogated the influx of T regulatory cells (Tregs) to the site of immunization. Our data suggest a model in which IFN-I recruits Tregs to the site of immunization, resulting in in situ regulation of vaccine-induced immunity. Altogether, we show in multiple viral vector regimens, different MHC backgrounds, and different routes, that localized IFN-I modulation improves vaccine-induced immunity. Our findings may be important to develop more potent viral vector vaccines against infectious diseases.
Classical splenic dendritic cell subsets, cDC1 and cDC2, from C57BL/6 mice are more potent in stimulating the Th1 immune response than those from BALB/c mice during mousepox
Authors: Toka Felix N , Szulc-Dąbrowska Lidia , Koper Michal , Struzik Justyna , Gierynska Malgorzata 
Published: January 2023

Abstract
Classical (conventional) dendritic cells (cDCs) specialize in presenting antigen to naïve T cells, and are divided into cDC1 (CD8α+) and cDC2 (CD11b+) subpopulations based on their lineage, surface phenotype and characteristics. Despite differences, both cDC subsets can stimulate CD4+ T cells and promote polarization toward a T helper 1 (Th1) phenotype. Many studies have shown that C57BL/6 (H-2b) and BALB/c (H-2d) mice readily mount vigorous Th1 or Th2 responses, respectively, upon infection with different infectious agents, including ectromelia virus (ECTV), responsible for mousepox in mice. In this work, we compared the ability of cDC subsets from mouse strains with different susceptibility to mousepox (C57BL/6 – resistant and BALB/c – susceptible) to stimulate the Th1 cytokine immune response during ECTV infection. Results showed that splenic cDC1 and cDC2 from BALB/c mice highly express MHC class II, CD83 and/or CD86 than those from C57BL/6 mice at 5 days post infection with ECTV. Despite higher activation status, both subsets of cDCs from BALB/c mice produce low amounts of Th1-polarizing cytokines, including IL-12 and IFN-γ, than those from C57BL/6 mice. Moreover, splenic cDC1 and cDC2 cells, from ECTV-infected C57BL/6 mice, stimulated higher proliferation and production of IFN-γ and IL-2 by allogeneic CD4+ T cells of C3H (H-2k) mice in a mixed leukocyte reaction than BALB/c mice. Both subsets of BALB/c cDCs up-regulated genes engaged in cell maturation and activation compared to C57BL/6 cDCs. Overall, our data indicate that both, cDC1 and cDC2 promote CD4+ T cell differentiation into IFN-γ-producing Th1 subset, and so ensure development of a strong cell-mediated immune response and recovery of C57BL/6 mice from mousepox.
Expression of the lupus associated Pbx1-d isoform induces pro-inflammatory phenotypes in mesenchymal stem cells (MSCs) in a mouse model of lupus
Authors: Robusto Brian Andres , Zeumer Leilani , Morel Laurence 
Published: January 2023

Abstract
Systemic Lupus Erythematosus (SLE) is an autoimmune disease that causes chronic inflammation. It is most prevalent in women, especially in women from minority populations and is heterogeneous. In previous experiments, it has been discovered that mesenchymal stem cells (MSCs) from a lupus-prone mouse strain (Sle1a1) express a defective allele of Pbx1 (Pbx1-d), a gene that controls stemness in MSCs. Sle1a1 MSCs grow faster, differentiate quicker into osteoblasts than the B6 control, and have impaired immunosuppressive function. This data together with a significant decrease in the expression of genes associated with stemness and an increase in expression of genes associated with differentiation suggests that the Pbx1-d allele disrupts the immunoregulatory functions of MSCs. This could contribute to lupus pathogenesis. We aimed to see if Pbx1-d expression in Sle1a1 MSCs increases the expression of genes promoting inflammation and activates the innate immune system. 26 genes were selected that showed an expression fold change greater than 2 in RNA sequencing as compared to B6 control MSCs. Some of the genes belong to metabolic pathways, which we are currently validating by comparing mTOR activation, glucose metabolism and mitochondrial respiration between B6 and Sle1a1 MSCs. Preliminary results suggest a different production of inflammatory cytokines and chemokines by activated Sle1a1 MSCs. Further the supernatants of activated Sle1a1 MSCs favors Th17 polarization and impairs Treg polarization in vitro. MSC cell therapy has been considered to treat lupus. Our studies provide unique insights on how a lupus susceptibility gene impairs MSC direct functions and their interactions with T cells.
The effects of germline STAT3-activating mutations from autoimmunity and lymphoid malignancy on mouse and human T cells
Authors: Masle-Farquhar Etienne , Payne Kathryn , Singh Mandeep , Rao Geetha , Al-Eryani Ghamdan , Jara Christopher , Jackson Katherine , Brink Robert Adrian , Tangye Stuart , Reed Joanne , Goodnow Christopher C 
Published: January 2023

