Impact of naturally forming human α/β-tryptase heterotetramers in the pathogenesis of hereditary α-tryptasemia

Le, Quang T.; Lyons, Jonathan J.; Naranjo, Andrea N.; Olivera, Ana; Lazarus, Robert A.; Metcalfe, Dean D.; Milner, Joshua D.; Schwartz, Lawrence B.

doi:10.1084/jem.20190701

Cited by 127Mast cells and histamineProtease and Inhibitor MechanismsCoagulation, Bradykinin, Polyphosphates, and Angioedema

Impact of naturally forming human α/β-tryptase heterotetramers in the pathogenesis of hereditary α-tryptasemia

Open access

Le, Quang T., Lyons, Jonathan J., Naranjo, Andrea N., Olivera, Ana, Lazarus, Robert A., Metcalfe, Dean D., Milner, Joshua D., Schwartz, Lawrence B.·2019·Journal of Experimental Medicine

DOI 10.1084/jem.20190701PMC PMC6780998

Open this paper in CoChat — free account

Abstract

Both α-tryptase and β-tryptase are preferentially expressed by human mast cells, but the purpose of α-tryptase is enigmatic, because its tetramers lack protease activity, whereas β-tryptase tetramers are active proteases. The monogenic disorder called hereditary α-tryptasemia, due to increased α-tryptase gene copies and protein expression, presents with clinical features such as vibratory urticaria and dysautonomia. We show that heterotetramers composed of 2α- and 2β-tryptase protomers (α/β-tryptase) form naturally in individuals who express α-tryptase. α/β-Tryptase, but not homotetramer, activates protease-activated receptor-2 (PAR2), which is expressed on cell types such as smooth muscle, neurons, and endothelium. Also, only α/β-tryptase makes mast cells susceptible to vibration-triggered degranulation by cleaving the α subunit of the EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2) mechanosensory receptor. Allosteric effects of α-tryptase protomers on neighboring β-tryptase protomers likely result in the novel substrate repertoire of α/β-tryptase tetramers that in turn cause some of the clinical features of hereditary α-tryptasemia and of other disorders involving mast cells.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1084/jem.20190701

