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Anthony Segal FRS FMedSci (born 24 February 1944) is a British physician/scientist.
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Anthony Segal FRS FMedSci (born 24 February 1944) is a British physician/scientist.
He was educated at the University of Cape Town (MB ChB, MD) and University of London (MSc, DSc, PhD). Fellow of: UCL, Royal College of Physicians, The College of Medicine of South Africa[ citation needed ]
Tony Segal was born in Johannesburg, South Africa, and grew up in Bulawayo, in a Jewish family, [1] in what was then Southern Rhodesia (now Zimbabwe). He was schooled locally and then studied medicine at the University of Cape Town and Groote Schuur Hospital, where he undertook house-physician and house-surgeon positions. After six months as a medical registrar in the cardiothoracic department of Wentworth Hospital in Durban he moved to London where he attended the Royal College of Surgeons and obtained his primary fellowship. He then worked in the Accident and Emergency department at the Hammersmith Hospital, followed by six months as senior house officer to the rheumatologist Eric Bywaters.[ citation needed ]
Segal then moved to the MRC Clinical Research Centre as registrar in Gastroenterology, during which time he studied Biochemistry at evening classes at Chelsea College of Science and Technology. Over the next decade he specialised as a gastroenterologist and held various positions at Northwick Park Hospital and Hammersmith Hospital before moving to University College London as a Wellcome Trust Senior Clinical Fellow. In 1986 he was appointed to the Charles Dent Chair of Medicine and Head of the Centre for Molecular Medicine, a position that he held until April 2020. In May 2020 he was a co-founder and appointed as CEO, of Imhotex, a company formed for the development of drugs to treat Crohn's disease.
Initially a clinical gastroenterologist, his interest in immunity resulted in him starting a clinical service for immunodeficiency. He served on the Council of the European Society for Clinical Investigation for four years, and in 1984 he started the Phagocyte Workshop of that society, which is running to this day. He was a member of three of the finding panels of the Wellcome Trust, chairing the International Interest group. In 1998 he was a founding Fellow of the Academy of Medical Sciences and was elected as a Fellow of the Royal Society, and has served on and chaired, several Royal Society committees. In 2014 he was awarded the UCL Prize Lecture in Clinical Science Prize. [2] His recent work is concerned with Crohn's disease and the role played by neutrophils in killing bacteria and fungi.
Segal has had diverse research interests. His major discoveries have been the NADPH oxidase and causes of Chronic Granulomatous Disease (CGD): The identity of the NADPH oxidase that generates superoxide in myeloid cells. He showed it to be a low potential flavocytochrome, and demonstrated that mutations in the gene coding for it, and for its activating proteins, cause the severe immunodeficiency disease of Chronic Granulomatous Disease (CGD).
He showed that the mechanism by which microbes are killed within the phagocytic vacuole of neutrophils is not through the toxic actions of oxygen free radicals or through the generation of HOCl by myeloperoxidase. The oxidase elevates the pH within the phagocytic vacuole, and drives potassium into this compartment to compensate the charge generated across the membrane by the passage of electrons. The elevated pH and potassium concentration activate the neutral proteases, cathepsin G and elastase, which kill and digest the microbes.
He determined the causes of Crohn's disease, a chronic granulomatous inflammation that predominantly affects the terminal small bowel and colon. He demonstrated that the common underlying pathogenesis of this condition is a failure of acute inflammation as a consequence of which faecal material gaining access through the mucosa of the bowel is not cleared from the tissues, where it festers, resulting in the characteristic chronic inflammation.[ citation needed ]
>300 publications H-Index 75
Inflammation is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function.
Neutrophils are a type of white blood cell. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in different animals.
Phagocytes are cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek phagein, "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek kutos, "hollow vessel". They are essential for fighting infections and for subsequent immunity. Phagocytes are important throughout the animal kingdom and are highly developed within vertebrates. One litre of human blood contains about six billion phagocytes. They were discovered in 1882 by Ilya Ilyich Mechnikov while he was studying starfish larvae. Mechnikov was awarded the 1908 Nobel Prize in Physiology or Medicine for his discovery. Phagocytes occur in many species; some amoebae behave like macrophage phagocytes, which suggests that phagocytes appeared early in the evolution of life.
A granuloma is an aggregation of macrophages that forms in response to chronic inflammation. This occurs when the immune system attempts to isolate foreign substances that it is otherwise unable to eliminate. Such substances include infectious organisms including bacteria and fungi, as well as other materials such as foreign objects, keratin, and suture fragments.
Chronic granulomatous disease (CGD), also known as Bridges–Good syndrome, chronic granulomatous disorder, and Quie syndrome, is a diverse group of hereditary diseases in which certain cells of the immune system have difficulty forming the reactive oxygen compounds used to kill certain ingested pathogens. This leads to the formation of granulomas in many organs. CGD affects about 1 in 200,000 people in the United States, with about 20 new cases diagnosed each year.
