bluuebunny/crossref_metadata_2025_split huggingface dataset:
Extensive genetic diversity of CD14 promoter gene (rs2569190) polymorphism is associated with regulation of Plasmodium falciparum parasitemia but not susceptibility to infection
Authors: Thomas Bolaji , Snyder Tara , Aziz Najihah , Falade Catherine , Ojurongbe Olusola 
Published: January 2023

Abstract
CD14 is a multifunctional receptor expressed on many cell types, and has been shown to mediate immune response resulting in the activation of an inflammatory cascade. Genetic polymorphisms of the CD14 promoter (rs2569190) has been found to be associated with susceptibility to several diseases. In malaria infection, CD14 gene demonstrates a pathogenic profile in regulating experimental cerebral malaria, with reports of elevated levels of soluble CD14 in serum of malaria patients, with no definitive conclusions. We present a detailed analysis of genetic diversity of CD14 promoter gene polymorphism between a malaria-infected group and uninfected controls, and its association with clinical parameters of disease. Genomic DNA samples obtained from 107 Plasmodium falciparum-infected (microscopy and PCR-confirmed) patients and 380 uninfected controls were subjected to a PCR-RFLP analysis. Our results show a significant diversity (p=3.32E-06) in the genotypic frequency (3.8% versus 22.4%) of the rs2569190 mutant variant between infected and uninfected controls respectively, with the mutant allele less frequent in infected group. Mean parasitemia (parasites/μl of blood) was significantly regulated based on CD14 genetic profile (19,855 vs 37,041 vs 49,396 for mutants, heterozygotes and wild type alleles respectively), but showed no association with other markers of disease severity (fever, age of patients or anemia). Our results show the mutant variant pushed Th1 cell differentiation resulting in interferon-γ response leading to reduced parasitemia. How this affects disease severity between sub-regional or continental malaria groups deserves elucidation, including extending this results among cerebral malaria patients.
Interleukin-6 receptor α signaling on CD4+ T cells drives RBC alloantibody generation and T follicular helper cell differentiation in a murine model of RBC alloimmunization.
Authors: Arneja Abhinav , Salazar Juan E. , Jiang Wenyu , Hendrickson Jeanne E. , Zimring James C. , Luckey Chance John 
Published: January 2023

Abstract
Alloimmunization to non-ABO red blood cell (RBC) antigens remains a significant clinical problem in transfusion medicine. Presence of these alloantibodies can lead to delayed hemolytic transfusion reactions resulting in significant morbidity and occasional mortality upon antigenic re-exposure. For patients that generate multiple alloantibodies, provision of compatible antigen-negative RBCs can be time and resource intensive. In rare cases, it can result in the inability to locate and provide a life-saving therapy. Despite the significant clinical consequences of RBC alloimmunization, our understanding of the fundamental molecular and cellular mechanisms regulating anti-RBC antibody generation is limited. We have combined a recently developed mouse model for transfusion mediated RBC alloimmunization with mice genetically deficient in interleukin-6 receptor (IL-6Rα) to investigate the role of IL-6Rα signaling in regulating RBC alloimmunization. We have demonstrated that IL-6Rα signaling plays a key role in the generation of anti-RBC alloantibodies in response to transfused RBCs. Additionally, we have shown that RBC alloimmunization requires IL-6Rα signaling specifically on T cells, and that these signals are required for maximal in vivo differentiation of naïve anti-RBC specific CD4+ T cells into T follicular helper (TFH) cells. We have identified for the first time a specific molecule (IL-6Rα), its downstream cellular target (CD4+ T cells) and resultant functional outcome (TFH differentiation) that regulates RBC alloimmunization. Collectively, our findings support the idea that currently available biologics targeting IL-6Rα could be a viable therapeutic option for the prevention of RBC alloimmunization.
Dynamic cytokine gene expression characterized by increased IL-1 and IL-27 but decreased IL-8 occurs during development of bovine neonatal immunity.
Authors: Kaushik Azad Kumar , Pasman Yfke , Merico Daniele 
Published: January 2023

