William M. Nauseef

University of Iowa

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Robert A. Clark

South Texas Veterans Health Care System

Kevin G. Leidal

University of Iowa

Frank R. DeLeo

National Institute of Allergy and Infectious Diseases

Sally McCormick

University of Iowa

Michael A. Apicella

University of Iowa

Alexander R. Horswill

University of Colorado Denver

Bryan D. Volpp

VA Northern California Health Care System

Jerrold Weiss

University of Iowa

Lee‐Ann H. Allen

University of Iowa

Mary C. Dinauer

Washington University in St. Louis

Cooperative Institutions

Milbank Memorial Fund

316

National Institutes of Health

University of Iowa

Harvard University

Park University

John Wiley & Sons (United States)

147

Cervantes Institute

119

Office of Infectious Diseases

104

Weatherford College

101

National Institute of Allergy and Infectious Diseases

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Depolarization blunts the oxidative burst of human neutrophils. Parallel effects of monoclonal antibodies, depolarizing buffers, and glycolytic inhibitors.

The Journal of Immunology (1988)

María Ángeles Martín William M. Nauseef Robert A. Clark

The anti-neutrophil mAb PMN 7C3 and IIC4 inhibited the respiratory burst of neutrophils as measured by the generation of superoxide anion or hydrogen peroxide in response to PMA, serum-treated zymosan, and FMLP. To examine the effect of these mAb on neutrophil transmembrane potential, a fluorescent probe was used in a continuous assay. Compared with control cells, antibody-treated neutrophils were partially depolarized at rest and had a blunted response when stimulated. The F(ab)2 fragment of PMN 7C3 had similar effects on both the respiratory burst and transmembrane potential, whereas the Fab fragment did not. The unrelated antineutrophil mAb 31D8 had no effect on either the respiratory burst or on transmembrane potential. Neutrophils suspended in high potassium buffers also exhibited partial depolarization of the resting cell membrane and a blunted depolarization response to stimuli and produced less superoxide anion and hydrogen peroxide in response to stimuli than did control cells in physiologic buffer. Exposure of neutrophils to 2-deoxy-D-glucose resulted in dose- and time-dependent depression of the respiratory burst. 2-Deoxy-D-glucose also caused depolarization of the resting membrane and impaired subsequent stimulus-induced depolarization. Similar effects were seen with addition of iodoacetamide or depletion of glucose. The parallel effects of anti-neutrophil mAb, depolarizing buffers, and glycolytic inhibitors on both neutrophil membrane depolarization and activation of the respiratory burst indicate a close association between these two events. The evidence suggests that the inhibitory effects of these antibodies are mediated through partial membrane depolarization which interferes with signal transduction on subsequent stimulation of the cells. The impairment in oxidative responses to phorbol esters as well as to receptor-dependent activating agents points to interruption at a distal step, e.g., subsequent to Ca2+ mobilization.

Respiratory burst

Zymosan

10.4049/jimmunol.140.11.3928

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Citations (25)

Cloning of the cDNA and functional expression of the 47-kilodalton cytosolic component of human neutrophil respiratory burst oxidase.

Proceedings of the National Academy of Sciences (1989)

Bryan D. Volpp William M. Nauseef J E Donelson David J. Moser Robert A. Clark

Neutrophil NADPH oxidase is a multicomponent enzyme that is activated to generate superoxide anion and is defective in the cells of patients with chronic granulomatous disease. It requires both membrane and cytosolic components, the latter including 47- and 67-kDa proteins recognized by the polyclonal antiserum B-1. Immunoscreening of an induced HL-60 lambda ZAP cDNA library yielded seven cross-hybridizing cDNAs encoding the 47-kDa component. Fusion proteins of 22-50 kDa were recognized by B-1. Antiserum against a fusion protein recognized a 47-kDa protein in normal neutrophils but not in those from patients with autosomal chronic granulomatous disease who lack the 47-kDa cytosolic oxidase component. In a cell-free NADPH oxidase system full-length and C-terminal fusion proteins augmented superoxide generation and reconstituted the cytosolic defect of a patient missing the 47-kDa protein. The cDNA hybridized with a 1.4-kilobase mRNA from induced HL-60 cells. The longest cDNA contained an open reading frame encoding a protein of 41,440 Da with a calculated pI of 10.4, an N-terminal glycine, sites favorable for phosphorylation, a nucleotide binding domain, and a region of homology to the src protein kinases, phospholipase C, and alpha-fodrin. These structural features are pertinent to proposed functional roles of the protein in the respiratory burst oxidase.

