CC BY
47
M.R. Khaitov, N.I. Ilyna, L.V. Luss, A.A. Babakhin
Mucosal immunity of the respiratory tract and its role in occupational pathologies
NRC Institute of Immunology FMBA of Russia, Moscow, Russian Federation
Keywords: mucosal immunity, immunoglobulin A, allergic response, occupational pathology of respiratory tract.
The article presents modern concepts of mucosal immunity (including the structure and function of lymphoid tissue associated with the mucosa), the role of immunoglobulin A (IgA), the role of the mucosa of the respiratory tract in the allergic immune response. Data on the features of mucosal immunity in chronic obstructive pulmonary diseases (COPD) and asthma are presented. The concept of a local
allergic response in the mucosa of the respiratory tract is considered. Changes in mucosal immunity in occupational respiratory pathology, as well as in athletes of higher achievements, are considered. Information on the effect on the respiratory system of chemical occupational pollutants, including nanosizedparticles is also given.
One of the main functions of the immune system is to remain tolerant of 'harmless' antigens and, at the same time, to provide an adequate response to substances (antigens) that are potentially dangerous from the point of view of lethal destruction of body tissues. In the process of evolution, that part of the immune system that is associated with the mucous membranes of various body systems (gastrointestinal, respiratory, urogenital tracts, as well as the eyeball) is formed, i.e. system of mucosal immunity. As the first line of protection, the main attribute of mucosal immunity is secretory IgA, which plays a protective and immunoregulatory role when exposed to the body of various components of the environment. In this respect airways and lungs, which are in direct contact and under constant influence of environmental components, including microorganisms, allergens, chemical compounds, all kinds of particles (including nano-sized diameters) possessa powerful immune system of protection localized in the mucosa. This review highlights the pathophysiological mechanisms of airways protection associated with the mucosal immunity system and secretory IgA, with special attention to the mucosal IgA response in COPD, asthma and adverse effects of occupational hazards.
Lymphoid tissue of the mucosa
Previously, it was shown that 'large' lymphocytes (lymphoblasts) that enter the bloodstream from the thoracic lymphatic duct
can migrate into the lamina propria of the intestinal wall and undergo final differentiation into plasmablasts and plasma cells. Most circulating lymphoblasts express the surface (sIgA). Initially, it was assumed that these lymphoid cells originate from Peyer's patches (PPs) because it was shown that PPs and drainage mesenteric lymph nodes (MLN) unlike peripheral lymph nodes and spleen, were enriched with precursors of IgA-producing plasma cells in the intestinal mucosa. It was also shown that the differentiation of plasma cells occurs during the spread of mucosal B cells. Thus, the fraction of cells with cytoplasmic IgA increases from the initial 2% in the PPs to 50% in MLN and up to 75% in the thoracic lymphatic duct and ultimately up to 90% in the lamina propria of the intestine [19; 63].
Further studies led to the formation of the concept of 'IgA cell cycle', when it was shown that B cells that carry on the surface other than IgA classes of immunoglobulins, as well as T cells, when activated in PPs, are present in the intestinal mucosa. Later it became clear that various secretory effector sites of the mucous membrane can attract activated effector B memory cells from various lymphoid tissues associated with the mucosa (LTAM) [20; 21]. This, in turn, gave rise to the notion that the mucosal immune system conditionally has inductive and effector structures. Inductive structures include LTAM along with lymph nodes draining the mucosa, whereas the effector structures are
represented by the mucosal epithelium and the underlying lamina propria, which contains stromal cells and the stroma itself (connective tissue). Mucous and associated endocrine glands are the largest activated B-cell system of the body, the main product of which, dimeric IgA (containing J-chains) and a certain amount of pentameric IgM. This product is always ready for immediate transport to the outside with a polymeric immunoglobulin receptor (pIgR) in the secretory epithelium, as well as in mucus containing layers on the surface of the mucosa to provide antibody-mediated immunity [26].
It should be noted that LTAM resembles B cell lymph node follicles, interfollicular T cell zones and various antigen-presenting cells (APCs), but does not have afferent lymphatic vessels and capsules. Nevertheless, LTAM contacts exogenous antigens located on the surface of the mucosa directly through the follicle-associated epithelium (FAE) which plays a major role in mucosal immunity. Representing a very small part of the mucosal surface, the FAE contains a unique type of epithelial cells ( M cells) whose primary function is to absorb and transfer microorganisms and other antigenic material through the epithelial barrier to dendritic cells (DCs) and lymphocytes located within and even under the epithelium [28]. The FAE is separated from the underlying lymphoid follicle by the zone of subepithelial dome filled with T and B cells, as well as the DCs, which effectively absorb the material transported by the M cells. Some DCs and lymphocytes migrate to intra-epithelial pockets formed by M cells [38].
