bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clonal expansion within circulating plasmblast populations lends support for an infectious disease etiology of Kawasaki disease
Authors: Hicar Mark , Hoffman Jonathon , Sojar Hakimuddin , Baron Sarah 
Published: January 2023

Abstract
Kawasaki Disease (KD) is a childhood vasculitis, marked by prolonged fevers and coronary artery inflammation/aneurysms in near one quarter of those untreated. The cause remains unknown; however, epidemiology and demographic data support a single preceding infectious agent may lead to KD.
Plasmablasts (PBs) are a stage of transitional B-cells that lead to plasma cells, the long-lived antibody producing cells of the bone marrow. After initial infection, peripherally circulating PB populations are enriched for cells with antibodies against the preceding infection. We have recently published data showing children with KD have similar PB responses to children with infections. We sought to define the antibody characteristics, including clonality, of these PBs during KD.
We used antibody repertoire next-generation sequencing to characterize memory and PB populations. Additionally, pairing of heavy and light chains was performed with Chromium Single Cell Gene Expression (10x Genomics, Pleasanton, CA) using the Human B cell Single Cell V(D)J Enrichment Kit.
From subject 24, antibody sequences using VH4-34 and a 19 amino acid length complementarity determining region 3 showed a massive expansion between day 4 and 6 of fever. Chromium single cell sequencing produced over 946 heavy and light chain paired sequences. Sequence comparison showed 40% of sequences demonstrated markers of clonal expansion, which represented 100 clonal groups. One clonal group (24-01) reflected the massive clonal expansion (VH4-34, CDR3 19) previously shown.

Conclusions
This clonal expansion within plasmablast populations supports that Kawasaki disease is caused by an infection. Antigen targeting of these monoclonal antibodies is currently being explored.
CD4 T cell transcriptomics reveal novel diagnostic and mechanistic immune signatures of tuberculosis
Authors: Burel Julie G , Lindestam Arlehamn Cecilia S , Pomaznoy Mikhail , Seumois Gregory , Greenbaum Jason A , Vidanagama Dhammika , Gunasena Bandu , Tippalagama Rashmi , de Silva Aruna D , Taplitz Randy , Vijayanand Pandurangan , Sette Alessandro , Peters Bjoern 
Published: January 2023

Abstract
As part of the Human Immune Project Consortium (HIPC) program, we are aiming to decipher CD4 T cell immune signatures of tuberculosis (TB) in the context of controlled (latent TB) and uncontrolled (active TB) infection. We found commonalities and differences in TB-specific CD4 T cell immune responses of latent TB vs active TB subjects. Both cohorts had higher frequency of peptide-reactive CD4 T cells compared to TB uninfected individuals, and showed strong upregulation of type I and type II interferon genes in response to antigen-specific in vitro stimulation. Conversely, we also detected differences in the transcriptome of CD4 T cells between latent vs active TB subjects that can inform us on TB-specific T cell immune signatures of controlled infection versus disease. In particular, active TB was associated with higher expression of genes associated with inflammation (TNF, IL-1 and TLR signaling) whereas latent TB was enriched for genes associated with metabolism, oxidative phosphorylation and neutrophil-mediated immunity. Looking at inter-individual variability, we also identified that some latent TB infected subjects showed similar expression patterns for a subset of genes to those with active TB, suggesting this molecular pattern might contain mechanistic and prognostic information on the risk of developing active TB. Overall, our approach has identified a plethora of TB-associated T cell immune signatures that allowed us to gain mechanistic insights into the key CD4 T cell components contributing to TB protective immunity. Additionally, our findings have the potential to be translated into new diagnostic and prognostic tools, in particular, identifying latent TB infected individuals at risk of developing active TB.
Eosinophilic esophagitis has a sub-epithelial regulatory adaptive immune response
Authors: Lin Edwin , Lucendo Alfredo , Appelman Henry , Delker Don , Hazel Mark , Wechsler Michael , Yandell Mark , Clayton Frederic 
Published: January 2023

Abstract

Introduction
Eosinophilic esophagitis (EoE) is food-triggered immune esophageal disease characterized by dysphagia and food impaction. The pathophysiology of EoE is poorly understood. Prior eosinophilic esophagitis studies showed abundant IgG4 with IgG4+ plasma cells in esophageal subepithelial tissue.

Methods
Seven esophagectomies and one deep biopsy from patients with active EoE were compared. Seven uninvolved esophageal areas from surgical resections for tumor and autopsy were used as controls. Histology, immunostains, RNA in situ hybridization, and RNA-seq findings were compared with EoE epithelial biopsy RNA-seq.

