Malt immunology. Unified mucosal immune system (MALT)
Maltoma of the stomach and duodenum (B-cell MALT /mucous-associated lymphoid tissue/ low-grade lymphoma) is a malignant low-grade B-cell tumor localized in the submucosal layer. Refers to non-Hodgkin's lymphoma.
It is relatively rare, accounting for 1–5% of all gastric malignancies.
It occurs somewhat more often in women. The peak age of incidence occurs in the seventh-eighth decade of life (average age is 65 years), although they can be detected at any age, incl. in children and adolescents.
A proven causative factor for MALT lymphoma is Helicobacter pylori (HP) - more than 90% of malts are associated with HP. The appearance of lymphoid tissue in the stomach is due to constant antigenic stimulation by the products of HP infection. Gastric mucosa-associated lymphoid tissue (MALT) eventually forms into low-grade and high-grade MALT lymphomas. MALT lymphomas result from monoclonal T-dependent proliferation of neoplastic B lymphocytes that can infiltrate the gastric glands. Maltoma rarely occurs in the duodenum. Its connection with HP infection has not yet been established, as well as the impact of successful eradication of HP on the course of the disease.
Clinical symptoms of MALT lymphomas are nonspecific. When localized in the stomach, the clinical manifestations are identical to those of peptic ulcer or chronic gastritis. Less frequently, patients are concerned about fever, general weakness, weight loss, and decreased tolerance to physical activity.
Diagnostics
The life history sometimes reveals the presence of autoimmune diseases: (Crohn's disease, celiac disease).
When performing FEGDS, rigidity of the mucous membrane, its hyperplasia, polypoid formations, ulcerations are detected, and the presence of HP is revealed. Endoscopic ultrasonography can provide additional diagnostic information.
Histological examination of the gastric mucosa is the main diagnostic method.
X-ray examination of the stomach and duodenum with a barium suspension can reveal the formation or local infiltration of the organ wall.
CT and MRI also determine lymphoma and its extent, but the results of these research methods do not distinguish malignant from benign.
Differential diagnosis is carried out with chronic gastritis, peptic ulcer, stomach cancer, gastric lymphoma, and other non-Hodgkin lymphomas.
Treatment
No special diet required.
When a proven etiological agent of HP is identified, eradication is carried out. Successful eradication of HP infection leads to regression of gastric MALT lymphomas in 75% of cases.
The effectiveness of surgical treatment, chemotherapy, and radiation therapy in combination and separately does not exceed the results of HP eradication.
Complete remission is achieved in 75% of cases.
The role of surgical treatment is limited. In rare cases (if other treatment methods are ineffective), a partial or complete gastrectomy is performed.
Prevention
An effective measure to prevent the development of MALT lymphoma is the elimination of the etiological factor - eradication of HP. Secondary prevention measures have not been developed; patients are monitored for several years after successful completion of treatment. After 3 months, FEGDS is performed with biopsy samples taken for morphological assessment. Repeated examinations are recommended after 12 and 18 months.
To carry out the specific function of monitoring the genetic constancy of the internal environment, preserving biological and species individuality in the human body, there is the immune system. This system is quite ancient; its rudiments were found in cyclostomes.
How the immune system works based on recognition "friend or foe" as well as the constant recycling, reproduction and interaction of its cellular elements.
Structural-functionalelements of the immune system
The immune system is a specialized, anatomically distinct lymphoid tissue.
She scattered throughout the body in the form of various lymphoid formations and individual cells. The total mass of this tissue is 1-2% of body weight.
AThe natomo-physiological principle of the immune system is organ-circulatory.
IN anatomically the immune system underdivided intocentral Andperipheral organs.
To the central authorities immunity include
Bone marrow
thymus (thymus gland),
Peripheral organs:
Encapsulated organs: spleen, lymph nodes.
Unencapsulated lymphoid tissue.
Lymphoid tissue of the mucous membranes (MALT - Mucosal–Associated Lymphoid Tissue). Including:
Lymphoid tissue associated with the gastrointestinal tract (GALT - Gut-Associated Lymphoid Tissue) - tonsils, appendix, Peyer's patches, as well as a subpopulation of intraepithelial lymphocytes of the gastrointestinal mucosa.
Lymphoid tissue associated with bronchi and bronchioles (BALT - Bronchus–Associated Lymphoid Tissue), as well as intraepithelial lymphocytes of the mucous membrane of the respiratory system.