LTAM is present in various organs and tissues of the body including the gastrointestinal tract, nasopharynx, oral cavity, lungs, eyes and urogenital tract and differs anatomically and physiologically. Despite the common features inherent in the above organs and tissues, the mucosal immune system possesses characteristics that reflect anatomical and physiological features. The main component of LTAM is the lymphoid tissue associated with the intestinal wall including the PBs the appendix and a series of single follicles called isolated lymphoid follicles. Induction of the mucosal immune response is also carried out at the expense of LTAM located in the nasopharynx and bronchi. Moreover, a small amount of LTAM-like lymphoid formations is found in the
conjunctiva and larynx. It should be noted that IgA is the main isotype that is secreted by all mucosal surfaces with the exception of the lower parts of the respiratory and genital tracts where the main secreted class of immunoglobulins is IgG. In humans IgA exists as two subclasses of IgA1 and IgA2 present in different ratios in different organs and tissues but the IgA1 content is higher than that of IgA2 in all organs and tissues except for the large intestine. Comparative studies of the structure of the IgA molecule showed that IgA2 is a phylogenetically later form. The structural differences between the two subclasses of IgA are in contrast to their a1 and a2 heavy chains of the immunoglobulin molecule at the level of the 13th amino acid sequence of the hinge region IgA1. Also IgA1 and IgA2 have differences in the number, location and type of glycosidic bonds. In blood plasma approximately 84% of the molecules belong to IgA1 and 16% belong to IgGA2 subclasses [31; 46].
Airway mucosa
Mucous airway is under the constant influence of chemical, physical, infectious and noninfectious antigens, as well as biotoxins, which represent a huge burden on the immune system, with an inhaled air volume of 7—12 l/min. Its surface is approximately 100 m2, on which the processes of recognition of 'dangerous' and 'non-dangerous' antigens take place, the formation of effective protection against pathogens, as well as mechanisms that prevent the development of inflammation. While alveolar macrophages carry out a 'sweep' of fine particles and antigens in the distal sections of the airways ( terminal and respiratory bronchioles) and in the alveoli, secretory IgA (SIgA) is the main component of the mechanisms of the 'first line' of protection in the upper (nose, pharynx, larynx) and lower ( trachea, bronchus and bronchioles) sections of the conducting airways. Secretory immunoglobulins are selected by prolonged evolution to protect the surface of the mucosa. They have unique properties for performing their role in the mucosa, such as high antigen-binding activity and relative resistance to proteolysis from the surrounding microflora. It is shown that local immunity dysfunction, primarily the deficiency of secretory immunoglobulin A (SIgA), underlies many chronic inflammatory
diseases of the mucous membranes and promotes the development of allergies [5]. 'Resident' cells in the wall of the airways can participate in a rapid response ( due to the innate immunity system) to stimuli by secretion of a number of mediators with anti-infective and antiinflammatory properties such as: lysozyme, phospholipase A2, a-defensins, mucins and lectins (surfactant proteins and galectins), club cell proteins (the former name of cells is Clara cells) [56]. Moreover, the epithelial cell layer is also a physical barrier possessing a negative electrical charge.
In animal experiments, it has been shown that so-called intraepithelial lymphocytes (IELs) expressing the yS T cell receptor (TCR) and CD8a homodimer are contained in mucosal tissue in contrast to conventional T cells expressing ap TCR (or CD3) or CD4 or CD8ap co-receptor. It is assumed that y5 T cells participate in the early stages of the immune response by recognizing and eliminating infected epithelial cells expressing class I molecules of the main histocompatibility complex, which is regarded as the 'first line' of protection. Presumably, the anti-infective properties of IELs are associated with direct cytolytic effect and/or with Th1 cell activity, activation of neutrophils and macrophages, and stimulation of epithelial cell survival through the production of growth factors [30].
Immunoglobulin A (IgA) — the main factor of mucosal immunity
IgA, being the main attribute of mucosal immunity can provide a link between innate and adaptive immunity. IgA can be produced by 'non-typical' B lymphocytes (B1 cells) along the so-called T-independent pathway. The polyclonal IgA antibodies obtained in this way play a major role in the 'first line' protection before the appearance of the adaptive immune response. In contrast, 'typical' B lymphocytes (B2 cells) are transformed into IgA-producing plasma cells by the specific (T-dependent) pathway of development of the adaptive immune response after specific stimulation as a result of the interaction of antigen-presenting cells and T cells [15; 18].
It is believed that the production rate of mucosal IgA is the highest (40 mg/kg-1/day-1)
among the products of other immunoglobulins. The number of IgA producing plasma cells together with a certain amount of IgG producing cells constitutes up to 20% of all cells secreting immunoglobulins in the bronchi. IgA synthesized locally is a polymeric (dimeric) isoform (pIgA) other than serum IgA synthesized by plasma cells of the bone marrow and which is a monomeric isoform. Mucosal pIgA has been shown to be covalently linked to a small (15 kD) polypeptide called a J-chain synthesized by concomitant pIgA-producing cells. This J-chain probably has a value in 'homing' B cells into the mucosa, as well as in the subsequent binding of IgA to the epithelial transmembrane receptor (pIgR) for polymeric IgA since most immunoglobulin-producing mucosal plasma cells including IgG producing cells express this polypeptide [36].
