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Hay fever is the common name for a condition called seasonal allergic rhinitis, which means an allergy that affects the nose. Most people get hay fever with spring, when airborne pollen from grasses, ragweed and other plants reach their peak. However, hay fever can occur at any time of the year. More and more adults found out they have pollinosis which causes sneezing, running nose, itchy eyes. The prevalence of allergic diseases increases significantly in both developed and developing countries. Allergic rhinitis is thought to affect up to 10-30% of the population in the world. Climate change, the introduction of new species of exotic plants into the country, new infections and the tendency to live in more sterile internal environment are four theories put forward to explain the rise. Many people thought that genetic predisposition is associated with hay fever but this may only be triggered later in life. Allergic rhinitis has a severe affect on quality of life of patients. Nasal congestion and sleep impairment are the most serious complaints in allergic rhinitis. It is estimated that more than 6 billion dollars was spent on prescription medications for AR in 2000 in US -following Stempel and Woolf's analysis. As for the management, hay fever is effectively managed by preventing or reducing the symptoms caused by the inflammation of the affected tissues. However, the treatment is not solved the main cause of the disease, patients still need to take medication during the pollen season or all the year.
Seasonal allergic rhinitis is an inflammatory disease of nasal mucosa induced by an IgE-mediated reaction, following exposure to an allergen. This disorder is characterized by sneezing, running nose, itchy eyes. AR is a global health problem, with prevalence between 10-30% of the population in the world in general. In particular, recently, a European study has calculated the prevalence of confirmed AR to be ranged from 17% in Italy to 29% in Belgium with an overall value of 23% for Europe (1). AR is the most common allergic disorder and one of the main causes of medical consultation - thus giving an important economical and social burden. Although it is not a life-threatening disease but it has a major impact on patients' life: affecting social life, school, and work performance. The development of allergic rhinitis is the combination of environmental exposure and genetic predisposition to different factors. We can use skin test (prick test, patch test, skin end point titration) or allergen-specific immunoglobulin E antibody test to diagnose AR. The goal of treatment of AR is preventing and reducing the symptoms also improving the quality of patients' lives. We can combine steroids with antihistamine, decongestants to get more effective result. Nowadays, allergen immunotherapy becomes the only treatment modality with the potential for long-term immunologic amelioration of AR.
WHAT IS POLLEN ALLERGY?
Pollen allergy is a nasal inflammation that occurs when pollen is in contact with mucosal epithelium. Pollen is inhaled by individual with a sensitize immune system. The pollens triggers the production of IgE which binds to mast cells and basophiles and causes the release of inflammatory mediators such as histamine.
Released histamine is responsible for many symptoms of hay fever such as: sneezing, running nose, watery and itchy eyes, swelling and inflammation of the nasal passages, and an increase of mucus production.
(2) Allergens may be grouped according to population-based IgE prevalence (major and minor allergens), their physicochemical structure or biological role in the organism. Major allergens belong to those which trigger the allergic response in more than 50% of the patients to a particular source. Minor allergens induce allergy in less than 50% of patients. Pan-allergens form a family of homologous and related proteins from different species (profilins, lipid-transfer proteins, polcalcinsâ€¦). People living in different areas will have different effects of pan-allergenicity. For example, patients living in central or northern Europe have lower impact than those living southern Europe because in central or northern Europe have grass and Betulaceae as the only source of allergic pollen while southern Europe, in addition to, grasses has other pollen species such as olive, pellitory, cypress and Russian thistle. Additionally, in some geographic areas, with peak counts 10000 grains/m3, minor allergens can become major allergens.
Following Barber et al's study, there are some figures as examples for the difference of the effect of major allergens, minor allergens and pan-allergens in different areas of Europe. Their study was done in Spain.
Figure 1 summarizes the geographical distribution of sensitization to the major allergens. As showed in the figure, the frequency of patients sensitive to major olive pollen allergen, especially in Jaen, was very high. The second rank was grass. In the western provinces, the frequencies can reach 80% for Phl p 1 allergy and more than 50% for Phl p 1. The third rank was Sal k1, the main allergen of Salsola kali pollen.
Figure 2 shows the comparison of major olive allergen Ole e1 and minor olive allergens Ole e7, Ole e9. But in some areas the percentages of Ole e7 and Ole e9 are still high due to higher olive exposure.
Figure 3 represents the specific IgE (sIgE) values of the three pan-allergens. In general the prevalence was low but in some areas it was also high. When comparing the data of figure 1 and figure 3, we can see there is a relationship between Mal d4 and grass allergens but there is no colleration between Mal d4 and Ole e1.
Figure 1. Prevalence of major allergen sIgE in the study area. Prevalence categories are defined as indicated, according to a color scale. A different scale is used for the most prevalent allergens (Phl p1, Phl p5 anf Ole e1). Numbers inside each province indicate the median sIgE value in positive samples.
Figure 2. Prevalence of minor olive allergen sIgE (Ole e7 and Ole e9) in the study area compared to the prevalence of the major allergen Ole e1. Categories are defined as indicated. Numbers indicate the median sIgE value in positive samples.
Figure 3. Prevalence of pan-allergen sIgE [profilin (Mal d4), polcalcin (Che a3) and LTP (Pru p3)] in the study area. Prevalence categories are defined as indicated, according to a color scale. Numbers indicate the median sIgE value in the positive samples.
3. Effects of the environment on incidence of hay fever
There is a rapid change in weather since the mid-20th century. The Earth's temperature is increasing and the following events are the warming of the oceans, melting glaciers, diminished snow cover in the Northern Hemisphere, rising sea levels. All of these events are due to the increase of green house gas concentration. Major changes in the climate have major effects on biosphere and human environment.
Furthermore, economic and industrial growth, air pollutants became the main element that affects the respiratory system. In urban areas with high volume of fuel combustion, the most abundant air pollutants are respiratory particulate matter (diesel particles, black carbon), nitrogen dioxide and ozone which damage the respiratory system when inhaled. These particles triggers oxidative stress, activate several mitogen- activated protein kinases and transcription factors and disturb the cellular function. People living in the urban areas have more likely to be affected by pollen-induced allergy than people living in the rural areas. Additionally, these air pollutants can bind to pollen grains and act as carriers. Other studies also showed that polluted air affect the amount of released pollen (i.e. timothy grass when treated with increasing concentration of NO2 and O3 releases more allergen-containing granules than when exposed to air only). Moreover, the release of pollen also is affected by humidity, extreme weather event (thunderstorm) -low humidity causes more pollen release and high humidity is associated with low pollen concentration (3). However, after rain, under hydration and hypotonic shock, pollen can release subpollen particles varying from 0.5 to 4.5 Âµm in size that can go deeper in the respiratory tract and increase the severity of symptoms (10).