Lymphoid tissue associated with the female reproductive tract (VALT - Vulvovaginal–Associated Lymphoid Tissue), as well as intraepithelial lymphocytes of their mucous membrane.
Lymphoid tissue associated with the nasopharynx (NALT - Nose–Associated Lymphoid Tissue), as well as intraepithelial lymphocytes of its mucous membrane.
Subpopulations of liver lymphocytes, which, as a lymphoid barrier, “serve” the blood of the portal vein, which carries all the substances absorbed in the intestine.
Lymphoid subsystem of the skin (SALT - Skin-Associated Lymphoid Tissue) disseminated intraepithelial lymphocytes and regional lymph nodes and lymphatic drainage vessels.
Lymphoid subsystem of the brain, including various subpopulations of lymphocytes and other immunocytes.
Peripheral blood- transport and communication component of the immune system.
Thus, it is quite justified to isolate the local immune subsystems of the mucous membranes, as well as the brain, liver, skin and other tissues.
In each tissue, populations of lymphocytes and other immunocytes have their own characteristics. Moreover, the migration of lymphocytes into a certain tissue depends on the expression on the membrane of the so-called homing-Рc (home - home, the place of “registration” of the lymphocyte).
From a functional point of view The following organs of the immune system can be distinguished:
reproduction and selection of cells of the immune system (bone marrow, thymus);
control of the external environment or exogenous intervention (lymphoid systems of the skin and mucous membranes);
control of the genetic constancy of the internal environment (spleen, lymph nodes, liver, blood, lymph).
Main functional cells are 1) lymphocytes. Their number in the body reaches 10 12. In addition to lymphocytes, functional cells in the composition of lymphoid tissue include
2) mononuclear and granularleukocytes, mast and dendritic cells. Some cells are concentrated in individual immune organs systems, others- free move throughout the body.
In barrier tissues (mucous membranes and skin) there is a multi-level system of protecting the body from foreign infectious and chemical agents, called “mucosal associated lymphoid tissue” (MALT). It includes humoral factors and cells of innate and adaptive immunity, as well as non-immune defense mechanisms. One of the important components of the protection of barrier tissues is the microbiota, the commensals of which, on the one hand, carry out metabolic function and direct antipathogenic activity, and on the other, constantly stimulate MALT at different levels and, thus, maintain the immunity of barrier tissues in a state of “smoldering” activation and readiness to respond quickly to invasion by foreign organisms or substances. Antibiotics, being one of the most frequently prescribed medications, disrupt the number, composition and activity of symbiotic microorganisms. As a result, the immunity of barrier tissues is weakened, which contributes to the colonization of mucous membranes and skin by pathogenic microorganisms and, in particular, their antibiotic-resistant strains. Awareness of this fact requires a change in the tactics of prescribing antibiotics and the introduction of additional medications in order to maintain MALT activity. Candidate drugs for addition to etiotropic anti-infective therapy are patterns of symbiotic microorganisms (microbial-associated molecular patterns (MAMP)) or, more realistically from a pharmacological point of view, their minimal biologically active fragments (MBAF).
Keywords: mucosal immunity, microbiota, antibiotics, immunosuppression, infections, antibiotic resistance, immunomodulation, replacement therapy.
For quotation: Kozlov I.G. Microbiota, mucosal immunity and antibiotics: subtleties of interaction // RMJ. 2018. No. 8(I). pp. 19-27
Microbiota, mucosal immunity and antibiotics: the fineness of the interaction
I.G. Kozlov
D. Rogachev National Medical Research Center for Pediatric Hematology, Oncology and Immunology, Moscow
There is a multi-level system for protecting the body from foreign infectious and chemical agents, known as “mucosa-associated lymphoid tissue” (MALT), in the barrier tissues (mucosa and skin). It includes humoral factors and cells of congenital and adaptive immunity, as well as non-immune defense mechanisms. One of the important components of protecting barrier tissues is the microbiota, whose commensals, on the one hand, carry out metabolic function and direct anti-pathogenic activity, and, on the other hand, constantly stimulate MALT at different levels and, thus, support the immunity of barrier tissues in the state of “smoldering activation” and readiness for a rapid response to the invasion of foreign organisms or substances. Antibiotics, being one of the most frequently prescribed medications, disrupt the number, composition and activity of symbiotic microorganisms. As a consequence, the immunity of barrier tissues is weakened, which contributes to the colonization of mucous and skin by pathogenic microorganisms and, in particular, their antibiotic-resistant strains. Awareness of this fact requires a change in the tactics of prescribing antibiotics and the introduction of additional medications to maintain MALT activity. Candidate drugs to supplement etiotropic anti-infective therapy are microbial-associated molecular patterns (MAMP) or, that is more real from the pharmacological point of view, their minimal biologically active fragments (MBAF).