Abstract
We analyzed 18 RNA-seq libraries from 3 bovine calves at day 0, 7, 14 and 28, together with their dams (day 0 and 7) for cytokine gene expression. Expression of IL7, required for B- and T-cell development, significantly increases from day 0 to day 28 post-birth (LogFC 1.98, FDR 0.0054). By contrast IL7R gene expression significantly declined from day 0 to day 7 (LogFC −1.22, FDR 6.1E-08). The IL21 was expressed at low levels but IL21R gene expression increased day 0 vs day 7 (LogFC 1.17, FDR 0.000140). IL12B expression, a subunit of IL-12, increased from day 0 vs day 7 (LogFC1.14, FDR 0.016) and then declined. In parallel, IL12RB1 expression increased from day 0 to day 7 to achieve adult levels (LogFC1.31, FDR 5.5E-10). By contrast, IL12RB2 declined significantly within 7 days post-birth (LogFC −1.46, FDR 3.1E-05). Both IL12RB1 and IL12RB2 constitute IL12 receptor complex involved in T cell differentiation. The IL27 was expressed at low levels at birth but reached adult levels by day 7 (LogFC 1,66, FDR 0.006). The IL1B expression increased post-birth by day 7 (LogFC 1.44, FDR 0.0083) whereas IL1R2 gene was highly expressed at birth but declined by day 7 (LogFC −3.22, FDR 5.9E-34). Expression of chemokine IL8 that encodes CXCL8 declined day 0 vs day 7 post-birth (LogFC −1.13, FDR 0.00015). The pro-inflammatory cytokine TNFα gene expression increased by day 14 (LogFC 1.04, FDR 0.015). While various cytokines are expressed in a dynamic manner, an increase in IL-1B, IL-7, IL-12B and a decrease in IL-8 appears to be of functional significance in the development of neonatal immunity. These observations are in contrast to other species such as humans. [Supported by NSERC Discovery Grant]
Mechanisms that diversify an otherwise intrinsically processive Trav-Traj recombination program
Authors: Carico Zachary Mark , Zhang Baojun , Choudhury Kingshuk , Zhuang Yuan , Krangel Michael S. 
Published: January 2023

Abstract
In DP thymocytes, the Tcra locus undergoes multiple rounds of V-J rearrangement in order to generate a functional TCRα chain. While Traj segment usage is strictly ordered from 5′ to 3′ as rearrangement proceeds, it is unclear to what degree Trav usage is also ordered. To test this, we assessed the Trav-Traj combinatorial repertoire in murine DP thymocytes using 5′ RACE followed by paired end sequencing. In 129Sv/J WT thymocytes, we found a clear bias toward proximal-proximal and distal-distal joins, but Trav-Traj pairings were highly diverse, even in primary V-J rearrangement. However, combinatorial diversity was highly constrained in HYα KI thymocytes, in which a fixed primary V-J rearrangement in the endogenous Tcra locus is the starting point for secondary rearrangements. Thus, secondary rearrangement is highly processive through the V and J arrays, but surprising diversity is introduced by primary rearrangement. Tcrd rearrangement precedes Tcra rearrangement in developing thymocytes. In INT1-2KO mice, CTCF site deletion biases Trdv usage toward the most proximal gene segments. These mice, like HYα KI, displayed a substantially constrained Tcra repertoire, with limited diversity of primary rearrangements. Thus, variable truncation of the Trav array by prior Tcrd rearrangement creates diversity in an otherwise highly processive Tcra rearrangement program by imparting combinatorial diversity to primary Tcra rearrangement. This diversification is functionally important, as Trav1-Traj33 pairing and MAIT cell abundance are substantially reduced in HYα and INT1-2KO mice.
E proteins are important for restraining the ILC2 differentiation potential in the thymus
Authors: Qian Liangyue Miranda , Wang Hong-Cheng , Zhao Ying , Mengarreli Joni , Adrianto Indra , Gray-Montgomery Courtney , Urban Joseph F. , Fung Kar-Ming , Sun Xiao-Hong 
Published: January 2023