Results
The superficial lamina propria (LP) of EoE patients has dense fibrosis, tertiary lymphoid tissue with abundant B cells, IgG4 plasma cells, and Foxp3+ regulatory T cells. RNA-seq confirms this, with abundant B cell related transcripts, IGHG4, organized lymphoid tissue marker CCL21, and regulatory T cell markers. IL-10 in situ hybridization is present in mononuclear cells, in and near lymphoid aggregate germinal centers. Edema and degranulating mast cells are absent. By RNAseq, the LP of both eosinophilic esophagitis patients and controls have abundant thrombospondin-1, which could activate TGFβ. Nuclear immunostaining for phosphoSMAD2 and phosphoSMAD3 (suggesting active TGFβ), is present the epithelium and the superficial lamina propria.

Conclusion
The EoE LP immune response has abundant IgG4 plasma cells, regulatory T cells, and a predominantly immunoregulatory transcriptome. Some LP immunoregulatory features are present even in controls. Further work is needed to determine whether the immunoregulatory infiltrate contributes to the dysphagia-inducing subepithelial fibrosis.
Harnessing single cell analysis to characterize the role of MAIT cells in ulcerative colitis
Authors: Sharma Siddhartha M , Gioia Louis , Abe Brian , Holt Marie , Costanzo Anne , Kain Lisa , Su Andrew , Teyton Luc 
Published: January 2023

Abstract
Ulcerative colitis (UC) is an increasingly prevalent form of inflammatory bowel disease, characterized by chronic T cell mediated inflammation of colonic mucosa. UC is likely caused by a confluence of immune dysregulation, genetics, gut microbiome dysbiosis, and environmental factors. Mucosal associated invariant T (MAIT) cells are a sub-population of CD8+ T cells that recognize microbial derived vitamin B2 based antigens and are a significant population in homeostatic mucosa. MAITs are likely a heterogenous population and a subset of MAITs may “link” microbiome dysbiosis, environmental factors and chronic colonic inflammation. To assess the role of MAIT cells in UC, we have analyzed MAITs isolated from matched colonic biopsies, both uninflamed and inflamed mucosa, and blood from a cohort of UC patients. Utilizing MR1 tetramers and single cell analysis techniques, we confirmed a decrease in MAIT cell frequency in peripheral blood of UC patients relative to healthy donors. We have also found an increase in MAIT frequency in inflamed colonic mucosa of UC patients relative to uninflamed mucosa. Single cell gene expression profiling revealed tissue specific differences between blood MAIT cells and colonic MAIT cells as well as a trend for higher expression of activation and pro-inflammatory genes in MAITs isolated from inflamed mucosa. Most intriguingly, single cell TCR sequencing revealed the expansion of a subset of MAITs in inflamed colonic mucosa with a distinct TCRVb and CDR3b sequence. This suggests that a sub-population of MAIT cells in inflamed colonic mucosa are reacting to unique microbial ligands. A new cohort will extend these findings, but our preliminary results support a role for MAIT cells in the pathology of UC.
Serum Antibody Profiling Healthy Toddlers Reveals Low, Intermediate and High Response Cohorts
Authors: van Oers Nicolai S , Pichilingue-Reto Patricia , Raj Prithvi , Dozmorov Igor , Li Quan_Zhen , Wakeland Edward K , Kelly Nancy , de la Morena M. Teresa Teresa 
Published: January 2023

Abstract
During their first two years of life, infant/toddlers produce their own antibodies in response to diverse environmental exposures, infections, and vaccinations. The specificity of these antibodies towards self-antigens, infections, and vaccine components and how they vary among individuals is poorly characterized. We developed a new antigen array comprising autoantigens, infectious agents, and vaccine antigens to assess the serum antibody specificities among a cohort of &gt;150 health toddlers. An analysis of their responses reveals a stratification of healthy toddlers into 3 groups, low, intermediate, and high responders. Among those 16% that are high responders, their serum IgGs were able to bind a diverse array of self-antigens as well as infectious agents. Longitudinal follow-up suggests this pattern is relatively stable over time. Comparing clinical data reveals a significant correlation with the high IgG responder cohort and a family history of asthma and maternal gestational diabetes. Targeted DNA sequencing in the high responder group revealed a strong genetic association signal at the HLA locus, with polymorphisms at this locus associated with high ANA and IgG titers to many antigens. Findings from this study may provide insights into the natural history of human autoantibody formation.
B cell-intrinsic and lymphocyte extrinsic miR-21 drive optimal germinal center and antibody responses
Authors: Schell Stephanie L , Choi Nicholas , Rahman Ziaur S.M. 
Published: January 2023

