The development of the adaptive immune response is an evolutionarily recent event present only in vertebrates and is characterized by events that require gene rearrangement. By contrast, the innate immune system consists of those elements of host defense against infection that are encoded in germline DNA and do not require prior exposure to antigen (4
). Thus, innate immunity is available for defense of the host at its initial encounter with infection. The innate immune system has been described as a primitive system, dating back hundreds of millions of years. It is present not only in animals but also plants. Seen a different way, the innate immune system has become highly refined over this time and highly preserved because of its efficacy. Adaptive immunity might be viewed as a luxury available only to vertebrates (paraphrased from Reference 5
). Antigen recognition sites on antibodies and T cell receptors in adaptive immunity are thus created specifically for each new antigen encountered. Innate immune responses are rapid and transient, whereas adaptive immune responses are slower, but last longer. Notably, immunological memory is characterized as a component of adaptive immunity, with a more powerful and rapid response upon reexposure to the same antigen. Though distinguished by significant differences, the innate and adaptive arms of the immune system are tightly integrated as a single defense. Adaptive immune responses are dependent upon cytokine production and regulation by the innate system (6
The innate immune system consists of afferent and efferent arms, with cellular and humoral elements. However, of particular importance is the afferent, sensing arm of innate immunity (5
) because of its ability to identify specific components of microbial organisms. These components of microbes have been termed pathogen-associated molecular patterns (PAMPs); however, these are molecules rather than patterns and they need not originate from pathogenic organisms, but can also be present in nonpathogenic organisms (7
). Thus, they are ligands of innate immunity receptors that are of microbial origin and specificity, with both humoral and cellular sensors (receptors).
Innate Immunity: Asthma and Allergy
The prevalence of asthma has increased dramatically during the last 20 to 40 years in the “Western,” industrialized world (8
). Many hypotheses have been proposed to explain this increase. The “hygiene hypothesis” has received the greatest attention and support from the scientific literature. This hypothesis links the increase in allergy, asthma, and autoimmunity in industrialized nations during the last half century to the fact that patients are less frequently challenged with microbes or their products. This reduction in infectious challenge is purported to result from a less agrarian life style, smaller family size, better infection control, more immunizations, frequent antibiotic prescriptions, better sanitation, and less oro-fecal burden early in life (9
). One postulate is that exposure to components of microbes early in life modulates the immune response and immunological phenotype of children from a predominant Th2 phenotype at birth to a Th1 phenotype as they proceed through childhood. As an extension of this concept, minimizing microbial exposure may support the development of the Th2 phenotype, and development of allergic asthma. However, New York City has a high microbial burden and yet asthma rates are high, suggesting that microbial exposure in relationship to asthma pathogenesis may be dependent upon a number of variables including, but not limited to, geographic location, genetics, and immune system interactions.
Receptors of Innate Immunity
Many microbes interact with the host through receptors that identify a specific pathogen or microbe-derived molecules. Microbes may limit the development of the allergic adaptive immune response through interaction with a group of these innate immune receptors, including receptors termed Toll-like receptors (TLRs), early in life. Thus, the innate immune system appears to play a critical role in determining the phenotype of the adaptive immune response.
In addition to TLRs, cellular receptors for innate molecules identified to date include NOD proteins, Dectin, CD14, and collectins (5
). Data have been published on 10 TLRs in humans thus far (10
). TLRs function in microbial sensing, with each TLR sensing a separate set of ligands (). TLRs are membrane proteins characterized by a cytoplasmic Toll/IL-1 receptor homology domain, or TIR domain, as well as ligand binding domain that contains a leucine-rich repeat sequence separated by a transmembrane domain () (10
). TLRs are pattern recognition receptors that bind different specific ligands, but the exact nature of these ligand–receptor interactions is still evolving as additional data become available. These receptors not only recognize bacteria (at least TLR1, 2, 4, 5, and 9), but also fungi (TLR6), protozoa, and viruses (TLR3 and 9) (5
). Some TLRs form heterocomplexes (TLR1 and 6 can bind with TLR2) and in turn can bind additional ligands. TLRs have no signaling domain, but bind adapter proteins that then initiate signaling cascades. There are five known adapter proteins, including MyD88, Mal/Tirap, Trif/Ticam-1, MyD88-4/TIRP, and MyD88–5 (5
). Space prohibits the discussion of the signaling pathways involved in detail, but it should be noted that TLRs 1, 2, 6, and 9 are thought to signal exclusively through MyD88 or via a heterodimer including MAL/Tirap. TLR4 signals through MyD88 and Trif (11
). Although these pathways overlap and both stimulate NF-κB activation, only Trif
leads to activation of IFN-releasing factor 3 (IRF-3) and the production of IFN-β (a Type I interferon) (14
). Binding of IFN-β to the Type I IFN receptor in turn leads to STAT1 activation in cells expressing this receptor, inducing nitric oxide synthase (NOS) expression and IP-10 production, to mention a few downstream responses.
