bluuebunny/crossref_metadata_2025 huggingface dataset:
Histamine-Releasing Factor Is a Novel Alarmin Induced by House Dust Mite Allergen, Cytokines, and Cell Death
Authors: Kasakura Kazumi , Kawakami Yu , Jacquet Alain , Kawakami Toshiaki
Published: January 2023

Histamine-releasing factor (HRF) is a multifunctional protein with fundamental intracellular functions controlling cell survival and proliferation. HRF is also secreted during allergic reactions and promotes IgE-mediated activation of mast cells and basophils. In this study, we investigated HRF secretion and its relevance to airway inflammation. HRF monomers were constitutively secreted from BEAS-2B human bronchial epithelial cells (HBECs) and converted to oligomers over the course of culture. Stimulation with house dust mite (HDM) extract increased HRF secretion substantially. Several cytokines involved in asthma pathogenesis showed moderate effects on HRF secretion but dramatically enhanced HDM-induced HRF secretion. HDM-induced HRF secretion from BEAS-2B cells and normal HBECs proceeded via TLR2. Consistent with this, multiple TLR2 ligands, including Der p 2, Der p 5, Der p 13, and Der p 21, induced HRF secretion. Der p 10 (tropomyosin) also promoted HRF secretion. Cell death or incubation with adenosine and ATP, compounds released upon cell death, also enhanced HRF secretion. Furthermore, intranasal administration of recombinant HRF elicited robust airway inflammation in HDM-sensitized mice in an FcεRI-dependent manner. Therefore, we conclude that HRF is a novel alarmin that promotes allergic airway inflammation.
Mechanisms of Corticosteroid Resistance in Type 17 Asthma
Authors: Hong Lingzi , Herjan Tomasz , Bulek Katarzyna , Xiao Jianxin , Comhair Suzy A A , Erzurum Serpil C , Li Xiaoxia , Liu Caini
Published: January 2023

IL-17A plays an important role in the pathogenesis of asthma, particularly the neutrophilic corticosteroid (CS)-resistant subtype of asthma. Clinical studies suggest that a subset of asthma patients, i.e., Th17/IL-17A–mediated (type 17) CS-resistant neutrophilic asthma, may improve with Th17/IL-17A pathway blockade. However, little is known about the mechanisms underlying type 17 asthma and CS response. In this article, we show that blood levels of lipocalin-2 (LCN2) and serum amyloid A (SAA) levels are positively correlated with IL-17A levels and are not inhibited by high-dose CS usage in asthma patients. In airway cell culture systems, IL-17A induces these two secreted proteins, and their induction is enhanced by CS. Furthermore, plasma LCN2 and SAA levels are increased in mice on a preclinical type 17 asthma model, correlated to IL-17A levels, and are not reduced by glucocorticoid (GC). In the mechanistic studies, we identify CEBPB as the critical transcription factor responsible for the synergistic induction of LCN2 and SAA by IL-17A and GC. IL-17A and GC collaboratively regulate CEBPB at both transcriptional and posttranscriptional levels. The posttranscriptional regulation of CEBPB is mediated in part by Act1, the adaptor and RNA binding protein in IL-17A signaling, which directly binds CEBPB mRNA and inhibits its degradation. Overall, our findings suggest that blood LCN2 and SAA levels may be associated with a type 17 asthma subtype and provide insight into the molecular mechanism of the IL-17A–Act1/CEBPB axis on these CS-resistant genes.
A Deficiency in the Cytokine TNFSF14/LIGHT Limits Inflammation and Remodeling in Murine Eosinophilic Esophagitis
Authors: Manresa Mario C , Miki Haruka , Miller Jacqueline , Okamoto Kevin , Dobaczewska Katarzyna , Herro Rana , Gupta Rinkesh K , Kurten Richard , Aceves Seema S , Croft Michael
Published: January 2023

Eosinophilic esophagitis (EoE) is a chronic type 2 allergic disease, with esophageal tissue remodeling as the mechanism behind clinical dysphagia and strictures. IL-13 is thought to be a central driver of disease, but other inflammatory factors, such as IFNs and TNF superfamily members, have been hypothesized to play a role in disease pathogenesis. We recently found that the cytokine TNFSF14/LIGHT is upregulated in the esophagus of patients with EoE and that LIGHT promotes inflammatory activity in esophageal fibroblasts. However, the global effects of LIGHT on EoE pathogenesis in vivo remain unknown. We investigated the impact of a LIGHT deficiency in a murine model of EoE driven by house dust mite allergen. Chronic intranasal challenge with house dust mite promoted esophageal eosinophilia and increased CD4+ T cell numbers and IL-13 and CCL11 production in wild-type mice. Esophageal remodeling was reflected by submucosal collagen accumulation, increased muscle density, and greater numbers of fibroblasts. LIGHT−/− mice displayed normal esophageal eosinophilia, but exhibited reduced frequencies of CD4 T cells, IL-13 expression, submucosal collagen, and muscle density and a decrease in esophageal accumulation of fibroblasts. In vitro, LIGHT increased division of human esophageal fibroblasts and selectively enhanced IL-13–mediated expression of a subset of inflammatory and fibrotic genes. These results show that LIGHT contributes to various features of murine EoE, impacting the accumulation of CD4 T cells, IL-13 production, fibroblast proliferation, and esophagus remodeling. These findings suggest that LIGHT may be, to our knowledge, a novel therapeutic target for the treatment of EoE.
Novel Dimeric Architecture of an IFN-γ–Related Cytokine Provides Insights into Subfunctionalization of Type II IFNs in Teleost Fish
Authors: Zhu Xiaozhen , Wang Junya , Jia Zhao , Feng Jianhua , Wang Bangjie , Wang Zixuan , Liu Qin , Wu Kaizheng , Huang Wenji , Zhao Xin , Dang Huifeng , Zou Jun
Published: January 2023

