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- Hindawi Publishing Corporation
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- Copyright © 2012 Aleksandra Szczawinska-Poplonyk. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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- 10.1155/2012/492761
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Abstract
Hindawi Publishing Corporation Journal of Allergy Volume 2012, Article ID 492761, 7 pages doi:10.1155/2012/492761 Review Article Development of Mucosal Immunity in Children: A Rationale for Sublingual Immunotherapy? Aleksandra Szczawinska-Poplonyk Department of Pediatric Pneumonology, Allergology and Clinical Immunology, Poznan University of Medical Sciences, Szpitalna Street 27/33, 60-572 Poznan, Poland Correspondence should be addressed to Aleksandra Szczawinska-Poplonyk, ola@malwa.com.pl Received 19 June 2011; Accepted 22 August 2011 Academic Editor: Seval Guneser Kendirli Copyright © 2012 Aleksandra Szczawinska-Poplonyk. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The mucosal immune system has bidirectional tasks to mount an effective defense against invading harmful pathogens and to suppress the immune response to alimentary antigens and commensal bacterial flora. Oral tolerance is a suppression of the mucosal immune pathway related to a specific immunophenotype of the dendritic cells and an induction of the regulatory T cells as well as with the silencing of the effector T cell response by anergy and deletion. The physiological dynamic process of the anatomical and functional maturation of the immune system occurring in children during pre- and postnatal periods is a significant factor, having an impact on the fine balance between the activation and the suppression of the immune response. In this paper, mechanisms of mucosal immunity and tolerance induction in terms of maturational issues are discussed with a special emphasis on the implications for a novel therapeutic intervention in allergic diseases via the sublingual route. 1. Introduction nal tract, protolerogenic mechanisms take place in this tissue and dominate over active immune responses. The mucosal immune system comprises the lymphoid- The development of mucosal immunity in children is a associated structures of the nasal, bronchial, gastrointestinal, time-dependent process initiated in the intrauterine growth and genitourinary tracts as well as lacrimal, salivary, and and is continuous during the postnatal period. Despite lactating mammary glands and the synovium of joints. It is the anatomical and functional immaturity of the mucosal composed of a dynamic network of highly specialized com- immune system and crosstalk between innate and adaptive ponents of the innate and adaptive immune responses, which immune responses, infants and young children are capable of give rise to the functional common mucosal immune system mounting effective immune defense mechanisms. However, (CMIS) and ensure fine, organ-specific balance between during this age, an imperfect regulatory immune response, activation and suppression. The fundamental challenge of which is of crucial importance in developing oral mucosal mucosalimmuneresponseistoprevent effectively the entry immunity, may pose an increased risk of food allergies. If of invading pathogens and the development and the dissem- developing new strategies of immunotherapy which exploit inating of infection, whereas simultaneously its exposition to the establishing of an oral mucosal tolerance has a rationale the external environment and to a high antigenic load elicits in pediatric patients is here the subject of discussion. immune tolerance. These interrelated processes of active promotion and suppression of immunity provide a defense against microorganisms and neoplasms and protect against 2. Mucosal Defense Mechanisms inflammatory pathologies such as allergy and autoimmunity as well. To maintain the immune homeostasis in the oral 2.1. Mucosal Barrier. Extensive noncellular physical bar- mucosa which represents the entry port to the gastrointesti- riers and chemical processes as well as cellular components 2 Journal of Allergy constitute mucosal barriers to antigen entry in the mucosa- The migration of T and B cells from the lymph nodes to associated lymphoid tissue (MALT). Structural differentia- the mucosa, which is related to the activation, recirculation, tion of the mucosal epithelium and the appearance of inter- and homing of lymphocytes is controlled by the specific sys- cellular tight junctions lead to the formation of an anatom- tem of integrin-type molecules, selectins [8] and chemokines ical basis for an epithelial barrier. A significant protective [9]. barrier