bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prominent antibody mediated auto-immune response in idiopathic CD4 lymphopenic patients
Authors: Perez-Diez Ainhoa , Wong Chun-Shu , Liu Xiangdong , Mystakelis Harry , Song Jian , Sheikh Virginia , Anderson Megan , Lisco Andrea , Siegel Richard M , Tsang John , Sereti Irini 
Published: January 2023

Abstract
Patients with Idiopathic CD4 Lymphocytopenia (ICL) have low circulating CD4 T cell numbers, accompanied sometimes by low numbers of CD8, B and/or NK cells, making them susceptible to opportunistic infections. The etiology is unknown and there is no familiar linkage. In spite of their immune deficiency 32% of ICL patients have clinically defined auto-immune disease. To analyze the presence of auto-antibodies in these patients we hybridized sera from 34 patients and 15 healthy control (HC) to a 9,000 proteins human array. When identifying positive targets as the ones with Z score ≥4 we found that all 34 ICL patients, unrelated to their autoimmune disease manifestations, had IgG antibodies against tens of proteins while the HC had none. There was considerable variability in both numbers and identities of targets. We next evaluated whether some of these antigens might be displayed on the T cell membrane. Using a flow-based assay we tested sera from 72 ICL patients and found that 50% of them had either IgG, mostly but not exclusively IgG1 and/or IgG4 isotypes, or IgM antibodies against T cell membrane proteins. Functionally, 50% of the plasma with IgG1 or IgG3 antibodies induced antibody dependent cell mediated cytotoxicity against healthy T-lymphocytes. In addition, sera from 20% of the patients with anti-lymphocyte antibodies induced complement deposition on healthy CD3 T cells and some of them induced complement dependent cytotoxicity. Furthermore, we observed complement deposition (C1q, C4c and C3b) on CD4 T cells in 14% of the 72 ICL patients when analyzed directly ex vivo. Our data support a high prevalence and pathogenicity of autoantibodies in ICL, which offers a potential therapeutic target.
Effect of combined low dose IL-2 and polyclonal Tregs infusion in Type 1 Diabetes patients
Authors: Dong Shen , Mowery Cody , Hiam Kamir , Herold Kevan C , Gitelman Stephen , Esensten Jonathan , Liu Weihong , Lares Angela , Nguyen Vinh , Lee Michael , Leinbach Ashley , Ye Jimmie , Tang Qizhi , Bluestone Jeffrey A 
Published: January 2023

Abstract

Background
IL-2 is a well characterized cytokine that drives the expansion of activated human T cells. Its mechanism of action involving the high affinity receptor CD25 confers to IL-2 a crucial role in the homeostasis and function of regulatory T cell (Treg) basally expressing CD25. It has been suggested that low doses of IL-2 treatment in vivo, selectively expands Tregs without altering effector T cell or NK populations. This preferential targeting is key to cell-based immunotherapeutics that aim to prevent autoimmunity such as Type 1 Diabetes.

Methods
A phase I protocol was initiated to treat recently diagnosed T1D patients with a single infusion of ex-vivo expanded autologous polyclonal Tregs followed by two 5-days courses of low-dose IL-2. Patients were monitored for safety and diabetes-related metabolic profiles. PBMCs were analyzed at different time points by CyToF and 10X genomic single-cell RNAseq to monitor T cell activation.

Results
The overall safety profile was excellent but all 9 patients treated with the combined therapy failed to maintain c-peptide production at pre-treatment levels. We observed an expansion of Tregs and granzyme B (GZMB)+ NK subsets. More interestingly, single cell T cell receptor and gene expression sequencing allowed us to detected in all the patients a population of (GZMB)-producing CD8+ T that expanded clonally after IL-2 treatment.

Conclusion
These data suggest that the usage of low-dose IL-2 together with polyclonal Tregs infusion exacerbate the expansion of Tregs but also of a GZMB+ CD8+ T cells and NK population already present in blood. Thus, the failure for all patients to maintain C-peptide level may be due to a shift of the immune balance toward activation rather than tolerance.
Lack of Polyfunctional Cytomegalovirus-specific T cells in Hemodialysis Patients
Authors: Lay Fang-Yun , Chen I-Yu , Shu Kai-Hsiang , Chia Jean-San , Chiu Yen-Ling 
Published: January 2023