Abstract
Signal transducer and activator of transcription 3 (STAT3) regulates gene expression downstream of cell surface cytokine and hormone receptors. Heterozygous germline loss of function STAT3 mutations lead to the primary immunodeficiency hyper-IgE syndrome while somatic activating STAT3 mutations recur in human solid organ and immune malignancies. Germline heterozygous activating STAT3 mutations result in early-onset autoimmunity with aspects of immunodeficiency. Affected individuals share characteristics with autoimmune lymphoproliferative syndrome and immunodysregulation polyendocrinopathy enteropathy X-linked syndrome, including reduced T regulatory cell numbers. They present with variable autoimmune symptoms including type 1 diabetes, rheumatoid arthritis, gut enteropathies and autoimmune cytopenias. Whilst many effects of STAT3 loss of function on immune cells have been described, the mechanisms behind autoimmunity and immunodeficiency in patients with activating STAT3 mutations remain unclear.
Here, we present a detailed characterisation of T cell development and maturation in young and old mice on two different backgrounds with Crispr-engineered germline activating mutations in two domains of STAT3. We use mixed chimeras, flow cytometry, T cell receptor deep sequencing and high throughput single-cell transcriptomics to reveal cell-extrinsic and -autonomous roles of overactive STAT3 in T cells in autoimmunity and immune malignancy. To our knowledge, this is the first report of mice with Stat3 germline activating mutations identical to those in autoimmunity or malignancy. We validate our key findings in humans with gain of function germline STAT3 mutations and childhood-onset autoimmunity.
Sleep-loss activates NLRP3 inflammasome-activity in astrocytes by increasing electroencephalogram slow-waves and activates microglia to increase NREM sleep amounts
Authors: Zielinski Mark R , Prabhala Rao H , Niznikiewicz Madaleine M , Desrosiers Gretchen 
Published: January 2023

Abstract
We previously found that NLRP3 inflammasome activity is a critical mechanism regulating sleep and slow-waves. Microglia and astrocytes play a major role in sleep regulation and altering slow-waves. We investigated the contribution of NLRP3 inflammasome activation in microglia and astrocytes on sleep and slow-waves after sleep loss. For this study, C57BL6/J mice were sleep deprived or allowed to sleep ad libitum. NLRP3 inflammasome-activity related molecules (inflammatory cytokines - interleukin (IL)-1 beta (IL-1β) and IL-18) from the cortex were determined in microglia and astrocytes using flow-cytometry. Additionally, NLRP3 floxed mice were crossed with CX3CR1- or GFAP-CRE mice to target microglia or astrocytes, and sleep and slow-waves were assessed by polysomnography. In CD11b+ cells (i.e., microglia), a significant enhancement (p&lt;0.05) in NLRP3+, NLRP3+IL-1β+, and NLRP3+IL-18+ cells were found after sleep deprivation compared to controls. In GFAP+ cells (i.e., astrocytes), we found a significant enhancement (p&lt;0.05) in NLRP3+ cells and NLRP3+IL-1β+ cells compared to controls but a near significant increase in NLRP3+IL-18+ cells (p=0.09). Mice with inhibited NLRP3-activity in microglia exhibited a significant attenuation in increased NREM sleep amounts after sleep deprivation, although slow-wave enhancements remained unaffected. Conversely, mice with inhibited NLRP3-activity in astrocytes had a significant lack of increased slow-waves after sleep deprivation, although they had significant enhancements in NREM sleep amounts. Our data indicate that NLRP3 inflammasome-activity in microglia contributes to increases in NREM sleep amounts after sleep loss while astrocytes contribute to slow-wave activity.
Anti-inflammatory effects of β-cry on 5FU-induced cytokine production in hOMF
Authors: Oseko Fumishige , Yamamoto Toshiro , Sato Yoshiki , Yamamoto Kenta , Adachi Keiji , Akane Mitsunori , Nishigaki Masaru , Kanamura Narisato 
Published: January 2023

Abstract

Objective
Beta-cryptoxanthin (β-cry), a carotenoid abundant in satsuma mandarin, has anticancer and antioxidant effects. We previously reported the anti-inflammatory effects of β-cry on the periodontal ligament. However, the effects of β-cry on oral mucositis, an adverse event due to cancer chemotherapy, remain unclear.
Fluorinated pyrimidines are frequently employed for oral cancers, with a high incidence of stomatitis. In the present study, we examined the effects of 5-fluorouracil (5-FU) and β-cry on oral mucosal fibroblasts.