Cites

54 of 54 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

In individuals with HαT, α/β-tryptase heterotetramers increase vascular permeability by cleaving and activating PAR2 on endothelial cells, resulting in increased vascular leakage.
“Recent studies have shown that in individuals with HαT, these heterotetramers increase vascular permeability by cleaving and activating protease-activated receptor-2 (PAR2) on endothelial cells, resulting in increased vascular leakage (14, 15).”
From Defining “Normal” basal serum tryptase levels: a context-dependent approach to improve diagnostics in systemic mastocytosis (2025) · cites this paper as [14]
The Results section (‘α/β-Tryptase heterotetramers activate PAR2’; page unavailable) shows PAR2 activation on Jurkat T cells, not endothelial cells. The Discussion (page unavailable) suggests that endothelial PAR2 activation might worsen hypotension during anaphylaxis, but does not establish increased vascular permeability or leakage in individuals with HαT. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Alpha/beta-tryptase heterotetrameric tryptases have expanded biologic functions relative to mature beta-tryptases and may offer a possible mechanism explaining mast cell activation in individuals with hereditary alpha-tryptasemia.
“A recent description of a / b -tryptase heterotetrameric tryptases, which have expanded biologic functions relative to mature b -tryptases, may offer a possible mechanism explaining MCA in these individuals. 128,129”
From Selecting the Right Criteria and Proper Classification to Diagnose Mast Cell Activation Syndromes: A Critical Review (2021) · cites this paper as [128]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Mast-Cell Infiltration of Airway Smooth Muscle in Asthma
Brightling, C. E., Bradding, P. H., Symon, F. A., Holgate, S. T., Wardlaw, A. J., & Pavord, I. D. (2002) · New England Journal of Medicine · doi:10.1056/nejmoa012705 · Cited by 1,240 · see citing works
Identification of a mast cell specific receptor crucial for pseudo-allergic drug reactions
McNeil, B. D., Pundir, P., Meeker, S., Han, L., Undem, B., Kulka, M., & Dong, X.-Z. (2014) · Nature · doi:10.1038/nature14022 · Cited by 1,164 · see citing works
Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism
Steinhoff, M. S., Vergnolle, N., Young, S. H., Tognetto, M., Amadesi, S., Ennes, H. S., Trevisani, M., Hollenberg, M. D., Wallace, J. L., Caughey, G. H., et al. (2000) · Nature Medicine · doi:10.1038/72247 · Cited by 936 · see citing works
Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis
Schwartz, L. B., Metcalfe, D. D., Miller, J. S., Earl, H., & Sullivan, T. (1987) · New England Journal of Medicine · doi:10.1056/nejm198706253162603 · Cited by 784 · see citing works
Proteinase-Activated Receptor-2 Mediates Itch: A Novel Pathway for Pruritus in Human Skin
Steinhoff, M. S., Neisius, U., Ikoma, A., Fartasch, M., Heyer, G., Skov, P. S., Luger, T. A., & Schmelz, M. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-15-06176.2003 · Cited by 652 · see citing works
Interactions of Mast Cell Tryptase with Thrombin Receptors and PAR-2
Molino, M., Barnathan, E. S., Numerof, R. P., Clark, J., Dreyer, M. L., Cumashi, A., Hoxie, J. A., Schechter, N. M., Woolkalís, M. J., & Brass, L. F. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.7.4043 · Cited by 591 · see citing works
Quantitation of histamine, tryptase, and chymase in dispersed human T and TC mast cells.
Schwartz, L. B., Irani, A. M., Roller, K., Castells, M., & Schechter, N. M. (1987) · The Journal of Immunology · doi:10.4049/jimmunol.138.8.2611 · Cited by 500 · see citing works
Proteinase-activated receptor-2 and hyperalgesia: A novel pain pathway
Vergnolle, N., Bunnett, N. W., Sharkey, K. A., Brussee, V., Compton, S. J., Grady, E. F., Cirino, G., Gerard, N. P., Basbaum, A. I., Andrade‐Gordon, P., et al. (2001) · Nature Medicine · doi:10.1038/89945 · Cited by 465 · see citing works
Time course of appearance and disappearance of human mast cell tryptase in the circulation after anaphylaxis.
Schwartz, L. B., Yunginger, J. W., Miller, J., Bokhari, R., & Dull, D. (1989) · Journal of Clinical Investigation · doi:10.1172/jci114051 · Cited by 456 · see citing works
Expression of Mas-related gene X2 on mast cells is upregulated in the skin of patients with severe chronic urticaria
Fujisawa, D., Kashiwakura, J., Kita, H., Kikukawa, Y., Fujitani, Y., Sasaki-Sakamoto, T., Kuroda, K., Nunomura, S., Hayama, K., Terui, T., et al. (2014) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2014.05.004 · Cited by 410 · see citing works
Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number
Lyons, J. J., Yu, X., Hughes, J. D., Le, Q. T., Jamil, A., Bai, Y., Ho, N., Zhao, M., Liu, Y., O'Connell, M. P., et al. (2016) · Nature Genetics · doi:10.1038/ng.3696 · Cited by 394 · see citing works
Self-citation
Peripheral and Central Mechanisms of Itch
Dong, X., & Dong, X. (2018) · Neuron · doi:10.1016/j.neuron.2018.03.023 · Cited by 382 · see citing works
The alpha form of human tryptase is the predominant type present in blood at baseline in normal subjects and is elevated in those with systemic mastocytosis.
Schwartz, L. B., Sakai, K., Bradford, T. R., Ren, S., Zweiman, B., Worobec, A. S., & Metcalfe, D. D. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118337 · Cited by 371 · see citing works
Regulation of tryptase from human lung mast cells by heparin. Stabilization of the active tetramer.
Schwartz, L. B., & Bradford, T. R. (1986) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)38401-6 · Cited by 348 · see citing works
Acid hydrolases and tryptase from secretory granules of dispersed human lung mast cells.
Schwartz, L. B., Lewis, R. A., Seldin, D. C., & Austen, K. F. (1981) · The Journal of Immunology · doi:10.4049/jimmunol.126.4.1290 · Cited by 328 · see citing works
Human β-tryptase is a ring-like tetramer with active sites facing a central pore
Pereira, P. J. B., Bergner, A., Macedo‐Ribeiro, S., Huber, R., Matschiner, G., Fritz, H., Sommerhoff, C. P., & Bode, W. (1998) · Nature · doi:10.1038/32703 · Cited by 301 · see citing works
Vibratory Urticaria Associated with a Missense Variant in ADGRE2
Boyden, S. E., Desai, A., Cruse, G., Young, M. L., Bolan, H., Scott, L. M., Eisch, A. R., Long, R. D., Lee, C. R., Satorius, C. L., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1500611 · Cited by 201 · see citing works
Cloning and characterization of complementary DNA for human tryptase.
Miller, J. S., Westin, E. H., & Schwartz, L. B. (1989) · Journal of Clinical Investigation · doi:10.1172/jci114284 · Cited by 199 · see citing works
Cloning and characterization of a second complementary DNA for human tryptase.
Miller, J. S., Moxley, G. F., & Schwartz, L. B. (1990) · Journal of Clinical Investigation · doi:10.1172/jci114786 · Cited by 179 · see citing works
Tryptase and agonists of PAR-2 induce the proliferation of human airway smooth muscle cells
Berger, P., Perng, D., Thabrew, H., Compton, S. J., Cairns, J. A., McEuen, A. R., Marthan, R., de Lara, J.-M. T., & Walls, A. F. (2001) · Journal of Applied Physiology · doi:10.1152/jappl.2001.91.3.1372 · Cited by 172 · see citing works
A novel heparin-dependent processing pathway for human tryptase. Autocatalysis followed by activation with dipeptidyl peptidase I.
Sakai, K., Ren, S., & Schwartz, L. B. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118523 · Cited by 159 · see citing works
Evaluation of the Substrate Specificity of Human Mast Cell Tryptase βI and Demonstration of Its Importance in Bacterial Infections of the Lung
Huang, C. B., Sanctis, G. T. D., O'Brien, P. J., Mizgerd, J. P., Friend, D. S., Drazen, J. M., Brass, L. F., & Stevens, R. L. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m102356200 · Cited by 145 · see citing works
Mendelian inheritance of elevated serum tryptase associated with atopy and connective tissue abnormalities
Lyons, J. J., Sun, G., Stone, K. D., Nelson, C., Wisch, L., O'Brien, M., Jones, N., Lindsley, A., Komarow, H. D., Bai, Y., et al. (2014) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2013.11.039 · Cited by 136 · see citing works
Mast cells in human keloid, small intestine, and lung by an immunoperoxidase technique using a murine monoclonal antibody against tryptase.
Craig, S. S., Deblois, G., & Schwartz, L. B. (1986) · PubMed · Cited by 123 · see citing works
Tryptase Precursors Are Preferentially and Spontaneously Released, Whereas Mature Tryptase Is Retained by HMC-1 Cells, Mono-Mac-6 Cells, and Human Skin-Derived Mast Cells
