Brain-derived Neurotrophic Factor (BDNF) Single Nucleotide Gene Polymorphism and Nerve Growth Factor as Risk Factors That Increase Severity of Allergic Rhinitis

Allergic diseases such as asthma, allergic rhinitis (AR) and atopic dermatitis affect more than 25% of the world population and are the leading cause of illness in children. The complex interplay between genetic, environmental and immunological risk factors results in the manifestation of allergic diseases . The pathological presentation of allergic disease involves the activation of both the innate and adaptive immune systems, resulting in a multifaceted response in specific target tissues such as the airways . This response results in the recruitment of inflammatory cells to target tissues and the production of specific IgE antibodies, cytokines and other inflammatory mediators [11], [12]. It is well established that allergic inflammation triggers neuronal dysfunction, which activates specific inflammatory mechanisms, potentially leading to structural changes in the diseased tissue . Neurotrophins are a family of structurally related proteins initially discovered to be involved in regulating neuronal development and now known to govern both peripheral and central nerve growth.

BDNF is a secretory protein belonging to the neurotrophin family and is involved in a range of neural processes during human development [19], [20]. In the early stages of development BDNF is essential for neurogenesis, survival and maturation of neuronal pathways. In the adult, alongside neurotransmitters, hormones and other neurotrophins, BDNF maintains synaptic plasticity, dendritic growth and the consolidation of long-term memory. The biological effect of BDNF is mediated via its binding to the trkB receptor. The activation of these receptors on eosinophils may be important in regulating the inflammatory cascade leading to allergic disease [15], [24]. Neurotrophin mediated activation of bronchial eosinophils might therefore play a role in the regulation of eosinophilic inflammation in allergic asthma .

The BDNF gene is located on chromosome 11p13 and is alternatively spliced resulting in several different transcripts [26]. Genetic polymorphisms in BDNF have been associated with allergic phenotypes such atopic dermatitis [27] and asthma [28], [29], [30], [31] in different populations. The functional polymorphism rs6265 (Val66Met) has been shown to regulate intracellular trafficking and affect the secretion of BDNF [32]. Nerve growth factor (NGF), a neurotrophin that is expressed in the glandular, nasal epithelium, and peripheral nerves in the nasal mucosa, has been shown to induce biochemical and structural changes in nerves that can lead to hyper-responsiveness [33], [34], [35] The biological effects of neurotrophins are mediated by binding either to the high-affinity tyrosine kinase (trk) receptors or to the low-affinity receptors known as pan-neurotrophin receptor p-75.