Gene duplication leads to subfunctionalization of paralogs. In mammals, IFN-γ is the sole member of the type II IFN family and binds to a receptor complex consisting of IFN-γR1 and IFN-γR2. In teleost fish, IFN-γ and its receptors have been duplicated due to the teleost-specific whole-genome duplication event. In this study, the functions of an IFN-γ–related (IFN-γrel) cytokine were found to be partially retained relative to IFN-γ in grass carp (Ctenopharyngodon idella [CiIFN-γrel]). CiIFN-γrel upregulated the expression of proinflammatory genes but had lost the ability to activate genes involved in Th1 response. The results suggest that CiIFN-γrel could have been subfunctionalized from CiIFN-γ. Moreover, CiIFN-γrel induced STAT1 phosphorylation via interaction with duplicated homologs of IFN-γR1 (cytokine receptor family B [CRFB] 17 and CRFB13). Strikingly, CiIFN-γrel did not bind to the IFN-γR2 homolog (CRFB6). To gain insight into the subfunctionalization, the crystal structure of CiIFN-γrel was solved at 2.26 Å, revealing that it forms a homodimer that is connected by two pairs of disulfide bonds. Due to the spatial positions of helix A, loop AB, and helix B, CiIFN-γrel displays a unique topology that requires elements from two identical monomers to form a unit that is similar to IFN-γ. Further, mutagenesis analyses identified key residues interacting with CiIFN-γrel receptors and those required for the biological functions. Our study can help understand the subfunctionalization of duplicated IFN-γ paralogs in fish.
Synergistic Protection against Secondary Pneumococcal Infection by Human Monoclonal Antibodies Targeting Distinct Epitopes
Authors: Gingerich Aaron D , Royer Fredejah , McCormick Anna L , Scasny Anna , Vidal Jorge E , Mousa Jarrod J
Published: January 2023

Streptococcus pneumoniae persists as a leading cause of bacterial pneumonia despite the widespread use of polysaccharide-based vaccines. The limited serotype coverage of current vaccines has led to increased incidence of nonvaccine serotypes, as well as an increase in antibiotic resistance among these serotypes. Pneumococcal infection often follows a primary viral infection such as influenza virus, which hinders host defense and results in bacterial spread to the lungs. We previously isolated human monoclonal Abs (mAbs) against the conserved surface Ag pneumococcal histidine triad protein D (PhtD), and we demonstrated that mAbs to this Ag are protective against lethal pneumococcal challenge prophylactically and therapeutically. In this study, we elucidated the mechanism of protection of a protective anti-pneumococcal human mAb, PhtD3, which is mediated by the presence of complement and macrophages in a mouse model of pneumococcal infection. Treatment with mAb PhtD3 reduced blood and lung bacterial burden in mice, and mAb PhtD3 is able to bind to bacteria in the presence of the capsular polysaccharide, indicating exposure of surface PhtD on encapsulated bacteria. In a mouse model of secondary pneumococcal infection, protection mediated by mAb PhtD3 and another mAb targeting a different epitope, PhtD7, was reduced; however, robust protection was restored by combining mAb PhtD3 with mAb PhtD7, indicating a synergistic effect. Overall, these studies provide new insights into anti-pneumococcal mAb protection and demonstrate, to our knowledge, for the first time, that mAbs to pneumococcal surface proteins can protect against secondary pneumococcal infection in the mouse model.
Immune–Metabolic Interactions and T Cell Tolerance in Pregnancy
Authors: Moldenhauer Lachlan M , Hull M Louise , Foyle Kerrie L , McCormack Catherine D , Robertson Sarah A
Published: January 2023

Pregnancy depends on a state of maternal immune tolerance mediated by CD4+ regulatory T (Treg) cells. Uterine Treg cells release anti-inflammatory factors, inhibit effector immunity, and support adaptation of the uterine vasculature to facilitate placental development. Insufficient Treg cells or inadequate functional competence is implicated in infertility and recurrent miscarriage, as well as pregnancy complications preeclampsia, fetal growth restriction, and preterm birth, which stem from placental insufficiency. In this review we address an emerging area of interest in pregnancy immunology–the significance of metabolic status in regulating the Treg cell expansion required for maternal–fetal tolerance. We describe how hyperglycemia and insulin resistance affect T cell responses to suppress generation of Treg cells, summarize data that implicate a role for altered glucose metabolism in impaired maternal–fetal tolerance, and explore the prospect of targeting dysregulated metabolism to rebalance the adaptive immune response in women experiencing reproductive disorders.
RIG-I–like Receptor Regulation of Immune Cell Function and Therapeutic Implications
Authors: Solstad Abigail , Hogaboam Octavia , Forero Adriana , Hemann Emily A
Published: January 2023

Retinoic acid–inducible gene I–like receptors (RLRs) are cytosolic RNA sensors critical for initiation of antiviral immunity. Activation of RLRs following RNA recognition leads to production of antiviral genes and IFNs for induction of broad antiviral immunity. Although the RLRs are ubiquitously expressed, much of our understanding of these molecules comes from their study in epithelial cells and fibroblasts. However, RLR activation is critical for induction of immune function and long-term protective immunity. Recent work has focused on the roles of RLRs in immune cells and their contribution to programming of effective immune responses. This new understanding of RLR function in immune cells and immune programming has led to the development of vaccines and therapeutics targeting the RLRs. This review covers recent advances in our understanding of the contribution of RLRs to immune cell function during infection and the emerging RLR-targeting strategies for induction of immunity against cancer and viral infection.
A Novel Organized Nasopharynx-Associated Lymphoid Tissue in Teleosts That Expresses Molecular Markers Characteristic of Mammalian Germinal Centers
Authors: Garcia Benjamin , Dong Fen , Casadei Elisa , Rességuier Julien , Ma Jie , Cain Kenneth D , Castrillo Pedro A , Xu Zhen , Salinas Irene
Published: January 2023