More recently, it has been shown that circulating IgA plasmoblasts and IgA-secreting plasma cells in various mucosal tissues express CCR10, a receptor for CCL28 lymphocytes produced by mucosal epithelial cells and being a subpopulation of CCR4+ T blood cells. However, T lymphocytes of bronchoalveolar lavage (BAL) express a low level of CCR4 suggesting that they are unresponsive to CCR4+ ligands such as chemokines produced by monocytes. These pulmonary T lymphocytes express high levels of CXCR3 and CCR5 but these receptors are also present on most tissue leukocytes including those found in the skin and synovial fluid. In vitro experiments have shown that the expression of chemokine receptors is phenotype-specific but not tissue-specific when Th2 differentiation is associated with increased regulation of CCR4 and CCR8 while Th1 cells express mainly CXCR3 and CCR5. Thus, while the profile of lymphocytes 'homing' into the airway mucosa and lungs remains unclear [25; 27; 41].
IgA immune response
The sequence of events during the development of the mucosal immune response can be represented as follows. Antigen getting on the surface of the mucosa is absorbed by M-cells and transported to mucosal APCs (mainly dendritic cells). The antigen is processed by DCs which after 'maturation' migrate to the area with a high T cell content. Activation of T cells by DCs either locally ( mucosal T cells) or in draining lymph
nodes (systemic T cells) occurs. Further B cells are activated by mucosal T cells ( monoclonal activation) or directly APCs carrying an intact antigen ( polyclonal activation) . Recycling and migration of B cells to mucosal sites where primary exposure (primary immunization) with antigen ('homing') occurs and where they undergo several functional changes associated with the conversion of antigen-specific B cells into IgA-producing plasma cells. The process involves several stages: 1) switching production of immunoglobulins to production of IgA (class switching) , in which the main role is played by the cytokine-transforming growth factor-p;
2) clonal proliferation of antigen-specific IgA-commited B cells with the participation of IL-10, IL-2, IL-5 and IL-6 which originate from resident air wall cells, such as bronchial epithelial cells. In case of an allergic response, the switching of B cells to IgE production is carried out with the participation of IL-4 and/or IL-13 originating from mast cells or infiltrating Th2 lymphocytes;
3) somatic hypermutation of the variable regions of genes of mucosal plasma cells which is twice as intense as that observed in the corresponding immunoglobulin producing plasma spleen cells. The fact that is associated with a high antigenic load on the mucosa probably makes it possible to develop a high degree of 'affinity maturation' of the mucosal antibody response in comparison with the systemic response. pIgA containing the J-chain produced in lamina propria should be transported through the epithelium to get into the secretion (bronchial) fluid. Although some of the IgA (predominantly monomeric serum IgA) can passively diffuse through the epithelium (especially in inflammatory processes associated with extravasation of plasma proteins) most of the IgA found in the secretions is actively transported through the bronchial epithelium via the pIgR-mediated transcellular pathway. pIgR expressed at the basolateral pole of epithelial cells binds pIgA and transports it towards the apical pole from where the extracellular part of the receptor (called the secretory component, SC) covalently bound to pIgA is released to generate secretory IgA (SIgA), after which unbound pIgR releases a free SC containing SIgA into the bronchial secret. In vitro studies have shown that pIgR expressed in bronchial epithelial cells is functionally activated by cytokines such as
interferon-y, IL-4 or tumor necrosis factor-a (TNF-a) through signaling pathways including interferon-y regulatory factor-1 and nuclear factor kappa B (NF-kB) [57; 65].
Function of IgA
Initially it was assumed that the main role of IgA produced on the surface of the mucosa is the neutralization of bacteria. In vitro experiments have shown that SIgA binds in particular to the protein A of pneumococcus suppressing its virulence [33]. Later this situation spread to viruses and it was shown that IgA-containing immune complexes are formed in lamina propria. It has also been shown that IgA reduces the viscosity of secrets in the airways, and also participates in the mechanisms of complement-dependent microbial lysis and phagocytosis so that IgA immune complexes are capable of inducing only an alternative way of complement activation. IgA can regulate the activation of leukocytes through the IgA-Fc receptor (FcaR) (CD89) via the signal Y-chain of the FcR homodimer which is also associated with high affinity FcsR and TCR. It has also been found that IgA can inhibit the release of TNF-a from activated monocytes as well as the opsonizing effect of serum IgG against Haemophilus influenza that indicates its anti-inflammatory properties different from those observed in other immunoglobulins. At the same time IgA can trigger the process of phagocytosis, the inactivation of pathogens, the release of proinflammatory mediators by phagocytes. The result of the interaction between IgA and leucocytes expressing FcaR as shown in studies of alveolar macrophages expressing the splicing variant of FcaR probably depends on several factors such as the stage of pre-activation, the nature of the stimuli and the cytokine environment. In addition to the above pIgA or SIgA can enhance the secretion of TNF-a by alveolar macrophages by activating of NF-kB indicating that IgA can exert both a stimulating and inhibitory effect on innate immunity [42; 80; 81].