is constituted by the presence of digestive enzymes starting in the mouth and extending down to the stomach, 2.3. Adaptive Immune Response. The mucosal immune sys- the small bowel, and the colon, which not only allow the tem has generated two arms of an adaptive response, namely, process of digestion, but also modify potentially immuno- antigen exclusion, performed by different T cell subsets, B genic antigens and alter antigen exposure. Mucin glycopro- cells and secretory antibodies to inhibit or modulate adher- teins, lining the surface epithelium, produce a barrier in ence or colonization of microorganisms and prevent pene- which particles and pathogens are trapped and protect the tration of potentially harmful antigens, as well as suppres- underlying epithelium (the so-called nonimmune exclusion) sive mechanisms to avoid overreaction against innocuous as well as serving as a reservoir for the secretory IgA [1]. substances which are in contact with the mucosal surfaces. A A number of antimicrobial components of saliva contribute central role in this interrelated network of lymph cell subsets to protection against microbial colonization and infection. is played by dendritic cells (DCs), which are important These include peptides such as salivary peroxidase, lysozyme, initiators of adaptive immunity. DC prime naıve T cells lactoferrin, cystatins, SLPI (secretory leukocyte protease to expand clonally and differentiate into T-cell subsets—T inhibitor), agglutinin, peptides of the histatin family, and helper Th1, Th2, Th17, or T regulatory (Treg) cells. It has cathelicidin (LL-37) as well as α-and β-defensins, which been demonstrated that these cells may have discrete subsets are expressed and secreted by salivary glands and/or ducts. and functions, namely, CXC3CR1(+)DC which promote In addition to exerting an antimicrobial response, these Th1/Th17 cell differentiation, whereas CD103(+)DC induce peptides facilitate and amplify innate and adaptive immune Treg cell differentiation on an animal model [10]. At the responses [2, 3]. Interestingly, it has been recently demon- mucosal site, dendritic cells and T lymph cells interact with strated that the expression and antimicrobial activity of B cells promoting their differentiation and the production cathelicidin in the oral mucosa is induced by vitamin D of antibodies. Most immunoglobulin class-switching is T [4, 5]. cell dependent; however, it has been demonstrated that T- cell independent process may also occur, whereby DC and 2.2. Innate Mucosal Immune Response. The crucial elements mucosal epithelial cells excrete BAFF (B cell activating factor of the innate arm of immunity are pattern recognition belonging to the TNF family) or APRIL (a proliferation receptors (PRRr), such as Toll-like receptors (TLRr), retinoid inducing ligand) directly stimulating B cells to become IgA acid-inducible gene-I- (RIG-I-) like receptors (RLRr) and secreting plasma cells [11, 12]. IgA is the major class of nucleotide-binding oligomerization domain (NOD)-like re- antibodies in mucosal secretions and occurs predominantly ceptors (NLRr), which recognize pathogen-associated mo- in a secretory IgA (sIgA) form along with secretory IgM lecular patterns (PAMPs) and molecular structures specific (sIgM). The distribution of IgA subclasses varies at different for microbial pathogens. Signaling by pattern-recognition mucosal sites—in the salivary glands and oral mucosa IgA1, receptors on antigen-presenting cells induces costimulatory associated with a response to protein antigens predominates, molecules and cytokines, and furthermore activating a re- whereas in the distal portion of the gastrointestinal tract sponse in B and T cells. The stimulation of Toll-like receptors mainly IgA2, active in response to polysaccharide antigens by PAMPs initiates signaling cascades that involve a num- is found [13]. The recently characterized Th17 lymphocytes ber of proteins, including MyD88 (myeloid differentiation subset is important for the induction of a mucosal adaptive primary response gene 88), IRAK (interleukin- (IL-) recep- immune response. It has been demonstrated that IL-17 tor associated kinase), Toll/IL-1 receptor (TIR) domain- elevates secretory IgA levels by upregulating A polymeric containing adapter-inducing interferon (IFN)-β (TRIF). immunoglobulin receptor expression in mucosal epithelia Subsequent activation of nuclear factor NFκB triggers the [14]and promotes Bcelldifferentiation in IgA-secreting production of proinflammatory cytokines, such as tumor plasma cells on a T cell-independent manner [15]. Further- necrosis factor (TNF)-α, IL-1, and IL-12, which direct adap- more, IL-17 plays a protective role in infectious diseases