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Mast Cells Malfunction

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发表于 7-24-2019 09:09:30 | 显示全部楼层 |阅读模式
Lisa Sanders, The Young Woman Was Extremely Mindful of Her Nut Allergy. So What Was Causing These Terrible Reaction?  New York Times Magazine, July 21, 2019.
https://www.nytimes.com/2019/07/ ... hylactic-shock.html

My comment:
(a)
(i) I read this article, and was highly skeptical until I read the diagnosis -- and then do a research on this disease. You see, there is nothing in this article to suggest anything trigger the anaphylaxis, which is always life0endagering. (The most common known anaphylaxis is induced by penicillin, bee sting and nuts). These three, as well as hay fever (allergy to pollens causing itchy eyes and runny nose) are triggered by immunoglobulin E (IgE) on the surface of mast cells through Fc receptor. (An immunoglobulin is composed of Fab and Fc, standing for Fragment antigen-binding and Fragment crystallizable.)
https://en.wikipedia.org/wiki/Fc_receptor
(section 1 Class, section 1.3  Fc-epsilon receptors)
(ii) There are three kinds of Fc receptor: for immunoglobin G, A and E respectively.  The one for immunoglobulin E )generated by B cells, of course) is called Fc-epsilon receptor, which is further divided into high-affinity FcεRI (or FcεR1) and FcεRII (or FcεR2). Disregard FcεR2.  FcεR1 is on the surface of mast cells; an antigen's (penicillin, chemicals from bee sting, nuts or pollens) binding to a specific immunoglobulin on mast cells triggers these cells releasing granules which contain histamines.
(iii) Anaphylaxis calls for epinephrine, as in EpiPen.

(b) Bradley Benson, MD, FACP, FAAP  Professor of Medicine (MD Vanderbilt 1994, BSUniversity of Illinois, 1990; "board certified in both Internal Medicine and Pediatrics")
https://www.dom.umn.edu/bio/dom-a-z/bradley-benson

FACP = Fellow, American College of Physicians
FAAP = Fellow, American Academy of Pediatrics
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 楼主| 发表于 7-24-2019 09:12:00 | 显示全部楼层
(c) "There are unusual disorders caused by the development of too many mast cells. The most common of these is called systemic mastocytosis, in which many of those mast cells develop a mutation that makes them more excitable and more easily triggered. * * * To test his theory, Benson explained to the patient, right after her next [anaphylaxic] attack she needed to get her blood tested for the two most important chemicals in the mast-cell armamentarium: histamine and tryptase. If she had a mast-cell disorder, these would be sky-high. * * * Both chemicals were elevated. Additional testing revealed that she had the mutation found in systemic mastocytosis. This patient, like most people with this disorder, has an indolent form. They have too many mast cells, but the number of cells is stable. * * * To prevent these attacks, the patient's mast cells have to be controlled. Twice a day, she takes an antihistamine and an antacid — medications that block histamine, the primary actor in allergies. And once a day, she takes vitamin D to make her overexcitable mast cells less likely to erupt into an allergic reaction. She recently added a new medication — a shot she gets every three weeks — to block mast-cell triggers."
(i) armamentarium (n; from Latin armāmenta [plural of noun neuter armāmentum "(chiefly in the plural)": Wiktionary] tools, equipment, rigging +‎ Latin suffix -ārium place where things are kept [eg aquarium]): "arsenal"
https://en.wiktionary.org/wiki/armamentarium
(ii) "mast-cell armamentarium: histamine and tryptase. If she had a mast-cell disorder, these would be sky-high."  This is no brainer: everybody with medical knowledge can see she was in anaphylactic shocks.
(iii) trypsin
(A) A pancreas-secreted proteolytic enzyme, trypsin
https://www.etymonline.com/word/trypsin
was discovered and named by German Wilhelm Kühne.
https://en.wikipedia.org/wiki/Wilhelm_Kühne