Figure 4. Possible effects of air pollutants in allergic diseases
How does climate change affect allergic pollen?
Air temperature together with the length of day-light, water and nutrients play an important role in the development of plant species. Due to an increasing of air temperature, the timing of life cycle events of many species has also changed. Based on data provided by the International phonological gardens network, spring events come 6 days earlier and this also lengthens the duration of the pollen season. An earlier start of the season is confirmed through the studies of allergenic species: birch, mugworth, Urticaceae grass, and Japanese cedar. In experimental conditions, increasing of CO2 and temperature induce an increase in pollen production from ragweed. Beside air temperature, altered circulation of the atmosphere takes part in changing the transport of allergic pollen due to the effect on wind patterns. These changes may facilitate long-distance transport of new allergenic pollen particles. Even though the map for distribution of allergenic plants is not clear it is explanatory in cases of grass and ragweed. Grass pollen is responsible for world-wide pollinosis and in the last decades, variations in total pollen count have been identified. In the analysis of UK time series of aerobiological data demonstrated a increase in yearly grass pollen counts and a severity of pollen season and an earlier start of the season. But the results are different in each study sites (London, Derby, and Cardiff) due to the role of local determinants (climate), plants adaption (tolerance to environmental factors), changes in land use, changes in species and effects of air pollutants. Like grass, since the last decades of the 19th century, ragweed has affected large areas of Central and Eastern Europe. However, in Eastern Europe the development of ragweed is associated with major socioeconomic transitions rather than with climate change. Additionally, the global warming affects all phases of the plant development but it is not certain that it also affects the length, start and end of pollen season (3).
Following G. D'Amato and L. Cecchi, pollen grains carry their antigens that can irritate the respiratory system. When adhering to the surface of these pollens, air pollutants (diesel exhaust particles, nitrogen dioxide and ozone) change their antigenic properties. Factors that can affect this interaction: type of air pollutant, plant species, nutrient balance, climate factors, degree of airway sensitization and hyperresponsiveness of exposed subjects. Consequently, in response to the aeroallergens, IgE-mediated reaction is induced which exacerbates inflammation (3).
Figure 5. Effects of climate change on patients with respiratory allergy
In figure 5, the number of patients with allergic rhinitis is shown to increase or decrease based on the temperature. For example, in 2005, there was a large drop in the temperature which led to a decrease in tree pollen counts and less patients with allergic rhinitis compared to 2003 and 2004. But after this time, the temperature increased every year since 2006, the tree pollen counts also increased and the number of patients with allergic rhinitis significantly rose from 100 patients to 200 patients.
Changes in the air quality and the climate including global warming induced by human activities (factories, urbanization with its high levels of emissions by combustion engines and westernized lifestyles) have an impact on the environment and the biosphere. It seems like people living in urban areas have an increase in increased risk for respiratory allergy compared to those living in rural areas.
GENETIC BACKGROUND OF POLLINOSIS
As discussed above, environment is a factor that significantly influences pollinosis all over the world but we also need to know how genetic factors, risk factors play a part in the development of hay fever.
1. Environmental factors vs genetic factors
Include: duration of breast feeding, maternal age, heating of wood or coal and exposure of diesel exhaust fumes, tobacco smoke, air pollution, diet, socioeconomic status (4).
Effects: lengthen the duration of pollen season; modify the antigenic properties of pollen, large-scale effect.
Search for susceptibility genes that contribute to pollinosis. Use of 2 major techniques: linkage mapping, candidate gene approach.
Linkage mapping: scan the entire of DNA, various members of families affected by pollinosis.
Candidate gene approaching: evaluate the association between a particular allele that involves and presences in the disease (5).
Table 1: Comparison of environmental factors and genetic factors
2. Genetic aspects of allergic rhinitis
Allergic rhinitis is the final outcome of the combination of environmental factors and genetic factors. But this inheritance doesn't follow Mendel's law; the heredity is demonstrated by studies twins- the percentage of monozygous twins to get AR is higher than dizygous ones (5). The change in huge genetic materials which complex the disease seems to be related to the interference of particular single nucleotide polymorphisms (SNPs). SNPs can be located at the coding regions which will change the structure of proteins or can be at promoter regions which modify the protein expression or can be considered to be silent in that they do not vary the encoded amino acid. "In order for a give SNP to contribute a disease, it must meet a number of criteria: it must induce an alteration in the function or in the expression of the genic product; a linkage study of sufficient statistical power must exist, confirming association to the disease; and the mechanism must be plausible from the biological perspective." (5).
Linkage mapping is the process to find the association between pollinosis and the presence of genetic markers to localize sensitivity loci within the genome. It shows the relationship between certain phenotypes (bronchial hyperreactivity, total serum IgE, eosinophilia, and positive allergy skin test) and markers on chromosomes 4, 6, 7, 11, 13 and 16 (5).
Candidate gene approaching determines the alleles that relate to allergic rhinitis. They can be genes that produce regulators of specific immune response such as human leukocyte antigen D (HLAD), T cell receptor, IL-4, IL-4 receptor, interferon-Î³, FÎµRIÎ² or parts of inflammatory process as TNF-Î± (5).
Based on linkage mapping and candidate gene approaching, a number of genomic searches have been made.
Table 2. Genomic searches conducted in allergic rhinitis (5).
Table 2 shows the candidate regions and susceptibility genes which are associated with allergic rhinitis. In the 1st study, Haagerup et al. performed their study on Danish families with at least two siblings diagnosed with allergic rhinitis. The authors analyzed the principal candidate region in 4q24-q27 and 11 selected candidate regions corresponding to chromosomes 3p, 3q, 4p, 4q, 5q, 6p, 9p, 12q, 12qter, 18q and Xp. But after that, the same authors analyzed 97 polymorphic markers on 424 individuals in 100 families and concluded that some susceptibility genes located on 3q, 4q (the most intense region 4q32.2) and Xp could have an important role in AR inheritance. In another study, Yokouchi et al. was able to link AR to chromosomes 1p36.2, 4q13.3 and 9q34.3. When doing study on 295 French families, Dizier et al. concluded that 1p31 could be the common genetic determinant for AR (5).
Table 3. Polymorphisms for which a positive association to AR has been described (5).
