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j.imbio.2017.10.035

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Immunobiology xxx (xxxx) xxx–xxx
Contents lists available at ScienceDirect
Immunobiology
journal homepage: www.elsevier.com/locate/imbio
Review article
House dust mite allergy: Its innate immune response and immunotherapy
Fang-Liang Huanga,b, En-Chih Liaoc, Sheng-Jie Yud,
⁎
a
Department of Pediatrics, Taichung Veterans General Hospital, Taichung, Taiwan
Department of Physical Therapy, Hungkuang University, Taichung, Taiwan
Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
d
Chinese Medicine Research Center, China Medical University Hospital, Taichung, Taiwan
b
c
A R T I C L E I N F O
A B S T R A C T
Keywords:
House dust mite allergy
Innate immune response
Immunotherapy
Over the past few decades, allergic diseases have become increasingly prevalent worldwide. House dust mite
(HDM) is the most important domestic source for allergic diseases such as allergic rhinitis, asthma and atopic
dermatitis. Dermatophagoides pteronyssinus (Der p) is the major environmental allergen in southeast Asia because of the humid and warm environment is suitable for its growth. In the recent year, role of HDM allergen in
allergic inflammation through innate immune system has been well studied. Toll-like receptors (TLRs), proteaseactivated receptors (PARs) and DC-SIGN could be activated by different HDM major allergens and proinflammatory cytokines also be upregulated. Treatment efficacy for HDM allergy is unsatisfied to the patients and
the medication is limited. Immunotherapy provided an alternative option for treating HDM allergy through
targeted to the mechanisms of allergic reaction and represented a long-term symptoms relief. Gene specific
immunotherapy was currently being developed and it could decrease allergic inflammation and improve the
efficacy of treatment. In this report, we reviewed recent studies about the role of HDM allergy in innate immune
system and its immunotherapy. Understanding the HDM allergen induced signal transduction pathway and
developed allergen specific immunotherapy could help physicians to create precise diagnosis and solve unmet
need in HDM allergy.
1. Introduction
Allergic diseases are the commonest immune disorder worldwide.
Around 30% of the general population have allergic symptoms.
Increasing evidence showed that the frequency of atopic diseases (including allergic rhinitis, asthma, and atopic dermatitis) has been on the
rise over the last few decades (Pawlinska-Chmara et al., 2008). For any
atopic person, the effects of allergen exposure could be immediate, with
eczema, rhinitis, conjunctivitis, bronchoconstriction, asthma, and in
rare cases anaphylaxis. Allergy, given its complexity in symptom, severity and organ manifestation, the social-economic burden keeps
growing dramatically in recent years. House dust mite (HDM) is the
commonest aeroallergen in Asian countries. HDM is a well-established
origin of allergic diseases, such as atopic dermatitis (AD), allergic rhinitis (AR) and allergic asthma (AA) (Platts-Mills et al., 2009; Meng
et al., 2016). It is present in dust and stuffing, such as mattresses, pillows, stuffed animals, and bedding (Baxi and Phipatanakul, 2010). The
common species of HDM are pteronyssinus (Der p), Dermatophagoides
farina (Der f) and Blomia tropicalis (BT). Warmth and humidity were
major factors for promoting the growth of dust mites. In children and
⁎
adults with asthma, the prevalence of HDM allergy is > 50% (Ulrik and
Backer, 1999). Activated TH2 cells orchestrate the HDM-induced allergic response through stimulating the production of HDM allergenspecific IgE and the recruitment of inflammatory cells, leading to
structural changes in the lung, nose and skin (Thomas and Hales, 2007).
Furthermore, group 2 major allergen of Der p was reported to induce
autoantigen and autoantibody production in SLE patients (Yu et al.,
2014). The allergic inflammation is considered by more and more investigators to result not only from an exacerbated TH2-biased adaptive
immune response, but also to be heavily influenced by the direct activation of innate immune cells. This direct activation is mediated by
both the allergens themselves and the danger signals present in the
allergen sources, or in the environment (Willart and Lambrecht, 2009).