Nasal immunity is an ancient and conserved arm of the mucosal immune system in vertebrates. In teleost fish, we previously reported the presence of a nasopharynx-associated lymphoid tissue (NALT) characterized by scattered immune cells located in the trout olfactory lamellae. This diffuse NALT mounts innate and adaptive immune responses to nasal infection or vaccination. In mammals, lymphoid structures such as adenoids and tonsils support affinity maturation of the adaptive immune response in the nasopharyngeal cavity. These structures, known as organized NALT (O-NALT), have not been identified in teleost fish to date, but their evolutionary forerunners exist in sarcopterygian fish. In this study, we report that the rainbow trout nasal cavity is lined with a lymphoepithelium that extends from the most dorsal opening of the nares to the ventral nasal cavity. Within the nasal lymphoepithelium we found lymphocyte aggregates called O-NALT in this study that are composed of ∼ 56% CD4+, 24% IgM+, 16% CD8α+, and 4% IgT+ lymphocytes and that have high constitutive aicda mRNA expression. Intranasal (i.n.) vaccination with live attenuated infectious hematopoietic necrosis virus triggers expansions of B and T cells and aicda expression in response to primary i.n. vaccination. IgM+ B cells undergo proliferation and apoptosis within O-NALT upon prime but not boost i.n. vaccination. Our results suggest that novel mucosal microenvironments such as O-NALT may be involved in the affinity maturation of the adaptive immune response in early vertebrates.
Follicle-Stimulating Hormone Provokes Macrophages to Secrete IL-1β Contributing to Atherosclerosis Progression
Authors: Han Jing-li , Song Yu-xuan , Yao Wei-juan , Zhou Jing , Du Yiqing , Xu Tao
Published: January 2023

Abnormally high follicle-stimulating hormone (FSH) has been reported to associate with cardiovascular diseases in prostate cancer patients with specific androgen deprivation therapy and in menopausal women. All of the cardiovascular diseases were involved in atherosclerosis. However, the pathogenic mechanism of FSH-associated atherosclerosis remains uncertain. Apolipoprotein E–deficient mice were chosen to develop atherosclerosis, of which the plaques were analyzed with administration of short- and long-term FSH imitating androgen deprivation therapy–induced and menopausal FSH elevation. The study showed that short- and long-term exposure of FSH significantly accelerated atherosclerosis progression in apolipoprotein E–deficient mice, manifested as strikingly increased plaques in the aorta and its roots, increased macrophage content, reduced fibrin, and an enlarged necrotic core, suggesting a decrease in plaque stability. Furthermore, expression profiles from the Gene Expression Omnibus GSE21545 dataset revealed that macrophage inflammation was tightly associated with FSH-induced atherosclerotic progression. The human monocyte cell line THP-1 was induced by PMA and worked as a macrophage model to detect inflammatory factors and cellular functions. FSH remarkably promoted the expression of IL-1β in macrophages and strikingly increased the chemotactic migratory capacity of macrophages toward MCP-1, but the promigratory capacity of FSH was attenuated in foam cells. Overall, we revealed that FSH significantly promoted the inflammatory response and migration of macrophages, thereby provoking atherosclerosis development.
The Drosophila Toll Pathway in Innate Immunity: from the Core Pathway toward Effector Functions
Authors: Valanne Susanna , Vesala Laura , Maasdorp Matthew K , Salminen Tiina S , Rämet Mika
Published: January 2023

The fruit fly Drosophila melanogaster Toll signaling pathway has an evolutionarily conserved role in controlling immune responses. Whereas the microbial recognition mechanisms and the core signaling pathway leading to activation of the humoral immune response via the NF-κB transcription factors have been well established for many years, the mechanistic understanding of the effector functions at the molecular level is currently rapidly evolving. In this review, we discuss the current developments in elucidating the role of the Drosophila Toll signaling pathway in immunity. We discuss the emerging role of Toll in viral infections and sex-specific differences in immunity. Mainly, we focus on Toll pathway regulation, the effector molecules, and cellular immunity.
Spring Viremia of Carp Virus N Protein Negatively Regulates IFN Induction through Autophagy-Lysosome–Dependent Degradation of STING
Authors: Wang Xue-li , Li Zhuo-Cong , Zhang Can , Jiang Jing-Yu , Han Ke-jia , Tong Jin-Feng , Yang Xiao-Li , Chen Dan-Dan , Lu Long-Feng , Li Shun
Published: January 2023

Fish possess a powerful IFN system to defend against aquatic virus infections. Nevertheless, spring viremia of carp virus (SVCV) causes large-scale mortality in common carp and significant economic losses to aquaculture. Therefore, it is necessary to investigate the strategies used by SVCV to escape the IFN response. In this study, we show that the SVCV nucleoprotein (N protein) negatively regulates cellular IFN production by degrading stimulator of IFN genes (STING) via the autophagy-lysosome–dependent pathway. First, overexpression of N protein inhibited the IFN promoter activation induced by polyinosinic-polycytidylic acid and STING. Second, the N protein associated with STING and experiments using a dominant-negative STING mutant demonstrated that the N-terminal transmembrane domains of STING were indispensable for this interaction. Then, the N protein degraded STING in a dose-dependent and autophagy-lysosome–dependent manner. Intriguingly, in the absence of STING, individual N proteins could not elicit host autophagic flow. Furthermore, the autophagy factor Beclin1 was found to interact with the N protein to attenuate N protein–mediated STING degradation after beclin1 knockdown. Finally, the N protein remarkably weakened STING-enhanced cellular antiviral responses. These findings reveal that SVCV uses the host autophagic process to achieve immune escape, thus broadening our understanding of aquatic virus pathogenesis.
JMJD3 Is Required for Acute Pancreatitis and Pancreatitis-Associated Lung Injury
Authors: Chen Li , Zhang Xiangxian , Liu Yu , Liu Li , Liang Xiao , Yang Shengqun , Xia Qing , Jin Tao , Ma Yun , Chen Yonghua , Yuan Xia , Tie Yan , Gu Yangzhuo , Fang Chunju , Chen Siyuan , Mo Fei , Yu Ting , Hu Yuzhu , Qian Zhiyong , Peng Yong , Geng Jia , Zhou Zongguang , Wu Min , Ding Jiansheng , Yang Daoke , Wei Xiawei
Published: January 2023