Single-nucleotide polymorphisms coming from large scale genome sequencing studies have been processed for the last few years. These studies were mainly done in Asian countries (Japan, Korean, Turkey, and Czech Republic). The aim of these studies is to group the common polymorphisms associated with AR.
2.1. Polymorphisms in genes encoding chemokines and chemokine receptors
Chemokines and chemokine receptors play in important role in inflammatory process of allergic diseases in general and in AR in particular. There are many studies on those genes that encode chemokines and chemokine receptors to find out the relationship between these inflammatory components and allergic rhinitis.
Nakamura et al. did the research on a Japanese population who are allergic to Japanese cedar pollen and he discovered genes that encode CXC chemokines receptor (CCXCR)-1, CCR1, CCR2, CCR3, and CCR5 which are localized at 3p21.3 and 8 polymorphisms associated with this disease. Lately, they have confirmed that SNP 64Il6e in CCR2 and 51C in CCR3 had strong association with AR and the presence of 64Ile/780C/51C in patients with hay fever is more than that in the control (5).
In another study, Zhang et al. did their experiment with children and their relatives who were susceptible to orchard grass, the major cause of seasonal allergic rhinitis (SAR). First, the study showed the correlation between chemokines (C-X-C motif) ligand (CXCL)-9, CXCL10, CXCL11 and SAR. Even though, these chemokines share the same receptor but their expression is different in different diseases. Moreover, these chemokines are T1-type chemokines induced by IFN-Î³ stimulation and allergic rhinitis is T2-type disease, but CXCL9, CXCL10 and CXCL11 are expressed in allergy test reaction. In addition, the function of the SDA 1 domain containing 1 (SDAD1) is known as the strongest genetic association with SAR. Next, they confirmed that CXCL9, CXCL10, CXCL11 and SDAD1 located on 4q21 are synonymous polymorphisms which are associated with SAR and these haplotypes were transmitted to the offspring (6).
Additionally, Kim et al. showed the frequencies of RANTES (regulated on activation, normal T-cell expressed and secreted) alleles (-403A and -28G) were higher in patients than in controls. Chae et al. also obtained the alleles +2497T>G and eotaxin-3 located on 7q11.22 associated with AR (5).
2.2. Polymorphisms in genes encoding for interleukins and interleukin receptors
Cytokines are multifunctional proteins that mediate both of innate and adaptive immunity. Immune responses by binding to their receptor on target cell, they induce signaling pathways within target cells. Recently identified single nucleotide polymorphisms on genes encoding cytokines and their receptors have been related to AR.
-607 IL-18 on chromosome 11q22
IL-18 is one of the most important regulators of innate and adaptive immune response and is presence in chronic inflammatory site. IL-18 not only triggers Th1 cytokines but also induces Th2 cytokine production, IgE levels and eosinophil recruitment in allergic inflammation. In study of allergic rhinitis on Korean population, Lee et al. found that the frequency of polymorphism IL-18/-607 of promoter regions was higher in patients with AR than in the control. In contrast, there were some studies found that there was no relationship between IL-18/-607 polymorphism and AR. Because the polymorphism is functional, susceptibility genes to AR are different in different ethnic groups (7).
G>A IL-28RA on chromosome 1p36.11
Interleukin-28RA is the receptor for IL-28 which is responsible for immune defense against viruses. IL-28 increases the sensitivity to viral infection and inflammation, but the relationship between SNP of IL-28RA and patients susceptible to AR has been poorly understood. Recently, Chae at al. performed their study on the entire coding regions of IL-28RA as well as promoter regions and identified 18 SNPs and two variation sites (8).
2.3. Polymorphisms in genes encoding IL-4 or IL-13 and IL-4RA
Allergic rhinitis is caused by exuberant Th2-type immune response. IL-4 and IL-13 are two cytokines secreted by Th2 cells that induce isotype class switching of B cells to produce IgE. Receptors for IL-4 and IL-13 (IL-4R and IL-13R, respectively) share the IL-4RÎ± chain and induce signal transducers and activator of transcription (STAT6) activation. Seven studies found that the polymorphism Gln551Arg of IL-4RÎ± chain is associated with allergic rhinitis. On the other hand, the frequency of allele 2044A present in exon 4 of the gene coding IL-13 was different between controls and patients (9).
2.4. Polymorphisms in genes encoding for eosinophil peroxidase (EPO)
Eosinophils play an important role in controlling the mechanism of allergy. Nakamura et al. found out the polymorphism of Pro358Leu of EPO has a relation to the Japanese cedar pollinosis. Also, the same group discovered the silence mutation of Arg202Arg has been associated with Japanese adult populations who have allergic rhinitis (5).
"But up to now, it is clear that no single genetic risk factor is responsible for the development of allergic rhinitis."
MECHANISM OF POLLEN ALLERGY
1. What make pollen grains allergic?
Pollens that cause hay fever belong to anemophilous plants. These plants produce a large number of lightweight pollen which can be carried over a great distance by the wind and easily inhaled into nasal passages. Opposite to those plants, entomophilous plants produce heavy, sticky pollens which are carried by insects, hence do not "fly" and thus they are not able to enter the respiratory tract. Oak, birch, ragweed, pecan, grasses are anemophilous plants which are the main cause in hay fever.
Pollens are complex biological packages containing many proteins. Pollen grains and subpollen particles can enter the lower respiratory tract and cause allergy. On one hand, pollens consist of different antigenic proteins such as the pectase lyase Amb a 1 in ragweed, defensin like Art v 1 in mugwort, Ole e 1-like allergens Pla l 1 in plantain and Che a 1 in goosefoot and non-specific lipid transfer protein Par j 1 and Par j 2 in pellitory. These antigenic proteins are recognized by antigen presenting cells and presented to Th2 cells, thus activating the adaptive immune response. On the other hand, pollens also possess several other proteins, some with enzymatic activities. One of the most important enzymes found in plants is NADPH oxidase which takes a crucial part in physiological functions of the plant (defense against pathogens and growth and development). When pollen grains enter the body, pollen-induced NADPH oxidases induce reactive oxygen species (ROS) in airway epithelium within minutes, which in turn causes the oxidative stress, independent of the adaptive immune response (signal 1). The production of oxidative stress such as oxidized glutathione (GSSG) and 4-hydroxynonenal (4 HNE) develop the airway inflammation induced by pollen antigen (signal 2). GSSG and 4 HNE in the airway lining fluid contribute to p38 MAPK activation, recruitment of neutrophils and IL-8 production (10). Besides NADPH, pollen grains also release proteases which are recognized by protease-activated receptors (PARs). The release of proteases causes the inactivation of lung regulatory neuropeptides, such as peptide P and vasoactive intestinal peptide. Proteases from pollen not only increase the paracelluler permeability of the epithelium by disruption of transmembrane adhesion proteins: occluding, claudin-1 and E-caherin, in vitro, but also help the allergen cross the epithelial barrier and contact with DCs to activate the immune response, in vivo (29).
