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• W2034368220 abstract "The concept of a common immune system operating at the level of all external mucosal surfaces was first proposed almost 30 years ago. The mucosal surfaces of the gastrointestinal and respiratory tracts are replete with organized lymphoid follicles containing immunocompetent B and T lymphocyte precursors and are endowed with specialized cellular elements necessary for antigen uptake, processing and presentation to specific lymphoid precursors in the mucosal epithelium. Available evidence concerning the mucosal immune responses relevant to the development of immunity in the middle ear, nasopharynx and upper airway is summarized. COMMON MUCOSAL IMMUNE SYSTEM The common mucosal immune system comprises of intestine-associated lymphoid tissue (GALT) and the lymphoid tissues associated with bronchus and lower respiratory tract (BALT), male and female genital tract, mammary glands and the products of lactation, ocular tissue, upper airway, nasopharynx (NALT), salivary gland and tonsils and the mucosa of the middle ear cavity. The lymphoid follicles in GALT and BALT are considered to be the principal inductive sites of mucosal immune responses. Exposure to antigens and other environmental macromolecules results in the activation of responsible B and T lymphocyte precursors in the follicles of the GALT and BALT. 1, 2 From these inductive sites antigen-sensitized B and T lymphoblasts and memory cells migrate to mucosal effector sites. These sites include the epithelial lamina propria and other scattered subepithelial sites in the distant mucosal epithelial sites identified above. The migration of antigen-sensitized lymphoid cells from the inductive cells to effector cells is preferentially determined by expression of adhesion molecules in the tissue endothelium and specific receptors (integrins) expressed by the lymphoid cells. Homing of lymphocytes from Peyer’s patches and the GALT appears to be mediated by interaction between alpha-4-beta-7 lymphocyte integrins and mucosal addressin cell adhesion molecule 1 expressed on the vascular endothelium in the lamina propria. 3 The antigen-sensitized B cells undergo terminal differentiation in the mucosal lamina propria to Ig-producing plasma cells involving interaction with a variety of cytokines and T cell subsets (Table 1). Locally produced IgA consists mainly of J chain-containing dimers and larger polymeric IgA (collectively called pIgA) that are selectively transported through epithelial cells by a polymeric Ig receptor called the secretory component. The resulting secretory IgA antibodies are designed to perform immune exclusion and other immunologic functions at the mucosal surface. 4 IgG also contributes to such surface defense. It often reaches the secretions by passive diffusion and, less frequently, by local synthesis. However, its proinflammatory properties render IgG antibodies of potential immunopathologic importance when IgA-mediated mucosal elimination of antigens is unsuccessful. T helper (Th) cells activated locally may, by a Th2 cytokine profile, promote persistent mucosal inflammation with extravasation and priming of inflammatory cells, including eosinophils. This development may be considered as “pathotopic potentiation” of local defense. It appears to be part of the late phase allergic reaction, perhaps initially driven by interleukin 4 (IL-4) released from mast cells subjected to IgE-mediated or other types of degranulation and subsequently maintained by further Th2 cell stimulation. Eosinophils are potentially tissue-damaging, particularly after priming with IL-5. Various cytokines up-regulate adhesion molecules on endothelial and epithelial cells, thereby enhancing accumulation of eosinophils and, perhaps in addition, causing aberrant immune regulation within the epithelium. Soluble antigens available at the epithelial surfaces normally appear to induce various immunosuppressive mechanisms, but such homeostasis seems to be less potent in the airways than the induction of systemic hyporesponsiveness to dietary antigens operating in the gastrointestinal tract. Numerous cytokines and chemokines have been shown to be intimately involved in the induction and maintenance of mucosal immune responses and the level of mucosal inflammation during infections or other environmental exposures (Table 2). During the past decade the immunologic events associated with otitis media (OM) have been studied quite extensively. 5, 6 The components of immunity in middle ear cavity, nasopharynx and salivary glands and upper airway have been reexplored, and exciting new information has been generated regarding their role in the development of immune responses and the pathogenesis of OM in childhood. Table 1: Events of immunologic activity associated with mucosal immune responseTable 2: Functional role of different cytokines in the mucosal tissuesMIDDLE EAR The normal middle ear cavity (under physiologic conditions) contains little or no organized lymphoid tissue and only occasional immunocompetent cells. However, studies performed in children with different forms of OM have revealed that middle ear mucosa exhibits distinct characteristics of mucosal immunity similar to those of other external mucosal surfaces. These include the immunohistologic demonstration of in vitro synthesis of free secretory component, presence and local production of secretory IgA and other immunoglobulins and the appearance of macrophages and polymorphonuclear leukocytes and different subset of T lymphocytes in the mucosal epithelium. 