Acute pancreatitis (AP) can be complicated by inflammatory disorders of remote organs, such as lung injury, in which Jumonji domain-containing protein 3 (JMJD3) plays a vital role in proinflammatory responses. Currently, we found that JMJD3 expression was upregulated in the pancreas and lung in an AP male mouse model, which was also confirmed in AP patients. Further experiments revealed that the upregulation of JMJD3 and proinflammatory effects were possibly exerted by mitochondrial DNA (mtDNA) or oxidized-mtDNA from tissue injury caused by AP. The release of mtDNA and oxidized-mtDNA contributed to the infiltration of inflammatory monocytes in lung injury through the stimulator of IFN genes (STING)/TLR9-NF-κB-JMJD3-TNF-α pathway. The inhibition of JMJD3 or utilization of Jmjd3-cKO mice significantly alleviated pulmonary inflammation induced by AP. Blocking mtDNA oxidation or knocking down the TLR9/STING pathway effectively alleviated inflammation. Therefore, inhibition of JMJD3 or STING/TLR9 pathway blockage might be a potential therapeutic strategy to treat AP and the associated lung injury.
Maintenance of Lineage Identity: Lessons from a B Cell
Authors: Belcheva Kalina T , Chaudhuri Jayanta
Published: January 2023

The maintenance of B cell identity requires active transcriptional control that enforces a B cell–specific program and suppresses alternative lineage genes. Accordingly, disrupting the B cell identity regulatory network compromises B cell function and induces cell fate plasticity by allowing derepression of alternative lineage-specific transcriptional programs. Although the B lineage is incredibly resistant to most differentiating factors, loss of just a single B lineage–specific transcription factor or the forced expression of individual non–B cell lineage transcription factors can radically disrupt B cell maintenance and allow dedifferentiation or transdifferentiation into entirely distinct lineages. B lymphocytes thereby offer an insightful and useful case study of how a specific cell lineage can maintain a stable identity throughout life and how perturbations of a single master regulator can induce cellular plasticity. In this article, we review the regulatory mechanisms that safeguard B cell identity, and we discuss how dysregulation of the B cell maintenance program can drive malignant transformation and enable therapeutic resistance.
Immunity to Cryptosporidium: Lessons from Acquired and Primary Immunodeficiencies
Authors: Cohn Ian S , Henrickson Sarah E , Striepen Boris , Hunter Christopher A
Published: January 2023

Cryptosporidium is a ubiquitous protozoan parasite that infects gut epithelial cells and causes self-limited diarrhea in immunocompetent individuals. However, in immunocompromised hosts with global defects in T cell function, this infection can result in chronic, life-threatening disease. In addition, there is a subset of individuals with primary immunodeficiencies associated with increased risk for life-threatening cryptosporidiosis. These patients highlight MHC class II expression, CD40–CD40L interactions, NF-κB signaling, and IL-21 as key host factors required for resistance to this enteric pathogen. Understanding which immune deficiencies do (or do not) lead to increased risk for severe Cryptosporidium may reveal mechanisms of parasite restriction and aid in the identification of novel strategies to manage this common pathogen in immunocompetent and deficient hosts.
Regulation of Cytotoxic CD8+ T Cells by the Circadian Clock
Authors: Cermakian Nicolas , Labrecque Nathalie
Published: January 2023

Most aspects of physiology, including immunity, present 24-h variations called circadian rhythms. In this review, we examine the literature on the circadian regulation of CD8+ T cells, which are important to fight intracellular infections and tumors. CD8+ T cells express circadian clock genes, and ∼6% of their transcriptome presents circadian oscillations. CD8+ T cell counts present 24-h rhythms in the blood and in secondary lymphoid organs, which depend on the clock in these cells as well as on hormonal rhythms. Moreover, the strength of the response of these cells to Ag presentation varies according to time of day, a rhythm dependent on the CD8+ T cell clock. The relevance of CD8+ T cell circadian rhythms is shown by the daily variations in the fight of intracellular infections. Such a circadian regulation also has implications for cancer, as well as the optimization of vaccination and immunotherapy.
ER-phagy Is Involved in the Degradation of Collagen I by IL-1β in Human Amnion in Parturition
Authors: Mi Ya-Bing , Liu Xiao-Hua , Wang Wang-Sheng , Wang Lu-Yao , Ling Li-Jun , Sun Kang , Ying Hao
Published: January 2023

