Mast cells in atopic dermatitis
Introduction
Mast cells are hematopoietic cells that originate from progenitor cells in the bone marrow. Mast cell progenitors enter the circulation and become mature mast cells after entering destination tissues under the influence of local microenvironment [1]. Mast cells have been long understood as the key effector cell type in IgE-mediated immediate hypersensitivity and allergic disorders, as well as in protective immune responses to certain parasites and bacteria [2, 3]. However, recent progress in the field has broadened their roles in many immune responses [4], ranging from innate defense against venoms of bees and snakes [5] to multiple aspects of adaptive immune responses such as antigen presentation and leukocyte recruitment to draining lymph nodes [6] as well as downmodulation of immune responses [7]. Their pathogenic roles have been extended to include not only allergic diseases and helminth and bacterial infection, but also autoimmune diseases [8, 9], allograft tolerance [10], angiogenesis in tissue repair [11], and carcinogenesis [12, 13].
The high-affinity receptor for IgE (FcɛRI) expressed on mast cells (and basophils) consists of four subunits (αβγ2): an IgE-binding α chain, a signal-amplifying, receptor-stabilizing β chain, and two disulfide-bonded γ chains that are the main signal transducers [14]. Upon encounter with multivalent antigen, IgE-bound FcɛRI on mast cells become aggregated or crosslinked, leading to cell activation [15]. Activated mast cells secrete three classes of substances: (1) preformed chemical and protein mediators, such as histamine, serotonin, heparin and chondroitin sulfates, proteases, major basic protein, acid hydrolases, cathepsin, and so on, (2) lipid mediators, such as prostaglandins, leukotrienes, and platelet-activating factor (PAF), and (3) preformed and/or de novo synthesized growth factors, cytokines, and chemokines, such as tumor necrosis factor (TNF)-α, TGF-β, MIP-1α, MCP-1, VEGF, IFN-α/β/γ, GM–CSF, IL-1α/β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-16, IL-18, IL-25, and so on (Figure 1).
Anaphylactic responses to insect stings, injected medications, foods, and other agents are thought to be caused by IgE/antigen-dependent mast cell activation [16]. In addition to this classic pathway of systemic anaphylaxis [17, 18], IgG antibodies can also induce anaphylaxis in a basophil-dependent manner in the mouse [19]. Histamine is primarily responsible for the development of shock in the classic pathway. By contrast, PAF is responsible in the latter alternative pathway. Despite the earlier controversy on the role of mast cells in asthma [20], recent studies clearly showed their importance [21, 22]: mast cells can markedly enhance antigen-dependent airway hyperresponsiveness, airway eosinophil infiltration, and an increase in the number of proliferating cells in the airway epithelium that are induced in mouse models of asthma that either omit artificial adjuvants or use low doses of antigen challenge; mast cells’ roles were also shown in a chronic asthma model [23]. In asthmatics, mast cells infiltrate airway smooth muscle and contribute to persistent inflammation in the airways [24, 25, 26]. The best evidence for the pivotal role of IgE and therefore that of FcɛRI in human asthma came from clinical studies demonstrating that anti-IgE mAb Omalizumab decreases serum IgE levels and allergen-induced bronchoconstriction [27, 28].
The most crucial tool that has driven the high-paced findings is mast cell engraftment into mast-cell-deficient animals, by which one can confirm that ‘defects’ or abnormal observations on mast-cell-deficient animals can be reversed by providing exogenous mast cells [29]. Stem cell factor (SCF) is a crucial growth and differentiation factor for mast cell development [30, 31]. c-Kit is its receptor tyrosine kinase. Loss-of-function mutations in gene loci for this ligand (Sl)/receptor (W) pair lead to profound reductions of mast cells. Mast-cell-deficient KitW/W−v mice have been a choice for mast cell engraftment for more than two decades. However, these mice have various other hematopoietic and non-hematopoietic abnormalities and are cumbersome to breed. By contrast, another strain of mast-cell-deficient mice, KitW−sh/W−sh do not have anemia or neutropenia and are easy to breed, therefore KitW−sh/W−sh mice have become a favorite animal to study the mast cell function. However, because of multiple cellular abnormalities in KitW−sh/W−sh and KitW/W−v mice, it is essential to demonstrate that abnormalities in these mice can be rectified by ‘knockin’ experiments before one can conclude that such abnormalities are due to mast cell deficiency [32].
