The Role of the House Dust Mite-Induced Innate Immunity in Development of Allergic Response

House dust mite (HDM) represents one of the most common sources of aeroallergens worldwide and more than 50% of allergic patients are sensitized to these allergenic molecules. HDM allergy research in the past has been mainly focused on adaptive, mite allergen-dependent immune responses. In recent years it has become clear that, although the allergenspecific CD4+ Th2 cells orchestrate HDM allergic response, the innate immune system also plays a critical role in HDMinduced allergy pathogenesis. This review will summarize insights into diverse determinants that contribute to the HDM allergenicity through the activation of innate immunity. In addition to the capacity of mite allergens to directly activate mainly skin keratinocytes and airway epithelial cells, innate pattern recognition receptor ligands derived from HDM carriers are also involved in the development of allergic response by HDM. Copyright © 2010 S. Karger AG, Basel Published online: December 22, 2010 Correspondence to: Dr. Alain Jacquet, Division of Allergy and Clinical Immunology Chulalongkorn University, Department of Medicine, Faculty of Medicine Oor-Por-Ror Building, 10th Floor Room #1010/5, 1873 Rama IV Road Pathumwan, Bangkok 10330 (Thailand) Tel. +66 2 256 4579, Fax +66 2 652 3100, E-Mail alain.j @ chula.ac.th © 2010 S. Karger AG, Basel 1018–2438/11/1552–0095$38.00/0 Accessible online at: www.karger.com/iaa D ow nl oa de d by : 54 .7 0. 40 .1 1 10 /6 /2 01 7 5: 15 :2 6 A M Jacquet Int Arch Allergy Immunol 2011;155:95–105 96 as to histological changes of the epithelium and thickening of the basal membrane. It is increasingly considered that the allergic inflammation results not only from an exacerbated Th2-biased adaptive immune response but is heavily influenced by the direct activation of the innate immune cells such as bronchial epithelial cells, keratinocytes, DCs, mast cells, basophils and eosinophils by both the allergens themselves and danger signals present in the allergen sources. In addition to their characterized allergens [4] , HDMs produce thousands of proteins and macromolecules that might serve for the stimulation of the innate immunity. Whereas many studies evidenced that the biological functions of HDM allergens amplify their allergenicity (see below), new reports demonstrated that contaminating microbial compounds in HDM play a critical role as adjuvant factors to mount a typical Th2-biased allergic responses. The purpose of this review is to put in evidence the direct activation of innate immune cells by some HDM allergens as well as by contaminating microbial compounds in HDM. We will discuss how the innate immunity triggered by HDM contributes to allergic disease by programming and maintaining Th2-bias adaptive immunity and by the recruitment of inflammatory cells. Microbial Compounds in HDM Extracts: Biocontaminants or Endosymbiont-Derived Molecules? The microbial compounds lipopolysaccharide (LPS) and -glucan can be routinely detected in HDM extracts obtained from whole-mite cultures or mite bodies [5] . Moreover, chitin, a glucosamine-based polymer forming the mite exoskeleton as well as the fungi cell wall, could be more likely present in extracts. Whether these microbial compounds derived from endosymbionts and/or stable contaminants in mite cultures remains to be fully addressed. However, although the presence of large amounts of LPS and/or bacteria as well as -glucans and/or fungi in house dust, the mites’ natural home environment, supports the microbial contamination hypothesis, bacterial 16S ribosomal DNA were identified in washed Dermatophagoides farinae or D. pteronyssinus as well as in sterilized poultry red mite [6, 7] . These data suggest that endosymbiotic bacteria could also represent the source of contaminating LPS. Ecological relationships between xerophilic fungi and HDM were demonstrated with the presence of penicilloides conidia in the digestive system and fecal pellets of HDM [8] . Moreover, yeast enters frequently in the composition of mite growth medium. Finally, pieces of dust mite cuticle, containing chitin, have been found in fecal pellets [9] . HDM Adjuvant Factors and Airway Innate Immunity Amongst the microbial compounds contaminating HDM extracts and harboring adjuvant activity, LPS was certainly the most studied danger signal in the context of the airway allergic inflammation. Animal models provided mechanistic insight into the role of LPS in the regulation of allergic asthma. In relation with the hygiene hypothesis, it appeared that the LPS dose is a determining factor in the course of allergic responses: low doses of inhaled LPS promoted Th2 