Schwartz, L. B., Min, H.-K., Ren, S., Xia, H.-Z., Hu, J., Zhao, W., Moxley, G., & Fukuoka, Y. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.11.5667 · Cited by 120 · see citing works
Self-citation
PAR2 absence completely rescues inflammation and ichthyosis caused by altered CAP1/Prss8 expression in mouse skin
Frateschi, S., Camerer, E., Crisante, G., Rieser, S., Membrez, M., Charles, R., Beermann, F., Stehle, J., Breiden, B., Sandhoff, K., et al. (2011) · Nature Communications · doi:10.1038/ncomms1162 · Cited by 116 · see citing works
Glycosylation of human proteinase-activated receptor-2 (hPAR2): role in cell surface expression and signalling
Compton, S. J., Sandhu, S., Wijesuriya, S. J., & Hollenberg, M. D. (2002) · Biochemical Journal · doi:10.1042/bj20020706 · Cited by 116 · see citing works
Antagonism of Protease-Activated Receptor 2 Protects against Experimental Colitis
Lohman, R., Cotterell, A. J., Suen, J. Y., Liu, L., Anh, T., Vesey, D. A., & Fairlie, D. P. (2011) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.111.187062 · Cited by 103 · see citing works
Expression and Function of Proteinase-activated Receptor 2 in Human Bronchial Smooth Muscle
Schmidlin, F., Amadesi, S., VIDIL, R., Trevisani, M., Martinet, N., Caughey, G. H., Tognetto, M., Cavallesco, G. N., Mapp, C. E., Geppetti, P., et al. (2001) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/ajrccm.164.7.2101157 · Cited by 99 · see citing works
Interactions of human mast cell tryptase with biological protease inhibitors
Alter, S. C., Kramps, J. A., Janoff, A., & Schwartz, L. B. (1990) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(90)90005-j · Cited by 97 · see citing works
Genetic deficiency of human mast cell a‐tryptase
Soto, D., Malmsten, C., Blount, J. L., Muilenburg, D. J., & Caughey, G. H. (2002) · Clinical & Experimental Allergy · doi:10.1046/j.1365-2222.2002.01416.x · Cited by 89 · see citing works
Induction of Ets-1 in endothelial cells during reendothelialization after denuding injury
Tanaka, K., Oda, N., Iwasaka, C., Abé, M., & Sato, Y. (1998) · Journal of Cellular Physiology · doi:10.1002/(sici)1097-4652(199808)176:2 · Cited by 88 · see citing works
Human Tryptases α and β/II Are Functionally Distinct Due, in Part, to a Single Amino Acid Difference in One of the Surface Loops That Forms the Substrate-binding Cleft
Huang, C. B., Li, L., Krilis, S. A., Chanasyk, K., Tang, Y., Li, Z., Hunt, J. E., & Stevens, R. L. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.28.19670 · Cited by 87 · see citing works
The Crystal Structure of Human α1-Tryptase Reveals a Blocked Substrate-binding Region
Marquardt, U., Zettl, F., Huber, R., Bode, W., & Sommerhoff, C. P. (2002) · Journal of Molecular Biology · doi:10.1016/s0022-2836(02)00625-3 · Cited by 85 · see citing works
Human mast cells present antigen to autologous CD4+ T cells
Lotfi‐Emran, S., Ward, B. R., Le, Q. T., Pozez, A. L., Manjili, M. H., Woodfolk, J. A., & Schwartz, L. B. (2017) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2017.02.048 · Cited by 75 · see citing works
Human subjects are protected from mast cell tryptase deficiency despite frequent inheritance of loss-of-function mutations
Trivedi, N. N., Tamraz, B., Chu, C., Kwok, P., & Caughey, G. H. (2009) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2009.07.026 · Cited by 73 · see citing works
First Identification of an Inherited TPSAB1 Quintuplication in a Patient with Clonal Mast Cell Disease
Sabato, V., Chovanec, J., Faber, M., Milner, J. D., Ebo, D., & Lyons, J. J. (2018) · Journal of Clinical Immunology · doi:10.1007/s10875-018-0506-y · Cited by 73 · see citing works
Immunologic and physicochemical evidence for conformational changes occurring on conversion of human mast cell tryptase from active tetramer to inactive monomer. Production of monoclonal antibodies recognizing active tryptase.
Schwartz, L. B., Bradford, T. R., Lee, D. C., & Chlebowski, J. F. (1990) · The Journal of Immunology · doi:10.4049/jimmunol.144.6.2304 · Cited by 71 · see citing works
Regulation of human mast cell beta-tryptase: conversion of inactive monomer to active tetramer at acid pH.
Ren, S., Sakai, K., & Schwartz, L. B. (1998) · PubMed · Cited by 49 · see citing works
Agonists of proteinase-activated receptor 2 excite guinea pig ileal myenteric neurons
Linden, D. R., Manning, B. P., Bunnett, N. W., & Mawe, G. M. (2001) · European Journal of Pharmacology · doi:10.1016/s0014-2999(01)01447-9 · Cited by 47 · see citing works
Activation of Adhesion GPCR EMR2/ADGRE2 Induces Macrophage Differentiation and Inflammatory Responses via Gα16/Akt/MAPK/NF-κB Signaling Pathways
Kuan-Yu, I., Huang, Y.-S., Hu, C.-H., Tseng, W.-Y., Cheng, C.-H., Stacey, M. A., Gordon, S., Chang, G.-W., & Lin, H. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00373 · Cited by 47 · see citing works
Mast cells in cutaneous mastocytosis: accumulation of the MCTC type
Irani, A.-M. A., Garriga, M. M., Metcalfe, D. D., & Schwartz, L. B. (1990) · Clinical & Experimental Allergy · doi:10.1111/j.1365-2222.1990.tb02775.x · Cited by 44 · see citing works
Regulation of Human Mast Cell β-Tryptase: Conversion of Inactive Monomer to Active Tetramer at Acid pH
Ren, S., Sakai, K., & Schwartz, L. B. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.160.9.4561 · Cited by 43 · see citing works
Formation of Enzymatically Active, Homotypic, and Heterotypic Tetramers of Mouse Mast Cell Tryptases
Huang, C. B., Morales, G., Vagi, A., Chanasyk, K., Ferrazzi, M., Burklow, C., Qiu, W.-T., Feyfant, E., Šali, A., & Stevens, R. L. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.1.351 · Cited by 40 · see citing works
The B12 Anti-Tryptase Monoclonal Antibody Disrupts the Tetrameric Structure of Heparin-Stabilized β-Tryptase to Form Monomers That Are Inactive at Neutral pH and Active at Acidic pH
Fukuoka, Y., & Schwartz, L. B. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.5.3165 · Cited by 35 · see citing works
Self-citation
Diverse Stability and Catalytic Properties of Human Tryptase α and β Isoforms are Mediated by Residue Differences at the S1 Pocket
Selwood, T., Wang, Z., McCaslin, D. R., & Schechter, N. M. (2002) · Biochemistry · doi:10.1021/bi015662v · Cited by 34 · see citing works
Processing of Human Protryptase in Mast Cells Involves Cathepsins L, B, and C
Le, Q. T., Gomez, G., Zhao, W., Hu, J., Xia, H.-Z., Fukuoka, Y., Katunuma, N., & Schwartz, L. B. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1001806 · Cited by 32 · see citing works
Restricted ability of human mast cell tryptase to activate proteinase-activated receptor-2 in rat aorta
Compton, S. J., McGuire, J. J., Saifeddine, M., & Hollenberg, M. D. (2002) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/y02-125 · Cited by 31 · see citing works
Dual functionality of β-tryptase protomers as both proteases and cofactors in the active tetramer
Maun, H. R., Liu, P. S., Franke, Y., Eigenbrot, C. W., Forrest, W. F., Schwartz, L. B., & Lazarus, R. A. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.812016 · Cited by 26 · see citing works
Alpha‐tryptase gene variation is associated with levels of circulating I g E and lung function in asthma
Abdelmotelb, A., Rose-Zerilli, M. J. J., Barton, S. J., Holgate, S. T., Walls, A. F., & Holloway, J. W. (2013) · Clinical & Experimental Allergy · doi:10.1111/cea.12259 · Cited by 24 · see citing works
Characterization of two highly polymorphic human tryptase loci and comparison with a newly discovered monkey tryptase ortholog
Guida, M., Riedy, M., Lee, D., & Hall, J. (2000) · Pharmacogenetics · doi:10.1097/00008571-200007000-00002 · Cited by 22 · see citing works
Promiscuous Processing of Human α/β-Protryptases by Cathepsins L, B, and C
Le, Q. T., Min, H., Xia, H.-Z., Fukuoka, Y., Katunuma, N., & Schwartz, L. B. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1001804 · Cited by 18 · see citing works
Alpha tryptase allele of Tryptase 1 (TPSAB1) gene associated with Dengue Hemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS) in Vietnam and Philippines
Velásquez, C. V., Roman, A. D., Lan, N. T. P., Huy, N. T., Mercado, E. S., Espino, F. E., Perez, M. L. M., Huong, V. T. Q., Thúy, T. T., Tham, V. D., et al. (2015) · Human Immunology · doi:10.1016/j.humimm.2015.03.009 · Cited by 18 · see citing works
A Simple, Sensitive and Safe Method to Determine the Human α/β-Tryptase Genotype
Le, Q. T., Lotfi‐Emran, S., Min, H., & Schwartz, L. B. (2014) · PLoS ONE · doi:10.1371/journal.pone.0114944 · Cited by 11 · see citing works

