Asthma is a chronic inflammatory disease that affects people of all ages, with the increasing total prevalence rate [¹,²]. Asthma is a clinical diagnosis that incorporates genetic predisposition and clinical symptoms with objective measures of lung function and disease severity, and is determined by pulmonary function measurements, asthma symptoms, and the need for rescue medication [³,⁴]. While asthma is classified based on severity, at the moment there is no clear method for classifying different subgroups of asthma beyond this system, and in the most severe form, called ‘Severe persistent allergic asthma’, diagnosis is based on whether symptoms are precipitated by allergens [⁵,⁶]. Different patients will respond differently to the same treatment, thus it is clear that the cases within a classification have significant differences. Finding ways to identify patients who will respond well to different types of treatments is a current critical goal of asthma research.

Omalizumab (trade name Xolair), a recombinant humanized monoclonal antibody to IgE, is recommended as a new option for the treatment of severe persistent allergic (IgE mediated) asthma [⁷,⁸]. In our previous study, we reported the omalizumab treatment is clinically effective in severe persistent asthma patients with co-morbid allergic conditions [⁹].

Apoptosis (programmed cell death) is an active physiological process that leads to the ordered destruction of cells without the release of intracellular contents into the extracellular environment (which would cause an inflammatory reaction and tissue damage) [¹⁰]. Apoptosis in the immune system is a fundamental process regulating the maturation and homeostasis of the lymphocytes. It can be induced passively through the lack of essential survival signals, or actively, through the ligand induced trimerization of specific death receptors of the tumour necrosis factor (TNF) receptor family, such as Fas, the TNF receptor, or the TNF-related apoptosis-inducing ligand (TRAIL) receptor [¹¹].

The Fas/FasL system plays a crucial role in apoptosis in many diseases, including cancer and inflammatory diseases [¹²]. The importance of the other death pathways is, however, uncertain. Recent interest has focused on TRAIL, with several studies indicating that sTRAIL is involved in the pathophysiology of different disease states, including cancer, viral infections, autoimmune diseases and inflammation. Defective apoptosis due to its interaction with its ligand preventing signaling for apoptosis may contribute to these diseases [¹³–²³].

Previously, it was reported that allergic rhinitis is a sFas-reduced disease, and it was suggested that sFas might play a new role in allergic rhinitis [²⁴]. Previous studies also showed unexpected difference in serum sFas levels between allergic rhinitis patients and bronchial asthma patients, but no difference in sFas-L between the adults with asthma and healthy controls [²⁴,²⁵]. These studies suggested the possibility of different apoptosis systems in the pathogenesis of the allergic diseases.

TRAIL (APO-2 ligand) is a transmembrane (type II) glycoprotein which also belongs to the TNF superfamily. The extracellular domain of TRAIL is homologous to that of other family members and shows a homotrimeric subunit structure. Like TNF and FasL, TRAIL also exists physiologically in a biologically active soluble homotrimeric form [²⁶].

In this study, our aim was to identify the role of sTRAIL in the pathophysiology of allergic asthma and in omalizumab efficacy as a new treatment modality in severe asthma in general.

In this clinical follow-up study, 14 patients had already been receiving omalizumab therapy and these subjects were included for further analysis. The patients had had severe persistent asthma for periods ranging from 2 to 5 years, and had been diagnosed as having allergic asthma for 5–25 years. The study subjects’ baseline characteristics are shown in Tables 1 and 2.

The mean total serum IgE levels were as follows: in Group I, 459.785 IU/mL; in Group II, 124.8 IU/mL; and in Group III, 39.88 IU/mL. ANA, RF and hepatitis markers were negative in all patients. Complement 3 and 4 levels were normal in all patients. Prick tests in both patient groups (Group I and II) were positive for mite, and grass allergens. These results correlated with specific IgE.

As shown in Figure 1, there were no differences in the mean values of sTRAIL levels between the severe persistent allergic asthma patients before the omalizumab treatment (n=14; mean ±SD 1663±120.4 pg/ml), newly diagnosed allergic asthma patients (n=14; mean ±SD 1873±142.9 pg/ml), and healthy controls (n=14; mean ±SD 1751±161.6 pg/ml). But in contrast, serum sTRAIL levels in patients with severe persistent allergic asthma after the omalizumab treatment (n=14; mean ±SD 1443±80.93 pg/ml) were lower than those in healthy individuals (n=14; mean ±SD 1751±161.6 pg/ml).

However, 3 of 14 severe persistent allergic asthma patients showed an increase or no change in sTRAIL levels (Figure 2). Those patients (n=3) whose sTRAIL levels were increased or not changed, are the patients in whom the omalizumab treatment was clinically effective after the twelfth dose, while the other patients had a decrease in symptoms, mostly after the second or third dose. The patient whose sTRAIL level was increased about 2-fold was the patient who had newly diagnosed diabetes mellitus after the omalizumab treatment had started. However, the circulating soluble TRAIL is a negative marker for inflammation, and the levels were affected by autoimmune conditions [¹⁴,¹⁷].

As a mechanism in allergic conditions, there was an increase in both T and B cells and eosinophils in both of our 2 patient groups. IT was previously reported that the increase in the eosinophil levels in allergic asthma was due to the increase in peripheral blood eosinophil survival promoted by TRAIL [¹³]. The exact role of TRAIL in vivo still remains unknown. In this study, we showed that soluble TRAIL levels of severe persistent allergic asthma patients were decreased after the anti-IgE treatment using omalizumab. The TRAIL levels of only 1 patient increased after omalizumab treatment. The possible explanation of the 2-fold increase in this patient may be due to the uncontrolled, newly-diagnosed diabetes mellitus (glucose levels were higher than 400 mg/dl and the patient was not using any anti-diabetic drugs).

These results suggest that TRAIL may act as a soluble effector, and the decrease after the omalizumab treatment may be an indicator of clinical improvement.

Omalizumab was evaluated as a treatment for asthma in large, multicenter, double-blind placebo control trials involving patients with moderate to severe asthma who required corticosteroids; when added to oral or inhaled corticosteroids, omalizumab reduced symptoms and exacerbations, improved lung functions and quality of life [²⁷].

The physiological functions of sTRAIL in allergic conditions, and the elucidation of the molecular mechanisms of the TRAIL signaling pathways, will be of significant interest to the scientific allergy community in the coming years.

fn9-medscimonit-18-3-pi11Competing interests

The authors declare that they have no competing interests.

fn10-medscimonit-18-3-pi11Authors’ contributions

ADY was involved in patient recruitment, followed-up the patients, participated in the design of the study and drafted the manuscript. AB carried out the immunoassays, participated in its design and drafted the manuscript. AK researched the literature and participated in coordination. RMG drafted the manuscript and participated in its coordination. All authors read and approved the final manuscript.

fn11-medscimonit-18-3-pi11Source of support: Departmental sources