Abstract
Innate lymphoid cells (ILCs) have gained recognition as important regulators in various immune responses. Current paradigm states that all ILCs originate from common lymphoid progenitors (CLP) in the bone marrow through an array of downstream ILC progenitors. Id2, a member of the Id family that inhibits E protein transcription factors, is expressed in these ILC progenitors and is indispensable for ILC differentiation. Interestingly, we found that down-regulating E protein function in the thymus by Id1 overexpression or deletion of two E protein genes resulted in massive expansion of ILC2s in the thymus as well as other organs where ILC2 normally reside. The phenotypic thymic ILC2s expressed ILC2 signature genes and down-regulated T lineage-specific genes. Moreover, Id1 transgenic mice exhibited spontaneous infiltration of eosinophils and heightened type 2 immune responses to the allergen, papain, in the lung. Furthermore, these mice had increased ability in the expulsion of helminth parasites, N. Brasiliensis. These results raise an interesting question as to whether the thymus is a natural site for ILC2 production and the phenotypes of the mutant mice simply highlight such capacity. Indeed, we found that wild type DN1 and DN3 thymocytes can differentiate into IL-5 and IL-13-producing ILC2 cells in vitro. Ablation of E proteins in DN3 cells accelerated the differentiation while gain of E protein function inhibited the process. Together, our data reveal a new ILC2 differentiation program occurring in the thymus and a critical role of E proteins in restraining such a differentiation potential while ensuring proper T cell production.
Partially Maintaining E Protein Activity During ILC Development Selectively Inhibits ILC2 Development
Authors: Berrett Hannah R , Alberola-Ila Jose 
Published: January 2023

Abstract
Innate lymphoid cells (ILCs) provide an early response to pathogenic damage at mucosal barrier surfaces. They have beneficial roles in infection and tissue repair, as well as pathogenic roles in chronic inflammatory diseases. ILC effector subsets are defined by transcription factor expression patterns and cytokine production profiles. Recent evidence suggests ILC cytokine profiles are not static and cells can be pushed into producing different cytokines. The possibility of manipulating ILCs toward beneficial immune responses or away from pathogenic responses increases the urgency to understand how ILC effector programs are established during ILC development and maintained during homeostasis and immune responses. All ILCs are generated from a common precursor derived from the common lymphoid progenitor, and differentiation of this precursor into ILC1s, ILC2s, and ILC3s is characterized by induction of distinct transcription factors. All ILC subsets share a developmental requirement for Id2 induction. Id2 is an inhibitor of E protein transcription factor activity, but its specific functions in ILC development have not been elucidated. We have used expression of ET-2, a chimeric protein that acts as an Id dominant negative inhibitor, to partially block Id2 function during ILC development. Our experiments show that while ILC1s and ILC3s are mostly undisturbed by ET-2, ILC2s experience a profound block in development. These results demonstrate that, while all ILCs require Id2 expression, ILC2s are uniquely sensitive to the effects of ET-2 and require a more complete inhibition of E protein activity.
NF-κB signaling pathway mediates respiratory syncytial virus-induced HMGB1 release in airway epithelial cells to promote an inflammatory response
Authors: Hosakote Yashoda Madaiah , Garofalo Roberto P , Kurosky Alexander 
Published: January 2023

Abstract
Respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract infections in young children, the elderly and immunocompromised individuals. In addition to acute morbidity, RSV infections have been linked to both the development and severity of asthma. No effective treatment or vaccine is currently available for RSV. High mobility group box 1 protein (HMGB1) is a multifunctional protein that serves as both a DNA regulatory protein and an extracellular cytokine signaling molecule that promotes airway inflammation as a damage-associated molecular pattern. Although HMGB1 is implicated in the pathogenesis of many inflammatory diseases, its involvement in RSV-induced lung inflammation is not yet investigated. The goal of this study is to investigate the molecular mechanisms that induce the release of HMGB1 and the involvement of the NF-κB and TLR4 pathway in RSV pathogenesis. Human lung epithelial cells were infected with RSV in the presence or absence of human recombinant HMGB1 and harvested over time to analyze HMGB1, NF-κB and TLR4 expression by Western blot, immunohistochemistry and qRT-PCR. Our studies with airway epithelial cells clearly show that RSV-induces a significant release of HMGB1 from cells as a result of its translocation from the nucleus to the cytoplasm and subsequently to the extracellular space; that secreted HMGB1 triggers immune responses by activating primary human monocytes via NF-κB-TLR4 signaling pathway. Blockage of one of these molecules could represent a novel therapeutic strategy in the treatment not only for RSV infection, but also for other respiratory diseases that affect human population at any age.
Influenza A virus (IAV) infection in humans leads to expansion of highly diverse CD8 T cell repertoires cross-reactive with Epstein Barr virus (EBV)
Authors: Gil Anna , Mishra Rabinarayan , Song InYoung , Aslan Nuray , Luzuriaga Katherine , Selin Liisa K 
Published: January 2023