Flagged first, then by citations

Sorted by citations

Heritable risk for severe anaphylaxis associated with increased α-tryptase–encoding germline copy number at TPSAB1
Lyons, J. J., Chovanec, J., O’Connell, M. P., Liu, Y., Šelb, J., Zanotti, R., Bai, Y., Kim, J., Le, Q. T., DiMaggio, T., et al. (2021) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2020.06.035 · Cited by 230 · see citing works
Self-citation
Human Mast Cell Proteome Reveals Unique Lineage, Putative Functions, and Structural Basis for Cell Ablation
Plum, T., Wang, X., Rettel, M., Krijgsveld, J., Feyerabend, T. B., & Rodewald, H.-R. (2020) · Immunity · doi:10.1016/j.immuni.2020.01.012 · Cited by 194 · see citing works
Hereditary α tryptasemia is a valid genetic biomarker for severe mediator-related symptoms in mastocytosis
Greiner, G., Sprinzl, B., Górska, A., Ratzinger, F., Gurbisz, M., Witzeneder, N., Schmetterer, K. G., Gisslinger, B., Uyanik, G., Hadzijusufovic, E., et al. (2021) · Blood · doi:10.1182/blood.2020006157 · Cited by 189 · see citing works
The ingenious mast cell: Contemporary insights into mast cell behavior and function
Dahlin, J. S., Maurer, M., Metcalfe, D. D., Pejler, G., Sagi‐Eisenberg, R., & Nilsson, G. P. (2021) · Allergy · doi:10.1111/all.14881 · Cited by 154 · see citing works
AAAAI Mast Cell Disorders Committee Work Group Report: mast cell activation syndrome (MCAS) diagnosis and management
Weiler, C. R., Austen, K. F., Akin, C., Barkoff, M. S., Bernstein, J. A., Bonadonna, P., Butterfield, J. H., Carter, M., Fox, C. C., Maitland, A., et al. (2019) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2019.08.023 · Cited by 123 · see citing works
Hereditary alpha-tryptasemia: UK prevalence and variability in disease expression
Robey, R. C., Wilcock, A., Bonin, H., Beaman, G., Myers, B., Grattan, C., Briggs, T. A., & Arkwright, P. D. (2020) · The Journal of Allergy and Clinical Immunology In Practice · doi:10.1016/j.jaip.2020.05.057 · Cited by 119 · see citing works
Diagnosis of mast cell activation syndrome: a global "consensus-2"
Afrin, L. B., Ackerley, M. B., Bluestein, L. S., Brewer, J. H., Brook, J. B., Buchanan, A. D., Cuni, J. R., Davey, W. P., Dempsey, T. T., Dorff, S. R., et al. (2021) · Diagnosis · doi:10.1515/dx-2020-0005 · Cited by 115 · see citing works
An Allosteric Anti-tryptase Antibody for the Treatment of Mast Cell-Mediated Severe Asthma
Maun, H. R., Jackman, J. K., Choy, D. F., Loyet, K. M., Staton, T. L., Jia, G., Dressen, A., Hackney, J. A., Bremer, M. C. D., Walters, B. T., et al. (2019) · Cell · doi:10.1016/j.cell.2019.09.009 · Cited by 112 · see citing works
Allergy, Anaphylaxis, and Nonallergic Hypersensitivity: IgE, Mast Cells, and Beyond
Vitte, J., Vibhushan, S., Bratti, M., Montero-Hernández, J. E., & Blank, U. (2022) · Medical Principles and Practice · doi:10.1159/000527481 · Cited by 95 · see citing works
Selecting the Right Criteria and Proper Classification to Diagnose Mast Cell Activation Syndromes: A Critical Review
Gülen, T., Akin, C., Bonadonna, P., Siebenhaar, F., Broesby-Olsen, S., Brockow, K., Niedoszytko, M., Nedoszytko, B., Oude Elberink, H. N. G., Butterfield, J. H., et al. (2021) · The Journal of Allergy and Clinical Immunology: In Practice · doi:10.1016/j.jaip.2021.06.011 · Cited by 83 · see citing works
“A recent description of a/ b-tryptase heterotetrameric tryptases, which have expanded biologic functions relative to mature b-tryptases, may offer a possible mechanism explaining MCA in these individuals.(128,129) It has also been reported that increased germline copies of TPSAB1 are more prevalent among individuals w…”
Background
Use and Interpretation of Acute and Baseline Tryptase in Perioperative Hypersensitivity and Anaphylaxis
Vitte, J., Sabato, V., Tacquard, C., Garvey, L. H., Michel, M., Mertes, P.-M., Ebo, D. G., Schwartz, L. B., & Castells, M. C. (2021) · The Journal of Allergy and Clinical Immunology In Practice · doi:10.1016/j.jaip.2021.03.011 · Cited by 79 · see citing works
Primary Atopic Disorders
Milner, J. D. (2020) · Annual Review of Immunology · doi:10.1146/annurev-immunol-042718-041553 · Cited by 76 · see citing works
The Genetic Basis and Clinical Impact of Hereditary Alpha-Tryptasemia
Luskin, K. T., White, A. A., & Lyons, J. J. (2021) · The Journal of Allergy and Clinical Immunology In Practice · doi:10.1016/j.jaip.2021.03.005 · Cited by 67 · see citing works
Clinical relevance of inherited genetic differences in human tryptases
Glover, S. C., Carter, M. C., Korošec, P., Bonadonna, P., Schwartz, L. B., Milner, J. D., Caughey, G. H., Metcalfe, D. D., & Lyons, J. J. (2021) · Annals of Allergy, Asthma & Immunology · doi:10.1016/j.anai.2021.08.009 · Cited by 64 · see citing works
Allosteric binding sites at the receptor–lipid bilayer interface: novel targets for GPCR drug discovery
Wang, Y., Yu, Z., Xiao, W., Lu, S., & Zhang, J. (2020) · Drug Discovery Today · doi:10.1016/j.drudis.2020.12.001 · Cited by 63 · see citing works
Mast Cells in Liver Fibrogenesis
Weiskirchen, R., Meurer, S. K., Liedtke, C., & Huber, M. (2019) · Cells · doi:10.3390/cells8111429 · Cited by 59 · see citing works
Mast cell activation syndromes: Collegium Internationale Allergologicum update 2022
Valent, P., Hartmann, K., Bonadonna, P., Niedoszytko, M., Triggiani, M., Arock, M., & Brockow, K. (2022) · International Archives of Allergy and Immunology · doi:10.1159/000524532 · Cited by 55 · see citing works
Hymenoptera venom-induced anaphylaxis and hereditary alpha-tryptasemia
O’Connell, M. P., & Lyons, J. J. (2020) · Current Opinion in Allergy & Clinical Immunology · doi:10.1097/aci.0000000000000678 · Cited by 53 · see citing works
Genetic Regulation of Tryptase Production and Clinical Impact: Hereditary Alpha Tryptasemia, Mastocytosis and Beyond
Sprinzl, B., Greiner, G., Uyanik, G., Arock, M., Haferlach, T., Sperr, W. R., Valent, P., & Hoermann, G. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22052458 · Cited by 51 · see citing works
Inherited and acquired determinants of serum tryptase levels in humans
Lyons, J. J. (2021) · Annals of Allergy, Asthma & Immunology · doi:10.1016/j.anai.2021.06.019 · Cited by 52 · see citing works
Selected recent advances in understanding the role of human mast cells in health and disease
Levi‐Schaffer, F., Gibbs, B. F., Hallgren, J., Pucillo, C. E. M., Redegeld, F. A., Siebenhaar, F., Vitte, J., Mezouar, S., Michel, M., Puzzovio, P. G., et al. (2022) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2022.01.030 · Cited by 51 · see citing works
Mast cell tryptases in allergic inflammation and immediate hypersensitivity
Lyons, J. J., & Yi, T. (2021) · Current Opinion in Immunology · doi:10.1016/j.coi.2021.04.001 · Cited by 54 · see citing works
Emerging mechanisms contributing to mast cell-mediated pathophysiology with therapeutic implications
Falduto, G. H., Pfeiffer, A., Luker, A. J., Metcalfe, D. D., & Olivera, A. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107718 · Cited by 50 · see citing works
Incorporating Tryptase Genotyping Into the Workup and Diagnosis of Mast Cell Diseases and Reactions
Lyons, J. J., Greiner, G., Hoermann, G., & Metcalfe, D. D. (2022) · The Journal of Allergy and Clinical Immunology In Practice · doi:10.1016/j.jaip.2022.05.003 · Cited by 48 · see citing works
Mediator-Related Symptoms and Anaphylaxis in Children with Mastocytosis
Brockow, K., Plata‐Nazar, K., Lange, M., Nedoszytko, B., Niedoszytko, M., & Valent, P. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22052684 · Cited by 48 · see citing works
Mast cell activation syndrome: Current understanding and research needs
Castells, M., Giannetti, M. P., Hamilton, M. J., Novak, P., Pozdnyakova, O., Nicoloro-SantaBarbara, J., Jennings, S. V., Francomano, C., Kim, B., Glover, S. C., et al. (2024) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2024.05.025 · Cited by 45 · see citing works
Patients with mast cell activation symptoms and elevated baseline serum tryptase level have unique bone marrow morphology
Giannetti, M. P., Akin, C., Hufdhi, R., Hamilton, M. J., Weller, E., van Anrooij, B., Lyons, J. J., Hornick, J. L., Pinkus, G., Castells, M., et al. (2021) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2020.11.017 · Cited by 43 · see citing works
Distinct small intestine mast cell histologic changes in patients with hereditary alpha-tryptasemia and mast cell activation syndrome
Hamilton, M. J., Zhao, M., Giannetti, M. P., Weller, E., Hufdhi, R., Novak, P., Mendoza-Alvarez, L. B., Hornick, J., Lyons, J. J., Glover, S. C., et al. (2021) · American Journal of Surgical Pathology · doi:10.1097/pas.0000000000001676 · Cited by 44 · see citing works
Hereditary alpha-tryptasemia: a commonly inherited modifier of anaphylaxis
Wu, R., & Lyons, J. J. (2021) · Current Allergy and Asthma Reports · doi:10.1007/s11882-021-01010-1 · Cited by 43 · see citing works
Self-citation
Bivalent antibody pliers inhibit β-tryptase by an allosteric mechanism dependent on the IgG hinge
Maun, H. R., Vij, R., Walters, B. T., Morando, A., Jackman, J. K., Wu, P., Estevez, A., Chen, X., Franke, Y., Lipari, M. T., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-20143-x · Cited by 40 · see citing works
Clinical impact of the <i>TPSAB1</i> genotype in mast cell diseases: A REMA study in a cohort of 959 individuals
González‐de‐Olano, D., Navarro‐Navarro, P., Muñoz‐González, J. I., Sánchez‐Muñoz, L., Henriques, A., de‐Andrés‐Martín, A., Peralta‐Arjonilla, D., Mayado, A., Jara‐Acevedo, M., García‐Montero, A. C., et al. (2024) · Allergy · doi:10.1111/all.15911 · Cited by 38 · see citing works