Abstract
Polyfunctional T cells are critical for maintaining protection against pathogens. Patients with end-stage renal disease (ESRD) are at increased risks for infectious complications and their T cell immunity against viruses may be impaired. Our current study intends to investigate the effects of renal disease on T cell immunity by analyzing T cell differentiation and polyfunctionality response against cytomegalovirus (CMV), an ubiquitous pathogen. Based on our research, when compared to same-age healthy individuals, ESRD patients are characterized by a significant loss of polyfunctional CMV specific CD4+ and CD8+ T cells, upregulation of effector phenotypic markers and increased surface PD-1 and TIM-3 expression. Furthermore, we performed transcriptome experiment and identified the functional impairment pathway that is distinct from T cell exhaustion and cannot be reversed by checkpoint blockade. These results give the new insight of designing future immunomodulation therapies.
Increased NKG2D expressing NK cells in patients with chronic HBV infection
Authors: Gao Y , He Wenjing , Lang Dou 
Published: January 2023

Abstract

Introductions
Hepatitis B virus (HBV) infection remains a significant health issue worldwide. It is a major cause of cirrhosis, HCC and liver failure. A large number of studies showed that host immune responses are the key factor for HBV clearance and persistence. In here, we investigated the role of NK cells in chronic HBV infections.

Methods
We compared the expression frequency, and functionality of NKGs and KIRs repertoire on NK cells in 170 samples by multi-colour flow cytometry. To further investigate the functionality of the NK cells, we performed K562 target cell killing assay and cytokine driven perforin released assay.

Results
The percentage of circulation and liver resident NK cells did not significantly alter in HBV patients compared to the healthy controls (HCs). Enrichment of NK cells was observed in the healthy controls but not in the HBV infected patients. The intracellular expression of Granzyme B was significantly reduced in NK cells derived from HBV-infected patients as compared to HCs. No differences were observed in the expression of NKG2A and NKG2C. Interestingly, the levels of NKG2D was significantly increased in the circulating NK cells of HBV infection but not in the liver resident NK cells. The K562 target cell killing ability and IFN-gamma production correlated with the NKG2D expression, particularly in the HBV patients as compared to HCs.

Conclusions
Our study demonstrated that NK cells activity and status might play an important role in controlling HBV infection.
Longitudinal immunomonitoring across the virome using a highly-multiplexed serological assay and citizen science
Authors: Engelbrektson Anna Lynn , Fink Zane , Ladner Jason , Altin John 
Published: January 2023

Abstract
Hundreds of viral species are known to infect humans. During a typical year, the average adult is naturally infected with ~10 new viruses, many asymptomatically, but most leaving a humoral footprint. The detection of viral exposures and the associated immune responses is useful for various purposes – clinical diagnostics, epidemiological surveillance, immunological profiling, and potentially as biomarkers or risk factors for complex, immune-related diseases –however, current assays are incommensurate with the diversity of the human virome. Here, we present a new approach to chart the diversity and dynamics of humoral anti-viral responses across 3 axes – pathogens, population and time. In the pathogen dimension, we used a novel platform for highly-multiplexed DNA-barcoded peptide-based serology (‘PepSeq’) to comprehensively assay blood samples for reactivity across a set of 244,000 30mer peptides designed to represent the proteomes and known diversity of all viruses known to infect humans. To survey the population and time dimensions, we used Citizen Science to recruit a cohort of participants for self-collected longitudinal blood samples. In a pilot study of 48 volunteers, each giving 10 weekly samples, we detect humoral reactivity against ~5–20 commonly-encountered viruses in each individual, and resolve viruses encountered during the sampling period from historical infections with high confidence. We expect that cost-effective, longitudinal and deep immunomonitoring across the virome will provide a powerful new view into immunological dynamics and the contribution of viral exposures to disease.
Defective macrophage mediated immune responses in HIV negative Mycobacterium avium complex (MAC) patients with pulmonary diseases
Authors: Jung Bock-Gie , Samten Buka , Brown-Elliott Barbara A , Wallace Richard J , Idell Steven , Wadle Carly , Philley Julie V , Vankayalapati Ramakrishna 
Published: January 2023

