f433 Tri a 14, nsLTP, Triticum aestivum

Summary

Tri a 14 is a 9-kDa non-specific lipid transfer protein (nsLTP) present in the grains of Triticum aestivum (wheat). Tri a 14 sensitization has been associated with multiple clinical presentations, including food allergy to wheat with or without cofactor involvement, wheat-dependent exercise induced anaphylaxis, occupational baker’s asthma, and nsLTP syndrome. Clinically silent Tri a 14 sensitization is frequent.

Epidemiology

Worldwide distribution

T. aestivum grain, a cosmopolitan staple food, is associated with various adverse allergic and non-allergic reactions such as food allergy, baker’s asthma, contact urticaria, food protein-induced enterocolitis, eosinophilic esophagitis, and celiac disease [1]. T. aestivum flour contains a rich array of proteins. As of April 26, 2022, the IUIS/WHO Nomenclature comprises 28 allergens [2], out of a reported 70 IgE-binding wheat flour proteins [3].

Sensitization to wheat nsLTP Tri a 14 has been reported in patients from virtually all geographical areas, meaning that it is not limited to Mediterranean climate [4]. However, Tri a 14 sensitization is typically found in Mediterranean areas [4, 5]. Tri a 14 sensitization mainly affects adolescents and adults [6].

Environmental Characteristics

Source and tissue

Tri a 14 is found in the whole grain, bran and flour of T. aestivum [7]. Wheat bran contains 4.5-fold higher amounts of Tri a 14 compared with flour [7]. Following protein extraction procedures from raw and cooked wheat, Tri a 14 is demonstrated in the water-soluble albumin/globulin fraction [8].

Risk factors

Sensitization to Tri a 14 occurs through wheat ingestion [6] but inhalation of Tri a 14 can result in occupational baker’s asthma [4]. 

Detection methods

Assessment of Tri a 14 specific IgE, in conjunction with ω-5 gliadin Tri a 19 and wheat extract is recommended in both food and inhalation-induced wheat allergy [3, 9]. Insufficient detection sensitivity of Tri a 14 IgE using multiplex methods has been reported [9].

Clinical Relevance

Occupational asthma due to wheat flour inhalation

Inhalation challenge tests have demonstrated that Tri a 14 sensitization is a cause of occupational asthma developing in up to 10% of people exposed to inhalation of wheat flour, also known as baker’s asthma [3, 10]. The reported prevalence of Tri a 14 sensitization in bakers with wheat-induced occupational asthma varied from 2.5% in German patients (continental temperate area) [11] to 25% in Korean patients [12], to 45% - 60% in Spanish patients (Mediterranean area) [13]. Specificity was also variable, with Tri a 14 sensitization lacking in Spanish controls (allergic rhinitis or wheat-induced food allergy) [14] but demonstrated in 10% of German controls [11]. Of note, small patient and control samples as well as different Tri a 14 isoallergens were used for these studies: Tri a 14.0101 in Spain, and Tri a 14.0201 in Germany [11]. A later study was performed with sera from both climate areas and with both Tri a 14 isoallergens, confirming a 3-21% prevalence of Tri a 14 sensitization baker’s asthma irrespective of the climate area [15]. Thus, the current view of Tri a 14 is that of a clinically important, but immunologically minor allergen in baker’s asthma.

Wheat-induced food allergy

Wheat-induced food allergy refers to reactions induced by wheat ingestion, with or without the contribution of a cofactor [16]. Severe allergic reactions upon wheat ingestion occurring only in association with exercise or physical exertion are identified as wheat-dependent exercise-induced anaphylaxis (WDEIA) [16]. Tri a 14 sensitization may be found in any type of wheat-induced food allergy: WDEIA or classical food allergy with urticaria, angioedema and potentially anaphylaxis, often in association with a nsLTP syndrome. However, Tri a 14 is not the predominant allergen in any of the wheat-induced food allergy presentations, nor in any geographical area [6, 8, 12, 16].

Further data on Tri a 14 associated with nsLTP syndrome and WDEIA are provided below.

nsLTP syndrome

The nsLTP syndrome refers to complex sensitization profiles comprising more than one nsLTP often associated with the immunodominant nsLTP Pru p 3 or Art v 3, which can translate into clinical reactivity to multiple pollen and plant foods [4, 6].

Tri a 14 sensitization may be associated to nsLTP syndrome [4, 17]. Cannabis use has also been associated with an apparently Can s 3-driven nsLTP syndrome comprising Tri a 14 sensitization [5]. In Mediterranean as well as non-Mediterranean patients, Tri a 14 sensitization did not exceed a prevalence of 30% and, as opposed to other nsLTPs, inconsistently correlated with sensitization to other members of the nsLTP family as reflected by conflicting study reports [4, 17, 18]. Allergic reactions to cereals such as wheat as part of a nsLTP syndrome are rare [19], with 68% of Tri a 14-sensitized patients with a nsLTP syndrome tolerant to wheat consumption [9].

WDEIA (Wheat-Dependent Exercise-Induced Anaphylaxis)

WDEIA patients are more often sensitized to Tri a 19, the ω-5 gliadin, than to Tri a 14 [6, 12, 16]. Tri a 14 sensitization associated to WDEIA has been mainly reported in Mediterranean patients, adult as well as pediatric, and an associated history of Pru p 3-related peach allergy was reported  [20, 21].