at tive immune responses. Functional cooperation and cross- the oral mucosa through the recruitment of neutrophils and regulation between TLRs and the complement components, extracellular pathogen clearance [16]. such as C1q, properdin, and the mannose-binding lectin, using the pattern recognition strategy has been demon- strated. The complement-TLR interplay reinforces innate 3. Maturation of Mucosal Immunity in Children immunity or regulates excessive inflammation, through synergistic or antagonistic interactions [6]. Moreover, ficolin 3.1. Ontogeny of Mucosal Immunity During Prenatal Period. molecules (L-, M-, and H-ficolin) which recognize pathogen- The structures of the mucosal immune system are fully devel- associated molecular patterns and initiate the lectin pathway oped by the 28 gestational week, and thus, premature infants of complement activation are thus a further component older than 28 weeks of gestation are capable of mounting an of mucosal immunity linking innate and adaptive immune effective mucosal immune response [13]. Mucosal epithelial responses [7]. barrier formation commences from gestational week 10; Journal of Allergy 3 however, the immaturity of intercellular tight junctions [24] demonstrated comparable salivary IgA levels in preterm results in paracellular permeability, which is advantageous in and full-term infants, suggesting that the development of the the intrauterine period by allowing a bidirectional exchange oral mucosal immunocompetence in preterm infants is well of bioactive molecules between amniotic fluid and fetal established within the first 9 months of life. In preschool serum [17]. Salivary amylase, lysozyme, and lactoferrin children, the developmental profile of mucosal immunity concentrations are most prominent in the fetal period as depends on the degree of antigenic challenge they experience demonstrated by Thrane et al. [18], affording nonspecific as well as on the exposure to hazardous environmental protection in the absence of effective specific secretory agents, such as tobacco smoke [25]. immunity. Indeed, in the absence of intrauterine infection, the mucosal immune system is essentially devoid of IgA- 4. The Phenomenon of Mucosal Tolerance containing lymphocytes, and until birth, there are no active B cells in the intestinal lymphoid follicles or bronchus- 4.1. Induction of Tolerance. In parallel to local defense associated lymphoid tissue (BALT). In the salivary glands, mechanisms which protect against invading pathogens, the IgM positive cells have been reported from 110–140 days mucosal immune system has developed specialized regula- of gestation and IgA positive cells with predominance of tory and anti-inflammatory mechanisms for eliminating or IgA1 subclass at 180 days of gestation, but no IgD-, IgG- tolerating harmless food and airborne antigens as well as , and IgE-producing cells have been identified by the same commensal microorganisms. Mucosal tolerance induction is, authors [18]. The appearance of secretory antibodies in utero therefore, an active process and is seen as preferential the Th2 can be explained by the possibility that a fetus could have skewed immune response and the downregulation of Th1 been exposed to bacterial or viral protein antigens or by cell-mediated delayed type hypersensitivity and antibody the induction of a fetal immune response by maternal anti- production. These complex regulatory mechanisms include idiotypic antibodies. clonal deletion of T cells, clonal anergy, antigen-driven im- munosuppression as well as active inhibition by coinhibitory 3.2. Postnatal Maturation of Mucosal Immunity. Mucosal receptors [26]. Many different CD4+ T regulatory (Treg) permeability is rapidly reduced within the first 48 hours cell subsets have been identified capable of inhibiting the after birth. In the oral mucosa, disappearance of maternally responses of effector T cells. Thymus-derived CD4+CD25+ derived IgG reflects this postnatal mucous membrane closure Foxp3 (forkhead box protein 3)+Treg cells play a funda- [19]. This maturational process of the gut barrier function mental role in maintaining self-tolerance and preventing is enhanced by human milk [20]aswellasbyearly intesti- autoimmunization as well as contributing to tolerance of nal colonization with lactobacilli and bifidobacteria [21]. nonself antigens by the inhibition of immune responses The rapid increase of innate defense factors, such as salivary directed at commensal bacteria in the intestine [27]. Mucosal lysozyme, lactoferrin, and amylase during the first six post- Foxp3+ cells have been identified in the small and large natal months reported by Thrane et al. [18] may provide the intestinal mucosa as early as 