The process of parturition is associated with inflammation within the uterine tissues, and IL-1β is a key proinflammatory cytokine involved. Autophagy is emerging as an important pathway to remove redundant cellular components. However, it is not known whether IL-1β employs the autophagy pathway to degrade collagen, thereby participating in membrane rupture at parturition. In this study, we investigated this issue in human amnion. Results showed that IL-1β levels were significantly increased in human amnion obtained from deliveries with spontaneous labor and membrane rupture, which was accompanied by decreased abundance of COL1A1 and COL1A2 protein but not their mRNA, the two components of collagen I. Consistently, IL-1β treatment of cultured primary human amnion fibroblasts reduced COL1A1 and COL1A2 protein but not their mRNA abundance along with increased abundance of autophagy activation markers, including the microtubule-associated protein L chain 3β II/I ratio and autophagy-related 7 (ATG7) in the cells. The reduction in COL1A1 and COL1A2 protein abundance induced by IL-1β could be blocked by the lysosome inhibitor chloroquine or small interfering RNA–mediated knockdown of ATG7 or ER-phagy receptor FAM134C, suggesting that FAM134C-mediated ER-phagy was involved in IL-1β–induced reduction in COL1A1 and COL1A2 protein in amnion fibroblasts. Consistently, levels of L chain 3β II/I ratio, ATG7, and FAM134C were significantly increased in human amnion obtained from deliveries with spontaneous labor and membrane rupture. Conclusively, increased IL-1β abundance in human amnion may stimulate ER-phagy–mediated COL1A1 and COL1A2 protein degradation in amnion fibroblasts, thereby participating in membrane rupture at parturition.
Complement: The Road Less Traveled
Authors: Kemper Claudia , Ferreira Viviana P , Paz Jeanne T , Holers V Michael , Lionakis Michail S , Alexander Jessy J
Published: January 2023

The complement field has recently experienced a strong resurgence of interest because of the unexpected discovery of new complement functions extending complement’s role beyond immunity and pathogen clearance, a growing list of diseases in which complement plays a role, and the proliferation of complement therapeutics. Importantly, although the majority of complement components in the circulation are generated by the liver and activated extracellularly, complement activation unexpectedly also occurs intracellularly across a broad range of cells. Such cell-autonomous complement activation can engage intracellular complement receptors, which then drive noncanonical cell-specific effector functions. Thus, much remains to be discovered about complement biology. In this brief review, we focus on novel noncanonical activities of complement in its “classic areas of operation” (kidney and brain biology, infection, and autoimmunity), with an outlook on the next generation of complement-targeted therapeutics.
Therapeutic Opportunities for Immunoreceptor-Engineered T Cell Therapy for Modulation of Alloimmunity
Authors: Muralidharan Kavitha , Agarwal Divyansh , Naji Ali , Bhoj Vijay G
Published: January 2023

Achieving immunosuppression-free immune tolerance to an allograft is one of the central goals of transplantation. In this article, we review recent developments in the fields of T cell–based therapies and T cell engineering using chimeric Ag receptors and their potential for effective and targeted immune modulation of T and B cell activity in an effort to eliminate pre-existing alloantibodies (desensitization) and achieve long-term tolerance. Approaches that span preclinical to early clinical studies in transplantation will be reviewed, with specific emphasis on advances in T cell immunotherapy that have shown promise. Lastly, we conclude with a forward-looking discussion of how T cell–based therapies in other fields of medicine can be potentially applied to solid organ transplantation.
Neutrophil and Macrophage NADPH Oxidase 2 Differentially Control Responses to Inflammation and to Aspergillus fumigatus in Mice
Authors: Idol Rachel A , Bhattacharya Sourav , Huang Guangming , Song Zhimin , Huttenlocher Anna , Keller Nancy P , Dinauer Mary C
Published: January 2023

Aspergillus fumigatus is an important opportunistic fungal pathogen and causes invasive pulmonary aspergillosis in conditions with compromised innate antifungal immunity, including chronic granulomatous disease, which results from inherited deficiency of the superoxide-generating leukocyte NADPH oxidase 2 (NOX2). Derivative oxidants have both antimicrobial and immunoregulatory activity and, in the context of A. fumigatus, contribute to both fungal killing and dampening inflammation induced by fungal cell walls. As the relative roles of macrophage versus neutrophil NOX2 in the host response to A. fumigatus are incompletely understood, we studied mice with conditional deletion of NOX2. When NOX2 was absent in alveolar macrophages as a result of LysM-Cre–mediated deletion, germination of inhaled A. fumigatus conidia was increased. Reducing NOX2 activity specifically in neutrophils via S100a8 (MRP8)-Cre also increased fungal burden, which was inversely proportional to the level of neutrophil NOX2 activity. Moreover, diminished NOX2 in neutrophils synergized with corticosteroid immunosuppression to impair lung clearance of A. fumigatus. Neutrophil-specific reduction in NOX2 activity also enhanced acute inflammation induced by inhaled sterile fungal cell walls. These results advance understanding into cell-specific roles of NOX2 in the host response to A. fumigatus. We show that alveolar macrophage NOX2 is a nonredundant effector that limits germination of inhaled A. fumigatus conidia. In contrast, reducing NOX2 activity only in neutrophils is sufficient to enhance inflammation to fungal cell walls as well as to promote invasive A. fumigatus. This may be relevant in clinical settings with acquired defects in NOX2 activity due to underlying conditions, which overlap risk factors for invasive aspergillosis.
Restored Thymic Output after Androgen Blockade Participates in Antitumor Immunity
Authors: Polesso Fanny , Caruso Breanna , Hammond Scott A , Moran Amy E
Published: January 2023