Abstract
Germinal centers (GCs) generate high affinity B cell responses that are protective against infection but can produce autoreactive responses when dysregulated. MicroRNAs (miRNAs) have been implicated in the regulation of GC fate, though the role of many individual miRNAs remains uncharacterized. Here, we demonstrate that within the GC, miR-21 promotes T follicular helper cell (Tfh), T follicular regulatory cell (Tfr), and GC B cell responses, as well as downstream antibody production. Regulation of the GC response by miR-21 requires multiple mechanisms, occurring in both B cells and innate cells. B cell-intrinsic miR-21 drives GC B cell expansion by promoting B cell activation and proliferation. MiR-21 target gene expression arrays have revealed several putative target genes in B cells, suggesting that miR-21 targets negative regulators of proliferative pathways to enhance B cell proliferation and GC responses. In contrast, Tfh and Tfr are driven by miR-21 in a B and T cell extrinsic manner, likely by innate cells. Our data suggest that miR-21 modifies the cytokine microenvironment, which impacts regulatory T cell expansion and Tfh programs. Therefore, the synergy of B cell intrinsic and lymphocyte extrinsic miR-21 activity is required to generate optimal GC and Ab responses. Of clinical relevance, we also found that upregulation of miR-21 in autoimmune-prone mice drives autoantibody responses, implicating miR-21 in both anti-pathogen responses and its dysregulation in autoimmunity. Therefore, dampening miR-21 function may provide a strategy for autoimmune therapeutics. Alternatively, boosting miR-21 activity in healthy individuals could allow more efficient generation of protective antibody following vaccination.
Regulation of B cell-mediated immune responses by a PX domain-containing protein
Authors: Jung Da-Jung , You Gihoon , Park Areum , Kim You-Me 
Published: January 2023

Abstract
The humoral immunity is mediated by antibodies produced by plasma cells, which are terminally differentiated effector cells of the B cell lineage. The antibody production should be tightly regulated to prevent unwanted responses against self-molecules and efficiently defend the host against foreign antigens. In this study, we aimed to examine the roles of PX domain-containing kinase in B cell-mediated immune responses. PX domain-containing kinase is a cytosolic protein composed of a PX domain, a pseudokinase domain, and a WH2 domain. It is expected that PX domain-containing kinase regulates intracellular trafficking of membrane proteins based on its structural features and previously reported functions. PX domain-containing kinase is most highly expressed in B cells both in humans and mice. Furthermore, several reports indicated that SNPs of the PX domain-containing kinase gene are linked to autoimmune diseases commonly characterized by excessive production of autoantibodies, such as systemic lupus erythematosus, rheumatoid arthritis, and systemic sclerosis. However, the in vivo function of PX domain-containing kinase in immune responses has not been reported. In order to investigate the immunoregulatory functions of PX domain-containing kinase, we firstly generated PX domain-containing kinase-deficient mice. Although PX domain-containing kinase is not essential for the development of immune cells, we found that foreign antigen-induced antibody responses were affected by deletion of PX domain-containing kinase in mice. Currently, we are in the process of uncovering the underlying mechanisms. This study is expected to elucidate the functions of PXK as a novel modulator of antibody-mediated immune responses.
Cell-specific inhibition of SMAD2/3 restores lymph node cellularity and germinal center function in aged mice responding to acute chikungunya virus (CHIKV) infection
Authors: Uhrlaub Jennifer , Yang Yu-Sang Sabrina , Melo Mariane B , Irvine Darrell J , Nikolich-Zugich Janko 
Published: January 2023

Abstract
Targeted delivery of small-molecule inhibitors increases drug efficacy by focusing its action upon specific cell-types without global disruption of signaling pathways. TGFβ is a pleotropic cytokine involved in many cellular processes, including specific regulatory functions during anti-viral immune responses. Previously, we have shown that in aged mice, over-production of TGFβ correlates with decreased immune function. TGFβ neutralization during acute chikungunya virus (CHIKV) infection decreases acute- and chronic- disease severity and improves neutralizing antibody titers. Herein, we selectively interrupted TGFβ signaling during acute CHIKV infection via the delivery of lymph node (LN)-targeting nanoparticles coupled to a small-molecule inhibitor of SMAD2/3 phosphorylation. We show that LN-targeted inhibition of SMAD phosphorylation during the initiation of a viral immune response can restore – to the levels measured in adult mice - the cellular content of the draining lymph node. We further demonstrate that inhibition of TGFβ signaling decreases LN fibrosis and improves the germinal center reaction in aged mice.
Characterizing the movement strategy of CD8+ T cells in finding malaria parasites in the liver
Authors: Ganusov Vitaly V , Rajakaruna Harshana , O’Connor James , Zenkov Viktor S , Cockburn Ian A 
Published: January 2023