23 weeks of gestational age, infant necessary protection during the period when specific indicating a potential for intestinal immune regulation im- adaptive immunity at mucosal sites is not fully developed. mediately after birth [28]. In contrast to thymus-derived Postnatal maturation of B lymph cell at mucosal surfaces Treg cells, adaptive Treg cells, which are peripherally has its peak from birth until the 12 week of age and induced after feeding protein, are essential for mucosal corresponds with the increase of IgG-producing cells in the tolerance. These include TGF-β- (transforming growth fac- parotid salivary glands. Secretory IgM antibodies appear tor β-) producing Th3 cells, type 1 T regulatory cells (Tr1) in mucosal secretions only transiently during early infancy. which produce IL-10 as well as Foxp3+Treg cells. The ac- IgA-producing immunocytes, albeit they increase in number tive suppressive mechanisms may also induce a “bystander during neonatal period and reach an initial peak about 4– effect” in that suppressive cytokines released by regulatory 6 postnatal weeks, approach the low normal adult level at T cells in an antigen-specific pattern may also suppress about 18 months of age, subsequently with small increase ongoing immune response to an unrelated but anatomically throughout early childhood [17]. Qualitative changes in colocalized antigen [29]. secretory IgA are also seen after birth when a switch from It is worth of note that the term “mucosal tolerance” monomeric to polymeric sIgA is observed, indicating mat- is widely used to describe tolerance induction occurring in uration of the mucosal secretory immune system. Further- the intestinal MALT (mucosa-associated lymphoid tissue), more, in the perinatal period, IgA1subclass, associated with represented by B cell follicles and M cell containing lym- responses to protein antigens, predominates in mucosal phoid epithelium, where the uptaken antigens are passed secretions, but IgA2 subclass increases rapidly after birth by to APC (antigen-presenting cells), such as dendritic cells, 6 months of age to approach adult proportions. This pattern macrophages, and B cells. However, in contrast to the may also reflect postnatal changes in the type and load of intestine, the oral mucosa lacks inductive site represented by antigenic exposure, in particular to polysaccharide antigens MALT and most likely local organized lymphoid tissue and [22]. Interestingly, in preterm infants sIgA appears in secre- regional lymph nodes play a role in the induction of oral tions at a similar chronological age as in full-term infants mucosal tolerance [26]. although its concentrations may be significantly lower until the eighth month of life, as reported by Kuitonen and Dendritic cells, the most important components orches- Savilahti [23]. However, in contrast to these data, Seidel et al. trating the mucosal tolerance in the gastrointestinal tract, 4 Journal of Allergy Genotype Indigenous gut microbiota Predispositionto atopy Age-developmental Dietary factors (vitamin D, immunophenotype LC-PUFA and probiotics) Oral immune tolerance versus Effector immune response Pre- and postnatal Breastfeeding mothers exposure to microbial exposure to dietary pathogens antigens Mucosal maturity Exposure to alimentary (mucous membrane Breastfeeding as a source of antigens (timing, dose and protolerogenic and effector closure, secretory antigen nature) compounds immunoglobulins and antimicrobial peptides) Figure 1: Exo- and endogenous biological factors determining mucosal immune response profile in childhood. have an intrinsic noninflammatory activation state and a adiponectin, which modulate the immune system by the rich repertoire of receptors expressed by these cells, such regulation of cytokine expression [20]. as high-affinity receptor for IgE (FcεRI), high- and low- affinity receptors for IgG (FcγRI and FcγRII, resp.), Toll-like 5. Mucosal Tolerance: An Implication for receptors (TLR)2, and TLR4 and LPS (lipopolysaccharide) Sublingual Immunotherapy receptor CD14, are of crucial importance in the induction of antigen-specific regulatory T cells. Furthermore, several 5.1. Oral Mucosal Microenvironment. In the oral mucosa the network of resident dendritic cells (DCs) is mainly factors, such as the nature and dose of antigen, the frequency of its administration, age at first antigen exposure, mater- composed of the myeloid DC from the Langerhans cell (LC) subtype, expressing CD1a and CD207 antigens (HTA1 nal dietary exposure during pregnancy and breastfeeding, and langerin, the LC specific lectin, corresponding with the antigen transmission via breast milk, as well as genetic mannose-containing oligosaccharide receptor, respectively), background and immunological status of the child influence costimulatory molecules, such as B7.1 (CD80) and B7.2 the fine balance between tolerance and effector response (CD86) as well as other myeloid markers, eg CD11b (a com- [29]. Exo- and endogenous biological factors determining plement components receptor). These cells are also equipped mucosal immune response profile in childhood are summa- with a very specific receptor repertoire, such as a high- rized in Figure 1. affinityreceptorfor IgE(FcεRI) resulting in allergen uptake and IgE binding to specific receptors on their surfaces. 