Tryptases

PA S1 S01.143 Tryptase alpha Drug target for asthma and antigen-induced bronchoconstriction... 

Finally, patients suffering from mastocytosis have a higher risk of developing severe anaphylaxis after an insect sting [34]. In venom-allergic patients with mastocytosis, elevated baseline serum tryptase levels were foimd to be associated with severe anaphylactic reactions to stings [35]. 

Dybendal X Guttormsen AB, Elsayed S, Askeland 48 B, Harboe T, Florvaag E Screening for mast cell tryptase and serum IgE antibodies in 18 patients with anaphylactic shock during general anaesthesia. 

The histamine content of isolated HHMC (=3 pg/cell) was comparable to lung parenchymal and skin mast cells. The mean tryptase content of HHMC (=24 pg/10 cells)... 

Kaartinen M, Penttila A, Kovanen PT Accumulation of activated mast cells in the shoulder region of human coronary atheroma, the predilection site of atheromatous rupture. Circulation 1994 90 1669. Kaartinen M, Penttila A. Kovanen PT Mast cells of two types differing in neutral protease composition in the human aortic intima. Demonstration of tryptase- and tryptase/chymase-containing mast cells in normal intimas, fatty streaks, and the shoulder region of atheromas. Arterioscler Thromb 1994 14 966. 

The most frequent symptoms of anaphylaxis in patients with mastocytosis are decreased blood pressure and tachycardia. Also observed are dizziness, dyspnea, flushing, nausea and diarrhea [4]. Severe reactions are typical for patients with mastocytosis. In 55 patients with insect sting allergy and confirmed mastocytosis, 81% of patients experienced severe anaphylaxis with shock or cardiopulmonary arrest, whereas clinical reactions of this severity occurred in only 17% of 504 patients without evidence for mastocytosis and normal tryptase levels [29]. In another study in... 

Mastocytosis is recognized in most patients because of the presence of characteristic cutaneous lesions [10]. A positive Darier s sign and/or histological examination of the skin using metachromatic stains, or by immunohistochemistry using antibodies to mast cell tryptase, helps confirm the diagnosis of cutaneous disease. 

Bonadonna P, Perbellini O, Passalacqua G, et al Clonal mast cell disorders in patients with systemic reactions to Hymenoptera stings and increased serum tryptase levels. J Allergy Clin Immunol 2009 123 680-686. 

Brockow K, Akin C, Huber M. Metcalfe D Assessment of the extent of cutaneous involvement in children and adults with mastocytosis relationship to symptomatology, tryptase levels, and bone marrow pathology J Am Acad Dermatol 2003 48 508-516. 

Ludolph-Hauser D, Rueff F, Fries C, et al Con- 40 stitutively raised serum concentrations of mast-cell tryptase and severe anaphylactic reactions to Hyme-noptera stings. Lancet 2001 357 361-362. 

Florian S, Krauth MX, Simonitsch-Klupp I, et al Indolent systemic mastocytosis with elevated serum tryptase, absence of skin lesions, and recurrent severe anaphylactoid episodes. Int Arch Allergy 43 Immunol 2005 136 273-280. 

The latest consensus on the definition and management [1] of anaphylaxis agrees on the lack of imiversally accepted diagnostic criteria and reliable laboratory biomarkers to confirm the clinical impression. Sometimes it is not feasible to obtain the samples within the optimum time frame. Moreover, in spite of a correct collection of samples, histamine and/or tryptase are within normal levels. Hence, new markers should be explored and further research into the role of selected mediators is urgently needed. Recently however, studies from animal models have shown promising results. In this chapter we will seek to review our current knowledge on confirmed or putative markers for the in vitro diagnosis of anaphylaxis. 

Tryptase is at the present moment the main clinical marker for anaphylaxis and mastocytosis. There are two major human mast cells tryptases, a- and (3-tryptase, encoded by two genes located at chromosome 16. The haploid genotype for tryptase is (3a or (3(3.25% of individuals are a-tryptase-deficient a-tryptase shows a 90% amino acid sequence identity with (3-tryptase. 

Two immunoassays have been developed to measure tryptase in human fluids, one that measures mature a/(3-tryptases, i.e. total tryptase, available commercially, and one developed by Schwartz et al. [7] that measures both mature (3-tryptase and immature a/(3-tryptases. This distinction is of clinical relevance since immature tryptases reflect mast cell burden whereas mature tryptases indicate mast cell activation. Thus, for the diagnosis of anaphylaxis it would be extremely important to be able to differentiate between acute anaphylaxis and increases in tryptase due to increase in numbers of mast cells as happens in mastocytosis. Total tryptase would be high in both conditions, whereas mature tryptase will be only high in anaphylaxis but negligible in mastocytosis. 

In healthy subjects, mature tryptase levels in serum and plasma are undetectable (<1 ng/ml) whereas total tryptase levels range from 1 to 15 ng/ml. Gender or haplo-type does not affect amounts of total tryptase. 

Finally, it is worth mentioning that tryptase levels do not differentiate between immunologic and non-immimological mast cell activation and do not contribute to the identification of the cause of the anaphylactic reaction. To date, very few mediators [10] apart from histamine and tryptase have been investigated as markers for anaphylaxis. Recent studies also include other mediators that we will only examine briefly. A more extensive review can be found elsewhere [2,11]. 

As is the case with tryptase, chymase is also stored in mast cell granules. This mediator can activate the angiotensin system converting angiotensin I to angiotensin II. With this action it compensates the intravascular loss of volume and the permeability... 

Mast cell protease A3 is less well characterized than tryptase and chymase in terms of physiological substrates. It is involved, among its other functions, in angiotensin metabolism. 

Schwartz LB Diagnostic value of tryptase in anaphylaxis and mastocytosis 2. Immunol Allergy Clin North Am 2006 26 451-463. 

Jogie-Brahim S, Min HK, Fukuoka Y, Xia HZ, Schwartz LB Expression of a-tryptase and 3-tryptase by human basophils. J Allergy Clin Immunol 2004 113 1086-1092. 

Foster B, Schwartz LB, Devouassoux G, Metcalfe DD, Prussin C Characterization of mast-cell try-ptase-expressing peripheral blood cells as basophils. J Allergy Clin Immunol 2002 109 287-293. Schwartz LB, Bradford TR, Rouse C, Irani AM, Rasp G, Van der Zwan JK, Van del Linden PW Development of a new, more sensitive immunoassay for human tryptase use in systemic anaphylaxis. J Clin Immunol 1994 14 190-204. 

Schwartz LB, Yunginger JW, Miller J, Bokhari R, Dull D Time course of appearance and disappearance of human mast cell tryptase in the circulation after anaphylaxis. J Clin Invest 1989 83 1551-1555. 

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