Evaluation of a tryptase depletion index for better pathologic identification of mast cell activation syndrome

Tomasz Zienkiewicz; Jürgen Homann; Martin Mücke; Holger Seidel; Hans-Jörg Hertfelder; Leonard B. Weinstock; Lawrence B. Afrin; Gerhard J. Molderings

doi:10.1055/a-1833-9226

Zeitschrift für Gastroenterologie, Inhaltsverzeichnis

Z Gastroenterol 2023; 61(03): 268-274
DOI: 10.1055/a-1833-9226

Originalarbeit

Evaluation of a tryptase depletion index for better pathologic identification of mast cell activation syndrome

Evaluierung eines Tryptase-Freisetzungsindex zur verbesserten pathologischen Identifizierung des Mastzellaktivierungssyndroms

Tomasz Zienkiewicz

¹Institute of Pathology Bonn-Duisdorf, Bonn, Germany

,

Jürgen Homann

²Division of Internal Medicine, Gemeinschaftskrankenhaus Bonn, Bonn, Germany

,

Martin Mücke

³Institute for Digitalization in General Practice and Center for Rare Diseases Aachen (ZSEA), University Hospital Aachen, Aachen, Germany (Ringgold ID: RIN39058)

,

Holger Seidel

⁴Center for Bleeding Disorders and Transfusion Medicine (CBT), Bonn, Germany

,

Hans-Jörg Hertfelder

⁴Center for Bleeding Disorders and Transfusion Medicine (CBT), Bonn, Germany

,

Leonard B. Weinstock

⁵Departments of Medicine, Missouri Baptist Medical Center and Washington University School of Medicine, St. Louis, MO, United States

,

Lawrence B. Afrin

⁶AIM Center for Personalized Medicine, Purchase, NY, United States

,

Gerhard J. Molderings

⁷Institute of Human Genetics, University of Bonn, Bonn, Germany

› Institutsangaben

Abstract

Background Laboratory evidence supporting diagnosis of the prevalent condition of mast cell activation syndrome (MCAS) currently includes elevated levels in blood or urine of mediators relatively specific to mast cells (MCs) and/or increased numbers of MCs in luminal gastrointestinal (GI) tract tissues. However, identification of elevated mediators is technically challenging and expensive, and controversy persists regarding the normal ranges of numbers/counts of MCs in various GI tract segments, let alone challenges in determining how many of the visualized MCs are activated. To aid diagnosis of MCAS, we developed a potential new approach for the pathologist to identify the extent of GI tract MC activation easily and inexpensively.

Participants and Methods Visualization of MCs in gastrointestinal biopsies from 251 patients vs. 95 controls using antibodies against CD117 and tryptase; MC counting per mm²; calculation of the difference between the CD117-positive MCs (identifying all MCs) vs. tryptase-positive MCs (identifying non-activated tryptase-containing MCs), which we define as the tryptase depletion index (TDI).

Results Mean total MC counts did not differ significantly between patients and controls, but mean TDIs differed significantly. Non-overlapping confidence intervals at the 99.9% level identified cut-offs of TDIs between patients vs. controls of 26, 45 and 32 MCs/mm² in gastric antrum, duodenum, and colon, respectively.

Conclusions The TDI may discriminate between MCAS patients vs. controls. If this preliminary work can be independently confirmed, the TDI may become a useful additional minor diagnostic criterion for MCAS.

Zusammenfassung

Hintergrund Laborwerte, die die Diagnose des häufig auftretenden Mastzellaktivierungssyndroms (MCAS) stützen, umfassen derzeit erhöhte Blut- oder Urinspiegel von Mediatoren, die relativ spezifisch für Mastzellen (MCs) sind und/oder eine erhöhte Anzahl von MCs in der Mukosa des Gastrointestinaltrakts (GIT). Der Nachweis erhöhter Mediatorspiegel ist jedoch technisch anspruchsvoll und teuer, und die Angaben für die normale Mastzelldichte in den verschiedenen GIT-Segmenten sind umstritten, ganz abgesehen von den Schwierigkeiten des Nachweises, wie viele der visualisierten MCs aktiviert sind. Um die Diagnose einer MCAS zu stützen, haben wir einen potenziellen neuen Ansatz für die pathologische Untersuchung entwickelt, der eine einfache und preiswerte Bestimmung der MC-Aktivität im GIT erlaubt.

Studienteilnehmer und Methodik Visualisierung der MCs in gastrointestinalen Biopsien von 251 MCAS-Patienten und 95 Kontrollpersonen mittels CD117- und Tryptase-Antikörper; Zellzählung pro mm²; Berechnung der Differenz der Mastzellzahl zwischen CD117- (Anfärbung aller MCs) und Tryptase-positiven MCs (Nachweis nicht aktivierter tryptasehaltiger MCs), die wir als Tryptasefreisetzungsindex (TDI) bezeichnen.

Ergebnisse Die mittleren Mastzelldichten der Patienten unterschieden sich nicht signifikant von denen der Kontrollgruppe, wohingegen sich die Mittelwerte der TDIs signifikant unterschieden. Die nicht überlappenden Konfidenzintervalle auf dem 99,9% Niveau erlaubten eine Definition von Grenzwerten für die TDIs zur Unterscheidung von Patienten und Kontrollpersonen von 26, 45 und 32 Mastzellen/mm² im Magenantrum, Duodenum bzw. Kolon.