Materials & Methods
Human oral mucosal fibroblasts (hOMF) were cultured with 5FU (1 mg/mL) and/or β-cry (100 nM). Then, a cell proliferation test was performed by WST assay and the expressions of inflammatory cytokines and apoptosis-related genes were examined by real-time RT-PCR.

Results
The proliferation of hOMF was inhibited by the addition of 5-FU, and the inhibition was suppressed with β-cry. Inflammatory cytokines, such as IL-1β, IL-6, and IL-8, and the ratio of Bax/Bcl-2 in hOMF were increased with 5-FU, and the increase was suppressed with β-cry.

Conclusion
Beta-cry may have anti-cytotoxic and anti-inflammatory effects on oral mucositis caused by 5-FU, suggesting that it may provide a novel method for preventing oral mucositis due to cancer chemotherapy.
Developing & Validating an Approach for Diagnosing and Prognosticating Cancer from Biochemical Motifs in T-cell Receptors
Authors: Ostmeyer Jared L , Cowell Lindsay G , Christley Scott 
Published: January 2023

Abstract
Immune repertoire deep sequencing allows profiling T-cell populations and enables novel approaches to diagnose and prognosticate diseases by identifying T-cell receptor sequence patterns associated with clinical phenotypes and outcomes. Our study objective is to develop a method to diagnose and prognosticate cancer using T-cell receptors sequenced from tissue biopsies. To determine how to profile the specificity of a T-cell receptor, we analyze 3D X-ray crystallographic structures of T-cell receptors bound to antigen. We observe a contiguous strip typically 4 amino acid residues in length from the complimentary determining region 3 (CDR3) lying in direct contact with the antigen. Based on this observation, we extract 4 residue long snippets from every receptor’s CDR3 and represent each snippet using biochemical features encoded by its amino acid sequence. The biochemical features are combined with information about the abundance of the snippet or the receptor and scored using a logistic regression model. Each logistic regression model is fitted and validated under the requirement that at least one positively labelled snippet appears per tumor and no positively labelled snippets appear in healthy tissue. Using a patient-holdout cross-validation, we fit logistic regression models to distinguish colorectal tumors from healthy tissue matched controls with 93% accuracy, breast tumors from healthy tissue matched controls with 94% accuracy, ovarian tumors from non-cancer patient ovarian tissue with 95% accuracy (80% accuracy on a blinded follow-up cohort), and regression of preneoplastic cervical lesions over 1 year in advance with 96% accuracy. In conclusion, immune repertoires can be used to diagnose and prognosticate disease.
Formation of human lymphoid organoids and their immunological function
Authors: Watanabe Takeshi , Kobayashi Yuka , Kawamoto Hiroshi 
Published: January 2023

Abstract
We previously reported that the artificially synthesized and immunologically active lymphoid tissues (aLTs) could be stably constructed in mice by implantation of lymphoid stromal cell-embedded biocompatible scaffold (collagen sponge) as well as by applying the chemokine/lymphokine-trapped gel-embedded scaffold. The aLTs possessed the structures and functions resemble to the secondary/tertiary lymphoid organ. The antigen-specific immune response was effectively induced in the aLTs. In the present study, we have aimed to generate the aLTs composed of human lymphoid cells and human stromal cells expressing LTbR, VCAM-1, ICAM-1 and several lymphoid chemokines. The spheroids were formed as the scaffolds from the stromal cells. Then, the stromal cell spheroids were transplanted into renal subcapsular space of the immunodeficient mice together with human PBMCs absorbed in the collagen sponges. After 3 weeks, the secondary lymph node-like three-dimensional organoids (LTOs) containing clusters of the human T and B cells and the scattered human DC cells were stably formed. Next, the human LTOs were constructed by using the PBMCs prepared from healthy donors who had received once the vaccination of varicella zoster virus (VZV). The immunodeficient mice carrying human LTOs were immunized with inactivated VZV. The GC-like B cell proliferation and the production of the anti-VZV specific antibody as well as human IFNg was remarkedly induced in the LTOs. These data indicate that the immunologically functional human LTOs could be generated by applying human PBMCs with the appropriate human lymphoid stromal cells. Currently, induction of immune responses against various protein antigens as well as human cancers is under investigation.
Single-center report of antibody deficiencies in Azerbaijan
Authors: Fazal Nadeem , Nasrullayeva Gulnara , Mammadova Vafa , Aliyeva Gunay , Mollayeva Nushaba 
Published: January 2023