But see trypsin (etymology)
https://www.merriam-webster.com/dictionary/trypsin
(B) Kuhne. Farlex Partner Medical Dictionary, 2012
https://medical-dictionary.thefreedictionary.com/Kuhne
(pronunciation)
(iv) Vanderslice P et al, Human Mast Cell Tryptase: Multiple cDNAs and Genes Reveal a Multigene Serine Protease Family. PNAS, 87: 3811 (1990)
https://www.pnas.org/content/pnas/87/10/3811.full.pdf
(sentence 1: "Tryptase, a major constituent of mast cell secretory granules, has emerged recently as the most specific marker in vivo of mast cell activation in humans; tryptase and trypsin are similar in function and in gene structure (see Fig 4).
(v) Antiacid is to relieve gastrointestinal symptoms.
(vi) Liu Z-Q et al, Vitamin D Contributes to Mast Cell Stabilization. European Journal of Allergy and Clinical Immunology, 72: 1184 (2017)
https://onlinelibrary.wiley.com/doi/abs/10.1111/all.13110
("The mechanism of mast cell stabilization is not fully understood. Cumulative reports indicate that vitamin D (VitD) contributes to the homeostasis" of mast cells)

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 楼主| 发表于 7-24-2019 09:12:38 | 显示全部楼层
(d) About the disease.
(i)
(A) "Mastocytosis is a disorder characterized by abnormal proliferation and accumulation of mast cells deriving from a clonal [arising from a single cell] progenitor carrying a gain-of-function mutation in KIT [which is 'highly expressed by mast cells']. The most common KIT mutation is D816V, which involves the intracellular tyrosine kinase portion of the gene. * * * Although in vitro data suggest that pathways involved in KIT signal transduction cooperate with IgE-mediated pathways of mast cell activation, involvement of the gain-of-function KIT mutations in these activation pathways remain to be proved." (citations omitted).
Akin C, Mast Cell Activation Syndromes. Journal of Allergy and Clinical Immunology, 140: 349 (2017).
https://www.jacionline.org/article/S0091-6749(17)31025-4/fulltext

The quotation means
* that the single mutation in the (intracellular) kinase part of c-KIT, which replaces V with D, increases kinase activity. (A kinase is an enzyme that adds a phosphate to a protein and activate the latter.)  (This mutation is signature of (indolent) systemic mastocytosis.)
* that this mutation SOMEHOW causes mast cells to release contents of its own granules WITHOUT having been triggered by an antigen binding a corresponding immunoglobulin E, wrecking havoc, but that why this happens remains unclear.
(B) Pisters PWT and O'Sullivan B, Signal Transduction Inhibition for Gastrointestinal Stromal Tumors and Dermatofibrosarcoma Protuberans. In Kufe DW et al (eds), Holland-Frei Cancer Medicine. 6th ed. Hamilton, Ontario: BC Decker (2003)
https://www.ncbi.nlm.nih.gov/books/NBK13397/
("The proto-oncogene c-Kit is the cellular homolog of the oncogene v-Kit (a feline sarcoma virus which derived the abbreviated term 'kit' from the word 'kitten')" )
(ii) Komi DEA, Rambasek T and Wöhrl S, Mastocytosis: from a Molecular Point of View. Clinical Review in Allergy and Immunology, 54: 397 (2018)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6002427/
("Nagata et al. identified a point mutation consisting of a substitution of valine [one-letter symbol for this amino acid: V] for aspartic acid [one-letter symbol: D -- because there is another amino acid (alanine) with symbol A] in the catalytic domain of c-KIT (ASP816VAL or D816V) in the peripheral blood of patients with mastocytosis. A year later, this discovery was followed by identification of the same mutation in CM and aggressive systemic mastocytosis (SM) [42]")

The first sentence in the quotation is based on
Nagata H, Worobec AS, Semere T and Metcalfe DD, Elevated expression of the proto-oncogene c-kit in patients with mastocytosis. Leukemia, 12:175 (1998).
This citation is not provided, because reference 42 is a review penned by principal investigator (and senior author) Metcalfe.
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