However, pollens do not enter epithelia with only pure allergens, but together with pollen granules, starch grains, and non-protein substances with chemical and functional similarities to leukotriens and progtaglandins -the pollen associated lipid mediators (PALMs). There are two main groups of PALMs: the immunostimulatory PALMs activating innate immune cells (eosinophils and neutrophils) and the immunomodulatory E1-phystoprostanes blocking IL-12 production of dendritic cells, resulting in the induction of Th2 responses. In innate immune response, the immunostimuatory PALMs attract and activate polymorphonuclear neutrophils (PMN) and eosinophils leading to the release of myeloperoxidase and eosinophilic cationic protein, respectively (27). Furthermore, PALMs upregulate the production of Î²2-intergrin (CD11b) which facilitates the transmigration of PMN into the tissue (28). In adaptive immune response, the immunomodulatory PALMs induce the expression and function of CXCR4 which is vital for the movement of dendritic cells to the lymph node. At the same time, PALMs decrease the LPS-induced production of the Th1 attracting chemokines CXCL10 and CCL5, which in turn enhance the release of Th2 chemokine CCL22. Pollen allergens do not come alone: PALMs shift the human immune system towards a Th2-dominated response (27).
2. How do pollens trigger an immune response?
Allergy is hypersensitivity to foreign, but innocuous substances. The allergic response occurs when the nature immune system against the environmental particles, is disturbed. The respiratory tract contains epithelial cells, dendritic cells, alveolar macrophages and granulocytes such as neutrophils, and eosinophils which are responsible for interacting with inhaled particles or allergen bound particles (28). When inhaled antigens, pollen grains in particular, passed through the upper airways without filtration, they will get contact with the epithelial cells of the trachea or even that of the lower respiratory tract. In the epithelium barrier, pollens produce proteases which, in turn, increase the permeability of the epithelium which makes pollen pass the epithelium barrier easier. After crossing the epithelium barrier, pollen contact with dendritic cells, macrophages which trigger the activation of innate and adaptive immune systems. The system has 2 components:
The humoral: antibodies (IgM, IgG, IgE, IgA) and complement system.
The cellular immunity: presenting antigen cell (macrophages, dendritic cells), lymphocytes T and B, monocytes and granulocytes) (12).
In the early phase response, activation of dendritic cells occurs when pollens get contact with dendritic cells through toll-like receptor (TLR)-4. Mature dendritic cells migrate to the draining mediastinal nodes via the afferent lymphatics, a process that needs C-chemokine receptors CCR7 and CCR8. In the lymph node dendritic cells present the antigen to T cells, selection and differentiation of T-cells begins (12). After activation, mature T cells contact with B cells and cause the maturation of B cells. Mature B cells produce specific IgE which, in turn, enters the blood stream. In the blood, specific IgE attaches to immature mast cells, which play important role in the allergic inflammation, via FcÎµRI. The activation of mast cells occurs in the presence of antigen that can cross-link the IgE molecules. Histamine, which is released from mast cells due to the binding of antigen, is the main mediator of allergic rhinitis; it also induces the symptoms of allergic rhinitis: sneezing, running nose, itchy eyes. In the late phase response, the symptoms are prolonged around 18-24h. This phase is characterized by T lymphocytes, basophiles, and eosinophils. The early phase connects to the late phase by the release of cytokines, chemokines like IL-4, IL-13 from mast cells which will increase the expression of vascular cell adhesion molecule 1 (VCAM-1) on endothelial cells helping the extravasation of eosinophils, T lymphocytes and basophiles to the nasal mucosa. Moreover, chemokines, RANTES, eotaxin, MCP-4 and thymus activation regulated chemokine (TARC) secreted by epithelial cells also participate in the infiltration of these cell to the site exposed to the allergen. In addition to regulation of T-cell differentiation, dendritic cells also take part in the recruitment of eosinophils, neutrophils (15).
3.1. The role of dendritic and epithelial cells in allergic rhinitis
Figure 6: Movement of dendritic cells to lymph node
Dendritic cells (DCs) are sentinels; the most efficient professional antigen-presenting cells that can sample the environment internalize antigens process concomitant information (e.g danger signals) received at any time and instruct differentiation and activation of naÃ¯ve and effector T-lymphocytes accordingly. In allergic rhinitis the T-cell response is stronglyâ€¦ towards a Th2 response. When antigens enter the body through the mucosa surfaces (such as the airways), they bind to the pattern recognition receptors (PRR) expressed on the surface of DCs. Activation of DCs via PRRs induces the migration of activated DCs into the draining lymph node where they home into the T cell area. This movement requires the presence of chemokines receptors CCR7 (12). During this process that usually takes about 12-24 hours dendritic cells undergo a so-called maturation process that manifest in the upregulation of MHC recptors, and co-stimulatory receptors (i.e. CD40, CD80, CD86, OX40) enables DCs to efficiently present antigens to the T-cells and regulate their differentiation various effector T-cell types (described later).
When DCs arrive at the T-cell area of the regional lymph nodes they make contact with the Th-cels. During the contact time, the combination of interaction cell surface receptors and soluble factors (cytokines) produced by the DCs will determine the characteristics of the T-cell response. Next, T helper cells -T follicular helper cells move into the B cell follicle to help immunoglobulin class switching and affinity maturation of the B-cell receptor, and help the B cells to become plasma cells or memory B cells. Other T-cells (Th1 cells, and cytotoxic T-cells or CTLs) leave the lymph nodes and migrate back to the site of infection where they help innate immune cells to kill pathogens.
