Allergens are usually harmless substances but can induce specific IgE-mediated type I hypersensitivity responses in atopic individuals [30]. Allergens can be broadly categorized as outdoor versus indoor and biological versus chemical allergens [29, 47]. Common outdoor allergens can come from biological origin such as pollens, fungi, and molds [8, 9, 48]. Indoor allergens have a huge impact on most, as people often spend more than 90% of their time indoors [24, 26]. They consist of dust mites, dogs, cats, cockroaches, and molds. Indoor allergens are also impacted by air pollutants, which depend on the amount of air penetrating from the outside and presence of indoor air pollution sources. Different sensitization patterns for inhalation allergens are summarized in Tables 2 and 3.

Table 2 Summary table for allergen sensitization and atopic diseases in different localitiesTable 3 Summary table for allergen sensitization and atopic diseases in different European countries [15, 44, 49]

Climate change and air pollution play important roles in altering aeroallergen content [15, 34]. Global warming prolongs pollen seasons, increasing the frequency, duration and severity of pollen exposures [29, 31]. It favors the growth and spread of highly invasive plant species (e.g., ragweed) into areas that were never present before. Besides, it also increases the formation and spread of air pollutants like ground-level O3, dust storms, infections, thunderstorms, and wildfires. Indeed, wildfire smoke is an ambient natural source of many air pollutants. Air pollution and climate change can affect both the quality and quantity of allergenic protein in pollen grains [9, 27, 34] via various mechanisms. For example, pollutants in the air can induce chemical modifications in pollens and agglomerate pollens; climate change can affect the bioavailability and abundance of pollens through changes in the rainy season, vegetation cover, and pollen season [16]. In general, increased allergen abundance in the air exacerbates inhalation-triggered allergic conditions such as asthma.

Inhalant allergens are found in airborne substances that you breathe in. It can be biological or chemically derived. Here we will discuss the characteristics of common biological allergens, their epidemiology of sensitization, and pathophysiology of allergic sensitization.

Dust Mite (DM) Allergy

DM are one of the most common indoor allergens [16, 19, 24]. High indoor humidity (at least 50%) and high temperatures (20 to 25 °C) favor the spread of DM [44]. DM are commonly found in curtains, furniture, beddings, carpets, and other soft furnishings. The dead skin cells humans and animals expel, which is common in locations with significant dust buildup, are food sources for DM. Allergenic proteins (mainly proteases) of dust mites are present in their body parts, and persistent in their feces.

The molecular identities of DM allergens are well-defined; they include Dermatophagoides pteronyssinus (Dp; major allergen: Der p 1, Der p 2, Der p 23) [51, 52], Dermatophagoides farinae (Df; major allergen: Der f 1, Der f 2) [51], and Blomia tropicalis (Blomia; major allergen: Blo t 1) [30], with variation in distribution according to locations. Df (59.8%) sensitization is more prevalent than Dp (50.4%) and Blomia (49.6%) in Vietnam patients with allergy [53]. Dp (85%) sensitization is similar to Df (83.5%) in Southern China [5]. Patients often have co-sensitization to more than one type of dust mites [53]. Besides, Der p 10 shares homology with tropomyosin of shrimp and crab as a cross-reactive allergen [51]. Therefore, Der p 10 monosensitization can signify food rather than dust mite allergy.

Epidemiology of Allergic Sensitization to Mites

DM is the dominant allergen associated with allergic rhinitis and asthma worldwide [2, 14, 15, 53]. Early exposure to high levels of dust mite allergens in the perinatal period is associated with asthma later in life [32]. In general, dust mite sensitization is more common in the parts of the world with higher humidity, e.g., East China (65.38% for Dp) [14], Canada (50.3%) [2], and Portugal (65.3%) [15]. It is less common in regions with lower humidity (36.1% in Australia [48], 21% in South Korea [3], 12.6% in Austria [15]) and tropical countries with poor hygiene (prevalence of Dp and Df sensitization in Angola, Africa, is 4.9% and 2.2%, respectively [47]).

Pathophysiology of Allergic Sensitization to Mites

Take Dp as an example. Der p 1 is the major allergen, while Der p 2 is another important allergen [8]. Besides the action of increasing epithelial barrier permeability, Der p 1 also cleaves lymphocyte surface receptors, like IL- 2 receptor (CD25) and FcεRII. This cysteine protease digests other proteins, as well as itself, producing fragments of altered allergenicity. Der p 2 is a homolog of the adapter protein and myeloid differentiation protein 2 (MD- 2). It facilitates lipopolysaccharide (LPS)-mediated signaling through Toll-like receptor (TLR) 4, increasing allergen update as an “autoadjuvant.”