Abstract
Movement strategies by which antigen-specific CD8+ T cells search for sites of infection in peripheral tissues are not fully understood. Measurable quantities, such as the distance traveled per unit of time, that follow Lévy statistics are common in nature, for example, in bacterial and higher animal foraging; in mussels, marine predators, monkeys. A recent study has shown that moving according to Lévy flights enables CD8+ T cells in the brain to find “rare targets” (Toxoplasma gondii-infected cells) in an order of magnitude more efficiently than using Brownian and other walking strategies. It has been, thus, suggested that such efficient strategy of T cell searching for infection may have been evolutionarily selected. However, T cells in the brain (or other tissues) are often constrained by the structure of the physical environment in which cells move. Whether the emerged statistical pattern of T cell movement is due to a cell-intrinsic program or a consequence of environmental constrains is, thus, unknown. Here, we address this question by using intravital imaging of movement of Plasmodium-specific CD8+ T cells in murine livers and mathematical modeling and analyses of the generated data. We investigate whether the physical structure of the movement paths in the liver plays a role in shaping the walking strategy of T cells in finding malaria parasites. Here, we map out liver sinusoids in 3D using intravital microscopy and use simulations to parameterize the alternative walking models by fitting them to empirical data having no references to the physical structure. Our preliminary data suggest that constraints imposed by the structure of liver sinusoids significantly impact the moving pattern of the T cells.
Upregulation of intestinal Tumor Growth Factor-β1 is associated with increased intestinal epithelial cell apoptosis in pathogenic simian immunodeficiency virus infection
Authors: Pahar Bapi , Pan Diganta , Srivastav Sudesh , Das Arpita 
Published: January 2023

Abstract
Mucosal Transforming Growth Factor-β1 (TGF-β1), a pleiotropic, potent immunoregulatory cytokine, demonstrated to manage phosphorylated AKT and IFNγ expressions, are associated with intestinal epithelial cells (iECs) survival in macaque colon explants and suggest a potential role of mucosal TGF-β1 in regulating intestinal homeostasis and iEC integrity. It is important to monitor and further explore the role of mucosal TGF-β1 in HIV/SIV pathogenesis and HIV/SIV enteropathy, which may lead to the development of improved therapeutic strategies to prevent iEC damage and systemic immune activation during acute and chronic infection. Our data showed an increased production of intestinal TGF-β1 in T-, B- and non-T/B cell populations during acute and chronic SIV infection in rhesus macaques, without a change in the expression of TGF-βRII. The increased levels of immunosuppressing TGF-β1 were also associated with increased production of IFNγ, suggest the lack of TGF-β1 mediated anti-inflammatory responses in SIV infection. An appropriate balance between inflammatory and anti-inflammatory cytokine responses are crucial for maintenance of a successful immune responses in HIV infection. TGF-β1 induced immune defects contribute to intestinal inflammation, loss of tight junction protein, and apoptosis by overexpression of SMAD3, and downregulation of inhibitory SMAD7 transcription factors. Together, these results indicate that SMAD mediated pathway play a crucial role in regulating TGF-β1 expression and that was thought to be a key contributor to the dysfunction of CD4+ and CD8+ T-cells, iEC apoptosis and disease progression.
Effect of malaria pathology on CD4 and immune cells
Authors: Amadi Emmanuel Chike , Eze Emmanuel , Chigor Vincent 
Published: January 2023