Clonal mast cell disorders and hereditary α-tryptasemia as risk factors for anaphylaxis
Kačar, M., Rijavec, M., Šelb, J., & Korošec, P. (2023) · Clinical & Experimental Allergy · doi:10.1111/cea.14264 · Cited by 37 · see citing works
High burden of clonal mast cell disorders and hereditary α‐tryptasemia in patients who need Hymenoptera venom immunotherapy
Korošec, P., Sturm, G. J., Lyons, J. J., Marolt, T. P., Svetina, M., Košnik, M., Zidarn, M., Kačar, M., Frelih, N., Lalek, N., et al. (2024) · Allergy · doi:10.1111/all.16084 · Cited by 40 · see citing works
Clinical Impact of Inherited and Acquired Genetic Variants in Mastocytosis
Nedoszytko, B., Arock, M., Lyons, J. J., Bachelot, G., Schwartz, L. B., Reiter, A., Jawhar, M., Schwaab, J., Lange, M., Greiner, G., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22010411 · Cited by 37 · see citing works
Elevated Serum Tryptase in Non-Anaphylaxis Cases: A Concise Review
Lee, A. Y. S. (2020) · International Archives of Allergy and Immunology · doi:10.1159/000506199 · Cited by 36 · see citing works
The Role of Mast Cells in the Induction and Maintenance of Inflammation in Selected Skin Diseases
Woźniak, E., Owczarczyk-Saczonek, A. B., Lange, M., Czarny, J. H., Wygonowska, E., Placek, W. J., & Nedoszytko, B. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24087021 · Cited by 35 · see citing works
Degranulation of Mast Cells as a Target for Drug Development
Yang, B., Kim, A.-R., Lee, D., An, S. B., Shim, Y. A., & Jang, M. H. (2023) · Cells · doi:10.3390/cells12111506 · Cited by 35 · see citing works
Highly Selective Cleavage of TH2-Promoting Cytokines by the Human and the Mouse Mast Cell Tryptases, Indicating a Potent Negative Feedback Loop on TH2 Immunity
Fu, Z., Akula, S., Thorpe, M., & Hellman, L. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20205147 · Cited by 35 · see citing works
Severe food allergy reactions are associated with α-tryptase
Lang, A., Kubala, S., Grieco, M. C., Mateja, A., Pongracic, J., Liu, Y., Frischmeyer-Guerrerio, P. A., Kumar, R., & Lyons, J. J. (2023) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2023.07.014 · Cited by 36 · see citing works
Tryptase in type I hypersensitivity
Michel, M., Klingebiel, C., & Vitte, J. (2022) · Annals of Allergy Asthma & Immunology · doi:10.1016/j.anai.2022.08.996 · Cited by 31 · see citing works
Mast cell activation in the context of elevated basal serum tryptase: genetics and presentations
Khoury, P., & Lyons, J. J. (2019) · Current Allergy and Asthma Reports · doi:10.1007/s11882-019-0887-x · Cited by 30 · see citing works
Small intestinal immunopathology and GI-associated antibody formation in hereditary alpha-tryptasemia
Konnikova, L., Robinson, T. O., Owings, A. H., Shirley, J. F., Davis, E. M., Tang, Y., Wall, S. M., Li, J., Hasan, M., Gharaibeh, R. Z., et al. (2021) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2021.04.004 · Cited by 30 · see citing works
Clinical response to omalizumab in patients with hereditary α-tryptasemia
Alvarez, L. B. M., Barker, R., Nelson, C. G., DiMaggio, T., Stone, K. D., Milner, J. D., Rosenthal, J. A., Petroni, D., Glover, S. C., & Lyons, J. J. (2019) · Annals of Allergy Asthma & Immunology · doi:10.1016/j.anai.2019.09.026 · Cited by 29 · see citing works
Critical Signaling Events in the Mechanoactivation of Human Mast Cells through p.C492Y-ADGRE2
Naranjo, A. N., Bandara, G., Bai, Y., Smelkinson, M. G., Tobío, A., Komarow, H. D., Boyden, S. E., Kastner, D. L., Metcalfe, D. D., & Olivera, A. (2020) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2020.03.936 · Cited by 28 · see citing works
Urticaria and Angioedema: Understanding Complex Pathomechanisms to Facilitate Patient Communication, Disease Management, and Future Treatment
Konstantinou, G. Ν., Riedl, M. A., Valent, P., Podder, I., & Maurer, M. (2023) · The Journal of Allergy and Clinical Immunology In Practice · doi:10.1016/j.jaip.2022.11.006 · Cited by 28 · see citing works
Mast Cells at the Crossroads of Hypersensitivity Reactions and Neurogenic Inflammation
Aitella, E., Romano, C. P., Ginaldi, L., & Cozzolino, D. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26030927 · Cited by 26 · see citing works
Differential mast cell mediators in systemic mastocytosis and hereditary α-tryptasemia
Giannetti, M. P., Godwin, G., Weller, E., Butterfield, J. H., & Castells, M. (2022) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2022.04.025 · Cited by 25 · see citing works
Vibratory Angioedema Subgroups, Features, and Treatment: Results of a Systematic Review
Kulthanan, K., Ungprasert, P., Tapechum, S., Rujitharanawong, C., Kiratiwongwan, R., Munprom, K., Terhorst‐Molawi, D., & Maurer, M. (2020) · The Journal of Allergy and Clinical Immunology In Practice · doi:10.1016/j.jaip.2020.09.009 · Cited by 25 · see citing works
Secretory and Membrane-Associated Biomarkers of Mast Cell Activation and Proliferation
Parente, R., Giudice, V., Cardamone, C., Serio, B., Selleri, C., & Triggiani, M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24087071 · Cited by 25 · see citing works
Targeting Mast Cells with Biologics
Lyons, J. J., & Metcalfe, D. D. (2020) · Immunology and Allergy Clinics of North America · doi:10.1016/j.iac.2020.06.007 · Cited by 27 · see citing works
Alpha-tryptase as a risk-modifying factor for mast cell–mediated reactions
Shin, H., & Lyons, J. J. (2024) · Current Allergy and Asthma Reports · doi:10.1007/s11882-024-01136-y · Cited by 24 · see citing works
Self-citation
Low Prevalence of Idiopathic Mast Cell Activation Syndrome Among 703 Patients With Suspected Mast Cell Disorders
Zaghmout, T., Maclachlan, L., Bedi, N., & Gülen, T. (2024) · The Journal of Allergy and Clinical Immunology: In Practice · doi:10.1016/j.jaip.2023.11.041 · Cited by 23 · see citing works
Regulation of pulmonary surfactant by the adhesion GPCR GPR116/ADGRF5 requires a tethered agonist-mediated activation mechanism
Bridges, J. P., Safina, C., Pirard, B., Brown, K. R., Filuta, A. L., Panchanathan, R., Bouhelal, R., Reymann, N., Patel, S. J., Seuwen, K., et al. (2022) · eLife · doi:10.7554/elife.69061 · Cited by 22 · see citing works
Diagnostic Significance of Tryptase for Suspected Mast Cell Disorders
Beyens, M., Toscano, A., Ebo, D., Gülen, T., & Sabato, V. (2023) · Diagnostics · doi:10.3390/diagnostics13243662 · Cited by 22 · see citing works
“One hypothesis is that the pathological potency of H α T is caused by active heterotetrametric α / β -tryptase and that these are more abundant in patients with a higher α / β ratio [42].”
Background
Resolving the genetics of human tryptases: implications for health, disease, and clinical use as a biomarker
O’Connell, M. P., & Lyons, J. J. (2022) · Current Opinion in Allergy and Clinical Immunology · doi:10.1097/aci.0000000000000813 · Cited by 20 · see citing works
Role of Adhesion G Protein-Coupled Receptors in Immune Dysfunction and Disorder
Tseng, W.-Y., Stacey, M. A., & Lin, H. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24065499 · Cited by 19 · see citing works
Hereditary alpha-tryptasemia
Bonadonna, P., Nalin, F., & Olivieri, F. (2022) · Current Opinion in Allergy & Clinical Immunology · doi:10.1097/aci.0000000000000849 · Cited by 18 · see citing works
New developments in the field of mastocytosis and mast cell activation syndromes: a summary of the Annual Meeting of the European Competence Network on Mastocytosis (ECNM) 2019
Arock, M., Sotlar, K., Gotlib, J. R., Sperr, W. R., Hartmann, K., Schwartz, L. B., Akin, C., Horny, H., & Valent, P. (2019) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428194.2019.1703974 · Cited by 18 · see citing works
The clinical features of hereditary alpha-tryptasemia
von Bubnoff, D., Koch, D., Stocker, H. R., Ludwig, R. J., Wortmann, F., & von Bubnoff, N. C. C. (2024) · Deutsches Ärzteblatt international · doi:10.3238/arztebl.m2023.0287 · Cited by 17 · see citing works
Mast cell activation syndrome: is anaphylaxis part of the phenotype? A systematic review
Sabato, V., Michel, M., Blank, U., Ebo, D. G., & Vitte, J. (2021) · Current Opinion in Allergy and Clinical Immunology · doi:10.1097/aci.0000000000000768 · Cited by 16 · see citing works
On the complexities of tryptase genetics and impact on clinical phenotypes
Lyons, J. J. (2021) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2021.08.011 · Cited by 16 · see citing works
Detecting Changes in Mast Cell Numbers Versus Activation in Human Disease: A Roadblock for Current Biomarkers?
Akin, C., Siebenhaar, F., Wechsler, J. B., Youngblood, B. A., & Maurer, M. (2024) · The Journal of Allergy and Clinical Immunology In Practice · doi:10.1016/j.jaip.2024.03.010 · Cited by 15 · see citing works
Hereditary α-tryptasemia is Associated With Anaphylaxis to Antibiotics and Monoclonal Antibodies
Korošec, P., Lyons, J. J., Svetina, M., Koudová, M., Bittóova, M., Zidarn, M., Sedláčková, L., Rijavec, M., & Kopač, P. (2025) · The Journal of Allergy and Clinical Immunology In Practice · doi:10.1016/j.jaip.2025.04.013 · Cited by 16 · see citing works
Update on Mast Cell Proteases as Drug Targets
Caughey, G. H. (2023) · Immunology and Allergy Clinics of North America · doi:10.1016/j.iac.2023.04.006 · Cited by 14 · see citing works
Thymic Stromal Lymphopoietin (TSLP) Is Cleaved by Human Mast Cell Tryptase and Chymase
Canè, L., Poto, R., Palestra, F., Iacobucci, I., Pirozzi, M., Parashuraman, S., Ferrara, A. L., Illiano, A., Rocca, A. L., Mercadante, E., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25074049 · Cited by 14 · see citing works