Mucosal immunity in chronic obstructive pulmonary diseases (COPD) and asthma
It is believed that the mucosal immune system plays a major role in the formation of allergic asthma and chronic obstructive
pulmonary diseases (COPD) which are the main chronic pulmonary inflammatory diseases. Both asthma and COPD are characterized by airway obstruction, but in the case of asthma it is variable and reversible whereas in COPD it progresses and is irreversible. COPD is often associated with a history of smoking and includes chronic obstructive bronchitis, emphysema and inflammation of the small bronchi that progresses with time and is irreversible. Inflammation in COPD is characterized by the presence of neutrophils, Th1 and CD8 T cells, the development of fibrosis around the small bronchi and the destruction of the alveoli. Controversial data were received about the presence of IgA in BAL. A lower concentration of IgA in BAL fluid was observed in some smokers with chronic bronchitis while their serum IgA levels were elevated. It was also noted that in patients with severe COPD the expression of pIgR on bronchial epithelial cells was significantly reduced compared to normal bronchial epithelium. It is interesting to note that a decrease in pIgR expression was an inverse correlation with peribronchial neutrophil infiltration. These observations are consistent with the previously noted association between local production of IgA and inflammation. I.e. neutrophils can potentiate the transport of IgA through the normal bronchial epithelium by activating the NF-kB and the p38-mitogen-activated protein kinase pathway. It is assumed that with COPD the reactivity of epithelial cells may be of a different nature, not permitting an increase in pIgR activity in the presence of activated neutrophils. Thus, the functioning of the IgA system within the bronchial mucosa in COPD appears to be associated with neutrophilic inflammation which may contribute to the pathogenesis of the disease in terms of the relationship between decreased pIgR expression in small airways and airway obstruction determined by measuring of function of external respiration [16; 48; 58; 59]. At present there is a perception that asthma is a heterogeneous disease that has several forms (phenotypes) with different pathogenetic mechanisms. These mechanisms include allergic ( adaptive immunity) and non-allergic (innate immunity) pathways of development induced by contact with an allergen, a viral infection, oxidative stress and the involvement of a large
number of cells belonging to the systems of innate and adaptive immunities including eosinophils, basophils, Th2 cells, dendritic cells, neutrophils, natural killer T (NKT) cells, epithelial cells, Th17 cells and macrophages. At the same time, not only cytokines and chemokines produced by Th2 cells are involved in the pathogenesis of asthma, but also IL-17, IL-25, IL-33, thymic stromal lymphopoietin (TSLP) — cytokines produced by innate immunity cells including epithelial cells, Y^-cells and NKT-cells. Despite of the fact that asthma can be developed due to several independent ways these ways can coexist and interact [14; 17; 40].
Allergen-specific IgA in allergic response
A number of studies have shown that mucosal and systemic production of IgA specific for the allergen is observed in patients with asthma and allergic rhinitis. Mucosal IgA response is well pronounced in patients with allergic rhinitis after allergen challenge. The increase in IgA level in nasal secretion is biphasic: during the reaction of the early phase (in 10—15 min.) and during the reaction of the late phase. It is noteworthy that the IgA / allergen ratio was reduced in the early phase and increased in the late phase which is supposedly associated with an increase in vascular permeability in the beginning of response and increased local production of IgA and its trans-epithelial transport in the late phase. The specific IgA response is well studied in the nasal mucosa and bronchi in patients with atopic asthma and rhinitis, sensitized to house dust mites Dermatophagoides farina, grass pollen and ragweed pollen. Simultaneously in patients with asthma there was an increase in BAL IgM, which correlated with the level of a2-macroglobulin and IgM in serum which in turn indicated local production but not about transudation from peripheral blood [12; 54].
In asthma mucosal B cells preferentially switch the synthesis of immunoglobulin classes to Cs. This process is controlled by IL-4 and IL-13 and leads to IgE production in the bronchial mucosa in response to allergenic exposure. Production of IgE in the mucosa and subsequent degranulation of mast cells after cross-linking of the cell-bound IgE by allergen is the main mechanism providing the inflammatory response in asthma. As regards mucosal IgA it is believed
that it still plays some role in the allergic response. This concerns primarily the activation and subsequent degranulation of eosinophils which are one of the main cells involved in inflammation in asthma. In vitro experiments have shown that the incubation of blood eosinophils with serum IgA results in the release of significant amounts of eosinophilic cationic protein, eosinophilic peroxidase, eosinophilic neurotoxin and also IL-4 and IL-5. This effect of IgA is mediated (at least in part) by the FcaR receptor whose elevated content is presented on eosinophils of patients with bronchial asthma. Moreover, in vitro experiments have shown that eosinophils obtained from patients with atopic bronchial asthma do not need priming with IL-4 or IL-5 cytokines in contrast to eosinophils obtained from healthy donors. This supports the notion that in vivo eosinophils are primed (preactivated) to bind IgA and that this preactivation is implemented via p38 and PI-3 kinase pathways [6; 23; 51; 70].
Immnoregulatory properties of IgA
It is believed that IgA can participate in the regulation of the immune response by modulating the cytokine profile. IgA-mediated activation of eosinophils leads to the production of IL-4 and IL-5. At the same time eosinophils secrete interferon-y in response to activation of CD28 and IgA complexes can inhibit this effect through stimulation of IL-10. I.e. IgA can act in favor of the Th2 response by modulating the cytokine response of eosinophils, which allows the IgA response to be considered as a pathogenetic mechanism for asthma along with IgE. On the other hand, it is known that selective IgA deficiency in early childhood is considered as a risk factor for atopy development. In mice experiments it has been shown that intranasal treatment of mice with antigen -specific monoclonal IgA antibodies prevents the development of bronchial hyperreactivity, tissue eosinophilia, IL-4 and IL-5 production after allergen challenge. Neutralization of aeroallergens with IgA can be a protective mechanism in inducing tolerance by high-dose allergenic immunotherapy which induces in allergic patients a switch from the production of allergen-specific IgE to the production of allergen-specific IgA and IgG4 [35; 69; 79].