7 In addition specific antibody activity against a wide variety of bacteria and viruses has been repeatedly observed in the secretory IgA and other immunoglobulin isotypes in the middle ear fluid. Several studies have demonstrated the presence of immunoregulatory as well as proinflammatory cytokines or their specific messenger RNA in the middle ear fluid or mucosal epithelial cells. Messenger RNA for several cytokines including IL-1-beta, IL-6 and tumor necrosis factor alpha have been detected in the middle ear fluid collected from patients with OM associated with infection with respiratory syncytial virus. However, IL-3, IL-5 and interferon-gamma have been detected less frequently. Expression of cell adhesion molecules such as intercellular adhesion molecule 1 have also been observed in the middle ear mucosa during active viral infections. These observations suggest that many of the cytokines may be produced locally in the middle ear cavity. It has been proposed that Th2 subsets of lymphocytes (IL-2- and IL-4-producing cells) are more common in the middle ear during acute infection and IL-5-producing cells are more frequent in chronic ear disease. IL-5 preferentially stimulates IgA-B cells, transforming growth factor beta is involved in the switch of IgM-B cells to an IgA phenotype and IL-2 and IL-4 stimulate B cell response in general including mucosal IgA responses. Because the production of IgA is dependent on several cytokines, the increase in IgA concentration, especially during certain chronic ear infections, may reflect specific cytokine-mediated immunoregulatory changes in the middle ear. 6 Earlier studies have shown that the source of immunocompetent cells observed in inflamed middle ear mucosa is the follicular lymphoid tissue of the inductive sites in GALT and BALT. For example immunization of the respiratory or intestinal tract with live poliovirus vaccine is associated with the appearance of virus-specific IgA antibodies in the middle ear. 7 Antigen-specific IgA cells have also been demonstrated in the middle ear after intraduodenal or intratracheal immunization in experimental animal models. However, the lymphocytes that home to the middle ear have not been shown to express any specific ligand or receptors for selective recruitment in the middle ear cavity. It is, however, interesting that Peyer’s patch lymphocytes seem to adhere more efficiently to inflamed, but not to normal middle ear mucosa. 6 These observations suggest that activation of certain precursor mucosal lymphoid cells may express integrins specific for cell adhesion molecules available on inflamed middle ear mucosa. NOSE AND NASOPHARYNX Recent studies in the rat, mouse and hamster have shown the presence of organized lymphoid tissue situated at the entrance of nasopharyngeal duct. This represents an important component of mucosal lymphoid tissue in the rodents. Such NALT bears striking morphologic and functional resemblance to other central lymphoid tissue, such as GALT or BALT (Table 3). The NALT appears to have better developed lymphoid follicles, with marked intraepithelial infiltration by lymphocytes. The follicular areas are organized into B cells and intrafollicular (T cell) areas of approximately similar size. The rodent NALT contains a wealth of dendritic cells. The lymphoid follicles are covered by ciliated epithelium containing few goblet cells and numerous M cells. The NALT M cells appear to be identical with those in Peyer’s patches and BALT and are involved in similar immunologic functions. These include antigen uptake and subsequent mucosal immune responses to specific antigens. Table 3: Characteristics of Peyer’s patches, NALT, and BALT*In humans the nasopharyngeal lymphoid tissue is represented by the salivary glands and other glandular tissue in the Waldeyer’s ring, which consists of paired palatine and tubal tonsils and unpaired pharyngeal and lingual tonsils. It is not clear how comparable the functional role of Waldeyer’s ring in humans is to the NALT in rodents. 