Abstract
Knowledge of immunity in malariology can help in understanding the pathology, treatment and vaccine production. The effect of malaria disorder on CD4 and immune cells counts was carried out at a Teaching Hospital in Enugu, Eastern Nigeria between October-December 2018. Patients on doctor’s provisional diagnosis of malaria were examined for Plasmodium infections and the degree of parasitaemia (0, +, ++, and +++). Positive samples and negative ones (0) were thereafter examined for their CD4 (Flow cytometry) and immune cells (Automated blood cell counter) counts. 45 patients were studied. All the Plasmodium-negative specimens were within reference ranges of CD4 cell count (464–1308); with mean value of 835. The (+) parasitaemia showed lower ranges of CD4 count (502–1282); mean = 678; with immune falls in one (427). The 12 (++) parasitaemia showed crash in 9 CD4 cells counts; range: 301–415; mean = 399. All the 7 (+++) parasitaemia showed crashes in CD4 cell counts, range: 160–357; mean = 225. The CD4 cells falls and crashes were detected only in Plasmodium falciparum parasitaemia infections. Depending on the CD4 cells count, also a reflex of parasitaemia, variances occur in the various immune cells’ percent and numeric. TWBC count fell in only 3 patients (1.99, 3.42 & 3.64) × 109 cells/L, corresponding to (+++), (++) & (+) parasitaemia, respectively. Low CD4 counts does not always produce low lymphocyte numeric, probably because other CD or killer cells compensates it. In conclusion, Plasmodium falciparum infection causes immuno-suppression in patients. Corollary, it means that malaria infection in the immunodeficients and AIDS patients will accelerate the complications as well as death, unlike prevailing reports.
CD28 Regulates Autophagy to Enhance Plasma Cells Survival
Authors: Peng Peng , Chavel Colin , Utley Adam , Carlson Louise , Lee Kelvin P 
Published: January 2023

Abstract
Lifelong humoral immunity depends on the longevity of long-lived plasma cells (LLPC). We have shown that CD28 signaling in LLPC is critical to their survival but the molecular mechanisms are unclear. Here, we report that CD28 mediates a pro-survival response through autophagy in multiple myeloma (MM). As the transformed LLPC, MM is similar to LLPC in CD28 signaling and survival regulation. CD28 in MM is activated by antibody crosslinking or co-culture with dendritic cells that express CD80/CD86. With chemotherapy (melphalan) treatment or serum starvation, CD28 activation increases MM viability from 30% to 70%. Pharmacologic inhibition of autophagy (Baf-A1 or 3-MA) or ATG5 knockdown, a critical autophagy protein, abrogates the CD28 pro-survival effects. CD28 activation up-regulates the autophagy marker LC3II as well as increases autophagosome numbers assessed by Cyto-ID. Conversely, knockdown of CD28 decreases these effects. CD28 signals via GRB2-VAV-PLC in LLPC, and we found that blocking PKC activity in MM by inhibitor Gö6983 diminishes CD28 pro-survival effects and CD28-mediated LC3II up-regulation. Upon activation of CD28, ATG5 protein levels are elevated not through transcriptional up-regulation but enhanced by ATG5 protein modification. Taken together, these data suggest CD28 signaling via GRB2-VAV-PLC-PKC induces autophagy by ATG5 induction. CD28 regulates metabolic fitness in T cells, and we also found inhibition of autophagy by 3-MA minimizes CD28-mediated increase of oxidative phosphorylation. This indicates that CD28-mediated autophagy maintains metabolic homeostasis to improve survival. Our findings suggest a novel mechanism by which CD28 signaling regulates metabolism, survival and function in LLPC.
O-GlcNAcylation of c-Myc dynamically regulates pre-B cell proliferation
Authors: PARK SUNG-KYUN 
Published: January 2023

Abstract
O-GlcNAc modification regulates the activity of hundreds of nucleocytoplasmic proteins involved in a wide variety of cellular processes such as gene expression, signaling and cell growth. However, the mechanism underlying the regulation of B cell development and function by O-GlcNAcylation is largely unknown. Here, we demonstrate that changes in cellular O-GlcNAc levels significantly affect the growth of large pre-B cells transiently expressing pre-B cell receptors on their surface membrane, which are known to rapidly proliferate for the expansion of functional clones that express successfully rearranged heavy chains during early B cell development. Our study first show that overall O-GlcNAc levels in these proliferative pre-B cells are highly induced compared to pro-B cells, depending on pre-B cell receptor expression. Mechanistically, inhibition of O-GlcNAcylation in pre-B cells markedly decreases c-Myc expression, which results in downregulation of cell proliferation through the blocking of E- and A-type cyclin expressions. In addition, restriction of glucose uptake in pre-B cells also reduces cellular O-GlcNAc levels as well as c-Myc expression and subsequently decreases cell proliferation. Furthermore, the population of large pre-B cells in the bone marrow is significantly reduced by the administration of O-GlcNAc inhibitor to mice. Thus, our study strongly suggests that O-GlcNAcylation dependent expression of c-Myc is a new component in regulation of pre-B cell proliferation and also a potential therapeutic target for the treatment of pre-B cell acute lymphoblastic leukemia.