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Item Accumulation of Neutrophil Phagocytic Antibody Features Tracks With Naturally Acquired Immunity Against Malaria in Children(Oxford University Press, 2023) Nziza, Nadege; Tran, Tuan M.; DeRiso, Elizabeth A.; Dolatshahi, Sepideh; Herman, Jonathan D.; de Lacerda, Luna; Junqueira, Caroline; Lieberman, Judy; Ongoiba, Aissata; Doumbo, Safiatou; Kayentao, Kassoum; Traore, Boubacar; Crompton, Peter D.; Alter, Galit; Medicine, School of MedicineBackground: Studies have demonstrated the protective role of antibodies against malaria. Young children are known to be particularly vulnerable to malaria, pointing to the evolution of naturally acquired clinical immunity over time. However, whether changes in antibody functionality track with the acquisition of naturally acquired malaria immunity remains incompletely understood. Methods: Using systems serology, we characterized sporozoite- and merozoite-specific antibody profiles of uninfected Malian children before the malaria season who differed in their ability to control parasitemia and fever following Plasmodium falciparum (Pf) infection. We then assessed the contributions of individual traits to overall clinical outcomes, focusing on the immunodominant sporozoite CSP and merozoite AMA1 and MSP1 antigens. Results: Humoral immunity evolved with age, with an expansion of both magnitude and functional quality, particularly within blood-stage phagocytic antibody activity. Moreover, concerning clinical outcomes postinfection, protected children had higher antibody-dependent neutrophil activity along with higher levels of MSP1-specific IgG3 and IgA and CSP-specific IgG3 and IgG4 prior to the malaria season. Conclusions: These data point to the natural evolution of functional humoral immunity to Pf with age and highlight particular antibody Fc-effector profiles associated with the control of malaria in children, providing clues for the design of next-generation vaccines or therapeutics.Item Altered Macrophage Function Associated with Crystalline Lung Inflammation in Acid Sphingomyelinase Deficiency(American Thoracic Society, 2021) Poczobutt, Joanna M.; Mikosz, Andrew M.; Poirier, Christophe; Beatman, Erica L.; Serban, Karina A.; Gally, Fabienne; Cao, Danting; McCubbrey, Alexandra L.; Cornell, Christina F.; Schweitzer, Kelly S.; Berdyshev, Evgeny V.; Bronova, Irina A.; Paris, François; Petrache, Irina; Medicine, School of MedicineDeficiency of ASM (acid sphingomyelinase) causes the lysosomal storage Niemann-Pick disease (NPD). Patients with NPD type B may develop progressive interstitial lung disease with frequent respiratory infections. Although several investigations using the ASM-deficient (ASMKO) mouse NPD model revealed inflammation and foamy macrophages, there is little insight into the pathogenesis of NPD-associated lung disease. Using ASMKO mice, we report that ASM deficiency is associated with a complex inflammatory phenotype characterized by marked accumulation of monocyte-derived CD11b+ macrophages and expansion of airspace/alveolar CD11c+ CD11b− macrophages, both with increased size, granularity, and foaminess. Both the alternative and classical pathways were activated, with decreased in situ phagocytosis of opsonized (Fc-coated) targets, preserved clearance of apoptotic cells (efferocytosis), secretion of Th2 cytokines, increased CD11c+/CD11b+ cells, and more than a twofold increase in lung and plasma proinflammatory cytokines. Macrophages, neutrophils, eosinophils, and noninflammatory lung cells of ASMKO lungs also exhibited marked accumulation of chitinase-like protein Ym1/2, which formed large eosinophilic polygonal Charcot-Leyden–like crystals. In addition to providing insight into novel features of lung inflammation that may be associated with NPD, our report provides a novel connection between ASM and the development of crystal-associated lung inflammation with alterations in macrophage biology.Item Clonal hematopoiesis driven by mutated DNMT3A promotes inflammatory bone loss(Elsevier, 2024) Wang, Hui; Divaris, Kimon; Pan, Bohu; Li, Xiaofei; Lim, Jong-Hyung; Saha, Gundappa; Barovic, Marko; Giannakou, Danai; Korostoff, Jonathan M.; Bing, Yu; Sen, Souvik; Moss, Kevin; Wu, Di; Beck, James D.; Ballantyne, Christie M.; Natarajan, Pradeep; North, Kari E.; Netea, Mihai G.; Chavakis, Triantafyllos; Hajishengallis, George; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthClonal hematopoiesis of indeterminate potential (CHIP) arises from aging-associated acquired mutations in hematopoietic progenitors, which display clonal expansion and produce phenotypically altered leukocytes. We associated CHIP-DNMT3A mutations with a higher prevalence of periodontitis and gingival inflammation among 4,946 community-dwelling adults. To