9, 10 There is increasing evidence to suggest that human tonsillar and adenoidal tissues are important components of mucosal immunity and function in a manner similar to those of GALT or BALT. The tonsils consist of several lymphoid elements. These include follicular germinal centers, mantle zones of lymphoid follicles, the extrafollicular areas and the reticular crypt epithelium on the surface in constant contact with external environment. The tonsillar epithelium contains significant number of dendritic cells, M cells, memory B cells and scattered B and T cells. The formation of the germinal center takes place shortly after birth, secondary to the activation by environmental antigens, and plasma cells appear in tonsils by 2 to 3 weeks of age. Unlike Peyer’s patches, tonsils exhibit considerable in situ differentiation to plasma cells. The germinal centers (which typically arise during T cell-dependent B cell response) generate plasma blasts and plasma cells of the IgG and IgA isotype. There is, however, predominance of IgG isotype (60 to 70% for IgG vs. 15 to 20% for IgA). The follicular germinal centers are often associated with clonal expansion of B cells, somatic hypermutation in the B cell immunoglobulin variable region gene, positive selection of B cells and eventual B cell differentiation to memory cells and isotype-specific plasma cells. The tonsils, nasal and bronchial mucosa and salivary glands exhibit similar distribution of IgA and IgD immunocytes. In addition scattered areas in the crypt epithelium of nasopharyngeal tonsils (but not palatine tonsils) express secretory component. Another important feature of mucosal lymphoid tissue and the follicular germinal center is the induction of J chain gene in some B cell subsets. Tonsillar germinal centers express a very high percentage of extrafollicular immunocytes with J chain expression. More than 90% of these immunocytes are of IgA isotype. 10 THROAT Some evidence suggests the existence of larynx-associated lymphoid tissue (LALT) in humans. Lymphoid aggregates have been observed at the laryngeal side of the epiglottis in >80% infants and children younger than 22 months of age. In the follicular areas of the aggregates, most cells appear to be B lymphocytes with some CD4+ lymphocytes in the germinal centers, and the interfollicular areas contain equal numbers of B and T cells. 11 Other investigators have also observed scattered lymphocytes in the laryngeal epithelium. It remains to be determined whether LALT is a distinct physiologic entity or a pathologic reaction in response to local infections or other environmental insults. Many children in whom LALT was identified postmortem had died because of sudden infant death syndrome. 9, 11 Little or no information is available regarding the role of LALT in antigen processing or presentation or the development of immunologic reactivity in the upper airway. CELL TRAFFIC IN EAR, NOSE AND THROAT Almost 30 years ago it was proposed that tonsillectomy and adenoidectomy had profound effect on mucosal immune response in the nasopharynx. 12 Combined tonsillectomy and adenoidectomy was shown to result in significant decline in poliovirus-specific IgA antibody levels in the nasopharynx. Subsequently other children immunized with oral poliovaccine after tonsillectomy and adenoidectomy exhibited reduced antibody responses to the virus. A number of other studies have also suggested a decline in secretory and/or serum IgA and to a smaller extent to IgG and IgM concentrations after tonsillectomy and adenoidectomy. The effect may last up to 3 years. 10, 13 More recent studies have shown that engraftment of human tonsillar lymphocytes in severe combined immunodeficient mice resulted in selective repopulation of the lung, but not of the gastrointestinal tract in the recipient animals. Investigations by Quiding-Järbrink et al. 14, 15 have shown that human palatine tonsils serve as expression sites for immune response in the upper airway and nasopharynx and contribute specific cells for the development of immunologic memory. Other investigations have shown that IgA- and IgD-positive lymphocyte distribution in NALT, BALT and the salivary glands is very similar. Thus tonsils and adenoids possibly represent an important inductive site for expression of immune response in other mucosal sites in the nasopharynx and upper airway. 14, 15 Antigen-specific IgA-producing cells have been repeatedly observed in the middle ear. Their source of origin remains to be defined. It has been observed that lymphocytes from Peyer’s patches adhere to inflamed middle ear mucosa in large numbers, but not to normal middle ear mucosa. 16 Furthermore Peyer’s patch lymphocytes binding to middle ear mucosa appear to be associated largely with IgA isotype. An interesting report has recently suggested that IgA antibody-secretory cells induced after intratonsillar immunization frequently display L-selectin and, less often, alpha-4-beta-7 integrin, whereas oral immunization frequently resulted in the production of more alpha-4-beta-7 than L-selectin. 14 Based on these observations it has been proposed that activation of Peyer’s patch lymphocytes by oral immunization results in expression of integrins such as alpha-4-beta-7 which may form receptors for mucosal addressin cell adhesion molecule 1 and thus determine the nature of cell traffic between different mucosal sites. However, L-selectin may be an important adhesion molecule in BALT, in NALT and possibly in the genital tract. 