Besides, the dust mite fecal particles also contain mite DNA, bacterial DNA, endotoxin, and chitin [16]. They can act as adjuvants by triggering innate signaling pathways. Notably, mite DNA and bacterial DNA are unmethylated and are natural TLR9 ligands. TLR9 is expressed by B cells, monocytes, NK cells, and plasmacytoid DCs. TLR9 activation leads to the production of various proinflammatory cytokines such as type I interferon, IL- 6, TNF, and IL- 12. LPS is a TLR4 ligand. TLR4 signaling triggers the MyD88 and TRIF dependent pathway. MYD88-dependent pathway induces proinflammatory cytokines production, and TRIF-dependent pathway induces the production of type I interferon and cytokines. Chitin is a C-type lectin. Interestingly, the acidic mammalian chitinase (AMCase) has been linked to asthmatic inflammation [54].

Pet Allergy

Over 50% of US and European families have household pets, with dogs being the most common, followed by cats [16]. They act as a major source of indoor allergens, released through secretions, excretions, and dander. The prevalence of allergies to dogs has increased because of increasing ownership. Allergens are contained in their hair, shed skin cells, saliva, and urine.

Epidemiology of Allergic Sensitization to Pets

Dog sensitization varies on their prevalence in households and mirrors that of cat sensitization. The sensitization rate is higher in Denmark (29.4%) and Netherlands (28.3%) [15], but much lower in China (13.94%) [5], Vietnam (2.6%) [53], South Korea (0–2.8%) [3], and Portugal (7.7%) [15]. In general, they are considered less allergenic and less frequently blamed for allergic reactions [16]. To date, six dog allergens have been identified (Can f 1–6) [55]. Can f 1 is a salivary lipocalin protein [56] and can be easily transferred to fur and skin when dogs groom themselves or shed to the environment, which then easily remains airborne for prolonged periods. Sensitization to dog allergens is associated with asthma and allergic rhinitis [8, 16].

Cats are another common allergen source resulting in allergic rhinitis and asthma. The incidence of its sensitization is higher in industrialized nations like Canada (53.1%) [2], Denmark (32.0%) [15], and the UK (27.8%) [15]. On the other hand, its sensitization is lower in China (11.3%) [14], Vietnam (8.2%) [53], South Korea (0.8–4.7%) [3], and Australia (8.6%) [48].

Nevertheless, there are several studies demonstrating the paradoxical effect of intensive cat exposure in early childhood, especially in the first year of life [26]. This potentially results in a modified Th2 response (Fig. 2), associated with high IgG4 to cat allergens, especially to Fel d 1 and lower risk of cat allergy [57]. Interestingly, in countries with higher exposure to pollen, dust mite, and cat allergens, there is less cat sensitization than that for mite or grass pollen [15, 16].

Fig. 2

Schematic representation of Th2 versus modified Th2 immune response. Sensitization by pollens, dust mites, and cockroaches induce classic Th2 response, resulting in IL- 4 and IL- 13 secretion, which stimulate IgE class-switch in B cells and plasma cells to produce allergen-specific IgE (sIgE). On the other hand, intense sensitization by cats and dogs can induce “modified Th2 response” if they are kept as pets at home since early childhood. Induced regulatory T (Treg) cells secrete IL- 10, TGF-β and IL- 35, which induce regulatory B (Breg) cell formation. This inhibits allergen sIgE secreted by B cells and plasma cells. The allergen-specific IgG4 and IgA antibodies produced by Breg also exert blocking actions. This induces “immune tolerance.”

Pathophysiology of Allergic Sensitization to Pets

A Swedish study reported that Can f 1 (43%) and Can f 5 (33%) sensitization were the most common allergens for dog dander sensitization [58]. Moreover, polysensitization with elevated IgE levels to Can f 3 (albumin), Can f 4, and Can f 6 was more common in patients with asthma, while monosensitization to Can f 5 was more common in allergic rhinitis without asthma [58].

As discussed above, the major cat allergen, Fel d 1, can remain airborne for long periods due to its small size [16, 26]. sIgE to Fel d 1 correlates strongly with cat allergic asthma [59]. Besides, there are two other important allergens [16]: Fel d 2 (albumin) and Fel d 5w (cat IgA). sIgE to Fel d 2 cross-reacts with dog, beef, and pork albumin, resulting in pork/cat syndrome. sIgE to Fel d 5w is mostly direct against the oligosaccharide galactose α− 1,3-galactose (α-gal). The latter is induced by tick bites and can result in delayed anaphylaxis to red meat.