Disease severity and prediction

Tri a 14 sensitization was not associated with oral allergy syndrome in Mediterranean or non-Mediterranean areas [17, 18]. In a study conducted in Italian patients, Tri a 14 sensitization was correlated with a history of food-induced systemic reactions, with an odds ratio of 2.32 [18]. Taking a different approach based on sensitization to Tri a 14 or Tri a 19 as a classification criterion, followed by clinical history and evaluation of wheat-induced food allergy, the clinical relevance of Tri a 14 sensitization was better delineated [16]. This study showed that, in wheat-sensitized patients, Tri a 14 sensitization was most often a clinically silent finding (72% of 79 patients). Severe reactions to wheat ingestion were recorded in 19% of patients with Tri a 14 sensitization, as compared with 55% of those with Tri a 19 sensitization. Cofactor involvement was present in 16% of Tri 14 sensitized patients, while atopy was present in 67%. IgE levels to Tri a 14 were directly correlated to those measured to Pru p 3 and to whole allergen extracts of LTP-containing cereals (wheat, barley, oats, rye, maize, and rice) and nuts (peanut, hazelnut, walnut, and almond) [16].

Cross-reactive molecules

Tri a 14, a member of the nsLTP family, exhibits moderate cross-reactivity with other nsLTPs, and is capable of inducing sensitization in the absence of Pru p 3 [6]. Importantly, Tri a 14 does not cross-react with grass pollen, and thus may help distinguish cross-reactivity between wheat and grass pollen from genuine wheat sensitization [6, 8]. Studies addressing Tri a 14 sensitization in the context of other allergenic nsLTPs showed that Tri a 14 is one of the most infrequent nsLTP sensitizations, both in Mediterranean and non-Mediterranean areas [4, 17, 18]. Tri a 14 sensitization shares with Ole e 7 and Par j 2 this relative independence from other nsLTPs [18].

Tri tu 14, a 9-kDa nsLTP from T. turgidum (durum wheat), exhibited significant cross-reactivity with Tri a 14 despite interindividual variability and a relatively low sequence identity of 49% [22]. Conversely, maize LTP displayed cross-reactivity with Tri a 14 in only 1/22 wheat-allergic patients, despite relatively high sequence identity at 59% [8].

Prevention and Therapy

Experimental trials

Not relevant.

Molecular Aspects

Biochemistry

Tri a 14 is one of T. aestivum nsLTPs [1, 2], with a molecular weight of 9.1 kDa (isoallergen Tri a 14.0101) or 9.7 kDa (isoallergen Tri a 14.0201), and therefore recognized as a type 1 nsLTP. It displays a typical nsLTP secondary structure, made up of a majority of α helices which fold into a globular protein stabilized by four disulfide bonds and featuring an internal, hydrophobic cavity for ligand binding [23, 24]. Similar to other nsLTPs, Tri a 14 is a stable protein, not affected by heating up to 70°C, partially denatured at 90°C but losing up to 73% of its secondary structure after heating at 100°C, and resistant to proteolysis, retaining IgE-binding ability after experimental physico-chemical treatment in a fashion similar to that observed with Pru p 3 under the same conditions [8, 23]. However, IgE binding to Tri a 14 from cooked as compared to raw wheat albumin/globulin fraction may be abolished in a minority of wheat-allergic patients [8]. Other cereal LTPs, e.g. from maize, reportedly exhibit greater resistance to physico-chemical denaturation than Tri a 14 [8]. Known ligands of Tri a 14 are fatty acids, such as palmitic acid and linoleinic acid [24].

Isoforms, epitopes, antibodies

As of April 28, 2022, two isoallergens, Tri a 14.0101 and Tri a 14.0201, have been included in the World Health Organization (WHO) and International Union of Immunological Societies (IUIS) Allergen Nomenclature [2]. There is a 43.5% sequence identity between Tri a 14.0101, a 9.1 kDa nsLTP, and Tri a 14.0201, a 9.7 kDa nsLTP [11].

Cross-reactivity due to structural similarity

Tri a 14 shares moderate sequence identity with other nsLTPs, e.g. 45% between Tri a 14.0101 and Pru p 3, while Tri a 14.0201 exhibits higher sequence identity, at 47-49%, not only with Pru p 3 but also with Mal d 3 (Malus domestica, apple) [7, 11]. Tri a 14 displays both common and different epitopes when compared to Pru p 3, supporting moderate cross-reactivity [7, 10]. 

Diagnostic Relevance

Elucidation of sensitization profile and guidance for management

The demonstration of Tri a 14 sensitization is useful for the diagnosis of occupational and food-induced wheat allergy [3, 16]. Taking into account the 68-72% prevalence of clinically silent Tri a 14 sensitization, its demonstration in food-induced wheat allergy should be an incentive for applying an oral food challenge test in order to avoid unnecessary exclusion regimens [16].

Exposure

The main route of exposure to Tri a 14 is through wheat ingestion. Occupational exposure to Tri a 14 in inhaled wheat flour may result in baker’s asthma. Finally, a nsLTP syndrome may result in cross-reactivity to Tri a 14. 

Compiled By

Author: Joana Vitte

Reviewer: Dr.Christian Fischer

Last reviewed: June 2022