Key words: mucosal immunity, microbiota, antibiotics, immunosuppression, infections, antibiotic resistance, immunomodulation, replacement therapy.
For citation: Kozlov I.G. Microbiota, mucosal immunity and antibiotics: the fineness of the interaction // RMJ. 2018. No. 8(I). P. 19–27.
The review article is devoted to the intricacies of the interaction of microbiota, mucosal immunity and antibiotics
Introduction
Immunology in the first two decades of the 21st century. continued to delight with numerous discoveries, a number of which had a practical orientation and made it possible to decipher the pathogenesis of many diseases and understand the mechanisms of action of some commonly used drugs. During this period of time, the greatest interest from the point of view of practical medicine is the results of three intersecting areas of fundamental research, namely the study of mucosal immunity (immunity of barrier tissues) and the discovery of signaling receptors of innate immunity (pattern-recognition receptors - PRR), the characteristics of normal microflora (microbiota) and a description of its interaction with barrier immunity, as well as the consequences of antibiotic use on the mucosal immunity/microbiota system.Mucosal immunity and innate immune signaling receptors
Throughout the development of immunology, mucosal immunity (immunity of mucous membranes and skin, immunity of barrier tissues) has attracted the attention of researchers and especially doctors. This is due to the fact that the vast majority of immune responses occur precisely in barrier tissues, which are under continuous antigenic load due to attempts to penetrate the body by pathogenic microorganisms and xenobiotics (foreign or foreign substances with immunogenic properties).At the same time, completely physiological immune reactions aimed at maintaining homeostasis of the body are almost always accompanied by an inflammatory response (inflammation itself is an integral part of the successful implementation of immunity) and other negative symptoms from the patient’s point of view, which leads him to the need to seek help from a doctor. Runny nose, cough, sore throat, diarrhea and dyspepsia, inflammation of the skin, on the one hand, and allergic reactions, on the other - the occurrence of all these problems does not occur without the participation of mucosal immunity, they are the most common reasons for visiting doctors of various specialties. Oddly enough, despite the different localization and rather different manifestations, the pathogenesis of all these conditions (and many others) is based on the same mechanisms of activation of mucosal immunity.
Mucosal immunity is realized through a single structured system, called mucosa-associated lymphoid tissue (MALT). The structuring of MALT occurs on floors depending on where one or another barrier tissue is anatomically located:
TALT - nasopharynx, Eustachian tube, ear.
NALT - nasal cavity, mouth and oropharynx, conjunctiva.
BALT - trachea, bronchi, lungs, mammary glands (in women).
GALT - 1) esophagus, stomach, small intestine;
2) large intestine and proximal parts of the urogenital tract; distal parts of the urogenital tract.
SALT - skin (dermis).
MALT is the largest part of the immune system, where about 50% of immunocompetent cells are located on a total area of 400 m2. Cells of both innate and acquired immunity are represented here. In addition to cells, MALT also contains other defense mechanisms.
In any part of MALT, the protection mechanisms have a similar organization (although there are differences between floors -
mi) :
The top "inert" barrier is a mucus layer or, in the case of skin, a "dry" layer made of keratin. The main protective factors present at this level are the physical barrier, antimicrobial peptides, secretory IgA, components of the complement system and microbiota. It is obvious that the inertness of this structure is very conditional, since active killing reactions of microorganisms and many biochemical processes of a metabolic nature constantly occur here.
The epithelial layer has long been considered only as a physical barrier. Today, this idea has changed significantly. Firstly, it was found that epithelial cells express receptors responsible for interaction with microorganisms, which are capable of triggering the activation of these cells with the subsequent production of antimicrobial peptides, as well as a cascade of regulatory molecules (cytokines) and the expression of coreceptors for cells of the immune system on epithelial cells. Secondly, dendritic cells (mainly the oral cavity, respiratory system, urogenital tract, skin) and multifold, or M-cells (small intestine, tonsils, adenoids), carrying out controlled transfer through the barrier into the interior, were found as part of the “impenetrable” epithelial layer body of foreign material. This controlled “traffic” is necessary to maintain barrier immunity in “tone” and notify the immune system of a changing environment (for example, an imbalance of the microbiota or the contact of pathogenic microorganisms on the mucous membranes and skin). In other words, the immune system of barrier tissues is always in a state of “smoldering” activation, which allows it to quickly and effectively respond to aggression.