Local allergic response in the mucosa
In recent years the notion of a so-called local allergic rhinitis (LAR) characterized by symptoms similar to normal allergic rhinitis during the palliation season has appeared but there has been no increase in serum allergen-specific IgE [73]. At the same time it was shown that in such patients in the absence of serum IgE there is a local increase in the level of specific IgE in the nasal cavity (nasal secret) or in nasal lavage which is called 'local allergic rhinitis' [61; 62]. Thus, LAR was characterized by local production of IgE in the nasal cavity, Th2 cell infiltration of the nasal mucosa and a positive nasal provocative test in the absence of serum allergen-specific IgE [66]. It is important to note that over time patients with LAR go to the category of patients with systemic atopy and comorbid allergic diseases such as bronchial asthma [67].
The concept of local IgE synthesis with local allergic rhinitis was confirmed in the mouse LAP model. In mice sensitized intranasally there was a clinical picture similar to that of human LAR as well as eosinophilic infiltration of the nasal mucosa and local production of allergen-specific IgE in the absence of serum IgE. It has also been shown that local production of allergen-specific IgE occurs in the nasal cavity by switching B cells from IgM production to IgE production (class -switch recombination) by differentiating them into IgE-producing plasma cells. In addition, subpopulations of innate lymphoid cells of group 2 (ILC2s) characterized by the presence of ST2 (receptor for IL-33) and producing IL-5 and IL-13 were found in the nasal cavity. At the same time, it was found that repeated intranasal sensitization of mice with an allergen led to the appearance of a systemic ( serum) allergen-specific IgE. This confirms the concept of the natural course of the disease through the transition of LAR to systemic allergic rhinitis and that the first sign of this process can be the detection of local allergen-specific T cells [37].
Concepts of the formation of an allergic response
Currently, two mechanisms are considered for the formation of allergies. The first is based on the concept of activation by the allergen of Th2 cells producing interleukins IL-4, IL-5 and IL-13
[77]. The role of IL-4 and IL-13, as the factors necessary for switching B cells to IgE synthesis, was demonstrated in vitro experiments [13; 32; 60]. The second mechanism presupposes the presence of tissue lymphoid cells belonging to the ancient forms of innate lymphoid cells type 2 (ILC2s). It was shown that, for example, in the parasitic invasion of Rag -/- mice lacking T and B cells, IgE was formed and production of IL-4, IL-5, IL-13 was observed which was responsible for ILC2s cells [44]. The existence of ILC2s cells of innate immunity was confirmed by other authors and tissue lymphoid cells with T helper characteristics are known to date [50; 68; 76; 78].
Class E immunoglobulins of (IgE) are normally present in the peripheral blood (serum or plasma) in a minimal amount. In the formation of sensitization to the allergen, the concentration of IgE in the serum increases in parallel with the sensitization of the target cells of allergy ( mast cells and basophils) however, serum levels of total IgE often do not provide correct information on the amount of allergen-specific IgE. Also the presence of specific IgE does not always correlate with the clinical response to a causally significant allergen, especially in the long course of the disease when the contribution of IgE can differ significantly and when other mechanisms become more important in the pathogenesis of the disease at later stages. Nevertheless, it is generally accepted that the primary link in the pathophysiological process chain is the appearance of an allergen-specific IgE.
In this regard, the question of where and how B cells are switching the production of IgM isotype antibodies to the IgE isotype (class switch recombination, CSR) is the key. It was shown that under in vitro conditions human B cells undergo the CSR process under the influence of IL-4, both direct (from IgM to IgE) and sequential (from IgM to IgG and then to IgE) ways [84]. Under experimental conditions, parasitic infection of N. brasiliensis mice shows the formation of two B-cell subpopulations carrying out CSR in direct and sequential ways [83]. However, other authors have shown that switching of immunoglobulin isotypes (CSR) in this model occurs only in a direct way [72]. Probably sequential switching occurs when the allergen falls into
the draining lymph nodes, where Th2 cells can be formed while direct switching corresponds to another type of immune response that forms at the site of the allergen contact (local IgE synthesis) [82].
A number of studies have been devoted to the issue of local switching of B cells to IgE synthesis. Thus, direct switching of B cells to IgE synthesis in the nasal mucosa of patients with allergic rhinitis was demonstrated meaning that allergen-specific antibodies of other classes should be absent [24; 71]. In one study, it was found that direct B cell switching to IgE synthesis occurred in 90% of children from 1 to 7 years of age with sensitization to birch and grass pollen [52]. At the same time, independent formation of IgE and IgG antibodies both in children and adults was shown to allergens of cat hair and house dust [34; 64]. The above data on the local synthesis of IgE allow us to take a new look at the pathogenesis of allergic rhinitis and bronchial asthma, as well as to justify the concept of novel approaches to therapeutic effects through the mucosa of the airways in particular the possibility of suppressing allergic inflammation by RNA interference method [7; 11; 39].