The thymus is a hormone-sensitive organ, which involutes with age in response to production of sex steroids. Thymic involution leads to a decrease in the generation of recent thymic emigrants (RTEs), resulting in a reduced response to immune challenges such as cancer. Interestingly, the standard of care for prostate cancer patients is androgen deprivation therapy (ADT), which leads to thymic regeneration and an increase in thymic output. It remains unknown whether these newly produced T cells can contribute to the antitumor immune response. This study defines the kinetics of thymic regeneration in response to ADT in mice, determining that thymic epithelial cell proliferation is critical for the increase in RTE output. Using a mouse model to track RTE in vivo, we demonstrate that these newly generated RTEs can traffic to tumors, where they become activated and produce effector cytokines at levels similar to more mature T cells. Collectively, these data suggest that RTEs produced from ADT-induced thymic regeneration could be harnessed for the antitumor immune response.
Effect of serial plasma exchange sessions with albumin replacement on ABO antibody titers
Authors: Hassan Mohamed S. , Zaki Mahmoud M. , El Said Tamer W. , Abdelaziz Haitham E. , Al-Semrawy Mahmoud S.M. , Elsayed Hebatallah N. , Abdelmegied Shaimaa Z.
Published: January 2023

Background

Donor shortage in kidney transplantation stimulates trails of live-related transplants across the ABO antibody barrier. Successful desensitization was achieved by repeated plasmapheresis with intensified immunosuppression. This study estimates the effect of serial sessions of plasma exchange on different blood group antibody titers.

Patients and methods

This is a pilot study that included 25 prescribed plasma exchange treatments with albumin replacement for miscellaneous indications. Patients using plasma as a replacement during sessions, positive direct and indirect antiglobulin test and AB blood group were excluded. Blood group antibody titers were measured by the gel card method before starting plasma exchange and after each session for five sessions.

Results

The study included a total of 25 patients, 12 (48%) had A1 blood group, eight (32%) had blood group B, and five (20%) had blood group O. The baseline anti-(A) and anti-(B) antibody titers before plasma exchange were median (interquartile range) 128.00 (192) and 64 (64) with significant reduction after five sessions with median (interquartile range) 1 (4) and 2 (1), respectively, with P value less than 0.001. Anti-(A) and anti-(B) antibody titer percent reduction from baseline to fifth session were mean±SD=99.04 ± 0.72 and =97.93 ± 0.99%, respectively. Anti-(A) and anti-(B) antibody titers were negatively correlated with patient's age (r=0.731, P=0.005; r=0.793, P<0.001, respectively). Patients with age less than 50 (n=13) years have higher anti-(A) and anti-(B) antibodies compared with patients with age more than 50 years (N=12) with P value less than 0.001. Also, on comparing patients on immunosuppressive drugs with patients not on immunosuppressive drugs as regards baseline antibody titers before exchange sessions and after five plasma exchange sessions, there was no significant difference in anti-(B) while anti-(A) titer was higher in patients without immunosuppressive drugs with P valueless than 0.05 and on fifth session, P value of 0.01.

Conclusion

Serial plasma exchange sessions with albumin replacement is an effective method for ABO antibody titer reduction. Baseline titers seem to be affected by age and adjuvant immunosuppressive therapy.
The effect of cryopreserved and noncryopreserved stem cells on the outcome of autologous stem-cell transplantation in multiple myeloma patients
Authors: Uysal Ayşe , Erkurt Mehmet A. , Kuku İrfan , Kaya Emin , Berber İlhami , Sarıcı Ahmet , Biçim Soykan , Hidayet Emine , Kaya Ahmet , Merter Mustafa
Published: January 2023

Background

The CD34+ stem cells are either noncryopreserved (non-CP) or cryopreserved (CP) in autologous stem-cell transplantation (ASCT). Some retrospective studies have shown that engraftment failure and engraftment rate are similar in CP cells and infusion reactions are lower in CP cells due to the absence of dimethyl sulfoxide.

Objective

In this study, we presented our clinical experience comparing the outcomes and safety of ASCT with CP and non-CP stem cells.

Patients and methods

A total of 163 patients were enrolled between January 2019 and June 2021. Duration of neutrophil/platelet engraftment, rates of infusion-related reactions, febrile neutropenia, and duration of hospitalization were compared between the CP and non-CP groups.

Results

Fifty five (33.7%) received CP cells, 108 (66.3%) received non-CP cells. The median dose of CD34+ cells was similar in both groups (P=0.755). The median duration of neutrophil and platelet engraftment was not statistically significantly different in CP and non-CP groups (P=0.896 and 0.183, respectively). No statistical difference was observed in the median duration of hospitalization between the two groups [CP: 16 (13–26) vs. non-CP: 15 (11–31) days, P=0.124]. The febrile neutropenia rate was higher in the CP group, but there was no statistical difference between the two groups (CP: 56.4% vs. non-CP, 48.1%, P=0.301). The rates of infusion-related reaction such as nausea, vomiting, and rash were higher in the CP group (21.8 vs. 12%), with no statistically significant difference (P=0.159).

Conclusion

Non-CP cells have similar outcomes to CP cells and lower toxicity than CP cells, which are safe and effective in ASCT.
Mycobacterium bovis induced human tuberculosis in India: Current status, challenges & opportunities
Authors: Singh Ajay Vir , Yadav Virendra Singh , Chauhan Devendra Singh , Singh Shoor Vir
Published: January 2023

Tuberculosis (TB) caused by Mycobacterium tuberculosis is a leading cause of human deaths due to any infectious disease worldwide. However, infection of Mycobacterium bovis, primarily an animal pathogen, also leads to the development of ‘human tuberculosis’. Infected animals have been considered the major source of M. bovis infection and humans get exposed to M. bovis through close contact with infected animals or consumption of contaminated milk, unpasteurized dairy products and improperly cooked contaminated meat. The information on the global distribution of bovine TB (bTB) is limited, but the disease has been reported from all the livestock-producing middle- and low-income countries of the world. In recent years, there is a renewed interest for the control of bTB to minimize human infection worldwide. In India, while the sporadic presence of M. bovis has been reported in domestic animals, animal-derived food products and human beings from different geographical regions of the country, the information on the national prevalence of bTB and transmission dynamics of zoonotic TB is, however, not available. The present article reviewed published information on the status of M. bovis-induced zoonotic TB to highlight the key challenges and opportunities for intervention to minimize the risk of M. bovis infection in humans and secure optimum animal productivity in India.
Comparative diagnostic utility of different urinary biomarkers during pre-albuminuric stages of non-hypertensive type 2 diabetic nephropathy
Authors: Mahapatra Himansu Sekhar , Kulshreshtha Bindu , Goyal Parul , Chitkara Anubhuti , Kumari Anamika , Arora Arpita , Sekhar Venkatesan , Gupta Yadunandan Prasad
Published: January 2023