Subepithelial loose connective tissue lamina propria(lamina propria), where innate immune cells are located diffusely and in high concentration: several populations of dendritic cells, macrophages, natural killer cells, granulocytes, innate immune lymphocytes, etc.
Under the epithelium in lamina propria there are so-called “isolated lymphoid follicles”, which are a representative of adaptive immunity in barrier tissues. These follicles have a clear organization with T- and B-cell zones and a germinal center. T-cell zones contain almost all subpopulations of αβTCR CD4+ T-helper cells (Th1, Th2 and Th17), IL-10-producing T-regulatory cells, CD8+ T-effectors. The B-cell zones are dominated by B-lymphocytes that secrete IgA. It is to these follicles that dendritic cells and M cells deliver antigenic material, initiating an adaptive immune response. The adaptive immune system of barrier tissues is closely related to regional lymphatic formations: Peyer's patches, appendix, tonsils, etc., which allow the immune response to be transferred from the local level to the systemic level.
Thus, MALT provides multi-level protection of the body from the penetration of pathogens and foreign substances: from “passive” humoral, through active antigen-nonspecific innate immunity, to highly specific adaptive immunity, with the possibility of transition from the local level to the systemic one.
In addition to the unified structural organization described above, there is one more feature that makes MALT a separate (and even almost autonomous in some sense) subsystem within the framework of general immunity. This is the so-called “MALT law of homing”. In accordance with this law, activation of adaptive immunity in any part of the MALT leads to the formation of a pool of antigen-specific cells, part of which remains at the site of the onset of the immune response, while the other enters the systemic circulation and settles (homing) only in other compartments of the MALT. For example, if penetration of the pathogen occurred in the intestines (GALT), then after some time secreting pathogen-specific IgA B lymphocytes can be found in the bronchopulmonary lymphatic follicles lamina propria(BALT). Due to this mechanism, global protection of all barrier tissues is formed.
Interest in the discovery and characterization of innate immune signaling receptors (signal pattern-recognizing receptor - sPRR) is due not only to the 2011 Nobel Prize in Biology or Medicine, but also to important applied aspects: from understanding how the first events of anti-infective defense are carried out in the body, to the creation of new drugs for the treatment of chronic inflammatory, autoimmune and autoinflammatory diseases.
sPRRs are the main receptors that communicate between innate immune cells and other cells of the body, including non-lymphoid cells and adaptive immune cells. They bring together all the components of the immune system and coordinate its activities. With the help of these receptors, the innate immune system recognizes highly conserved structural molecules found in large taxonomic groups of microorganisms (Table 1).
These molecules are called “pathogen-associated molecular patterns” (PAMPs). The most well-known PAMPs are bacterial lipopolysaccharide (LPS) (Gram(-) - gram-negative bacteria), lipoteichoic acids (Gram(+) - gram-positive bacteria), peptidoglycan (PG) (gram-negative and gram-positive bacteria), mannans, bacterial DNA, double-stranded RNA viruses , mushroom glucans, etc.
The innate immune receptors that are responsible for recognizing PAMPs have been called pattern-recognition receptors (PRRs). Based on their function, they can be divided into two groups: endocytic and signaling. Endocytotic PRRs (mannose
receptors and scavenger receptors) have been known in immunology for a long time - they provide the processes of phagocytosis with subsequent delivery of the pathogen to lysosomes (the beginning of the adaptive immune response).
Among sPRRs, three families are of greatest importance: Toll-like receptors (TLRs), NOD-like receptors (NLRs), and RIG-like receptors (RLRs). The last two families each include 2 representatives of PRR (NOD-1 and -2; RIG-1 and MDA-5), localized intracellularly and forming a mechanism for “notifying an unauthorized breakthrough” of a bacterial (NLR) or viral (RLR) pathogen into the cell or “ its escape from the phagolysosome.
The most studied of the sPRRs are Toll-like receptors (TLRs). These receptors were first
described in Drosophila, in which they, on the one hand, are responsible for embryonic development, and on the other, provide antifungal immunity. Today, 15 TLRs have been characterized in mammals and humans, which are located on the membrane, in endosomes or in the cytoplasm of cells that provide the first line of defense (neutrophils, macrophages, dendritic, endothelial and epithelial cells of the skin and mucous membranes).