Figure 7: Role of dendritic cells in the immune system
The activation of dendritic cells by pollen is not direct. To activation dendritic cells, epithelial cells play an important role. Studies of TSLP (thymic stromal lymphopoietin), derived from epithelial cells, prove the activation of dendritic cells by epithelial cells. TSLP is type I cytokine that is a member of the IL-2 family. TSLP, originally, was discovered at thymic stromal cells which can support the development of T cells. Recently, it has become clear that TLSP is expressed by epithelial cells, especially those of lung, gut and skin. During inflammation, epithelial cells and stromal cells chiefly produce TSLP (Figure 7). For example, Bogiatzi et al. showed that proinflammatory cytokines TNFÎ± and IL-1Î² can cooperate with IL-4 and IL-13 to produce more TLSP from epithelial cells (13). In addition to epithelia, basophiles also have potential to produce TLSP during allergic rhinitis. In response to TSLP, human dendritic cells will upregulate their MHC II, CD40, CD80, CD-86 and DC- associated activation marker, DC-lamp. Moreover, TSLP induces production of chemokines by DCs (IL-8, eotaxin-2, TARC and I-309) which are required for the recruitment of eosinophils, neutrophils, and Th2 cells. After activated by TSLP, mature DCs express high level of TSLPR on their surface and induce the differentiation of naÃ¯ve CD4+T cells into Th2 cells to produce IL-4, IL-5, and IL-13. In addition, TSLP-activated DCs can also expand the Th2 memory cells while maintaining their central memory phenotype (12). Besides producing TSLP, epithelial cells induce the release of eicosanoids, endopeptidase, cytokines and chemokines (IL-6, IL-8, GM-CSF, TNFÎ±, RANTES, TARC, eotaxin, SCF) and express several adhesion molecules such as ICAM-1 and VCAM-1 to endow the development of allergic inflammation. Interstingly, nasal epithelial cells in allergic rhinitis were shown to produce matrix metalloproteases matrix metalloproteinase (MMP)-2, MMP-9 and MMP-13. They also are potent antigen-presenting cells due to their ability to express HLA-DR and CD86, thus they can present antigens directly to the naive T cells (15).
When entered the lymph node, mature DCs connect to naÃ¯ve T cells via 2 pathways: MHC II -T-cell receptor and OX40 -OX40L. The interaction OX40 -OX40L is the main key for the allergic inflammation. OX40L is expressed mainly on CD4 T cells, whereas OX40 is found on the TSLP-activated DCs, B cells, macrophages, Langerhan cells, and endothelial cells. Studies of OX40/OX40L also proved that OX40 deficient CD4+ T cell can increase in number but it cannot survive long term due to lower expression of anti-apoptosis agents such as Bcl-2, Bcl-xL, and Bfl-1. Therefore, OX40/OX40L is very crucial for the activation, survival and long-term memory of Th2 cells in allergic rhinitis (13).
The role of the IL-17 -family of cytokines in AR
TSLP-activated DCs not only affect the activation and proliferation of Th2 cells via their OX40L they also activate Th2 memory/effector cells through the expression of IL-25R to produce more cytokines and to against the relapse of Th2-mediated allergic diseases (13).
Besides OX40/OX40L, the induction of IL-17RB is also indispensable for the Th2 memory cells. TSLP-activated DCs initiate a high level expression of IL-17RB (IL-25R) expression by activated Th2 memory cells. IL-17RB is the receptor for both IL-17B and IL-17E (IL-25), with higher binding avidity to IL-25. IL-17E is the member of IL-17 family, which includes IL-17A and IL-17B-F. IL-17A is the most abundant member in IL-17 family. Its level increases in lungs in response to TSLP-DCs, sputum, bronchoaveolar lavage fluids or sera, which suggests that IL-17 cytokines have a crucial role in causing allergic inflammation. In reality, IL-17A and IL-17F go together to local inflammation by initiating the release of proinflammatory cytokines such as TNFÎ±, IL-1Î², G-CSF, and IL-6, as well as chemokines CXCL1/Gro-Î±, CXCL2 and CXCL8/IL-8 which will recruit neutrophils to the site of inflammation.
IL-25 was first implicated as a Th2 cell-derived cytokine. The increase in level of IL-25 will evoke the production of Th2 cytokines and eotaxin which cause eosinophilia, increasing serum IgE, mucus hyperplasia and many pathological changes in the tissues. Binding of IL-25 to its receptor on the CD4+T cells mediates the differentiation of Th2 memory cells, and amplifies Th2 polarization and cytokine production by increasing gene expression of the transcription factors, GATA-3, c-MAF and junB (13).
3.2. Effects of mast cells, basophiles and eosinophils in allergic rhinitis
The symptoms of allergic rhinitis such as sneezing, running nose, hard breathing, and itchy eyes are all caused by inflammatory mediators: histamine, proteases, chemotactic factors, cytokines and metabolites of arachidonic acid which are released mainly by mast cells. Histamine is released when exogenous substances enter the body or mast cells are injured. It causes the dilation of the blood vessels so more blood will flow to the infection site. Mast cells are derived from the bone marrow and their maturation is marked by the binding of stem cell factors to the receptor c-kit and by other cytokines: IL-3, IL-4, IL-9 and IL-10. The cytoplasm of mast cells have many organelles (granules) can be reeased in response to various stimuli including chemical substances (toxin, proteases), endogenous mediators, or crosslinking by the allergen of the IgE bound to the FcÎµ receptor.
Figure 8: Function of mast cell in immune system
As shown in figure 8, after isotype switching B cells produce allergen-specific IgE which will bind to mast cells through FcÎµRI even in the absence of the allergen and leave the Fab free on the surface. After entering the basement membrane, pollens will bind to the free Fab portion of IgE and via crosslinking multiple IgE/FcÎµR molecules, it will trigger Ca2+ influx followed by the degranulation which results in the release histamine (early response), or prostaglandin, arachidonic acid and cytokines (IL-4, IL-5, IL-6, IL-1Î², and IL-13 (late response)). These mediators will act on blood vessels, cause the recruitment of neutrophils, macrophages, and stimulate the proliferation, differentiation of B cells and induce isotype switching which provide more and more IgE for the immune system to initiate the allergic inflammation. Since more blood reaches the site of inflammation, more mast cell progenitors will also arrive to mediate the allergic response. (15) Recruitment of mast cell progenitors is done by stem cell factor (SCF) or RANTES. Mast cells are indispensable for the inflammatory process in allergic rhinitis; they not only mediate the early phase response but also regulate the late phase response.
Like mast cells, basophiles derived from pluriopotent CD34+ stem cells also play crucial role in the allergic inflammation (15). Besides producing IL-4, IL-13, basophiles like epithelial cells also produce TSLP. However, whether basophiles have direct effect on T cells is not clear. Some data suggest that basophils may have a direct effect on B-cell differentiation. Tomohiro et al. found that basophiles can capture antigen by antigen-specific IgE bound to the cell surface-FcÎµRI. After activation, basophiles will produce IL-4, IL-6, and induce expression of CD40L, the ligand for CD40, which by binding to B cells induce proliferation of B cells and IgE production (16).
