Thymus and activation-regulated chemokine (TARC)/CCL17 and IgE are associated with elderly asthmatics

Asthma is an allergic disease in the respiratory tract that is characterized by lung inflammation and mucus secretion resulting in airway obstruction, as well as allergen-specific IgE [1, 2]. Asthma is caused by a variety of elements including environmental, genetic and immunological factors. House dust mites (HDMs), including Dermatophagoides pteronissinus (DP) and Dermatophagoides farinae (DF), may be sources of many specific allergen proteins including Der p 1 and Der f 1 [3, 4]. More than half of asthmatics are sensitized to HDM and have elevated levels of HDM-specific IgE in their serum. Cytokine secretion, which is one of the most important allergic inflammatory responses, is increased by HDM via Toll-like receptor (TLR) and proteinase-activated receptor (PAR) [5, 6]. Cytokines including interleukin 4 (IL-4), interleukin 5 (IL-5), IL-6, IL-8, interleukin 10 (IL-10), monocyte chemoattractant protein (MCP)-1/CCL2, and thymus and activation-regulated chemokine (TARC)/CCL17 trigger secondary inflammatory events, aggravating asthma pathogenesis.

Aging is an unavoidable and complicated process characterized by progressive loss of functional activity, repair, and recovery. Interaction of the proinflammatory state with aging, which is very important, occurs via the inflamm-aging process [7, 8]. Aging studies have suggested that potential biomarkers containing proinflammatory cytokines, hypoxic indicators, and redox state may be related to inflammation-associated aging. Asthma in elderly subjects shows higher mortality than in younger members of the population, including children and younger adults, and is underdiagnosed by age-related alterations such as dyspnea, immunosenescence and decreased skin test sensitivity [9]. Although asthma in elderly subjects is associated with immunological and non-immunologic mechanisms, the exact interaction of aging and asthma has yet to be unveiled. In this study, we divided subjects into young adults, middle-aged adults, and elderly adults and studied the association of asthma and aging with biomarkers including cytokine and HDM-specific IgE in serum.

Asthma, which is one of the most prevalent allergic diseases, is caused by a variety of pathophysiological mechanisms [10]. HDMs are a major source of allergic asthma and DP and DF are of the most common HDMs [11]. IgE is considered a clear sign of allergic disease including asthma [11]. Der p 1 and Der f 1, major allergens proteins of HDMs, have a high IgE reactivity [12], and total IgE and Der p 1- or Der f 1–specific IgE are elevated in asthma [13]. In our study, total IgE, Der p1-specific IgE, and Der f1-specific IgE were elevated in asthmatic subjects when compared to normal subjects (Table 1). In a previous study, asthmatic subjects showed significantly more eosinophils, neutrophils, and cytokines such as IL-5, IL-6, IL-8, granulocyte colony stimulation factor (G-CSF) and RANTES in BALF when compared to healthy control subjects [14, 15]. As shown in Tables 1 and 2, neutrophils, IL-6, IL-8, RANTES, MCP-1, and MIP-1α in BALF of asthmatic subjects were also elevated relative to normal subjects. Both IL-8 and RANTES are major factors in increasing migration and proliferation of neutrophils and bronchial smooth muscle cells. These cytokines may be involved in increases in immune cells, particularly neutrophils. Although we also measured IL-5 and GM-CSF in BALF and serum. The difference between normal and asthmatic subjects was not significant.

Aging is an unavoidable and complicated process characterized by progressive loss of functional activity, repair and recovery [16]. As shown in Table 2, hematological indices such as Hb and Hct in the elderly adult group decreased significantly when compared to the young adult group, and physiological indices such as FVC, FEV1 and FEV₁/FVC ratio in the elderly adult group showed stronger decreases than in the young adult group or middle-aged adult group. Aging is related to a progressive decline of lung function [17], and subjects with severe persistent asthma were much older than those with mild asthma [18]. Neutrophils were increased in the sputum of elderly asthma subjects. Therefore, neutrophilic airway inflammation is more common in elderly and severe asthma subjects [19, 20]. In our study, neutrophils in serum and BALF of asthmatic subjects were elevated when compared to normal subjects (Table 1). In the elderly adult group, neutrophils in serum and BALF were elevated as compared to the young adult and middle-aged adult groups, although this difference was not significant (data not shown). Accordingly, the relationship between neutrophils and aging after sub-classification should be analyzed further according to severity.

It is becoming recognized that the immune system declines with age via a process known as immunosenescence, which leads to a higher incidence of infections, neoplasia and autoimmune diseases [21]. The age-dependent decline in the immune system could be attributed to the functional activity of hematopoietic stem cells in older subjects [22]. Previous studies have reported that total serum IgE in the elderly adult group is lower than in the younger group and total IgE and allergen specific IgE have decreased with age in allergic patients as well as healthy members of the population [23]. In the present study, the level of total IgE in the elderly adult group was decreased relative to the young adult and middle-aged adult groups. However, this difference did not achieve statistical significance (data not shown). As shown in Table 3, Der p 1-specific IgE(class) was decreased in the middle-aged adult and the elderly adult groups relative to the young adult group. More than 31 allergens in the HDMs extracts have been reported to date, and specific IgE reactivity profiles to purified allergens vary in subjects from different countries [24]. Future investigations will need to be conducted to examine the association of other specific-IgEs with aging.

Although we could not detect statistically significant differences in serum TARC between normal subjects and asthmatic subjects, serum TARC was elevated in the elderly adult group relative to the young adult and the middle-aged adult groups, in which serum TARC was not detected (Table 3). Moreover, TARC was positively related to total IgE (Table 4). TARC plays a dominant role in Th₂-type disease conditions by recruiting Th₂ cells into inflammatory sites [25]. Several studies have demonstrated that there were elevated levels of TARC in patients with atopic dermatitis [26, 27] and asthma [28, 29]. The elevated TARC in asthma patients may be a reflection of increased TARC expression at inflammatory sites of the asthmatic airway [30]. The normal levels of serum TARC in healthy children and adults differ depending on age, with TARC levels being higher in children [31, 32].

However, in our study, the level only increased in the elderly adult group of the asthmatic subjects. It should be noted that this study had a few limitations. First, the asthmatic subjects included in this study show various allergic status (GINA 1–4). The relationship between severity and other parameters cannot be evaluated in this study. Second, we do not have any information regarding whether asthma found in elderly adult groups developed as a result of late onset asthma or was diagnosed in their childhood. Further study will be need to investigate these limitations.

TARC in serum of the elderly adult group was increased when compared to members of other younger groups, and was positively related to total IgE in the total and elderly adult asthma group. Cytokines such as IL-6, IL-8, MCP-1, RANTES, and MIP-1α were significantly altered in the elderly adult group. The results presented herein will help elucidate the pathogenesis of allergic diseases such as asthma, as well as to mining of biomarkers associated with age.