Abstract
Mycobacterium avium complex (MAC), which includes M. avium and M. intracellulare, is widely distributed in the environment, and exposure to these organisms is inevitable. Despite widespread exposure, the disease is unusual in immunocompetent hosts. During the past two decades, MAC represents a common cause of progressive pulmonary disease in the United States. To gain insight into the immunologic factors that predispose persons to MAC infections, we evaluated the immune responses of HIV negative (-) MAC patients with pulmonary diseases in comparison to their healthy HIV− household contacts (HHCs). Whole blood from 20 pairs of HIV− MAC patients and healthy HHCs was immunolabeled, and the percentages of various immune cell populations were determined by flow cytometry. Among various cell types, MAC patients have significantly lower ratio of monocytes compared to healthy HHCs. In 11 pairs of HIV− MAC patients and healthy HHCs, peripheral blood mononuclear cells (PBMC) of MAC patients produced lower levels of interleukin (IL)-10 and IL-1 family (IL-1β, IL-18, IL-1α) out of 34 cytokines and chemokines measured by multiplex ELISA upon MAC stimulation, compared with that of healthy HHCs. In two MAC patients, PBMC restricted MAC growth less efficiently compared with their healthy HHCs despite there was no deficiency in restricting MAC growth by monocyte derived macrophages of six MAC patients. Our findings suggest that the interactions among various immune cells are required for efficient clearance of MAC by macrophages in MAC patients. Studies are underway to pinpoint the nature of defective immune responses that prevents efficient clearance of MAC by macrophages of MAC patients.
Phenotypic changes of mucosal-associated invariant T (MAIT) cells during and after acute human sepsis
Authors: Labuz Daniel , Trivedi Shubhanshi , Anderson Cole , Araujo Claudia , Blair Toni , Middleton Elizabeth , Campbell Robert A. , Hale Scott , Rondina Matthew T. , Leung Daniel T. 
Published: January 2023

Abstract
Sepsis is a devastating syndrome that is characterized by organ dysfunction caused by a hyperinflammatory environment following a dysregulated immune response to an infection. Aside from the initial insult of sepsis, patients who survive are at risk of immunosuppression, likely due to the impact of sepsis on both innate and adaptive immunity. There remains a lack of effective interventions for sepsis, possibly due to incomplete understanding of its pathobiology. MAIT cells are innate-like T cells that possess features of both innate and adaptive immunity and are activated by microbial-derived compounds of the riboflavin synthesis pathway, restricted by the evolutionarily conserved receptor MHC class-1 related protein (MR1). We aim to study the role that MAIT cells play during and after acute sepsis. We obtained blood and isolated peripheral blood mononuclear cells from 12 paired septic patients during acute sepsis and 90 days after diagnosis of sepsis, and age and sex-matched healthy donor controls. Using flow cytometry, we see that acute septic patients’ MAIT cells are highly activated and show higher inhibitory receptor expression compared to healthy donors and convalescent patients’ MAIT cells. We show that acute septic patient’s MAIT cells produced significantly less interferon gamma, and lower IFNG expression compared to paired convalescent patients after ex vivo stimulation with E. coli. Further investigation into other effectors of MAIT cells is ongoing. Our data suggest that acute septic patients’ MAIT cells are highly activated and are dysfunctional upon stimulation with E. coli. The understanding of the biological role of MAIT cells during and after acute sepsis can provide a novel therapeutic strategy for septic patients.
Fc-bridged immune cell activation and its role in infectious diseases and autoimmune diseases
Authors: Dai Hongsheng , Zhang Tongwen , Caligiuri Michael A 
Published: January 2023

Abstract
Immunoglobulin G (IgG) is critical to both humoral and cellular immunity. Conventionally, protective functions of IgG against infection and cancer require utilization of both its Fab and Fc domains. IgG Fab binds specific antigen and Fc engages complement or various Fcγ receptors (FcγRs) expressed on immune cells. We recently discovered that the IgG Fc domain alone can play a critical role in the immune cell’s recognition and elimination of certain pathogens, in vitro and in vivo, without the need for the Fab domain of IgG. Many human pathogens, such as herpes simplex virus 1 (HSV1), human cytomegalovirus (HCMV), and Staphylococcus aureus (S.A), express proteins capable of binding IgG Fc (called FcBP hereafter to differentiate from FcγR). FcBPs bind the IgG Fc domain at a site that is distinct and non-overlapping with the site bound by FcγRs. We have demonstrated that a trimeric FcBP-Fc-FcγR complex is formed when the FcγR-bearing immune cell with its bound IgG recognizes, binds to and is therefore activated by the pathogen expressing FcBP. The IgG Fc domain serves as a bridge between the FcγR positive immune cells and the FcBP-bearing pathogens. We have named this process “Fc-bridged cell-mediated cytotoxicity”, or FcBCC. We have demonstrated that FcBCC (1) results in the in vivo elimination of HSV1; (2) prevents fatal HSV1 infection; (3) depends on IgGFc and the FcγR+ NK cell, but (4) does not depend on IgG Fab. Thus IgG Fc alone is necessary and sufficient for engaging both the pathogens and the FcγR-bearing immune effector cells in FcBCC. Other than infectious diseases, results showing FcBCC in some autoimmune diseases will also be presented. Research in my lab is supported by Southern Medical University startup fund.
Studying platelet-HIV interactions and potential to promote viral spread
Authors: Simpson Sydney , Singh Meera V. , Dewhurst Stephen , Maggirwar Sanjay 
Published: January 2023