Proceedings from the Inaugural American Initiative in Mast Cell Diseases (AIM) Investigator Conference
Gotlib, J. R., George, T. I., Carter, M. C., Austen, K. F., Bochner, B. S., Dwyer, D. F., Lyons, J. J., Hamilton, M. J., Butterfield, J. H., Bonadonna, P., et al. (2021) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2021.03.008 · Cited by 14 · see citing works
HαT is associated with increased risk for severe Hymenoptera venom–triggered anaphylaxis
Šelb, J., Rijavec, M., Kopač, P., Lyons, J. J., & Korošec, P. (2022) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2022.11.017 · Cited by 14 · see citing works
Neurogenic Inflammation in Allergic Contact Dermatitis
Aitella, E., Martinis, M. D., Romano, C. P., Azzellino, G., & Ginaldi, L. (2025) · Biomedicines · doi:10.3390/biomedicines13030656 · Cited by 13 · see citing works
Paediatric perioperative hypersensitivity: the performance of the current consensus formula and the effect of uneventful anaesthesia on serum tryptase
Vlaeminck, N., van der Poorten, M. M., Madsen, C. N., Melchiors, B. B., Michel, M., Gonzalez, C., Schrijvers, R., Elst, J., Mertens, C. H., Saldien, V., et al. (2024) · BJA Open · doi:10.1016/j.bjao.2023.100254 · Cited by 13 · see citing works
Beyond type 2 cytokines in asthma - new insights from old clinical trials
Choy, D. F., & Arron, J. R. (2020) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2020.1744567 · Cited by 13 · see citing works
Clinically accessible amplitude-based multiplex ddPCR assay for tryptase genotyping
Svetina, M., Šelb, J., Lyons, J. J., Korošec, P., & Rijavec, M. (2024) · Scientific Reports · doi:10.1038/s41598-024-52983-8 · Cited by 13 · see citing works
Anaphylaxis: Advances in the Past 10 Years
Weiler, C. R., Schrijvers, R., & Golden, D. B. K. (2022) · The Journal of Allergy and Clinical Immunology In Practice · doi:10.1016/j.jaip.2022.09.019 · Cited by 11 · see citing works
Defining hereditary alpha-tryptasemia as a risk/modifying factor for anaphylaxis: Are we there yet?
Couto, M. L., Silva, M., Barbosa, M. J., Ferreira, F., Fragoso, A. S., & Azenha Rama, T. (2023) · European Annals of Allergy and Clinical Immunology · doi:10.23822/eurannaci.1764-1489.288 · Cited by 10 · see citing works
Chemically diverse activity-based probes with unexpected inhibitory mechanisms targeting trypsin-like serine proteases
Ramos-Llorca, A., Decraecker, L., Cacheux, V. M. Y., Zeiburlina, I., bruyn, M. D., Battut, L., Moreno-Cinos, C., Ceradini, D., Espinosa, É., Dietrich, G., et al. (2023) · Frontiers in Chemistry · doi:10.3389/fchem.2022.1089959 · Cited by 9 · see citing works
Thymic stromal lymphopoietin (TSLP) is a substrate for tryptase in patients with mastocytosis
Marcella, S., Petraroli, A., Canè, L., Ferrara, A. L., Poto, R., Parente, R., Palestra, F., Cristinziano, L., Modestino, L., Galdiero, M. R., et al. (2023) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2023.07.026 · Cited by 9 · see citing works
Pathogenic and diagnostic relevance of KIT in primary mast cell activation disorders
Muñoz‐González, J. I., García‐Montero, A. C., Órfão, A., & Álvarez‐Twöse, I. (2021) · Annals of Allergy Asthma & Immunology · doi:10.1016/j.anai.2021.07.014 · Cited by 9 · see citing works
Cold-induced anaphylaxis: new insights into clinical and genetic characteristics
Bizjak, M., Korošec, P., Košnik, M., Šelb, J., Bidovec‐Stojkovič, U., Svetina, M., Zver, S., Dinevski, D., & Rijavec, M. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1558284 · Cited by 10 · see citing works
What the clinician should know when ordering a mast cell tryptase test
Michel, M., Giusti, D., Klingebiel, C., Pham, B., & Vitte, J. (2025) · Annals of Allergy Asthma & Immunology · doi:10.1016/j.anai.2025.03.003 · Cited by 8 · see citing works
Mast cell activation syndrome: Myths and realities
Zhang, S., & Bernstein, J. A. (2021) · Allergy and Asthma Proceedings · doi:10.2500/aap.2021.42.210012 · Cited by 8 · see citing works
Genetic Variants Leading to Urticaria and Angioedema and Associated Biomarkers
Lyons, J. J., Farkas, H., Germenis, A. E., Rijavec, M., Smith, T., & Valent, P. (2023) · The Journal of Allergy and Clinical Immunology In Practice · doi:10.1016/j.jaip.2023.05.031 · Cited by 8 · see citing works
Case Report: Hereditary Alpha Tryptasemia in Children: A Pediatric Case Series and a Brief Overview of Literature
Zama, D., Muratore, E., Giannetti, A., Neri, I., Conti, F., Magini, P., Ferrari, S., & Pession, A. (2021) · Frontiers in Pediatrics · doi:10.3389/fped.2021.716786 · Cited by 7 · see citing works
Hereditary alpha-tryptasemia despite normal tryptase-encoding gene copy number owing to copy number loss in trans
Glover, S. C., Carlyle, A., & Lyons, J. J. (2021) · Annals of Allergy Asthma & Immunology · doi:10.1016/j.anai.2021.12.008 · Cited by 7 · see citing works
Hereditary alpha tryptasemia: elevated tryptase, female sex, thyroid disorders, and anaphylaxis
Puxkandl, V., Aigner, S., Hoetzenecker, W., & Altrichter, S. (2024) · Frontiers in Allergy · doi:10.3389/falgy.2024.1461359 · Cited by 6 · see citing works
Towards a Multi-omics Understanding of Anaphylaxis: Insights into Pathogenesis and Biomarker Identification
Svetina, M., Kunej, T., Korošec, P., & Rijavec, M. (2025) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-025-09069-8 · Cited by 6 · see citing works
Alpha-Tryptase Overexpression as a Modifier of Mast Cell–Mediated Reactions
Korošec, P., González‐de‐Olano, D., & Lyons, J. J. (2025) · The Journal of Allergy and Clinical Immunology In Practice · doi:10.1016/j.jaip.2025.10.018 · Cited by 6 · see citing works
Case Report: A family history of peanut allergy and hereditary alpha-tryptasemia
Chantran, Y., Renaudin, H., Arock, M., Guiddir, T., & Nemni, A. (2024) · Frontiers in Allergy · doi:10.3389/falgy.2023.1322117 · Cited by 6 · see citing works
Decoding the intricacies of the mast cell compartment
Carter, M. C., & Metcalfe, D. D. (2021) · British Journal of Haematology · doi:10.1111/bjh.17714 · Cited by 5 · see citing works
Appraisal of the evidence linking hereditary α-tryptasemia with mast cell disorders, hypermobility and dysautonomia
Lyons, J. J. (2024) · Allergy and Asthma Proceedings · doi:10.2500/aap.2025.46.240088 · Cited by 5 · see citing works
Management of indolent mastocytosis and mast cell activation syndrome
Akin, C., Butterfield, J. H., Castells, M., & Lyons, J. J. (2025) · Annals of Allergy Asthma & Immunology · doi:10.1016/j.anai.2025.06.032 · Cited by 4 · see citing works
Utility of tryptase genotyping in the screening, diagnosis, and management of systemic mastocytosis
McMurray, J. C., Schornack, B. J., Villar, J., George, T. I., & Boggs, N. A. (2025) · Frontiers in Allergy · doi:10.3389/falgy.2025.1599358 · Cited by 4 · see citing works
Platelet‐activating factor as an endogenous cofactor of food anaphylaxis
Pałgan, K., & Tretyn, A. (2023) · BioFactors · doi:10.1002/biof.1956 · Cited by 4 · see citing works
MRGPRX2-expressing mast cells are increased in the GI tract of individuals with active inflammatory bowel disease and hereditary α-tryptasemia
Galeas‐Pena, M., Lyons, J. J., Llivichuzhca-Loja, D., Everman, S., Yaghi, G., White, K., Sutradhar, S., Robinson, T. O., Owings, A. H., Dhaliwal, N. S., et al. (2026) · Frontiers in Allergy · doi:10.3389/falgy.2025.1726096 · Cited by 4 · see citing works
Risk factors in bee and Vespula venom allergy: state of the art
Stoevesandt, J., & Trautmann, A. (2021) · Allergo Journal International · doi:10.1007/s40629-021-00187-1 · Cited by 3 · see citing works
Hereditary alpha tryptasemia presenting as recurrent chemotherapy hypersensitivity reactions
Monahan, R., Alfaro, E., Ho, H., Otani, I. M., & Tsao, L. R. (2023) · Annals of Allergy Asthma & Immunology · doi:10.1016/j.anai.2023.12.021 · Cited by 3 · see citing works
What your HαT says about you
Gotlib, J. R. (2021) · Blood · doi:10.1182/blood.2020008466 · Cited by 3 · see citing works
When alpha meets beta, mast cells get hyper
Ong, M. S., & Tergaonkar, V. (2019) · The Journal of Experimental Medicine · doi:10.1084/jem.20191169 · Cited by 3 · see citing works
Defining “Normal” basal serum tryptase levels: a context-dependent approach to improve diagnostics in systemic mastocytosis
Crupi, F., Caroprese, J., & Mannelli, F. (2025) · Frontiers in Allergy · doi:10.3389/falgy.2025.1592001 · Cited by 2 · see citing works
“Recent studies have shown that in individuals with H α T, these heterotetramers increase vascular permeability by cleaving and activating protease-activated receptor-2 (PAR2) on endothelial cells, resulting in increased vascular leakage (14, 15).”
Sexual Dimorphism in Allergic and Mast Cell-Associated Diseases
Kotha, A., Maldonado, T. D., Hamze, H., Hussain, Z. Y., Gobinathan, N., Yao, A. Z., Abudulkadir, M., Ching, J. M., & Ryan, J. J. (2026) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-026-09150-w · Cited by 2 · see citing works
Mast cell proteases and their significance in physiology, pathology, and therapeutic approaches
Derakhshani, A., Mahajan, L., Lesack, K. J., Saranjam, N., Khazaie, K., Pejler, G., Krawetz, R. J., Edgington‐Mitchell, L. E., Maun, H. R., & Dufour, A. (2026) · Pharmacological Reviews · doi:10.1016/j.pharmr.2026.100144 · Cited by 2 · see citing works
Tryptase in drug-induced anaphylaxis: the need for acute and baseline values
Michel, M., Giusti, D., Klingebiel, C., & Vitte, J. (2024) · Current Opinion in Allergy and Clinical Immunology · doi:10.1097/aci.0000000000001012 · Cited by 2 · see citing works