Abstract
The most common type of Primary Immune Deficiencies (PID) are Antibody Deficiencies (AD) characterized by the recurrent bacterial infections. Usually the immune disbalance is observed as a decrease in B-cell function, hypogammaglobulinemia and deficiency of IgG and IgA or all three IgG, IgA and IgM antibodies. Early onset acute or chronic infections in gastrointestinal, respiratory and urinary tract are the most common symptoms of AD. The aim of the study was to analyze the data of 126 pediatric and adult patients diagnosed as AD in our PID center between 2010–2019. Immune status of the patients was examined by phenotyping of immune cells in peripheral blood, measurement of serum IgM, IgG, IgA and IgE levels, evaluation of phagocytic activity by NBT, and detection of CIC by photometric method. Additional abdominal CT and ultrasound examinations were also performed. From 126 pediatric and adult patients registered in PID Center, Baku, Azerbaijan, 9 patients were diagnosed with sIgA deficiency, 26 were common variable immune deficiency, 9-Bruton disease and 2 patients with Hyper IgM syndrome. Patient cohort included 5 adults and 41 between 12 months to 11 years age. At the time of the study, 37 patients were receiving intravenous immune globulin (IVIG) as a replacement therapy (31 patients were on regular IVIG). IVIG therapy was associated with decreased incidence of infections and overall improvement in well-being of the patients. It is important to consider hypogammaglobulinemia in patients with a history of recurrent and severe infections. We recommend that patients’ immune status should be examined including evaluation of serum immunoglobulin levels and B and T-cell subsets.
The role of Thymic Stromal Lymphopoietin (TSLP) in protection from Type II diabetes
Authors: Choa Ruth , Wada Shogo , Meng Hu , Pai Ruth-Anne Langan , Okumura Mariko , Tohyama Junichiro , Nace Arben , Hopkins Christian , Haldar Malay , Seale Patrick , Cotsarelis George , Seykora John , Fitzgerald Garret , Arany Zoltan , Kambayashi Taku 
Published: January 2023

Abstract
Within the past 30 years, obesity and associated disorders such as Type II diabetes are rapidly becoming world-wide epidemics. Type II diabetes, caused by the loss of insulin sensitivity, accounts for $327 billion annually in the U.S. Recent studies have shown that the immune system plays a critical role in regulating the metabolic function of adipose tissue. Importantly, Type II diabetes is a disease of chronic low-grade inflammation, and adipose T regulatory cells (Tregs) can help maintain insulin sensitivity by suppressing the inflammation caused by monocytes, CD8 T, and Natural Killer (NK) cells.
We have previously reported that topical application of the Vitamin D3 analog MC903 induces a two-fold increase in the proportion and absolute number of Tregs systemically. MC903 induces production of the cytokine Thymic Stromal Lymphopoietin (TSLP) from skin keratinocytes, and TSLP stimulates proliferation of Tregs through activation of dendritic cells. In a model of diet-induced Type II diabetes, we found that mice on high fat diet treated with MC903 compared to vehicle demonstrate improved metabolic parameters, including increased glucose tolerance and decreased insulin resistance, decreased fasting glucose and insulin, and lower liver triglycerides. Concordantly, treatment of mice with a TSLP-expressing adeno-associated virus also induced similar results, suggesting that TSLP is sufficient to improve insulin sensitivity. Importantly, there was a robust increase in Tregs and decrease in CD8 T cells and NK cells in the adipose of MC903 and TSLP-treated mice. Together, our results suggest that activation of TSLP signaling may be a therapeutic immunotarget for improving insulin sensitivity and preventing Type II diabetes.