model DNMT3A-driven CHIP, we used mice with the heterozygous loss-of-function mutation R878H, equivalent to the human hotspot mutation R882H. Partial transplantation with Dnmt3aR878H/+ bone marrow (BM) cells resulted in clonal expansion of mutant cells into both myeloid and lymphoid lineages and an elevated abundance of osteoclast precursors in the BM and osteoclastogenic macrophages in the periphery. DNMT3A-driven clonal hematopoiesis in recipient mice promoted naturally occurring periodontitis and aggravated experimentally induced periodontitis and arthritis, associated with enhanced osteoclastogenesis, IL-17-dependent inflammation and neutrophil responses, and impaired regulatory T cell immunosuppressive activity. DNMT3A-driven clonal hematopoiesis and, subsequently, periodontitis were suppressed by rapamycin treatment. DNMT3A-driven CHIP represents a treatable state of maladaptive hematopoiesis promoting inflammatory bone loss.Item Co-mobilization of CD11b/CD18 (Mac-1) and formyl peptide receptors (FPR) in human neutrophils(1993) Graves, Vicki L.Item The Complexity of Microglial Interactions With Innate and Adaptive Immune Cells in Alzheimer’s Disease(Frontiers Media, 2020-11-19) Wyatt-Johnson, Season K.; Brutkiewicz, Randy R.; Microbiology and Immunology, School of MedicineIn the naïve mouse brain, microglia and astrocytes are the most abundant immune cells; however, there is a complexity of other immune cells present including monocytes, neutrophils, and lymphocytic cells, such as natural killer (NK) cells, T cells, and B cells. In Alzheimer’s disease (AD), there is high inflammation, reactive microglia, and astrocytes, leaky blood–brain barrier, the buildup of amyloid-beta (Aβ) plaques, and neurofibrillary tangles which attract infiltrating peripheral immune cells that are interacting with the resident microglia. Limited studies have analyzed how these infiltrating immune cells contribute to the neuropathology of AD and even fewer have analyzed their interactions with the resident microglia. Understanding the complexity and dynamics of how these immune cells interact in AD will be important for identifying new and novel therapeutic targets. Thus, this review will focus on discussing our current understanding of how macrophages, neutrophils, NK cells, T cells, and B cells, alongside astrocytes, are altered in AD and what this means for the disorder, as well as how these cells are affected relative to the resident microglia.Item Coxiella burnetii Virulent Phase I and Avirulent Phase II Variants Differentially Manipulate Autophagy Pathway in Neutrophils(American Society for Microbiology, 2022) Kumaresan, Venkatesh; Wang, Juexin; Zhang, Wendy; Zhang, Yan; Xu, Dong; Zhang, Guoquan; Medical and Molecular Genetics, School of MedicineCoxiella burnetii is an obligate intracellular Gram-negative bacterium that causes Q fever in humans. The virulent C. burnetii Nine Mile phase I (NMI) strain causes disease in animal models, while the avirulent NM phase II (NMII) strain does not. In this study, we found that NMI infection induces severe splenomegaly and bacterial burden in the spleen in BALB/c mice, while NMII infection does not. A significantly higher number of CD11b+ Ly6G+ neutrophils accumulated in the liver, lung, and spleen of NMI-infected mice than in NMII-infected mice. Thus, neutrophil accumulation correlates with NMI and NMII infection-induced inflammatory responses. In vitro studies also demonstrated that although NMII exhibited a higher infection rate than NMI in mouse bone marrow neutrophils (BMNs), NMI-infected BMNs survived longer than NMII-infected BMNs. These results suggest that the differential interactions of NMI and NMII with neutrophils may be related to their ability to cause disease in animals. To understand the molecular mechanism underlying the differential interactions of NMI and NMII with neutrophils, global transcriptomic gene expressions were compared between NMI- and NMII-infected BMNs by RNA sequencing (RNA-seq) analysis. Interestingly, several genes involved in autophagy-related pathways, particularly membrane trafficking and lipid metabolism, are upregulated in NMII-infected BMNs but downregulated in NMI-infected BMNs. Immunofluorescence and immunoblot analyses indicate that compared to NMI-infected BMNs, vacuoles in NMII-infected-BMNs exhibit increased autophagic flux along with phosphatidylserine translocation in the cell membrane. Similar to neutrophils, NMII activated LC3-mediated autophagy in human macrophages. These findings suggest that the differential manipulation of autophagy of NMI and NMII may relate to their pathogenesis.Item Cytoskeletal interactions with the leukocyte integrin beta2 cytoplasmic tail: Activation-dependent regulation of associations with talin and alpha-actinin(Elsevier, 