responses to the sensitizing antigen and eosinophilic inflammation, whereas high doses of LPS induced protective Th1 responses [10] . Using a murine model of HDM allergic asthma (intranasal sensitizations with HDM extracts followed by airway challenge), it was demonstrated that mice deficient in MyD88 or TLR4 did not develop the common features of allergic asthma as airway inflammation, Th2 cytokine production and airway hyperreactivity [11] . This prevention of the allergen-specific Th2 response was associated with fewer OX40L-expressing myeloid DCs in the draining lymph nodes during allergic sensitization. HDM-specific IL-17 production and airway neutrophilia was attenuated in MyD88–/– but not TLR4–/– mice. These data suggested that the presence of microbial products in HDM extracts, more likely LPS, differentially regulates Th2and Th17-mediated inflammation and activates distinct MyD88-dependent pattern recognition receptors. Whereas the contribution of TLR4 in HDM allergy was clearly evidenced in this report, the nature of the TLR4-positive cells playing a major role in this process remained to be identified. Very recently, Hammad et al. [12] have investigated the contribution of airway epithelial cells through TLR4 to allergic responses in a murine model of HDM allergy. Using mice with selective ablation of TLR4 expression on either lung structural cells or hematopoietic cells that were treated with HDM extracts, containing 1 ng LPS per mg extract, these authors showed that TLR4 expression on lung structural cells, but not on DCs, is necessary and sufficient for DC activation in the lung and for the development of a robust eosinophilic and Th2 inflammatory response characterized by IL-5 and IL-13 production. TLR4 triggering on structural cells by conD ow nl oa de d by : 54 .7 0. 40 .1 1 10 /6 /2 01 7 5: 15 :2 6 A M HDM and Innate Immunity Int Arch Allergy Immunol 2011;155:95–105 97 taminating LPS caused production of the innate proTh2 cytokines thymic stromal lymphopoietin (TSLP), granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-25 and IL-33. Hammad et al. [12] also established that the absence of Toll-like receptor (TLR) 4 on structural cells, but not on hematopoietic cells, abolished HDM-driven allergic airway inflammation. Finally, inhalation of a TLR4 antagonist to target exposed epithelial cells suppressed the features of asthma, including bronchial hyperreactivity. These new findings give epithelial cells a pivotal position in the generation of allergic inflammation through the activation of TLR4 signaling pathway by the contaminating LPS from HDM. Intriguing results from in vitro experiments demonstrated that differentiated primary cultures of human airway epithelia or airway epithelial cell lines under a resting state are nevertheless hyporesponsive to LPS in comparison with phagocytic cells [13, 14] . This hyporesponsiveness could be explained by the intracellular TLR4 expression in pulmonary epithelial cells lines [13] . But, more interestingly, a deficiency of MD-2 expression, the LPS-binding accessory TLR4 coreceptor, was observed in the differentiated primary culture of epithelia and extracellular complementation with recombinant MD-2/LPS increased endotoxin responsiveness [14] . Chitin was shown to induce in mice the accumulation in tissue of IL-4-expressing innate immune cells, including eosinophils and basophils [15] . Moreover, chitin induced a dose-dependent expression of AMCase and eotaxin-3 mRNA, two pro-Th2 effector proteins in human sinonasal epithelial cells from patients suffering from chronic rhinosinusitis with nasal polyps [16] . The glucose-derived polymer  -glucan within the HDM extracts was also newly shown to participate in the early events of allergic airway responses. Indeed, HDM extracts induced CCL20 secretion in airway epithelial cells for the recruitment of immature DCs to the lung [17] . The CCL20 production was induced through a TLRindependent, protease-independent process but was dependent on -glucan structures in the HDM extracts. These effects could be more likely mediated by ligation of HDM-derived  -glucans to non-Toll pattern recognition receptors such as the C-type lectin receptor dectin, although the  -glucan receptor dectin-1 expression was not demonstrated in airway epithelial cells [18] . Whether the -glucans from HDM, as previously demonstrated for purified fungal -glucans, activate DCs and eosinophils and aggravate IgE-mediated histamine release remains to be explored [19–21] . Concomitantly, it was newly reported that HDM extracts stimulate cysteinyl leukotriene production by DC through recognition of dectin-2 by glycan-derived molecules [22] . Effects of HDM Extracts on Airway Innate Immune