Mucosal immunity in occupational respiratory pathology
Significant changes in mucosal immunity are detected in various pathological conditions caused by the presence of a chronic recurrent inflammatory process caused by infection, exposure to various environmental factors ( stress, ultrahigh physical loads, radiation, chemical factors, and many others. In particular, dysfunction of mucosal immunity is revealed in patients with chronic polypous rhinosinusitis (CPR) [9]. In determining the mucosal immunity parameters in the saliva of 60 patients with CPR such as IgG, secretory IgA (sIgA), lactoferrin, lysozyme activity, the following results were obtained. An increase in IgG levels (0.063±0.01 g/L) and lactoferrin (28107±3358 ng/ml), a decrease in lysozyme activity (28.99±1.2%) was revealed. IgA levels (0.07±0.004 g/l) and sIgA (0.14±0.018 g/l) were within normal limits, which may be one of the factors of recurrence of nasal polyps. The obtained results indicate the expediency of studying the parameters of mucosal immunity
as an additional factor in the research, which makes it possible to conduct an adequate correction of CPR therapy.
Mucosal immunity in elite athletes
Of particular interest is the study of the characteristics of mucosal immunity in persons subjected to ultra-high physical loads, typical of which are athletes of higher achievements (elite athletes). It is known that intensive loads of elite athletes are accompanied as a rule by a high level of emotional and psychological stress the aggregate of which can be considered as a powerful 'trigger' factor. Overcoming this 'trigger' factor the threshold of which is individual for each person, leads to activation of the hypothalamic-pituitary-adrenal and sympathetic systems, as well as to changes in innate, mucosal, adaptive immunity and the cytokine network of the immune system. In the US and Europe many studies have been conducted to evaluate the mucosal immunity parameters among athletes. For example, in France in a team of triathlon athletes the IgA content in saliva was evaluated in repeated competitions. It was found that an intensive exercise repeated daily had a cumulative negative effect on the level of saliva IgA [43]. Similar studies have been conducted among football players in Brazil [49], the United Kingdom and the United States. However, conflicting evidence was obtained in the United States that indicated that a decrease in IgA saliva is not a reliable marker for determining susceptibility to infections [75].
The undoubted interest is the question of the relationship between the intensity and duration of training loads and the severity of changes in the mucosal immune system. As is known, the deficiency of sIgA is the basis of many chronic inflammatory diseases of the mucous membranes and promotes the
development of allergic reactions [1]. In our studies conducted in the clinical department of NRC Institute of Immunology FMBA Russia 61% of elite athletes had a decrease in sIgA content in saliva (Table 1). Moreover, a direct correlation between the level of sIgA decrease in saliva and the presence of frequently recurring viral infections in elite athletes (herpes virus infection, acute respiratory viral infections, recurrent rhinosinusitis, etc.) was noted [10].
Reduction in the level of sIgA was more often noted in athletes with allergies. 64.3% of the examined athletes also showed a decrease in lysozyme activity in the saliva which is an indication of a decrease in local immunity. In 96% of the examined athletes an increase in the content of lactoferrin in saliva was detected. Lactoferrin possesses bacteriostatic activity. By binding to Fe3+ ions and other metals and depriving the bacteria of the vital microelements that make up the cytochrome of the respiratory chain (catalase, peroxidase) it increases their susceptibility to the toxic effect of reactive oxygen species [9]. The increase in the content of lactoferrin in saliva may indicate the presence of infectious diseases of the upper respiratory tract (URT) in athletes. 69.1% of elite athletes showed a decrease in IgA in saliva. Reduction of IgA in the saliva of the examined athletes may indicate a decrease in the barrier function of the URT mucosa, which may lead to an increase in the infectious morbidity of the URT. IgG content in saliva in 95.6% of the examined athletes was normal and only in 4.6% was increased which corresponds to the already published data indicating that in the normal URT mucosa no significant disturbance of IgG immune response were detected [10; 29]. This findings indicate that elite athletes have a decrease in mucosal immunity.
Indicators of mucosal immunity in elite athletes, n=213 Table 1
N/n Activity of lysozyme, % Lactoferrin, ng/ml IgG, g/l IgA, g/l sIgA, g/l
Normal values 32.8-50.2 1100-4200 0-0.05 0.07-0.12 0.12-0.23
Increased content, number/% Higher 50.2% 1/0.5 Higher 4200 ng/ml 127/96 Higher 0.05 g/l 6/4.4 Higher 0.12 g/l 5/3.7 Higher 0.23 g/l 22/16.2
Reduced content, number/% Below 32,8% 137/64.3 0 0 Below 0.12 g/l 94/69.1 Below 0.23 g/l 83/61
Normal content, number/% 75/35.2 5/4 130/95.6 37/27.2 31/22.8
The influence of chemical occupational pollutants on mucosal immunity
At present, the process of accumulation of data on the health status of people living in ecologically unfavorable regions, the features of their immunological and allergenic status is ongoing. The problem of the formulation of allergological status is extremely important since the allergy is a matrix for the onset and course of many somatic diseases determining not only the degree of severity, but also the prognosis of most diseases, work capacity and life expectancy of a person. Ecological status which is formed under the influence of chemical and other technogenic factors is also determined by the concentration of industrial enterprises which probably should be taken into account when mapping the most contaminated areas of the Russian Federation.