Abstract
HIV-infected individuals experience persistent inflammation, which is associated with increased platelet activation. There is growing evidence that platelets contribute to immune responses, through the release of inflammatory granules and complex formation with other cells including monocytes and CD4+ T-cells, both of which are susceptible to infection. Previous studies have found evidence that HIV is engulfed by platelets. However, such studies were primarily conducted in vitro. It is important to study consequences of HIV-platelet interactions, and to ascertain whether or not they occur in patients.
We confirmed previous in vitro findings through co-culturing platelets from healthy donors, with HIV virions, and using electron microscopy identified virus-like particles inside platelets. Utilizing RNAscope in tandem with RT-PCR we created a timeline of virus-platelet associations and found viral genomic RNA remained associated with platelets for a prolonged period of time. Importantly, platelet-associated virus remained infectious, as platelets were able to spread infection to activated CD4+ T-cells in coculture experiments. Furthermore, we established a system to screen for HIV-positive platelets. We isolated platelets from cART-naïve viremic patients and performed super resolution microscopy and imagestream flow cytometry. This analysis revealed evidence of HIV-positive platelets in these infected individuals. In contrast, the amount of HIV-positive platelets was drastically, although not entirely, reduced following 3 months of cART treatment. Our findings suggest that platelet-virus interactions may be important in contributing to viral spread, and the development and maintenance of viral reservoirs.
Expression of the Src-family kinase LynA tunes myeloid-cell signaling and function
Authors: Brian Ben F , Nunez Myra , Freedman Tanya S 
Published: January 2023

Abstract
The activity of Src-family kinases (SFKs), which phosphorylate immunoreceptor tyrosine-based activation motifs (ITAMs) upon receptor ligation, is a critical factor regulating myeloid cell activation. The SFK Lyn has roles in activating myeloid cells, by phosphorylating ITAMs, and also in inducing suppressive signaling via phosphatase activation. Alternative splicing of lyn mRNA produces two proteins, LynA and LynB, and emerging evidence from our lab and others suggests that LynA and LynB interact with different proteins and preferentially activate different signal cascades. In macrophages LynA is uniquely susceptible to rapid ubiquitin-mediated degradation and functions as a rheostat that regulates ITAM signal strength. Phosphorylation of tyrosine 32 in the unique region of LynA preferentially targets LynA for polyubiquitination by the E3 ligase c-Cbl. In contrast to macrophages, mast cells express little c-Cbl. Upon activation, LynA is not rapidly degraded in mast cells, and SFK-mediated signaling is amplified relative to macrophages. Previous studies of LynA have been hampered by knockout models that lack both LynA and LynB. To understand the role LynA plays in immune development and activation, we used CRISPR-Cas9 gene editing to generate novel mouse strains that express either LynA or LynB. Preliminary studies in these mice have demonstrated novel roles for LynA. Notably, LynA−/− mice have an enrichment in splenic dendritic cells and alveolar macrophages. Thus, LynA is not only an important regulator of myeloid cell activation, tuning cell-specific signaling thresholds, but also helps regulate the function of these cells. Further studies will investigate the impact of LynA deletion in myeloid inflammation sensing.
6-Methyladenine may enhance immunostimulatory activity of bacterial genomic DNA
Authors: Tsukamoto Yumiko , Tamura Toshiki , Maeda Yumi , Miyake Kensuke , Ato Manabu 
Published: January 2023

Abstract

Background and Aim
CpG motifs in DNA sequences are recognized by TLR9 and activate immune cells. Bacterial genomic DNA (gDNA) has modified cytosine bases (5-methylcytosine (5mC)) and modified adenine bases (6-methyladenine (6mA)). It is well-known that 5mC inhibits immune activation by CpG DNA; however, it is still unclear whether 6mA inhibits immune activation by CpG DNA. In this study, we tried to examine whether the existence of 6mA affected the immunostimulatory activity of gDNA.