Schlussfolgerungen Der TDI erlaubt eine Unterscheidung zwischen MCAS-Patienten und Kontrollpersonen. Wenn diese erstmalige Beobachtung in Studien anderer Untersuchergruppen bestätigt werden kann, könnte der TDI in der Diagnostik des MCAS ein nützliches zusätzliches Nebendiagnosekriterium werden.

Schlüsselwörter

Mastzellaktivierungssyndrom - Mastzelldichte - Mastzellaktivität - diagnostische Kriterien - CD117-Antikörperfärbung - Tryptase-Antikörperfärbung - Tryptasefreisetzungsindex

Keywords

mast cell activation syndrome - mast cell density - mast cell activation - diagnostic criteria - CD117-antibody staining - tryptase-antibody staining - tryptase depletion index

Volltext

Referenzen

References
1 Weinstock LB, Pace LA, Rezaie A Afrin LB. et al. Mast cell activation syndrome: a primer for the gastroenterologist. Dig Dis Sci 2021; 66: 965-982
2 Afrin LB, Butterfield JH, Raithel M. et al. Often seen, rarely recognized: mast cell activation disease – a guide to diagnosis and therapeutic options. Ann Med 2016; 48: 190-201
3 Molderings GJ, Haenisch B, Bogdanow M. et al. Familial occurrence of systemic mast cell activation disease. PLoS One 2013; 8: e76241
4 Maitland A, Brock I, Reed W. Immune dysfunction, both mast cell activation disorders and primary immune deficiency, is common among patients with hypermobile spectrum disorder (HSD) or hypermobile type Ehlers Danlos Syndrome (hEDS). EDS ECHO Summit, October 2–2, 2020; session 12, poster number 001.
5 Afrin LB, Ackerley MB, Bluestein LS. et al. Diagnosis of mast cell activation syndrome: a global "consensus-2". Diagnosis (Berl) 2020; 8: 137-152
6 Jakate S, Demeo M, John R. et al. Mastocytic enterocolitis: increased mucosal mast cells in chronic intractable diarrhea. Arch Pathol Lab Med 2006; 130: 362-367
7 Doyle LA, Sepehr GJ, Hamilton MJ. et al. A clinicopathologic study of 24 cases of systemic mastocytosis involving the gastrointestinal tract and assessment of mucosal mast cell density in irritable bowel syndrome and asymptomatic patients. Am J Surg Pathol 2014; 38: 832-843
8 Theoharides TC, Kempuraj D, Tagen M. et al. Differential release of mast cell mediators and the pathogenesis of inflammation. Immunol Rev 2007; 217: 65-78
9 Schwartz LB, Lewis RA, Austen KF. Tryptase from human pulmonary mast cells. Purification and characterization. J Biol Chem 1981; 256: 11939-11943
10 Molderings GJ, Kolck U, Scheurlen C. et al. Systemic mast cell disease with gastrointestinal symptoms – a diagnostic questionnaire. Dtsch Med Wochenschr 2006; 131: 2095-2100
11 Hahn HP, Hornick JL. Immunoreactivity for CD25 in gastrointestinal mucosal mast cells is specific for systemic mastocytosis. Am J Surg Pathol 2007; 31: 1669-1676
12 Sokol H, Georgin-Lavialle S, Canioni D. et al. Gastrointestinal manifestations in mastocytosis: A study of 83 patients. J Allergy Clin Immunol 2013; 132: 866-873
13 Sotlar K, Horny HP, Simonitsch I. et al. CD25 indicates the neoplastic phenotype of mast cells: a novel immunohistochemical marker for the diagnosis of systemic mastocytosis (SM) in routinely processed bone marrow biopsy specimens. Am J Surg Pathol 2004; 28: 1319-1325
14 Siegert SI, Diebold J, Ludolph-Hauser D. et al. Are gastrointestinal mucosal mast cells increased in patients with systemic mastocytosis ?. Am J Clin Pathol 2004; 122: 560-565
15 Roth-Walter F, Pacios LF, Bianchini R. et al. Linking iron-deficiency with allergy: role of molecular allergens and the microbiome. Metallomics 2017; 9 (12) 1676-1692
16 Marech I, Ammendola M, Gadaleta C. et al. Possible biological and translational significance of mast cells density in colorectal cancer. World J Gastroenterol 2014; 20: 8910-8920
17 Molderings GJ, Zienkiewicz T, Homann J. et al. Risk of solid cancer in patients with mast cell activation syndrome: Results from Germany and USA. F1000Res 2017; 6: 1889
18 Valent P, Akin C, Arock M. et al. Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol 2012; 157: 215-225
19 Valent P, Bonadonna P, Hartmann K. et al. Why the 20% + 2 Tryptase formula is a diagnostic gold standard for severe systemic mast cell activation and mast cell activation syndrome. Int Arch Allergy Immunol 2019; 180: 44-51
20 Ribatti D. The Staining of Mast Cells: A Historical Overview. Int Arch Allergy Immunol 2018; 176: 55-60
21 Watanabe I, Hikita T, Mizuno H. et al. Isolation and characterization of monoclonal antibodies specific for chondroitin sulfate E. Glycobiology 2015; 25: 953-962
22 Guilarte M, Santos J, de I Torres. et al. Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum. Gut 2007; 56: 203-209
23 Wouters MM, Vicario M, Santos J. The role of mast cells in functional GI disorders. Gut 2016; 65: 155-168