When alpha meets beta, mast cells get hyper
Ong, M. S., & Tergaonkar, V. (2019) · The Journal of Experimental Medicine · doi:10.1084/jem.20191169 · Cited by 3 · see citing works
Hereditary alpha-tryptasemia: Brief overview of current knowledge and proposal of indications
Chantran, Y., Hirsch, P., Stym‐Popper, G., Barète, S., & Arock, M. (2022) · Revue française d'allergologie · doi:10.1016/j.reval.2022.03.015
Genetic Regulation of Tryptase Production and Clinical Impact: Hereditary Alpha Tryptasemia, Mastocytosis and Beyond
Sprinzl, B., Greiner, G., Uyanik, G., Arock, M., Haferlach, T., Sperr, W. R., Valent, P., & Hoermann, G. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22052458 · Cited by 51 · see citing works
Appraisal of the evidence linking hereditary α-tryptasemia with mast cell disorders, hypermobility and dysautonomia
Lyons, J. J. (2024) · Allergy and Asthma Proceedings · doi:10.2500/aap.2025.46.240088 · Cited by 5 · see citing works
Hereditary alpha-tryptasemia
Bonadonna, P., Nalin, F., & Olivieri, F. (2022) · Current Opinion in Allergy & Clinical Immunology · doi:10.1097/aci.0000000000000849 · Cited by 18 · see citing works