Myeloperoxidase deficiency is a disorder featuring lack in either the quantity or the function of myeloperoxidase–an iron-containing protein expressed primarily in neutrophil granules. There are two types of myeloperoxidase deficiency: primary/inherited and secondary/acquired. Lack of functional myeloperoxidase leads to less efficient killing of intracellular pathogens, particularly Candida albicans, as well as less efficient production and release of neutrophil extracellular traps (NETs) from the neutrophils to trap and kill extracellular pathogens. Despite these characteristics, more than 95% of individuals with myeloperoxidase deficiency experience no symptoms in their lifetime. For those who do experience symptoms, the most common symptom is frequent infections by Candida albicans. Individuals with myeloperoxidase deficiency also experience higher rates of chronic inflammatory conditions. Myeloperoxidase deficiency is diagnosed using flow cytometry or cytochemical stains. There is no treatment for myeloperoxidase deficiency itself. Rather, in the rare cases that individuals experience symptoms, these infections should be treated.
Respiratory burst is the rapid release of the reactive oxygen species (ROS), superoxide anion and hydrogen peroxide, from different cell types.
NADPH oxidase is a membrane-bound enzyme complex that faces the extracellular space. It can be found in the plasma membrane as well as in the membranes of phagosomes used by neutrophil white blood cells to engulf microorganisms. Human isoforms of the catalytic component of the complex include NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1, and DUOX2.
Nitro blue tetrazolium is a chemical compound composed of two tetrazole moieties. It is used in immunology for sensitive detection of alkaline phosphatase. NBT serves as the oxidant and BCIP is the AP-substrate.
NADPH oxidase 2 (Nox2), also known as cytochrome b(558) subunit beta or Cytochrome b-245 heavy chain, is a protein that in humans is encoded by the NOX2 gene. The protein is a superoxide generating enzyme which forms reactive oxygen species (ROS).
Neutrophil extracellular traps (NETs) are networks of extracellular fibers, primarily composed of DNA from neutrophils, which bind pathogens. Neutrophils are the immune system's first line of defense against infection and have conventionally been thought to kill invading pathogens through two strategies: engulfment of microbes and secretion of anti-microbials. In 2004, a novel third function was identified: formation of NETs. NETs allow neutrophils to kill extracellular pathogens while minimizing damage to the host cells. Upon in vitro activation with the pharmacological agent phorbol myristate acetate (PMA), Interleukin 8 (IL-8) or lipopolysaccharide (LPS), neutrophils release granule proteins and chromatin to form an extracellular fibril matrix known as NET through an active process.
Apocynin, also known as acetovanillone, is a natural organic compound structurally related to vanillin. It has been isolated from a variety of plant sources and is being studied for its variety of pharmacological properties.
NCF1C is a human pseudogene related to NCF1, the latter being responsible for encoding the 47 kDA cytosolic subunit of NADPH oxidase. In chronic granulomatous disease, the functional NCF1 gene recombines with the two nearby pseudogenes and becomes inactivated.
Neutrophil cytosol factor 2 is a protein that in humans is encoded by the NCF2 gene.
Neutrophil cytosol factor 1, also known as p47phox, is a protein that in humans is encoded by the NCF1 gene.
Cytochrome b-245 light chain is a protein that in humans is encoded by the CYBA gene involved in superoxide production and phagocytosis.
Neutrophil cytosol factor 4 is a protein that in humans is encoded by the NCF4 gene.
Neutrophil oxidative burst test is a measure of neutrophil oxidation and is a useful assay in the diagnosis of chronic granulomatous disease and is also a useful means to determine the overall metabolic integrity of phagocytosing neutrophils. The NADPH oxidase enzyme is missing in CGD. From total blood, neutrophils can be purified and the NADPH oxidase activity can be measured with different methods in these cells after activation. Phagocytosis by polymorphonuclear neutrophils and monocytes constitutes an essential arm of host defense against bacterial or fungal infections. The phagocytic process can be separated into several major stages: chemotaxis, attachment of particles to the cell surface of phagocytes, ingestion (phagocytosis) and intracellular killing by oxygen-dependent and oxygen-independent mechanisms.
John I. Gallin is an American medical researcher who has contributed to the understanding of innate immunity but especially chronic granulomatous disease, a phagocyte disorder. Gallin was appointed director of the NIH Clinical Center on May 1, 1994, and served until January 8, 2017. He serves as the chief scientific officer for the Clinical Center and associate director for clinical research at the National Institutes of Health.
Edgar Pick is an Israeli immunologist who is Professor Emeritus of Immunology in the Department of Clinical Microbiology and Immunology at the Faculty of Medicine at Tel Aviv University, Israel.
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