15 DEVELOPMENT OF MUCOSAL IMMUNE RESPONSE IN THE EAR, NOSE AND THROAT Based on the information reviewed above, it appears that NALT and upper airway mucosal epithelium are able to process and present antigens and mount a specific immune response locally and spread to regional epithelium via distinct homing mechanisms. Such immunologic reactivity may also home to other mucosal sites such as GALT or BALT and possibly the genital tract and mammary glands. Other observations summarized above have suggested that it is also possible to induce effective immune response in the middle ear cavity as well as in the NALT and upper airway by introduction of antigens in the GALT or BALT. Available evidence based on vaccine antigens appropriate for prevention of OM has suggested that oral immunization can induce effective immune responses in the middle ear cavity, turbotympanic mucosa and nasopharyngeal tissues. Immunization via the use of enteric-coated capsules, oral administration of antigen with adjuvants, intraduodenal or intra-Peyer’s patch introduction of antigens has been quite effective in inducing specific immune responses in the middle ear, nasal cavity or oropharynx. In several experimental models such immunization uses P1 and P6 proteins of nontypable Haemophilus influenzae, Streptococcus pneumoniae, Pseudomonas spp. and respiratory syncytial virus. This information has been reviewed recently. 6, 8 Recently interest in vaccine delivery systems has shifted to immunization via the nasal route. It appears to be as effective as the oral route, may require smaller antigen dose, can be effective even with nonreplicating agents and frequently can induce mucosal and systemic responses that may be equal to or even superior to oral immunization. Studies in animal models have shown that intranasal immunization is highly effective in inducing protective immune response using as antigens heat-killed pneumococcal antigen with cholera toxin as adjuvant, outer membrane vesicles of Neisseria meningitidis group B, Streptococcus mutans, Pseudomonas aeruginosa, Moraxella (Branhamella) catarrhalis, H. influenzae, Bordetella pertussis, carrier-free synthetic peptides, influenza virus and respiratory syncytial virus. 6 Human experience with intranasal immunization is limited at this time. However, earlier studies with inactivated poliovaccine administered intranasally and recent studies with live attenuated influenza virus vaccine have clearly demonstrated that such immunization can provide effective protection against reinfection challenge. In other studies carrier-free peptides have also been used successfully as intranasal vaccines. Synthetic peptides containing T helper cytotoxic lymphocytes and or B cell epitopes have been tested successfully and induce effective systemic and mucosal immune responses. Thus it appears that mucosal administration of antigens, including intranasal inoculation, may offer significant protection against pathogens the primary portal of entry of which is the mucosa of the respiratory tract. Intranasal immunization has minimal side effects and can overcome maternal immunologic influences. Such immunization may also reduce or prevent the need for multiple injections with a parenteral vaccine. Mucosal immunization may also provide improved vaccine efficacy in the aging and elderly. However, the immune response after intranasal immunization may be quite variable and can range from antigen-specific systemic hyporesponsiveness (mucosal tolerance) to protective immunity, or pathogenic antibody- and cell-mediated immune response. 17 The outcome of intranasal immunization may be significantly influenced by the nature of the antigen, use of mucosal adjuvants, replicating nature of the organism and the target organ of disease. QUESTION/ANSWER Question: Why does Waldeyer’s ring regress with increasing age, and does NALT go away as rats age? Dr. Ogra: I don’t know if NALT goes away with increasing age. It does seem to regress. The same thing happens with Peyer’s patches. In humans there is a time, around 18 or so, where Peyer’s patches remain high and then start to diminish in number. The volume of tonsillar tissue decreases with age unless it’s diseased. I don’t know of any systematic, natural history studies on tonsillar tissue in the absence of disease. Dr. Bluestone: There are good data on the involution of adenoids, but there’s not such a great involution of tonsils except when they are infected. Question: What is the defect in immunodeficient children or adults who have recurring OM? Is it mucosal immunity? Dr. Ogra: That is a very important issue in terms of what component of the immune system may be involved in OM. On the other hand agammaglobulinemic patients typically have recurrent OM, very often pneumococcal in etiology. But there are other disease processes where antibody activity may be reasonably intact, and yet these patients continue to suffer from recurrent OM. These include patients with histiocytosis who have OM as part of the underlying disease. Therefore there may be a number of other factors which help retain the integrity of the mucous membrane that may be lost because of infections in spite of a reasonably intact immune system." @default.
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• W2034368220 title "Mucosal immune response in the ear, nose and throat" @default.
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