1998) Sampath, Rangarajan; Gallagher, Patricia J.; Pavalko, Fredrick M.; Anatomy, Cell Biology and Physiology, School of MedicineCirculating leukocytes are nonadherent but bind tightly to endothelial cells following activation. The increased avidity of leukocyte integrins for endothelial ligands following activation is regulated, in part, by interaction of the beta2 subunit cytoplasmic tail with the actin cytoskeleton. We propose a mechanism to explain how tethering of the actin cytoskeleton to leukocyte integrins is regulated. In resting leukocytes, beta2 integrins are constitutively linked to the actin cytoskeleton via the protein talin. Activation of cells induces proteolysis of talin and dissociation from the beta2 tail. This phase is transient, however, and is followed by reattachment of actin filaments to integrins that is mediated by the protein alpha-actinin. The association of alpha-actinin with integrins may stabilize the cytoskeleton and promote firm adhesion to and migration across the endothelium. Glutathione S-transferase-beta2 tail fusion protein/mutagenesis experiments suggest that the affinity of alpha-actinin binding to the beta2 tail is regulated by a change in the conformation of the tail that unmasks a cryptic alpha-actinin binding domain. Positive and inhibitory domains within the beta2 tail regulate alpha-actinin binding: a single 11-amino acid region (residues 736-746) is necessary and sufficient for alpha-actinin binding, and a regulatory domain between residues 748-762 inhibits constitutive association of the beta2 tail with alpha-actinin.Item Engineering chimeric antigen receptor neutrophils from human pluripotent stem cells for targeted cancer immunotherapy(Cell Press, 2022) Chang, Yun; Syahirah, Ramizah; Wang, Xuepeng; Jin, Gyuhyung; Torregrosa-Allen, Sandra; Elzey, Bennett D.; Hummel, Sydney N.; Wang, Tianqi; Li, Can; Lian, Xiaojun; Deng, Qing; Broxmeyer, Hal E.; Bao, Xiaoping; Microbiology and Immunology, School of MedicineNeutrophils, the most abundant white blood cells in circulation, are closely related to cancer development and progression. Healthy primary neutrophils present potent cytotoxicity against various cancer cell lines through direct contact and via generation of reactive oxygen species. However, due to their short half-life and resistance to genetic modification, neutrophils have not yet been engineered with chimeric antigen receptors (CARs) to enhance their antitumor cytotoxicity for targeted immunotherapy. Here, we genetically engineered human pluripotent stem cells with synthetic CARs and differentiated them into functional neutrophils by implementing a chemically defined platform. The resulting CAR neutrophils present superior and specific cytotoxicity against tumor cells both in vitro and in vivo. Collectively, we established a robust platform for massive production of CAR neutrophils, paving the way to myeloid cell-based therapeutic strategies that would boost current cancer-treatment approaches.Item Evaluation of neutropenia and neutrophilia in preterm infants(Informa UK (Informa Healthcare), 2012-10) Nittala, Solomon; Subbarao, Girish C.; Maheshwari, Akhil; Department of Pediatrics, IU School of MedicineOBJECTIVE: Neutrophil counts are used routinely as part of the sepsis evaluation in newborn infants. In this article, we review the normal blood neutrophil concentrations and the clinical approach to neutropenia and neutrophilia in the neonatal period. METHODS: A literature search was performed using the databases PubMed, EMBASE, and Scopus, and the electronic archive of abstracts presented at the annual meetings of the Pediatric Academic Societies. RESULTS: Neutropenia and neutrophilia are documented frequently in premature infants. Neutropenia can be seen in up to 8% of all infants admitted to neonatal intensive care. Neutrophilia is even more common, reported in up to 40% of all preterm infants. CONCLUSIONS: Neutrophil counts should be carefully evaluated in premature neonates. Maternal and perinatal history, physical examination, and a limited laboratory assessment is usually adequate for making a diagnosis in most infants.Item Green tea catechin inhibits the activity and neutrophil release of Matrix Metalloproteinase-9.(Elsevier, 2016-10) Kim-Park, Wan K.; Allam, Eman S.; Palasuk, Jadesada; Kowolik, Michael; Park, Kichuel K.; Windsor, L. Jack; Department of Biomedical and Applied Sciences, IU School of DentistryGreen tea (Camellia sinensis; 綠茶 lǜ chá) extracts have been shown to possess anti-oxidant and anti-inflammatory effects in various cell types. Green tea extract (GTX) has been shown to significantly inhibit the activity of collagenase-3 (matrix metalloproteinase-13 (MMP-13)) in vitro. MMPs, such as
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