Authors: Le, Q. T., Lyons, J. J., Naranjo, A. N., Olivera, A., Lazarus, R. A., Metcalfe, D. D., Milner, J. D., & Schwartz, L. B.
Affiliations: Virginia Commonwealth University (US)
National Institutes of Health (US)
Genentech (US)
Corresponding author: Schwartz, Lawrence B.
ORCID: Le, Quang T.
Lyons, Jonathan J.
Olivera, Ana
Lazarus, Robert A.
Metcalfe, Dean D.
Milner, Joshua D.
Schwartz, Lawrence B.
Venue: Journal of Experimental Medicine
Publisher: Rockefeller University Press
Published: 2019-07-23
Volume: 216
Issue: 10
Pages: 2348-2361
ISSN: 0022-1007 (ISSN-L)
1540-9538
DOI: 10.1084/jem.20190701
PMC: PMC6780998
OpenAlex: W2964163570
Cited by: 126
References: 54
Citations by year: 2026: 12 · 2025: 17 · 2024: 13 · 2023: 18 · 2022: 17 · 2021: 24 · 2020: 16 · 2019: 8
FWCI: 6.48
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-sa
www.rupress.org/terms/ (vor)
creativecommons.org/licenses/by-nc-sa/4.0/ (vor, 258 d)
Locations: The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
PubMed Central (publishedVersion, cc-by-nc-sa)
PubMed (publishedVersion)
Funders: Charles Thomas Research Fund
Medical College of Virginia Foundation
National Institutes of Health (U18AI77435, R0127517)
Division of Intramural Research of the National Institute of Allergy and Infectious Diseases
Topics: Life Sciences › Immunology and Microbiology › Immunology › Mast cells and histamine
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
Health Sciences › Medicine › Genetics › Coagulation, Bradykinin, Polyphosphates, and Angioedema
Keywords: hereditary alpha-tryptasemia, beta-tryptase, heterotetramer, mast cells, protease-activated receptor 2, mast cell degranulation, autonomic dysfunction, allosteric effects, protease specificity, mast cell disease
MeSH terms: Adult, Allosteric Regulation, Female, Humans, Male, Mast Cells, Vibration, Cell Degranulation, Genetic Diseases, Inborn, Receptors, G-Protein-Coupled, Receptor, PAR-2, Tryptases, Protein Multimerization

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Impact of naturally forming human α/β-tryptase heterotetramers in the pathogenesis of hereditary α-tryptasemia

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Self-check

Cites

Cited by

Related

Record

About these checks