Another important cell type in allergic inflammation is the eosinophil granulocyte which is derived from progenitor cell (CD34+) in the bone marrow. The recruitment and activation of eosinophils are mediated by RANTES and eotaxin secreted by epithelial cells. Eosinophils can survive for several days or weeks in the presence of IL-5 and GM-CSF. Mature eosinophils consist of secrete manna-binding lectin (MBP),eosinophil cationic protein ( ECP), and eosinophil-derived neurotoxin (EDN) which change the surface epithelium and enhance the inflammation (15).
TREATMENT AND MANAGEMENT
1. Tests for pollen allergy
1.1. Skin test
Skin allergy testing is the method for medical diagnosis of allergies that efforts to stimulate a small, controlled and allergic response. There are 3 types of skin tests:
Prick test: A few drops purified allergens are pricked into the skin surface. To ensure that the skin is reacting as expected, all skin allergy tests are also done with proven allergens like histamine or glycerin. Most people react with histamine and do not react with glycerin.
Patching test: Skin allergic test is a method using a large patch that contains different allergens on it. This patch is usually applied on the back. When the patch is on the back, the patient should not bath or exercise for at least 48 hours.
Skin end point titration uses intradermal injection of allergens that increasing concentrations to measure allergic response. It is more sensitive but not as specific as percutaneous testing (11).
1.2. The allergen-specific immunoglobulin E antibody test
This test is particularly useful if the percutaneous skin test is not practical or if a patient is taking drug that is contraindicated with the test. This test is highly specific but not as sensitive as skin test. It is done by detecting specific IgE antibodies to known allergens for the diagnosis of allergy (11). Nowadays, allergen test with specific IgE is preferred than skin prick test because it it safer and the result is not affected by the exogenous conditions, while skin prick test can get false positive result due to environmental factors.
2. Effects of pollen allergy on quality of life
The number of patients that suffer from allergic rhinitis increases every year and it is up to 40% of the Europe population (29). Among the symptoms of allergic rhinitis, nasal congestion is the one of the most disturbing and usually goes together with sleeping impairment. The result is a falling of quality of life and productivity and a raise of daytime sleepiness. Sleeping impairment makes the patient less energetic, fatigue, less productive, limits its ability to work. Nasal congestion occurs when edema is formed in the airways, increase airway resistance, cause nasal obstruction. Nasal congestion gets worse at night and in the early morning hours. The main mechanism for the obstruction is the reduction of cortisol level during the night. Even though the patients try to change position to compensate to decrease congestion it usually does not help. Together with nasal congestion, the other symptoms such as nasal puritus, sneezing, rhinorrhea, eye itching also impair the sleeping of patients. Cytokines and histamine released in the inflammation influence to the central nervous system. Histamine plays a role in the regulation of sleep-awake cycle and arousal. Cytokines such as IL-4, IL-10, and IL-1Î² are associated with increased latency of rapid eye movement (REM) sleep, decreased time in REM sleep and decreased latency to sleep onset. Because REM sleep is very important, its disruption can cause daytime fatigue, difficulty concentrating, and poorer performance in individuals with AR. Cytokines changes together with sleeping apnea can trigger a Th2 cell phenotype, which increases the inflammation and nasal congestion (17).
Therapy of allergic rhinitis is based on its symptoms. The goal of the treatment is to limit inflammation hence decrease the symptoms and increase the quality of patients' life. Intranasal corticosteroid and antihistamines are the first line drugs for rhinitis; it can be used to control the symptoms like sneezing, rhinorrhea, itching and nasal congestion. Steroid nasal spray is safe and effective even when using alone. Other drugs can be used as second line treatment as: decongestants, anticholinergics, and intranasal cromones. Furthermore, immunotherapy is the new treatment for allergic rhinitis. It is safer and more effective than traditional treatments; it redirects the unsuitable immune response in allergic patient by subcutaneous or sublingual administration of allergens.
3.1. Intranasal corticosteroid
Intranasal corticosteroid is the first line of drug for the treatment of pollen allergy to reduce the inflammation caused by histamine, cytokines (IL-4, IL-13, TNFÎ±â€¦). There are 2 generations of intranasal corticosteroid sprays available. Drugs in first generation are Triamcinolone acetonide, Flunisolide, Beclomethasone, Dexamethasoneâ€¦). Drugs in second generation are Mometasone Furoate nasal spray, Fluticasone propionate, Cliclesonide, Fluticasone Furoateâ€¦) (18).
Corticostreroids enter the cells and bind to the glucocorticoid receptor in the cytoplasm followed by nuclear localization of the complex where the transcription of target genes is either initiated
Figure 9: Mechanism of corticosteroids (18)
or supressed. When the glucocorticoid receptor homodimer binds to a glucocorticoid response element present in the promoter region steroid-regulated gene, the transcription of the gene encoding anti-inflammatory mediators (annexin-1, secretory leukoprotease inhibitor, IL-10 and the inhibitor of nuclear factor-ÎºB) starts. The nuclear factor-ÎºB will activate histone acetyltransferase (HAT) which will bind to glucocorticoid receptor -corticosteroid complex and repress the expression of the inflammatory genes (18).
Systemic bioavailability of intranasal corticosteroid is calculated by the sum of portion that is absorbed in nasal mucosa and the portion that is swallowed. Since the drug enters the gastrointestinal tract, it will undergo the first-pass metabolism in the liver; the pharmacokinetics of drug will change in patient with hepatic impairment. The second generation drugs have pharmacokinetic activities that reduce their systemic bioavailability so that minimize the systemic side effects. However, intranasal corticosteroids still cause some local adverse effects such as: epistaxis, throat irritating, and nasal dryness, burning and stinging. Epistaxis is the drying and thinning of the nasal mucosa which can be caused by nasal applicator tip pressing against the septum or the anterior end of the inferior turbinate. Furthermore, some severe local adverse effects are reported such as: nasal mucosal atrophy or ulceration and septal perforation. To avoid these adverse effects, the proper administration of intranasal corticosteroid spray should be applied (19).
Intranasal corticosteroids are considered as an effective and safe treatment for allergic rhinitis in general and for pollen allergy in particular for over 30 years. There are many drugs (Mometason furoate nasal spray, fluticasone propionate, Ciclesonide, Fluticasone furoate) that have the high safety profile via many clinical trials under extreme conditions.