4.2. Role of Breastfeeding. The newborn and infant gut is Interestingly, cross-linking of FcεRI on dendritic cells results hypersensitive to proinflammatory stimuli and vulnerable to in the induction of both pro- and, most importantly, anti- pathogens. Breastfeeding not only favors the transmission inflammatory mediators, such as IL-10 [34] and indoleamine of immunocompetence from the mother to the infant, as 2,3-dioxygenase (IDO) [35], which is involved in the sup- reviewed by Chirico et al. [30], but also has immunomodula- pression of T cell responses and tolerance. The expression tory and anti-inflammatory properties. The dietary antigens of high- and low-affinity receptors for IgG containing an present in breast milk coupled with immunosuppressive immunoreceptor tyrosine inhibitory motif (ITIM) enhances cytokines, such as IL-10 and TGFβ, promote tolerance to the induction of antigen-specific regulatory T cells, as shown food antigens and gut microflora. It has been demonstrated by Samsom et al.onananimal model[36]. Furthermore, in the study by Field et al. [31] that long chain polyunsat- TLR4 ligation on the oral DC surface leads to a subsequent urated fatty acids in human milk alter the infant’s ability to induction of Foxp3 expressing as well as IL10 and TGFβ produce cytokines enhance the anti-inflammatory effect of producing regulatory T cells [37], which are key players in IL-10. Soluble TNF-α (tumor necrosis factor) receptors and oral mucosal tolerance. These unique properties of DC to drive Treg cells differentiation relate to their being con- IL-1RA (interleukin 1 receptor antagonist) in human milk ditioned by commensal bacteria, TGFβ and IL-10, their effectively inhibit inflammatory response elicited by TNF-α expression of α β integrin (CD103) and retinoid acid [38]. E 7 and IL-1, respectively [32], and IL-10 exhibits a suppressive effect on IL-8 and neutrophilic inflammation [33]. Human milk also contains hormones, such as epidermal growth 5.2. Immunological Mechanisms of Sublingual Immunotherapy factor (EGF), insulin-like growth factor (IGF), as well as (SLIT). Multidirectional tolerogenic properties of an oral Journal of Allergy 5 immune response warrant antigen-specific tolerance induc- and continued during the neonatal period, and in infancy tion. Dendritic cells in the oral mucosa, which exhibit the and childhood, dynamically leading to a highly specialized high affinity receptor for IgE Fc fragment, take up allergens immune response. At mucosal sites, a subtle balance occurs administered in SLIT and induce specific immune responses. between effective defense mechanisms against the invasion An increase of serum IgG4 and IgA, noninflammatory and of harmful pathogens and triggers the limitation of effector noncomplement binding isotypes as well as reduced allergen immune reactions to food antigens and commensal flora. specific IgE locally in the target organ have been noted in Important factors, such as genetic predisposition and the age the occurrence of increased TGF-β and IL-10 in allergen of the host, pre- and postnatal exposure to antigens, as well specific peripheral blood mononuclear cells [39]. Similarly, as the properties and the dose of antigen contribute to the in the clinical study comprising a group of asthmatic/ development of mucosal tolerance, this being the rationale rhinitis pediatric patients, reported by Eifan et al. [40] the of critical importance for sublingual immunotherapy. The immunological mechanisms of SLIT were associated with results of hitherto prevailing clinical studies suggest the effi- significant increases of TGF-β and IL-10. Furthermore, T cacy and safety of this treatment option in children, hereby regulatory cell function has also been demonstrated by opening new perspectives in pediatric allergology. O’Hehir et al. [41], leading to the suppression of the allergen specific effector T (CD4+CD25-CD127hi) cell proliferation References and cytokine production. In a recent study of Angelini et al. [42] the downregulation of the costimulatory molecule [1] L. 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