Section snippets
Atopic dermatitis (AD)
AD, or eczema, is a chronic or chronically relapsing, pruritic inflammatory skin disease. The incidence of this disease has been increasing for the past three decades and affects at least 15% of children [33, 34, 35]. Clinical manifestations vary with age: eczematous lesions emerge on the cheeks and the scalp in infancy. Scratching causes crusted erosions. Later in the childhood, lesions involve flexures, the nape, and the dorsal skin of the limbs. In adolescence and adulthood, lichenification
Genetics of AD
Genome-wide association studies have identified several chromosomal loci as the possible locations of AD-associated genes, including 1q21, 3q21, 11q13, 16q, 17q25, 20p, and 3p26 [37, 38]. These studies identified the AD susceptibility genes that support both (I) immune dysregulation and (II) impaired skin barrier function hypotheses: the involvement of IL4, IL13, IL18, and TIM1 genes supports the importance of CD4+ T cells and dysregulation of Th1 and Th2 genes in the pathophysiology of AD [39,
Mouse models of AD
Numerous mouse models of human AD have been developed since the first description of AD-like skin lesions in the dermatitis-prone NC/Nga mice in 1997 [59]. These models are essential for our current understanding of human AD, as they have been providing novel insights into the disease pathogenesis. There are two types of mouse models: (I) some mice develop skin lesions spontaneously; (II) in another type of model, skin lesions are induced by epicutaneous or intradermal challenge of immunized
Pathogenic roles of mast cells
As most studies showed increased numbers of mast cells in skin lesions in the AD models, it is generally assumed that mast cells contribute to skin inflammation. Unfortunately, however, few studies have directly addressed whether, to what extent, or by what mechanism mast cells play a role in spontaneous or induced development of AD-like skin lesions. An EC OVA sensitization study showed that skin inflammation is comparable in wild type and KitW/W−v mice [79]. However, IFN-γ mRNA expression was
Extrinsic vs. intrinsic AD—IgE in AD
A majority of AD patients have elevated serum IgE levels. In contrast with this so-called extrinsic AD, 20–30% of patients have low or normal levels of IgE. The latter, intrinsic AD, patients sometimes experience increases in serum IgE later in their life. Although AD might well be a syndrome caused by multiple etiologies (i.e., involving different combinations of multiple sets of cell types or multiple signaling pathways), it is also possible that the presence of intrinsic AD followed by a
PGD2 and AD
Mast cells not only produce PGD2 abundantly upon FcɛRI stimulation but also express a functional receptor CRTH2 for PGD2 [90]. PGD2 binds to two membrane receptors, D prostanoid receptor (DP)1 and DP2 (aka CRTH2). A DP2 agonist (13,14-dihydro-15-keto-PGD2) increases eosinophil recruitment at inflammatory sites and skin inflammation in an EC OVA sensitization model, whereas a DP1 agonist failed to induce eosinophil chemotaxis [91]. Administration of a CRTH2 antagonist, compound A, ameliorated
Pruritogenic role of mast cells in AD
Pruritus is one of the most prominent clinical features of AD and it disturbs the everyday life of AD patients. Itch-scratch vicious cycle also exacerbates the dermatitis by damaging the skin barrier and enhancing the itch [95]. This effect was also demonstrated in mouse models. Established dermatitis of NC/Nga mice was dramatically alleviated by clipping their toe-nails [96], while those with intact nails had sustained dermatitis. Interestingly, skin scratching was suggested to switch immune
Conclusions and future perspectives
An emerging scenario supported by clinical observations and EC OVA sensitization models (Figure 2) is that impairment in skin barrier function will allow access of allergens and microbes to antigen-presenting cells such as Langerhans cells and dermal DCs and endow the microenvironment with a Th2 (and Th17) cell-nurturing capacity. These APCs will mature (lose the ability to uptake antigen and acquire antigen-presenting ability) during the migration to draining lymph nodes. Naïve T cells
Conflict of interest statement
No authors have any conflicts of interest.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We acknowledge support from National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases contract NO1 AI40030 to TK. This publication is no. 1163 from the La Jolla Institute for Allergy and Immunology.
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