Histamine is the main chemical that can trigger all symptoms of pollen allergy. Histamine is released by degranulation of mast cells after antigens bind to IgE on the surface of mast cells. Blocking the release of histamine will relieve the symptoms of pollen allergy and is the main target of therapy. There are 2 types of oral antihistamine drugs: oral antihistamines and intranasal antihistamines. The first generation of antihistamine (Dephenhydramine, Promethazine, Pheniramineâ€¦) typically had an effect on the Î±-adrenergic receptor and 5-HT receptors in the central nervous system and had a sedative side effect. The second generation antihistamines (Cetirizine, Loratadine, Bilastineâ€¦) target the peripheral H1 receptor and thus their sedative effect is strongly reduced compared to the first generation drugs.
Intranasal antihistamines There are many advantages of using intranasal antihistamines as treatment of hay fever such as: effective delivery to the nasal mucosa, direct onto the target tissue harboring histamine-filled mast cells and inflammatory mediators, fast onset and low incidence of unwanted systemic side effects. In patients with mild symptoms, it is considered as the first line of treatment. There are some intranasal antihistamines available such as: Azelastine hydrochloride with either a saline diluents or with sucralose/sorbitol -treatment of pollinosis in patients â‰¥ 5 years of age or â‰¥ 12 years of age. In another study, a randomized, double-blind studying comparing 0.4 and 0.6% intranasal Olopatadine to placebo, Olopotadine showed the reduction of symptoms in pollinosis and improvement in quality of life, functions (works and activities). Due to their main target on the nasal mucosa, intranasal antihistamines greatly decrease the nasal symptoms: nasal congestion, sneezing, itchy eyes. In the study of 151 patients with moderate to severe hay fever, Olopatadine 0.6% decreased all nasal symptoms compared with placebo, including stuffy nose (-21.7% vs. -13.2%), runny nose (-30% vs. -18.4%), itchy nose (-32.4% vs. -19.4%) and sneezing (-35.7% vs. -18.8%). There is no significant difference when comparing the effectiveness of intranasal antihistamines with intranasal costicosteroid. In addition, the combination of intranasal antihistamines and intranasal corticosteroid can achieve higher benefit in treatment. For example, the combination of Azalastine nasal spray with Fluticasone demonstrated a greater effect in nasal congestion in the treatment of moderate to severe seasonal allergic rhinitis. Another advantage of intranasal antihistamines is fast onset which can be as rapid as 30 minutes and its action can help patients to improve the symptoms immediately. Besides advantages, there are some disadvantages such as: side effects (headache, nose bleeding) and taste and odor of the medicine which can interfere the patients' usage. Finally, intranasal antihistamine has been shown to be very well tolerated, causing only mild side effects.
Oral antihistamines Like intranasal antihistamines, oral antihistamines are also considered as the 1st line in treatment of allergic rhinitis. Nowadays, the second generation is favored in using due to their non-sedative effect. Unlike intranasal antihistamines, oral antihistamines focus on the symptoms associated with histamines like sneezing, rhinorrhea, itchiness, watery eyes and eye redness. Furthermore, oral antishistamine is approved for young children (Desloratadine and Cetirizine, age 6 months and up; Levocetirizine, age 6 years and up; Loratadine and Fexofenadine, age 2 years and up). However, it does not have rapid onset like intranasal antihistamine but its onset is relatively fast (Cetirizine, 59-126 minutes; Loratadine, 102 minutes; Fexofenadine, 60minutes). Overall, oral antihistamines are effective for the treatment of histamine-associated symptoms of allergic rhinitis, but less effective for treating of nasal congestion. However, the combination of oral antihistamines and decongestants can improve their effect on nasal congestion. The onset of oral antihistamines is not rapid but it can be used at a one per day dose.
Intranasal antihistamine and oral antihistamine are applied to patients in different routes but their effects on allergic rhinitis are the same. They are considered as the 1st line drug in treatment of allergic rhinitis which improves the symptoms and quality of life (24).
3.3. Decongestants, intranasal anticholinergics, and intranasal cromones
Decongestants Nasal congestion is caused by the dilation of blood vessels in nasal mucosa. By acting on adrenergic receptors, oral and topical decongestants will cause vasoconstriction in nasal mucosa, resulting in decreased edema. The most common available decongestants are phenylepherine, Oxymetazoline, and pseudoephedrine, but their abuse potentials are against their benefits. Common side effects are sneezing and nasal dryness. Long duration of use is not recommended because it can cause rhinitis medicamentosa or rebound or recurring congestion. Additionally, it causes headache, elevated blood pressure, tremor, urinary retention, dizziness, tachycardia, and insomnia so it is caution for patients with cardiovascular conditions, glaucoma or hyperthyroidism (25).
Intranasal anticholinergics Like decongestants, intranasal anticholinergics cause constriction of blood vessels in nasal mucosa. Ipratropium is the most common intranasal anticholinergics that relieve only excessive rhinorrhea. It cannot cross blood brain barrier so it does not have systemic effect. Its side effects are nasal dryness, epistaxis (25).
Intranasal cromones Degranulation of mast cell is one of the main reasons for the symptoms of allergic rhinitis. Inhibition of degranulation by intranasal cromones will inhibit the release of histamine. However, it is considered as second line treatment because its ability to decrease symptoms is less effective compared to those of antihistamines or intranasal corticosteroids.
Figure 10: Effects of allergen-specific immunotherapy on immune parameters (18)
Immunotherapy is the treatment that can enhance, suppress or induce an immune response which is recommended in treatment of pollen allergy in moderate to severe patients. Targeted immunotherapy is the only treatment that can reduce the symptoms of pollen allergy by decreasing the recruitment of eosinophils, mast cells, and basophiles in the skin, nose, eye and bronchial mucosa. The mechanism of immunotherapy is increasing the production of Th1 cells, Il-10 from monocytes, macrophages, B cells and TGFÎ² which will contribute the Treg function and immunoglobulin class-switching IgA, IgG1, and IgG4. Binding of antigen to IgE in allergic inflammation decreases due to the competition of new immunoglobulin for the binding site (FcÎµRI anf FcÎµRII) on mast cells, which will reduce the degranulation of mast cell and the recruitment of basophiles and eosinophils (18). The treatment is based on the administration of allergen extractions given sublingually or subcutaneously for few years, with maintenance periods typically lasting between 3 to 5 years.