2. Mite major allergens
HDM is the major risk factor for asthma. Der p is the major species
in about 70% of dust mite samples found in Taiwan households, and the
prevalence of HDM allergy in Malaysia is over 50% (Kuo et al., 1999;
Lim et al., 2015 Lim et al., 2015). A total of 22 mite allergens have been
Corresponding author.
E-mail address: jim0929@msn.com (S.-J. Yu).
http://dx.doi.org/10.1016/j.imbio.2017.10.035
Received 14 March 2017; Accepted 14 October 2017
0171-2985/ © 2017 Elsevier GmbH. All rights reserved.
Please cite this article as: Huang, F.-L., Immunobiology (2017), http://dx.doi.org/10.1016/j.imbio.2017.10.035
Immunobiology xxx (xxxx) xxx–xxx
F.-L. Huang et al.
identified and the major allergens include group one and group two
allergens of D. pteronyssinus (Der p 1 and Der p 2) and D. farinae (Der f 1
and Der f 2). Since over 80% of patients develop high levels of specific
IgE antibodies to these allergens (Calderon et al., 2015). Recently, Der p
23 has also been identified as a mite major allergen. About 54% of HDM
allergy patients have Der p 23 specific IgE and the allergenicity of recombinant Der p 23 induces degranulation of rat basophils (Soh et al.,
2015). HDM allergen activated immune system through two pathways:
(a) the protease activity of group 1 allergen potentially impairs epithelial tight junctions, and (b) group 2 allergen mimics MD-2 which coactivates the TLR 4 signaling pathway.
human eosinophil cationic protein inhibit the NLRP3 inflammasome
activation induced by Der p 2, and the production of proinflammatory
cytokines through upregulating the expression of IFN-α (Yu et al.,
2015b). Another immunotherapy approach is to increase the tolerance
of allergen. It can be upregulated by repeated contacts with the allergen. In phase III trial, SQ HDM SLIT-tablet contains a 1:1:1:1 ratio of
the mite major allergens Der p 1, Der f 1, Der p 2 and Der f 2 has been
confirmed effective treating adults with HDM-induced AR. Patients
receiving SQ HDM tablets show reduced rhinitis symptoms as well as
medication scores resulting in better quality of life (Demoly et al.,
2016b).
3. Innate immune response and HDM allergy
6. MD-2 specific immunotherapy
In the past, HDM allergy was considered as immune response with
Th2 dominant and induction by IgE. More recently, HDM allergen has
been identified and which could induce innate immune response
(Porsbjerg et al., 2016; de Boer et al., 2014). HDM allergen can induce
rapidly mounted defense responses of the host. Such protective mechanisms are evolutionarily conserved in all multicellular organisms
and are collectively referred to as innate immunity (Jacquet, 2011). In
HDM allergy, when a host contacts an allergen, pattern recognition
receptors (PRRs) of the innate immune cells first recognize pathogenassociated molecular patterns (PAMPs) and then it is followed by the
secretion of cytokines and chemokines, which recruit other inflammatory cells and proinflammatory cytokines to amplify the inflammatory response. Der p 1 can activate PAR 2 signal pathway
through Akt and pp65 to increase the expression of IL-6 and IL-8 (Shi
et al., 2010). Der p 2 can also activate the TLR 2 signal transduction
pathway and it can also increase the activation of nuclear factor-kappa
B (NF-kappaB) and extracellular signal-regulated kinase (ERK) 1/2,
resulting in high levels of IL-6 and MCP-1 (Chiou and Lin, 2009). Another innate immune receptor, DC-SIGN, is related with HDM allergy.
Der p can be endocytosed into dendritic cells through DC-SIGN and
reduced DC-SIGN expression to change the polarization activity of
dendritic cells leading to the Th2 cytokine immune response (Huang
et al., 2011).