In our studies we determined the parameters of mucosal immunity in the employees working in the territories where mining and processing of uranium ores took place in the past. This included: IgA, IgG, sIgA content in the saliva of employees of OAO Hydrometallurgical Plant (HMP) and OAO Electromechanical Plant (EMP). Analysis of the mucosal immunity indices in the employees of OAO HMP and OAO EMP revealed changes that are characterized by an increase in the sIgA content in the saliva of HMP personnel (17.8%) and EMP personnel (9.7%) (Table 2). The decrease in sIgA content in saliva was detected in 2.8% of the personnel of OAO HMP and 8.3% of the personnel of OAO EMP. The increase in IgG level in saliva was revealed in 56.9% of the employees of OAO HMP, of which 12.4% had an increase in all three parameters of mucosal immunity (IgG, IgA, sIgA) and 54.8% of OAO EMP personnel,
of whom 6.8% had an increase in all three mucosal immunity parameters (IgG, IgA, sIgA). 19.2% of OAO HMP personnel who had an elevated IgG content in saliva had concomitant somatic diseases and 11% had allergic diseases. The most pronounced increase in IgG level in saliva, both for OAO HMP personnel and for OAO EMP, was noted in persons who had contact with the production factor (PF) and suffering from allergic diseases. The increase in IgA level in saliva was revealed in 26.4% of the surveyed workers of OAO HMP and in 23.3% of the surveyed workers of OAO EMP. Reduction of IgA in saliva was revealed only in 4.1% of OAO HMP personnel. The rest of the examined individuals had a normal IgA level in the saliva.
One of the significant problems of malfunction of the airway mucosa is the effect on the mucosa mainly the upper respiratory tract (URT) of the PF, associated with industrial aerosols (IA), in coal, woodworking, metallurgical, flour, textile, cotton processing, machine building, and agricultural industries. The main IA group consists of aerosols of predominantly fibrogenic and mixed action, including silicon dioxide and silicon containing silicate and silicate containing, asbestos and asbestos containing compounds; artificial fibrous and mineral substances; clay, chamotte, bauxite, limestone, cement; aerosols of metals and their alloys, iron ore and polymetallic concentrates, as well as abrasive and abrasive containing compounds; carbon dust ( anthracite, coke, industrial carbon, natural and artificial diamonds, carbon fiber materials); ores of polymetallic, non-ferrous and rare metals; welding aerosols containing manganese, chromium, nickel, fluorine compounds, beryllium, lead, aluminum, zinc, tungsten, molybdenum, etc.;
Indicators of mucosal immunity in personnel of OAO HMP and OAO EMP Table 2
Indicators of mucosal immunity IgG, mg/l IgA, mg/l SIgA, mg/l
Normal values Up to 50 mg/l 30-160 mg/l 70-250 mg/l
OAO «HMP» n=92 OAO «EMP» n=73 OAO «HMP» n=92 OAO «EMP» n=73 OAO «HMP» n=92 OAO «EMP» n=73
Normal content of mucosal immunity parameters, % 43.1% 45.2% 73.6% 72.6% 79.4% 82%
Increased content of muco-sal immunity indices, % Higher 50 mg/l 56.9% Higher 50 mg/l 54.8% Higher 160 mg/l 26.4% Higher 160 mg/l 23.3% Higher 160 mg/l 17.8% Higher 160 mg/l 9.7%
Reduced content of muco-sal immunity indices, % 0 0 0 Below 30 mg/l 4.1% Below 70 mg/l 2.8% Below 70 mg/l 8.3%
dust of vegetable and animal origin (cotton, flax, grain, tobacco, wood, peat, paper, wool, down, silk, etc.). All this list of unfavorable substances for the human body falls under the concept of occupational production hazards the impact of which on the mucosa of the airways is of great importance in the pathology of occupational diseases.
The impact of industrial aerosols of different concentrations, duration and intensity during labor activity causes the development of pathological changes in the URT. With the increase in the length of work in the 'dust' profession, the protective powers of the mucous membrane are gradually depleted, which leads to the development of cytochemical and functional changes. The clinical picture of dystrophic changes occurring in the area of the mucosa of the URT has practically no specific features and develops as catarrhal, subatrophic or hypertrophic rhinitis, pharyngitis, and laryngitis. The peculiarity of the formation of the dystrophic process is the descending character of the changes and the total defeat of all parts of the URT (nose, pharynx, larynx - rhinopharyngolaringitis), progression of the process as the length of work is increased under the impact of IA. Exposure to significant concentrations of vapors and dust of chemical substances with pronounced irritating and necrotic effect (acid, alkali, nickel, chromium, fluoride, arsenic, cement dust) may lead to ulcerative lesions of the mucous membrane of the nasal cavity and perforation of the nasal septum. Inhalation intake of IA in the body creates opportunities for adverse sensitizing effects of the chemicals on the entire respiratory tract. Therefore, those working in contact with the IA develop not only isolated but also total forms of allergic changes that extend to the nasal cavity, pharynx and larynx: allergic rhinitis, allergic pharyngitis, allergic rhinopharyngitis, allergic laryngitis, allergic pharyngolaryngitis. A characteristic feature of the dust effect on the upper parts of the respiratory tract is a shift in the pH of the nasal secretion to the alkaline side, a slowing down of the transport function of the ciliated epithelium, and morphological changes in the nasal mucosa [3].