Immunoscreening

Chronic Granulomatous Disease

10.1073/pnas.86.18.7195

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Citations (311)

The NADPH‐Dependent Oxidase of Phagocytes

Proceedings of the Association of American Physicians (1999)

William M. Nauseef

Polymorphonuclear leukocytes (PMNs) represent a prominent cellular element in the innate immune system, serving to ingest exogenous particles and microbes and to kill phagocytosed microorganisms. The microbicidal activity of PMNs depends on the interactions of a broad array of potent systems, including relatively stable degradative proteins as well as labile reactive radicals. These systems can be categorized as oxygen‐dependent and nonoxidative mechanisms, although the physiologically relative activity depends on the precisely orchestrated interplay between both systems. The enzyme complex responsible for the activity of the oxygen‐dependent system is the respiratory burst oxidase and its important contribution to host defense is best illustrated by the frequent and severe infections seen in individuals whose PMNs lack oxidase activity, namely patients with chronic granulomatous disease (CGD). Multiple elements comprise the oxygen‐dependent system, and significant advances have been made in the past decade in understanding the protein components of the respiratory burst oxidase, their subcellular distribution in resting PMNs, and their agonist‐dependent assembly into a functional system at phagosomal and plasma membranes. In parallel, substantial insights into the molecular bases of CGD have likewise been made. Nonetheless there remain significant gaps in our understanding of the precise functional contributions of particular components of the system, the molecular mechanisms that regulate their coordinated assembly, and the role of related proteins in nonphagocytic cells.

Respiratory burst

Chronic Granulomatous Disease

Phagocyte

10.1111/paa.1999.111.5.373

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Citations (89)

Assembly of the phagocyte NADPH oxidase

Histochemistry and Cell Biology (2004)

William M. Nauseef

Phagocyte

P22phox

Rac GTP-Binding Proteins

Alternative oxidase

Respiratory burst

10.1007/s00418-004-0679-8

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Citations (417)

Host Interception of Bacterial Communication Signals

Cell Host & Microbe (2008)

Alexander R. Horswill William M. Nauseef

Interception

10.1016/j.chom.2008.11.003

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Citations (10)

Front & Back Matter

Journal of Innate Immunity (2013)

Marine L. B. Hillaire Henk P. Haagsman Albert D. M. E. Osterhaus Guus F. Rimmelzwaan Martin van Eijk

10.1159/000351414

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Characterization of cDNA clones for human myeloperoxidase: Predicted amino acid sequence and evidence for multiple mRNA species

Nucleic Acids Research (1987)

Keith R. Johnson William M. Nauseef Alessandra Carè Margaret J. Wheelock S Shane

Myeloperoxidase is a component of the microbicidal network of polymorphonuclear leukocytes. The enzyme is a tetramer consisting of two heavy and two light subunits. A large proportion of humans demonstrate genetic deficiences in the production of myeloperoxidase. As a first step in analyzing these deficiencies 1n more detail, we have isolated cDNA clones for myeloperoxidase from an expression library of the HL-60 human promyelocytic leukemia cell line.Two overlapping plasmids(pMP02 and pMP062) were identified as myeloperoxidase cDNA clones based on the detection with myeloperoxidase antiserum of 1)70 kDa protein expressed 1n pMP02-conta1n1ng bacteria and 2) a 75 kDa polypeptide produced by hybridization selection and translation using pMP062 and HL-60 RNA. Formal identification of the clones was made by matching the predicted amino add sequences with the amino terminal sequences of the heavy and light sub-units. Both subunits are encoded by one mRNA in the following order: pre-pro-sequences -- light subunit -- heavy subunit.The molecular weight of the predicted primary translation product 1s 83.7 kDa. Northern blots reveal two size classes of hybridizing RNAs(approximately 3.0–3.3 and 3.5–4.0 kilobases) whose expression is restricted to cells of the granulocytic lineage and parallels the changes in enzymatic activity observed during differentiation.

10.1093/nar/15.5.2013

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Citations (169)

Molecular cloning of human myeloperoxidase using an hl 60 expression complementary dna library

Clinical research (1986)

Keith Johnson William M. Nauseef M J Wheelock A. D. Care G Rovera

Cloning (programming)

Library

Human cloning

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