Background & objectives:

Activation of renin-angiotensin system and tubulointerstitial damage might be seen in pre-albuminuria stage of diabetic nephropathy (DN). Here, diagnostic utility of four urinary biomarkers [Angiotensinogen (Angio), Interleukin (IL)-18, Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Cystatin] during pre-albuminuria stages of non-hypertensive type 2 diabetes patients was studied.

Methods:

A total of 952 type 2 diabetes mellitus (T2DM) patients were screened for nephropathy [estimated glomerular filtration rate (eGFR) ≥120 ml/min and albumin–creatinine ratio (ACR) ≥30], and 120 patients were followed up for one year. At one year, they were classified into hyperfiltration (43), normoalbuminuria (29) and microalbuminuria (48) groups. Another 63 T2DM patients without nephropathy were included as controls. Hypertension, patients on angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, eGFR <60 ml/min/1.73 m2 and all proteinuric conditions were excluded. All were subjected to testing for urine protein, ACR, HbA1C, eGFR, along with urinary biomarkers (IL-18, cystatin-C, NGAL and AGT). Comparative analysis of all the diagnostic tests among different subgroups, correlation and logistic regression was done.

Results:

Urinary IL-18/Cr, cystatin/creatinine (Cr) and AGT/Cr levels were higher in groups of hyperfiltration (13.47, 12.11 and 8.43 mg/g), normoalbuminuria (9.24, 11.74 and 9.15 mg/g) and microalbuminuria (11.59, 14.48 and 10.24 mg/g) than controls (7.38, 8.39 and 1.26 mg/g), but NGAL/Cr was comparable. The area under receiver operating characteristic curve (AUC) and sensitivity of AGT to detect early CKD were higher than ACR and eGFR (0.91 and 90.4%, 0.6 and 40% and 0.6 and 37%, respectively). AUC values of other biomarkers, namely IL-18/Cr, cystatin/Cr and NGAL/Cr, were 0.65, 0.64 and 0.51, respectively. Angio/Cr and IL-18/Cr showed correlation with log albuminuria (r=0.3, P=0.00, and r=0.28, P=0.00, respectively). NGAL showed correlation with log eGFR (r=0.28 P=0.00). Multivariate logistic analysis showed that odds ratio of developing nephropathy was 7.5 times with higher values of log Angio/Cr.

Interpretation & conclusions:

Urinary AGT showed a higher diagnostic value than ACR and eGFR followed by IL-18 and cystatin to diagnose DN during pre-albuminuric stages.
Impact of hydroxyurea on hospital stay & analgesic utilization in sickle cell anaemia with vaso-occlusive crises
Authors: Soren Uttam Kumar , Mohanty Pradeep Kumar , Meher Satyabrata , Sukla Sunil Kumar , Hiregoudar Mrutyunjay
Published: January 2023

Background & objectives:

Hydroxyurea (HU) has been useful in preventing sickle cell vaso-occlusive crises (VOC). A few studies also suggest utility of HU, during acute VOC. Sickle cell anaemia (SCA) is of high prevalence in western districts of Odisha State, India, and VOC is a common presentation, despite being mostly of Arab-Indian haplotype. This study was undertaken to evaluate the impact of HU on hospital stay and analgesic utilization in acute painful VOC of SCA.

Methods:

Homozygous sickle cell disease (HbSS) patients were categorized as cases who were receiving low-dose HU (10 mg/kg/day) and patients who were not on HU were considered as control. Days of hospital stay, analgesic utilization and visual analogue scale (VAS) score in patients were compared with that of control. Analgesics used to control pain were tramadol hydrochloride, ketorolac and diclofenac.

Results:

A total of 359 homozygous sickle cell disease (SCD) patients with VOC were studied (187 patients and 172 controls). The patient group had lesser mean days of hospital stay (1.4 days less than controls, P<0.001) and required lesser days of analgesic utilization than controls (1.18 days less than controls, P<0.001). Significant differences were observed between patients and controls concerning VAS score and amount of tramadol hydrochloride, ketorolac and diclofenac utilization (P<0.05).

Interpretation & conclusions:

In this study, HU was found to have beneficial effects in acute VOC of homozygous SCD, which includes shortening the duration of hospital stay and reducing the net amount of analgesic utilization during hospitalization.
Endometrial serous carcinoma: A retrospective review of histological features & their clinicopathological association with disease-free survival & overall survival
Authors: Agarwal Arti , Yadav Subhash , Dusane Rohit , Menon Santosh , Rekhi Bharat , Deodhar Kedar K.
Published: January 2023

Background & objectives:

Endometrial serous carcinoma (ESC) is a high-grade epithelial neoplasm with increased risk for metastasis and recurrence. This study was aimed to assess various histomorphological features of ESC and their clinicopathological association with disease-free survival (DFS) and overall survival (OS).

Methods:

A total of 205 slides (belonging to 120 patients) diagnosed as ESC from January 2009 to December 2015 were reviewed. Receiver operating characteristics (ROC) curves were established for the diagnostic performance of depth of invasion (DOI), tumour-free distance (TFD) to serosa and percentage myometrial invasion (MI%). OS and DFS were generated by Kaplan-Meier curves and prognostic significance by Cox regression analysis.