Subcutaneous immunotherapy (SCIT) concerns the regular subcutaneous injection of allergen extracts or recombinant allergens using incremental regimes, with the induction of tolerance taking from several days to several months depending on the regime used. There are 2 phases in the treatment: build-up phase (weekly injection) and maintenance phase (monthly injection) (18). There are many evidences proved that patients who suffer from pollen allergy have reduced the symptoms after treatment with subcutaneous immunotherapy. For example, children with Alternaria allergy were treated by SCIT for 3 years. The symptoms reduced significantly after the 1st and 2nd year of treatment and the decrease of symptom got 63% after the 3rd year. Furthermore, patients who got treated with SCIT 6 months before the pollen season showed improvement in tolerance to nasal allergen provocation test compared to patients treated with normal medicines (20). Treatment pollen allergy with SCIT has decreased the health cost significantly at the first 3 months treatment. However, SCIT also has its side effect: anaphylactic. To improve the efficacy and reduce the side effect, new SCIT has been launched with T-cell reactive peptides, hypoallergenic recombinant allergens, chemically modified allergens, replacing adjuvants such as alum with those containing tyrosine or calcium phosphate, incorporation of immunomodulators such as monophosphoryl lipid, and embedding of allergens into nanoparticles (18).
In 1987, sublingual immunotherapy (SLIT), which is safer, and more convenient than SCIT, was introduced as the treatment for allergic rhinitis. It involves the administration of soluble tablets or drops to be kept under the tongue for 1-2 minutes and then swallowed. SLIT has been applied either before the spring or fall allergy pollen season to prevent symptoms from pollinosis (22). However, the efficacy of SLIT is less than SCIT. In general, B cell response to SLIT to produce IgG4 is more limited than that in SCIT. Many meta-analyses were done to study about the efficacy of SLIT. For example, in 2005, Wilson et al. did the research on adult and children who had allergic rhinitis showing the high efficacy of SLIT, with a standardized mean difference (SMD) equivalent to -0.42 for symptom scores. Additionally, the clinical effect in patients receiving an amount of 275mcg/month of major allergen as cut-off separating low doses from high doses was much better than those with low doses. Even SLIT is safe for pollinosis, it still exists some adverse effects: local reactions in the mouth, gastrointestinal reactions (vomiting and diarrhea); systemic effects like asthma, rhinitis, or urticaria are very rare (21). Like SCIT, SLIT reduces not only the symptoms but also cost of health care.
Allergen immunotherapy (AIT) is a new treatment for allergic rhinitis in general and for hay fever in particular. The aim of this therapy is to reduce the symptoms of patient who suffer from the disease and increase the quality of life. Furthermore, it saves a huge amount of money for treating allergic rhinitis. For example, in America, children treated with AIT for AR had lower 18-month median total health care cost ($3247 vs. $4872), outpatients' costs ($1107 vs. $ 2626) and pharmacy costs ($1108 vs. $1316) (21).
3.5. Other treatments
Alternatively, there are some treatments that do not base on the imbalance of chemical in the body such as acupuncture, probiotics and herbal preparations. The mechanism of acupuncture is not clear but it suggests that the release of neurochemicals (beta-endophins, encephalins, and serotonin) which can regulate the inflammatory process of allergic rhinitis. Beside acupuncture, there are many studies of treating allergic rhinitis with herbals but the safety and effectiveness are not established.
The use and the mechanism of probiotics are not clear in treating pollinosis. There are some studies that proved the efficacy of probiotics in reducing the symptoms of pollinosis. For example, a Japanese study showed that the symptoms of Japanese cedar pollinosis reduced when intaking of Bifiobacterium lon gum BB536 as jogurt supplement. Another studies said that Lactobacillus gasseri TMC0356 in fermented milk changed the serum IgE concentration through a Th1 immune response in allergic rhinitis. But other studies did not show efficacy, for instance, patients with birch pollinosis that were treated with L.rhamnosus GG had no improvement, nor of sensitization to birch pollen after using Lactobacillus rhamnosus supplement (23).
3.6. Future of hay fever treatment
Understanding the pathway of inflammation in allergic rhinitis or hay fever is opening newer therapeutic for treatment of pollinosis. One of these future treatments is the blockage of histamine H4 receptors. H4 receptors are located in the hematopoietic cells and may have a role in the regulation of immune system. Multiple studies showed that the recruitment of eosinophils, expression of adhesion molecules and rearrangement of the actin cytoskeleton is dependent on the H4 receptors. Recently, the new compound named Palau Pharma's H4 antagonist UR-63325 has been informed that it can cause the reduction in histamine-induce shape change in isolated cells and in the whole blood (26).
Apart from cytokines causing the inflammation, bardykinin also plays a role in inducing the process directly or indirectly. Indirect effect is the induction of secondary mediators of inflammation like prostanoids, tachykinins, cytokines, mast cell-derived products and NO. Direct effect is the effect on B1 receptors, which are expressed on most tissues and B2 receptors, which are located at endothelial cells, nerve fiber, leukocytes and mast cells. JSM-10292 is the chemical under preclinical development by Jerini for treatment of allergic rhinitis and other inflammation (26).
Like immunotherapy, DNA sequences containing CpG also induce Th1 immune response to antigen. CpG DNA is in bacteria and bind specifically to TLR9 receptor expressed by cells of the innate immunity. Activation of TLR9 in dendritic cells induces the activation of MAPK, NF-ÎºB, and transcription of cytokine genes (IFN-Î±, IL-12, IL-10, and INF-Î²) and increases expression of co-stimulatory molecules. In mouse model, administration of CpG DNA was shown to prevent the nasal symptoms and inflammation in AR. Conjugated-allergen CpG also have become effective in treatment of AR and TLR7/8 become candidate drugs for treatment of AR (26).
Seasonal allergic rhinitis, pollinosis, is a disease associated with these symptoms: sneezing, nasal congestion, rhinorrhea, nasal itching. Hay fever is caused by various pollens depending on the geographical region. It affects about 10-30% population all over the world. It reduces the quality of life of patients who suffer from AR and increases the health cost year by year. There are 2 main factors that affect the development of allergic rhinitis: the environmental factors and genetic factors. People living in the urban areas have higher chance to get pollinosis than those living in rural areas. Environment elements such as air temperature, water, length of daylight, nutrients change which cause the change in pollen season. Furthermore, air pollutants when bind to the surface of pollen will change its antigenic properties. Some people are predisposed to AR. Children have a higher chance of getting AR if their parents have it. Allergic rhinitis is the nasal inflammation caused by mast cell, dendritic cells, recruitment of eosinophils, neutrophils which in turn activate the production of Th2 cells, B cells to produce cytokines (I-4, IL-10, IL-13) and IgE. Allergic rhinitis can be treated by intranasal corticosteroids, antihistamines as 1st line drug and decongestants, intranasal anticholinergics, intranasal cromones as 2nd line drug. Besides alternative treatment, immunotherapy is used as safer and more effective drug which improves the symptoms and quality of life of patients who suffer from AR.