Unlike the endocytic PRRs responsible for phagocytosis, the interaction of TLR with the corresponding PAMP is not accompanied by the absorption of the pathogen, but leads to changes in the expression of a large number of genes and, in particular, genes of pro-inflammatory cytokines, which is mediated through the sequential activation of adapter proteins (for example, MyD88), protein kinases (eg IRAK-4) and transcription factors (eg NF-κB).
At the body level, activation of the synthesis and secretion of proinflammatory cytokines (interleukins (IL) -1, -2, -6, -8, -12, tumor necrosis factor alpha (TNF-α), interferon-γ, granulocyte-macrophage colony-stimulating factor) causes development of an inflammatory reaction with the involvement of all available defense systems against infectious agents. At the cellular level, the effect is realized in three directions. Firstly, the cells themselves carrying sPRR are activated and their protective potential is significantly enhanced (production of antimicrobial peptides and complement, phagocytosis, digestive activity, production of reactive oxygen species). Secondly, existing antigen-specific adaptive immune cells enter an activated state and enhance their effector functions. In particular, mature B lymphocytes increase the production of immunoglobulins (sIgA) and become more sensitive to antigenic stimulation, and T-effectors increase killer functions. And thirdly, activation (priming) of naive lymphocytes occurs and prepares them for the onset of an adaptive immune response.
It is through sPRR that the barrier epithelium and mucosal dendritic cells recognize attempts at microbial invasion in the early stages. Through these same receptors, the cells of the innate and adaptive immunity of the submucosal layer or the dermis itself react to pathogens that have already penetrated the barrier. To realize the effect with sPRR, cell proliferation and the formation of an antigen-specific clone (necessary for the adaptive immune response) are not required, and effector reactions after recognition by these PAMP receptors occur immediately. This fact explains the high rate of pathogen elimination by innate immune mechanisms.
Microbiota: immunological mechanisms of symbiosis
It was with the study of microbiota or a set of microorganisms (normoflora, commensals) living in a macroorganism and being in symbiosis with it that the concept of a “superorganism” arose as an interspecific whole.Compound
Microbiota is present in any multicellular organism, and its composition is specific to each type of organism. There are differences within the species depending on the living conditions and feeding habits of individual individuals.The human microbiota includes more than 1000 species of microorganisms (bacteria, viruses, fungi, helminths, protozoa), although it is very difficult to accurately estimate this parameter (since many species are not sown, and the assessment was carried out on the basis of multiparameter parallel DNA sequencing). The volume of the microbiota is estimated at 1014 cells, which is 10 times the number of cells in the human body, and the number of genes in the microbiota is 100 times greater than that of the host.
The amount and composition of microbiota on different floors of MALT also differ significantly. The poorest microbiota is detected in the lower parts of the respiratory tract and distal parts of the urogenital tract (previously it was believed that they were sterile, but recent studies show the presence of normal flora there too). The largest microbiota inhabits the small and large intestines and is the most studied.
The intestinal microbiota is undoubtedly dominated by bacteria, and among them are anaerobes related to genera Firmicutes (95% Clostridia) And Bacteroides. Representatives of the genera Proteobacteria, Actinobacteria, Verrucomicrobia And Fusobacteria are represented to a much lesser extent. Bacteria in the intestine exist in two states, forming a mosaic interspecies biofilm in the upper part of the mucous layer or being in planktonic form in the parietal part of the lumen. It is believed that the composition and quantity of intestinal microflora are quite stable and are maintained both due to interspecific containment and due to influences from the macroorganism.
Functions
As already mentioned, the microbiota and the macroorganism are in a symbiotic relationship. Sometimes these relationships are of a very exotic nature. For example, microorganisms of the type Vibrio fischeri form colonies and form a fluorescent "lantern" in the deep-sea Hawaiian squid.The standard symbiosis of microbiota and macroorganism is based on mutual benefit: the host “provides” microorganisms with habitat and nutrition, and the microorganism protects the host from expansion by other microorganisms (infection), provides it with some nutrients, and also facilitates the digestion of food components. Among the most significant beneficial properties of microbiota are the following:
metabolism of non-degradable carbohydrates and provision of energy carriers (ATP) to the host;
participation in the metabolism of fatty and bile acids;
synthesis of vitamins, which the cells of the macroorganism are not capable of;
direct competition with pathogenic microorganisms and preventing them from colonizing the host’s intestinal tract;
stimulation of the host's mucosal immunity.