Pathological processes in the body of workers largely depends, both on the condition of the mucosa of the URT and on the state of
the reactive forces of the organism. The upper and lower divisions of the respiratory tract form an integral unit in the anatomical and physiological respect, and in the conditions of the whole organism the pathological process in one department adversely affects the condition of the other. Obstruction of nasal breathing and disruption of pulmonary ventilation leads to the development of hypoxia and hypoxemia and dystrophic changes in the URT tissues. In the initial stages there is irritation of the mucous membrane as a catarrhal inflammation. With a longer exposure these changes are transformed into subatrophic and atrophic (more often) or hypertrophic (less often) processes. Various forms of chronic inflammation in the URT have a certain pathomorphological picture, described in a number of studies [2].
Among respiratory diseases associated with the damage to the airway mucosa, bronchial asthma associated with occupational activity (BAOA) occupies a special place. Diagnosis and treatment of BAOA is directly related to the understanding of the multifactority of pathogenetic mechanisms. Clinical manifestations of BAOA are similar to those in bronchial asthma not associated with the profession but the unique relationship of BAOA with antigens in the workplace allows for early diagnosis and therapy. 90% of all cases of BAOA are associated with sensitization to antigens that have a high molecular weight. The low molecular weight chemical compounds that cause BAOA are generally not associated with IgE-dependent mechanisms. A number of factors, such as innate immunity mechanisms, non-immunological mechanisms of mucosal epithelial damage, airway remodeling, oxidative stress, neurogenic inflammation and genetic risk factors contribute to the development of BAOA [22; 45; 47; 74].
Effects of nanoparticles on the respiratory tract
Novel direction in occupational pathology is the study of pathological processes associated with the inhalation of nanoparticles (NPs) (including biological origin) formed or used in modern high-tech industries. As a rule, these are composite compounds based on materials such as alumina, carbon, carbon nanotubes,
dendrimers, fullerenes, iron oxide, polystyrenes, silicon dioxide ( amorphous and crystalline) , silver, titanium dioxide, zinc oxide, etc. There are several proposed mechanisms by which NPs affect the bronchopulmonary system and on other body systems. When the NPs hit the lungs the state of cellular oxidative stress is triggered. This process triggers the production of antioxidant enzymes and in case the cell does not overcome this stress, production of cytokines and chemokines occurs which causes a large-scale proinflammatory response. Moreover, in animal experiments it was shown that the proinflammatory ability of NPs is the higher, the smaller the particle size that penetrates the airways and lungs. It was shown that in order to achieve the same inflammatory effect, a 10fold smaller mass concentration of particles with a diameter of 0.02 pm is required as compared to particles with a diameter of 0.25 pm. At the same time, NPs can reach other 'extrapulmonary' organs by blood flow, and some NPs can overcome the blood-brain barrier and enter the brain tissue, where the processes of endocytosis or the reaction leading to their internalization are initiated. Thus, the pathological effect of NPs is specific to their size and chemical structure. Under experimental conditions, it was shown that the size of particles introduced into the mammalian organism determines the features of the immunological reaction. Intake into the bloodstream of particles larger than 1 pm in diameter, carrying, for example, pertussis antigen led to the activation of Th1 cells whereas the introduction of smaller diameter particles caused the appearance of Th2 cells. At present insufficient data on the influence of NPs on the immune system including mucosal immunity was obtained, thus further research in this direction can shed light on new aspects of pathogenesis which will allow to better understand the effect of NPs on the bronchopulmonary system and on the body as a whole [4; 8; 53; 55].
Conclusion
Thus, the available information, including those obtained in recent years, indicate the exceptional importance of mucosal immunity in terms of its pathophysiological role in protecting the body from external irritants, in the development and prognosis of various
respiratory tract diseases. The previously published data and our research data point to the variety of mechanisms participating in mucosal immunity and its changes under the influence of damaging factors of anthropogenic origin. This predetermines the need to find new opportunities for activation of the body's defense systems, especially mucosal immunity, with the purpose of substantiating and developing modern methodological approaches and algorithms for diagnostics, prevention and therapy of patients as well as the population exposed to technogenic and other anthropogenic influences.
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Contacts:
Khaitov Musa Rakhimovich,
Director of NRC «Institute of Immunology»
FMBA of Russia,
Doctor of Medical Sciences, Professor,
Corresponding Member of RAS.
Tel. Working: +7 - (499) - 617-1027;
Tel. Mobile: +7-985-776-1944.
E-mail: [email protected]
Address: 15478, Moscow, Kashirskoye shosse, 24.