Materials and Methods
We focused on adenine methyltransferases (MTases) expressed by Mycobacterium bovis BCG (BCG). Each adenine MTases has specific target sites. Therefore, we used oligodeoxynucleotides (ODNs) with 6mA on the target sequences of MTases from BCG. We stimulated murine bone-marrow derived macrophages (BMDMs) with ODNs harboring 6mA or ODNs without 6mA. We then compared the immunostimulatory activity of ODNs with 6mA to ODNs without 6mA using. We also developed adenine MTase-deficient BCG. We analyzed whether 6mA on gDNA from BCG is involved in the immunostimulatory activity of BCG gDNA.

Results
Our results showed that 6mA located at the target sequence of mamA, an adenine MTase from BCG, enhanced IL-12p40 production from BMDMs stimulated with CpG DNA.
We also observed that gDNA from mamA-deficient BCG induced less IL-12p40 from BMDMs than gDNA from mamA-intact BCG.

Conclusion
We concluded from these results that adenine methylation on ODNs may enhance immune activity induced by bacterial gDNA.
MAP Kinase Phosphatase (Mkp)-1 Controls Type I Interferon (IFN) and PD-L1 Expression during Sepsis
Authors: Liu Yusen , Kirk Sean G. , Cash Charles J. , Batty Abel J. , Wang Xiantao , Murphy Parker R. , Li Jinhui , Ackerman Williams E. , Hafner Markus 
Published: January 2023

Abstract
Mkp-1 is a critical negative regulator of the inflammatory response and plays a crucial role for bacterial clearance in an animal model of sepsis. Mkp-1−/− mice exhibit augmented inflammation, increased bacterial burden, elevated organ damage, and increased mortality relative to Mkp-1+/+ mice following systemic E. coli infection. To understand the immunological functions of Mkp-1, we performed RNA-seq analysis with mouse livers. Under normal conditions, 357 genes were differentially expressed between Mkp-1+/+ and Mkp-1−/− mice. However, following E. coli infection &gt; 5,400 genes displayed differential expression between the two groups. Among genes upregulated by E. coli infection and exacerbated by Mkp-1 knockout are IL-6, IL-10, as well as a large number of IFN-inducible genes including Mx1/2, Gbp2/3, Isg15, Usp18, Ifitm1-3, STAT3, and immune checkpoint protein PD-L1. qRT-PCR and Western blot analyses verified E. coli infection-induced PD-L1 expression and further exacerbation in Mkp-1−/− mice. Examination of the RNA-seq dataset also revealed a clear interferon signature. ELISA analyses on the serum revealed low IFN-β levels in uninfected Mkp-1+/+ and Mkp-1−/− mice, increased IFN-β levels in E. coli-infected Mkp-1+/+ mice, and further augmented IFN-β levels in E. coli-infected Mkp-1−/− mice. Similarly, Mkp-1−/− bone marrow-derived macrophages also produced more IFN-β than Mkp-1+/+ macrophages following stimulation with either LPS or heat-killed E. coli. Analysis of the signaling pathways critical for IFN-β expression indicates a marked increase in TBK1 activity. Our studies suggest that exaggerated expression of type I interferons and PD-L1 contribute to the phenotypes of Mkp-1−/− mice in the model of sepsis.
The study of a dendritic cells-based standardized evaluation system for immunity-boosting functional foods
Authors: Kwon Jaeyul , Kim Ye-Eun , Sun Pureum , Go Eunbyeol , Heo Bu Yeon , Choi In-Wook , Han Bok Kyung , Kwon Bo-In , Lee Young-Ha , Kang Seong Wook 
Published: January 2023

Abstract
Dendritic cells (DC) are specialized antigen-presenting cells that initiate and orchestrate the body’s immune response to bridge the innate and adaptive systems. Here we report developing a standardized evaluation system for immunity-boosting functional foodstuffs using bone marrow-derived dendritic cells. A DC-based evaluation system can indicate the type, magnitude, and specificity of immune responses elicited by an immune-boosting food item. We monitored the expression profile of DC maturation markers, including CD11b, CD11c, CD40, PD-L1/L2, CD80, CD86, and MHC, by flow cytometry to define immunity indexes. These indexes are then consolidated to a 4-point scale to describe the immunogenic and tolerogenic capabilities of the immunity-boosting food candidate. Among well-known immunoregulatory materials, red ginseng extracts, fucoidan, and polysaccharide-K were found to belong to the highest grade of immunogenicity, while extract of the Ostericum root was among the most tolerogenic foods. Extracts of Peucedanum japonicum Thunberg root and Psidium guajava L. leaves also showed high tolerogenic capabilities. Our results suggest that this assay is an effective method to characterize and screen the immune boosting effects of food and pharmaceutical materials in a standardized manner.