Abstract
The competence of T cell responses predominantly depends on how efficient T cell receptors (TCRs) are at recognizing antigenic epitopes. We show here that during acute severely symptomatic IAV infection there was an expansion of IAV-M1/EBV-BRLF1 and IAV-M1/EBV-BMLF1 double-tetramer+ cells directly ex-vivo in 5 HLA-A2+ patients. We questioned whether this expansion specific to these two different cross-reactive responses would lead to alterations in the IAV-M158, EBV-BRLF1109 and -BMLF1280 TCR repertoires from before and during acute IAV infection. Using staining with VB mAb we found that T cell responses generated to these epitopes became surprisingly more polyclonal, with the sharing of Vb between M1, BMLF1 and BRLF1 populations which is not seen in healthy donor. Furthermore, by using next generation sequencing and single-cell analysis of TCRα and TCRβ repertoire of tetramer sorted IAV-M1 cells we showed dramatic changes in specific clonotype usage during acute IAV infection compared to before infection. In summary, these changes in TCR repertoire during acute symptomatic IAV infection suggest that during severe infection there is a preferential expansion of highly diverse cross-reactive responses between IAV and the persistent virus, EBV, which leads to permanent changes in TCR repertoires to both of these two viruses (NIH AI049320 and NIH AI109858).
Pre-existing matched antigen exacerbates the disease of influenza virus infection by attenuating antigen-specific T cell immunity
Authors: Huang Ching-Tai , Dutta Avijit , Chen Tse-Ching , Lin Chun-Yen , Lin Yung-Chang , Chang Chia-Shiang , He Yueh-Chia , Huang Yu-Lin 
Published: January 2023

Abstract
Influenza virus infection causes mild and self-limiting illness in most of the healthy individuals, but some healthy people develops complications as a result of the infection and suffers from severe disease and eventually dies. Here we report that pre-existing matched antigens attenuate antigen-specific immunity to the infection. High virus load and associated increase of pathogenic innate response in the lungs exacerbates the disease. The C3-HAHigh and C3-HALow transgenic mice are with inherent expression of Hemagglutinin (HA) antigen from PR8 strain of H1N1 influenza virus. Compared to wild type mice, these mice suffered from severe disease and higher mortality upon infection of wild type PR8 virus but not upon infection of reverse genetically raised PR8 virus with replaced HA from H3N2 influenza virus. Adoptively transferred PR8 virus HA-specific 6.5 CD4+ and Clone-4 CD8+ T cells responded minimally to PR8 virus infection in C3-HA mice. There was less clonotypic expansion, T-bet induction and effector cytokines IFN-γ and TNF-α production of both 6.5 CD4+ and Clone-4 CD8+ T cells. Virus neutralizing antibodies were less as well. The attenuation was associated with increased LAG-3+ but not Foxp-3+ population of HA-specific T cells in the lungs. In contrast to the instigated weak antigen-specific immunity, PR8 virus infection caused neutrophils more efficient for inflammatory IL-6 secretion and robust bronchus infiltration in C3-HA mice. These results suggest that a host factor cross-reactive to the antigens of influenza virus may exacerbate the disease with similar attenuated antigen-specific adaptive immunity accompanied by augmented innate immunity to influenza virus infection.
Duration of antigen presentation to influenza-specific CD8+ T cells regulates the development of tissue resident memory populations.
Authors: Fuller Michael John , Botta Davide , Schultz Michael D. , Bachus Holly , Ballesteros-Tato Andre 
Published: January 2023