TLR4/MD-2 signaling pathway is involved in the allergic inflammatory response induced by Der p 2. Two SNPs (rs1809441 and
rs1809442) in the proximal promoter region of the MD-2 gene are overexpressed in HDM allergic patients. These SNPs of the MD-2 promoter
are associated with high levels of Der p and Der p 2-specific IgE in the
sera of HDM allergic patients (Liao et al., 2015). A pungent isolate from
ginger (Zingiber officinale), 1-dehydro-10-gingerdione (1D10G), inhibits
both the TLR4-mediated signaling cascade in the activation of NF-kB,
AP1 or IRF3 and gene expression of inflammatory cytokines in LPSactivated macrophage by direct blockade of LPS binding to MD-2 (Park
et al., 2012; Lee et al., 2012). Furthermore, type I diabetes caused by
pancreatitis was recently found to correlate with the activation of
TLR4/MD-2 signaling pathway (Bednar et al., 2015). TLR4/MD-2
monoclonal antibody is used to treat type I diabetes in the murine
model, and it suppresses insulitis, antigen presenting cell expansion and
upregulates IL-10 expressing cells. Through inhibition of the TLR4/MD2 signaling pathway, it may become a novel means to reverse allergeninduced allergic inflammation.
7. Conclusion
The HDM allergens played more important role in inducing innate
immune responses. TLRs, PARs and C-type lectin could be activated by
HDM major allergen and mediated signal transduction to cause allergic
inflammation. In our study, NLRP3 inflammasome could also activated
by Der p 2 and caused proinflammatory cytokine production (Fig. 1).
Although current medications such as cortical steroid, anti-histamine or
anti-IgE monoclonal antibody can reduce allergic symptoms, but these
modalities cannot satisfactorily treat all allergic patients. Through immunotherapy or gene-specific immunotherapy, allergic inflammation
could be markedly downregulated and prolonged its effects to treat
HDM allergy. Developing more well designed clinical trials to obtain
more clinical data can assist creating effective immunotherapy and
4. Treatment of HDM allergy
The three mainstream methods to treat HDM allergy are (a) avoid
contact with allergens, (b) symptomatic medications, and (c) allergenspecific immunotherapy. HDM is present in bedroom, pillow and quilt
(Lim et al., 2015). Using special mattress covers, frequent washing of
bed clothings, drying bedding under sunlight are means to create an
environment undesirable for HDM growth. Current medication guidelines suggest the use of antihistamines, corticosteroids, and β2-agonists
to relief allergic symptoms (de Vries et al., 2006; Demoly et al., 2016).
However, symptomatic relief is not the end of treatment, thus allergenspecific immunotherapy becomes an alternative choice for preventing
HDM allergy for a lasting benefit even after treatment ends.
5. HDM allergy immunotherapy
HDM allergy immunotherapy involves a repeated administration of
specific allergens to the allergic patient to develop immunological tolerance to the allergens and thereby reducing symptoms later to the
allergen exposure (Bousquet et al., 2008). The mechanism of immunotherapy involves a shift from Th2 dominant reaction to Treg responses, accompanied by an increase in the number of Treg cells and
the functional suppression of effector T cells (Pevec et al., 2012). Denatured HDM major allergen which lacked HDM IgE reactivity has been
used to treat HDM allergy. In the murine model, local nasal immunotherapy with denatured HDM crude extracts downregulates HDM
specific IgE production and reduces lung inflammation and allergic
asthma (Yu et al., 2015). Cell penetrating peptides derived from the
Fig. 1. Schematic diagram of the roles of HDM in allergen-induced inflammatory response and allergen-specific immunotherapy. CPPecp, cell penetrating peptide derived
from eosinophil cataonic protein; CASP1, caspase-1; 1D-10G, 1-dehydro-10-gingerdione.
2
Immunobiology xxx (xxxx) xxx–xxx
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