Results:

The mean age at diagnosis was 61.8 yr and the mean tumour size was 4.01 cm. Majority of the females were multiparous (84%; n=94) and postmenopausal (89.2%; n=107). On histopathology, <50 per cent of MI was identified in 37 of the 104 (35%), while 62/104 (59.61%) patients had ≥50 per cent MI. Seven (6.7%) patients had full-thickness invasion with serosal involvement, while five (4.8%) patients had no microscopic MI (minimal uterine serous carcinoma). Information about MI was not available in 16 patients. TFD ≥7.0 mm, DOI ≥6.0 mm and MI% ≥40 were significant variables in univariate analyses for OS; however, on multivariate analysis; none of these turned out to be an independent predictor in terms of OS. For DFS, DOI (≥6.0 mm) and MI% (≥40%) showed a significant association, in univariate as well as multivariate analysis; however, TFD (≤7.0 mm) did not show any significant association with DFS. Follow up data were available in 111 of the 120 (92.5%) patients with a five-year OS and DFS of 22.2 and 17.2 per cent, respectively.

Interpretation & conclusions:

Conventionally calculated DOI (less than or more than half thickness) did not show significance in the present study. Thus, calculating the actual myometrial DOI, MI% and TFD to serosa have the potential for contributing meaningfully to prognostication of ESC.
Down Syndrome with Umbilical Cord Hematoma
Authors: Naeem Ammara , Rahman Sajjad , Abdulghani Muhammad Hassan , Almalki Yahya
Published: January 2023

Umbilical cord hematoma (UCH) is the extravasation of blood in the umbilical cord. The condition is rare and asymptomatic but very important to recognize because it can potentially compromise fetal blood flow. Hence, UCH increases the chances of fetal mortality and morbidity. We are presenting the case report of a large but asymptomatic UCH in a newborn baby with Down syndrome. To the best of our knowledge, the association between Down syndrome and UCH has not been reported in medical literature till the time of writing of this manuscript.
An Unusual Course of Pneumonia in a Term Neonate with Suspected Multisystem Inflammatory Syndrome Secondary to Severe Acute Respiratory Syndrome Coronavirus 2 Infection
Authors: Ragireddy Ashish , Das Ratan Kumar , Mallick Bhabagrahi , Nanda Debasish
Published: January 2023

Neonatal multisystem inflammatory syndrome secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection is a relatively new entity with only a few cases being reported in the literature. We report the case of a 25-day-old term neonate who presented with severe respiratory distress, required respiratory support, and systemic antibiotics at admission. Two-dimensional echocardiography revealed the features of pulmonary arterial hypertension. Computed tomography scan of the chest was suggestive of features of organizing pneumonia. In view of multisystem involvement, raised inflammatory markers, and high anti-SARS-CoV2 antibody, intravenous immunoglobulin was administered, following which the baby improved and weaned off to room air and eventually discharged.
Linezolid-Induced Black Hairy Tongue
Authors: Siddiqui Moin A. , Adil Mohammad , Amin Syed S. , Xess Kritika
Published: January 2023

Black hairy tongue is an asymptomatic and benign condition presenting with black-to-brownish discoloration of the dorsum of the tongue with elongated filiform papillae. Several medications, particularly antibiotics, are implicated in its causation. Xerostomia, abnormal desquamation of the tongue, use of oxidizing mouthwashes, excessive intake of nicotine, coffee, and tea, and immunosuppressive states predispose to the development of this condition. Herein, we describe a case of a young female who developed black hairy tongue within 5 days of linezolid intake. The discoloration disappeared after 7 days of stopping the drug. We also summarize the various reports of black hairy tongue due to linezolid in a tabular form. We aim to highlight the importance of medication history in the identification of this uncommon condition. We also emphasize identifying risk factors for this condition and educating the patients about them.
Saudi Adolescent Present with New-Onset Vitiligo Post-COVID-19 Vaccination
Authors: Alnaim Abdullah A. , Al-Mulhim Amnah N. , Al-Momen Mohammed M. , Shaikh Lenah Y.
Published: January 2023

Coronavirus disease of 2019 (COVID-19) is a relatively new pandemic; the first reported case was in late 2019, and the first vaccine was given in December 2020. To this date, multiple side effects have been reported with COVID-19 vaccines. Nonetheless, autoimmune (AI) diseases with the COVID-19 vaccine have rarely been associated. We described herein a case of sudden onset of vitiligo occurring after the first dose of the COVID-19 vaccine. To date, there are less than 10 reported cases of vitiligo post-COVID-19 vaccine. This report aims to recognize AI disease presentation with vaccines, specifically COVID-19.
Spotted Fever Rickettsioses Should be Considered in the Differential Diagnosis of “Fever with Purpuric Rash” in Saudi Arabia
Authors: Nassar Ahmed H. , Abu-Aliat Abdullah S. , Jamil Salim , Alshahrani Mohammed S. , Hawwam Soha A. , Eid Esmat R.
Published: January 2023

There is a paucity of literature about human spotted fever rickettsioses (SFR) from the Arab Gulf Region, including Saudi Arabia. Here, we present an elderly Saudi man who had fever, headache, purpuric maculopapular skin rash, and an eschar. Together, the clinical findings, the serologic positivity, the presence of a vector tick in addition to the histopathologic changes, and the dramatic clinical response to oral doxycycline confirmed the diagnosis of SFR. This may be the first case of SFR reported to the health-care authorities in Saudi Arabia. We recommend considering SFR in the differential diagnosis of “fever with purpuric rash” in Saudi Arabia. Ideally, treatment with a tetracycline antibiotic should be considered for patients with fever and headache even before a purpuric rash develops.