Abstract
Some memory CD8+ T cells are programmed during the contraction phase of the primary response to have robust secondary responsiveness, a phenomenon termed memory programming. However, the underlying mechanism of the memory programming is not entirely understood. Using an influenza virus infection model, we show here that memory CD8+ T cell responses to the more abundant nucleoprotein (NP) antigen more vigorously proliferate than CD8+ T cell responses to the less abundant polymerase (PA) antigen. Interestingly, in spite of their differential abilities to mount secondary responses, memory NP and PA-specific CD8+ T cells are present in comparable frequencies in the lung parenchyma and airways during the memory phase. However, whereas NP-specific CD8+ T cells express low levels of CD103 and CD69, PA-specific CD8+ T cells are predominately CD103hiCD69hi, a phenotype characteristic of tissue resident memory (Trm) populations. Importantly, our data indicate that persistent antigen presentation during the contraction phase of the primary response prevented the differentiation of Trm cells. As a result, whereas prolonged antigen presentation by CD103− CD11bhi dendritic cells (DCs) during the late phase of the primary response programmed NP-specific CD8+ T cells to potently expand after re-challenge, it prevented the differentiation of NP-specific Trm cells. Collectively, our results demonstrate that CD8+ T cell responses to less abundant antigens, such as PA, preferentially develop into tissue resident memory populations.
Autophagy and TGF-β regulates innate immune response in human respiratory syncytial virus infected macrophages
Authors: Pokharel Swechha Mainali , Shil Niraj Kanti , Thapa Bhim Bahadur , Bose Santanu 
Published: January 2023

Abstract
Human respiratory syncytial virus (RSV) is a leading cause of hospitalization in infants and children worldwide. RSV infection manifest into two inflammatory diseases, pneumonia and bronchiolitis. Recently, we reported an involvement of transforming growth factor-β (TGF) activated SMAD2/3 signaling pathway in interferon-β (IFN-β) production from RSV infected macrophages. These studies also demonstrated a role of autophagy in triggering TGF production from RSV infected macrophages. Although IFN-β mediated antiviral response is a critical host-defense mechanism to combat virus infection, it is important to understand mechanism(s) regulating inflammation during RSV infection since it results in development of inflammatory diseases like pneumonia and bronchiolitis. Tumor necrosis factor-α (TNF) and interleukin-6 (IL-6) are critical pro-inflammatory cytokines shaping inflammation during virus infection. Therefore, we investigated the role of TGF-SMAD2/3 pathway in regulation of TNF and IL-6 production during RSV infection of macrophages. TGF-SMAD2/3 signaling pathway play an important role in pro-inflammatory response, since blockade of this pathway by TGF inhibitor and SMAD2 knockdown (via siRNA) led to diminished TNF and IL-6 production from RSV infected macrophages. Accordingly, reduced NF-κB activation was observed in RSV infected macrophages deficient in TGF-SMAD2/3 signaling. Furthermore, inhibiting autophagy in RSV infected macrophages diminished pro-inflammatory response. Thus our study has demonstrated a role of autophagy-TGF-SMAD2/3 signaling network in positively regulating NF-κB activation and subsequent production of pro-inflammatory cytokines following RSV infection of macrophages.
The role of Indoleamine 2,3-dioxygenase (IDO) in the survival of bone marrow resident long lived Plasma cells
Authors: Maharaj Shivana M , Carlson Louise M , Lee Kelvin P 
Published: January 2023

Abstract
Long lived plasma cells (LLPCs) are essential for sustained antibody responses and protective humoral immunity. How these cells maintain longevity and a durable antibody response is largely dependent on the complex nature of the bone marrow microenvironment in which these cells reside, and the pro survival factors produced in this niche. Work in our lab has shown that CD28 is required for LLPC survival, and that Indoleamine 2,3-dioxygenase (IDO), an enzyme that catabolizes tryptophan, is produced as a result of back signaling from CD28:CD80/86 interactions between plasma cells and bone marrow myeloid derived dendritic cells (DC). IDO is classically known to contribute to an immunosuppressive environment through its depletion of tryptophan (specifically with respect to T cells). However, to our great surprise we found that there are fewer LLPCs present in the bone marrow of IDO knockout mice in comparison to wild type mice. Additionally, live cell numbers of purified plasma cells in vitro in tryptophan free media and IDO conditioned media are greater than in media alone. These conditions also caused autophagy to occur in these plasma cells, a process shown to be required for LLPC survival. This leads us to propose a model where CD28, through back signaling to CD80/86, induces IDO production which leads to depletion of tryptophan and causes induction of autophagy, a mechanism LLPCs use to compete and survive within the bone marrow microenvironment.