The compartmentalization of immune responses into innate versus adaptive components was an important recent advance in immunology [1
]. As opposed to adaptive immunity, which is the major provenance of B and T lymphocytes, innate immune responses theoretically can encompass many other cell types that respond to infections or tissue injury. Epithelial cells and dendritic cells (DCs) are crucial components of the innate immune system in the airway because they sense and respond to inhaled allergens and particles. Key distinguishing features between the innate and adaptive arms of the immune system include the patterns or antigens recognized, kinetics of activation, and capacity for memory. In contrast to adaptive immune cells, which recognize an extremely broad repertoire of antigens due to genetic recombination of antigen receptor genes, innate immune cells respond to a more limited set of targets via a conserved set of pattern-recognition receptors (PRRs). Similarly, innate immune cells generally respond quickly to activating signals and have a limited capacity for long-term memory.
PRRs tend to be ancient and conserved, and likely evolved to recognize invading pathogens. For example, the Toll-like receptor (TLR) family recognizes a diverse family of pathogen-encoded patterns and evolved at least 100 million years before the rearranged antigen receptors that underlie adaptive immunity. In recent years, genetic epidemiology studies have associated single nucleotide polymorphisms in TLRs with different allergic phenotypes [2
]. Furthermore, animal models and in vitro studies have firmly implicated TLRs in allergen sensitization and regulation of allergic immune responses [5
]. The mechanisms by which TLRs regulate allergic sensitization and inflammation are complex and likely allergen and disease specific [7
]. Most studies to date have investigated asthma and atopic dermatitis, whereas less is known about TLRs in allergic rhinitis. One recent study found that a single nucleotide polymorphism in TLR4, which is part of the lipopolysaccharide signaling complex, conferred significant protection from hay fever [8
]. In addition to their potential role in disease pathogenesis, natural TLR ligands (as well as synthetic analogues) are being explored as novel adjuvants in allergen immunotherapy. Some TLR/ligand pairs potentially have protective effects in allergen immunotherapy (eg, TLR9 and CpG oligonucleotides [9
]). In contrast, other TLR ligands have been linked to allergen sensitization, although the dose and timing of exposure are critical modulating factors (eg, TLR4 and lipopolysaccharide).
In addition to recognizing cell wall components, nucleic acids, and carbohydrates derived from microbes, innate immune receptors respond to an array of endogenous danger signals that are produced or released extracellularly during tissue injury. There has been an explosion of research in this area in recent years, with new PRR-ligand interactions being discovered at a rapid pace [10
]. Endogenous ligands produced during inflammation or released by dead and injured cells include heat shock proteins, extracellular matrix components (eg, low molecular weight hyaluronic acid), extracellular adenosine triphosphate, high mobility group box 1, modified lipoproteins (eg, oxidized low-density lipoproteins), complement factors, and uric acid crystals that can also be sensed as dangerous [14
In addition to TLRs, other PRRs include the Dectin family of cell-surface C-type lectins that recognize fungal cell wall components [15
], as well as the intracellular Nod-like receptor (NLR) NLRP3. Upon activation, NLRP3 forms a complex with the adaptor protein ASC and pro-caspase-1, which is referred to as the inflammasome
]. Recent studies have linked the NLRP3 inflammasome with exposure to various pathogens or toxins with caspase-1-dependent processing of cytokines, including interleukin (IL)-1β, IL-18, and IL-33 [16
]. Interestingly, the inflammasome was recently demonstrated to be required for activity of the proallergic adjuvant alum [17
], suggesting that it may be involved in generation of T-helper type 2 (Th2)-dependent immune responses, although alum can also act in an inflammasome-independent manner [18
]. As these cytokines contribute to allergic inflammation [19
], targeting components of the inflammasome may hold therapeutic promise in allergic diseases.