Pollen Allergy

Pollen seasons vary geographically and seasonally [60,61,62]. A recent study showed that pollen allergy in spring can account for 25,000 to 50,000 asthma-related emergency department visits annually in the USA [28, 30, 34, 63, 64]. Tree pollens (like oak, birch, cedar, and pine) are released in springtime. Grass species (like Kentucky bluegrass, Bermuda grass, Timothy grass) release pollen in the late spring and summer. Weeds (e.g., ragweed, sagebrush, pigweed, lamb’s quarters) produce pollen in the late summer and autumn. Besides, the increased use of ornamental plants in parks, workplaces and homes provides new sources of aeroallergens [16]. There is extensive cross-reactivity within both grass and weeds. Pollen sensitization results in seasonal allergies like rhinoconjunctivitis, allergic rhinitis, and asthma.

Epidemiology of Allergic Sensitization to Pollens

Pollen sensitization depends on the pollen growth of a region. Grass pollen allergy (median prevalence of 33.4%) is the top respiratory allergy in most European countries [15], reaching 71.0% in Switzerland, 64.0% in Denmark, and 50.8% in the UK. However, in regions where the pollen growth is poor, the prevalence of sensitization can be very low: 0.5–1.7% in South Korea [3] and 2.48% in East China [14]. Even in different parts of the same country with variable vegetation patterns or in different seasons, the pattern of sensitization can be different [5, 28, 65].

Ragweed pollen is one of the most common environmental allergens in the USA. A total of 15.5% of Americans are sensitive to Ragweed [66]. Ragweed pollen usually peaks in late summer and early fall. Ragweed pollen can be carried for long distances by wind. Warmer summer temperatures and increased carbon dioxide can also lead to longer pollen seasons and thus greater pollen loads [66].

On the contrary, tree pollen sensitization is more common in East China (94.15%) [14]. There is also a variable sensitization pattern in Europe depending on type of plantations and risk factors linked to westernization such as hygiene, nutrition, and pollution [15].

Pathophysiology of Allergic Sensitization to Pollens

Allergic asthma is manifested as inflammation of the airway driven by Th2 cytokines and IgE. It is immunologically characterized by the infiltration and activation of eosinophils, mast cells, neutrophils, and immune lymphoid cells in the airway. Asthmatic patients suffer from airway smooth muscle hyperresponsiveness, airway constriction and airway thickening, mucus hypersecretion and impaired clearance, subepithelial cells inflammation, and fibrosis [67].

Thunderstorm asthma can be triggered by rainfall, dew, fog, and watering of lawns, which can rupture pollen grains within the anthers. Disturbances like wind, recreational activities, and lawn-mowing result in the release of tiny allergenic fragments that concentrate at ground level causing severe asthma crises in people with pollen allergic asthma [68].

Cockroaches and Molds

Cockroaches can be found in inner-city environments, especially in floor dust, kitchen cabinets, and basements. The major cockroach allergens include Per a 1 in American cockroaches and Bla g 1 and Bla g 2 in German cockroaches [16]. Patients allergic to cockroach tropomyosin (Bla g 7 and Per a 7) can be reactive to tropomyosin in dust mites and shrimps [69]. Cockroach sensitization is associated with allergic rhinitis, allergic rhinoconjunctivitis, and asthma [16]. Interestingly, atopic individuals often have co-sensitization of cockroaches with other allergens like in dust mites [47, 70] and cats [53]. The prevalence of cockroach allergy accounts for 21% in Portugal [15], 27% in China [70], and 17–41% in the USA [71]. Suggested pathophysiological mechanisms for cockroach allergens include the involvement of protease-activated receptor (PAR)− 2 for their penetration through epithelial cells and the induction of Th2 cytokines [69, 71].

Dark, humid, and poorly ventilated areas are the important sources of mold or fungi such as Alternaria, Cladosporium, Penicillium, and Aspergillus [30, 72]. Sensitization of mold or fungus is associated with allergic rhinoconjunctivitis and asthma. In general, their sensitization is low (< 10%) across different localities [3, 14, 15, 48, 53]. Alternaria is the most important fungal species for sensitization, as it has a universal distribution with the ability to withstand a wide range of climate conditions especially warm climate conditions [73]. Alt a 1, that is in the spore cell wall, is regarded as the predominant Alternaria allergen.

Th2 Versus Modified Th2 Response

Allergens like pollens, dust mites, and cockroaches induce classic Th2 response [26, 34]. Through the process of allergen sensitization and secretion of IL- 4 and IL- 13, sensitized Th2 cells stimulate IgE class-switch in B cells and plasma cells to pro