Figure 2. Toll-like receptors (TLRs), their ligands, and cellular location. TLR1, 2, 4, 5, and 6 are located on the plasma membrane, while TLR3, 7, 8, and 9 are located in intracellular compartments such as endosomes. Each TLR recognizes a discrete set of ligands (more ...)
Lipopolysaccharide (LPS), a ligand of TLR4, and apparently other innate immunity ligands, can serve an adjuvant role via the Trif adaptor protein with its downstream signaling pathway (14
). Antigen is presented to cells by antigen-presenting cells (APCs) via MHC II, but requires costimulatory molecule expression (e.g., CD80, CD86, and CD40) to generate an adaptive immune response. One of the most important functions of Trif, mediated via triggering the downstream production of IFN-β, is co-stimulatory molecule expression (14
). The failure of this innate signal may be involved in the development of allergy and asthma, although a mechanism for this remains to be determined.
LPS, a TLR4 ligand, is also termed endotoxin, and a significant component of gram-negative enteric bacterial cell walls. LPS exposure appears to both protect against and promote asthma. Epidemiologic studies indicate that exposure of children to LPS, in a rural setting or in bed sheets, or domestic pets within the first 6 months of life is associated with a decreased incidence of asthma, consistent with the hygiene hypothesis (18
). In contrast, adults that get exposed to very high concentrations of LPS in occupational settings (grain workers, farming occupations) develop asthma that is temporally related and made worse by additional exposure to LPS. LPS can inhibit the development of an allergic response in animal models. For example, LPS-containing, commercially available allergen preparations induce a less intense airway response in an animal model of asthma when compared with LPS-free allergens (12
). Similarly, as stated above, environmental endotoxin exposure in children inversely correlates with allergic asthma (19
). These findings point to the adjuvant role of innate immunity ligands and the role that they may play in allergic disease (13
), but by no means demonstrate that LPS is the only ligand capable of this response or that TLR4 is the only receptor involved. Many of these receptors trigger similar, if not identical, responses, but research on this topic has been clouded by contamination of innate ligands with ligands for other receptors in the innate immunity family. Finally, not all patterns may be the same. Ligands for TLR2 stimulate the release of IL-13 and IFN-γ, whereas ligands of TLR4 induce production primarily of IFN-γ and modest amounts of IL-13 in in vitro
studies in mice and humans (22
TLRs and Asthma
Some investigators have found that activation of TLR2 is associated with increased allergic inflammation and AR in a murine allergic models (14
). Other studies have found that TLR2 and TLR4 ligands decrease allergic response (15
). These studies underscore the complex response to LPS, and probably other innate immunity ligands. The timing and dose of LPS, as well as the genetic and environmental background of the host, appear to be important. This may help to explain how LPS can induce an asthma phenotype independent of antigen (16
). Thus, as a component of organic grain dust LPS can participate in the pathogenesis of asthma in adults and may exacerbate disease in individuals with allergic asthma (26
). These responses appear to be independent of the adjuvant role of LPS or other innate immunity ligands.
NOD proteins are intracellular, cytoplasmic receptors that are characterized structurally by a CARD (caspase activation and recognition domain) domain, a centrally located nucleotide-binding oligmerization domain (NOD) and multiple C-terminal leucine-rich repeats (17
). There are two NOD proteins that are known to exist in humans: NOD1 and NOD2. NOD1 has the natural ligand bacterial diaminopimelic acid (abbreviated iE-DAP) that is present in gram-positive and gram-negative bacteria. The NOD1 gene is on chromosome 7p14 and this region has been strongly linked to asthma in multiple linkage analyses performed in humans (28
). Moreover, the protective effect of living on a farm from birth for reducing the prevalence of asthma is lost in patients that have a mutation in this gene (18
). In a large cohort of adult Germans, those with a mutation in this gene had a higher frequency of atopy and asthma (30
). While data suggest that NOD1 may play a protective role in asthma, the influence of additional geographic locations and genetic background as well as underlying mechanisms remain to be investigated.