Interaction between microbiota and MALT
Initially, it was believed that the host's immune system simply ignores the presence of symbiotic microorganisms. This point of view is supported by the organization of the first line of defense - a “passive” barrier covering the epithelium. It consists of two layers, the upper one is more liquid and fluid and the lower one is more dense. Normally, the biofilm of commensals is located in the upper layer, which should exclude contact of microorganisms with the epithelium. In addition, the epithelium synthesizes antimicrobial peptides that can diffuse into the mucus layer and create a concentration gradient. At a certain level of the mucus layer, this concentration becomes sufficient to directly lyse bacteria attempting to penetrate the barrier. An additional, and no less effective, mechanism protecting against invasion is the translocation through the epithelium into the mucous layer of secretory IgA (sIgA), which contains antibodies against normal flora microorganisms. Obviously, sIgA is also distributed along the concentration gradient and, at a certain level of the mucous layer, “sticking around” the bacteria, stopping their passage into the underlying space.Another point of view suggests that in the process of evolution, mechanisms have developed to ensure tolerance of the host immune system to the microbiota. This point of view is also supported by the time factor of the appearance of the microbiota from the first seconds of the host’s life, when his immune system does not yet have a full arsenal to distinguish his own from someone else’s, i.e. the microbiota is perceived by the immune system as something of its own.
To date, there is no absolute understanding of all the intricacies of MALT interaction: the idea of microbiota and both previous concepts may be partially valid. However, numerous studies of the immunity of gnotobiont animals (laboratory animals that are kept in sterile conditions from birth), knockout animals (laboratory animals in which one or another immune response gene is selectively turned off) and animals receiving long courses of broad-spectrum antibiotics have made it possible experimentally substantiate how this interaction fundamentally occurs.
The presence of antibodies to symbiotic microorganisms in sIgA indicates that, despite the mucous mechanical barrier, they themselves or their components contact MALT and induce humoral adaptive immune responses. Moreover, judging by the constantly determined titers of these antibodies, this event is far from rare, and the absence of normal flora leads to a decrease in the production of sIgA and the size of Peyer's patches, where the plasma cells that synthesize it are located.
Moreover, it has been convincingly demonstrated that components of the cell wall and internal contents of commensals are well recognized by sPRRs (TLRs and NODs) expressed by epithelium and innate immune cells and are required for:
activation of the production of mucus and antimicrobial peptides by epithelial cells, as well as compaction of intercellular contacts, which makes the epithelial layer less permeable;
development of isolated lymphatic follicles lamina propria necessary for the implementation of effective adaptive immunity;
shift of the Th1/Th2 balance towards Th1 (adaptive cellular immunity, preventing hyperactivation of the proallergenic adaptive humoral response);
the formation of a local pool of Th17 lymphocytes, which are responsible for the activity of neutrophils and their timely inclusion in the antibacterial protection of MALT, as well as for switching classes of immunoglobulins in B lymphocytes;
synthesis and accumulation of pro-IL-1 and pro-IL-18 in MALT macrophages, which significantly accelerates the immune response when pathogens attempt to penetrate (only the processing of these cytokines into an active form is required).
Due to the fact that components of not only pathogens, but also normal flora are able to interact with signaling receptors of innate immunity, a revision of the term “PAMP” was proposed. A number of authors propose replacing the first letter “P” (from “pathogen”) with the letter “M” (from “microbe”). Thus, "PAMP" turns into "MAMP".
Considering the constant presence of microflora and the interaction of its or
its components with sPRR and based on the “pro-inflammatory” orientation of these
receptors and their signaling pathways, it would be quite obvious to expect that the microbiota should induce a continuous inflammatory response in the MALT and the development of severe diseases. However, this does not happen. On the contrary, the absence of normal flora causes such diseases or is at least closely associated with them. Why this happens remains unclear, but there is evidence indicating an immunosuppressive/tolerogenic effect of the microbiota. For example, polysaccharide A of one of the main components of the microbiota, Bacteroides fragilis, is capable of binding to TLR-2 on innate immune cells and blocking their proinflammatory activity. In addition, the presence of microbiota leads to “chronic” activation of commensal-specific T-regulatory cells (Treg and Tr1) and their production of the main anti-inflammatory cytokine - IL-10. But these mechanisms are clearly not enough to explain the paradoxical differences in the results of interaction between microbiota and pathogens with MALT.
Thus, despite the remaining questions, it can be confidently stated that the microbiota continuously signals MALT about its state and maintains barrier immunity in a state of activation without generating an inflammatory response. Attenuation of microbiota-mediated activation
associated with disruption of the MALT barrier function and the development of chronic inflammatory diseases.
Antibiotics and immunosuppression
The topic of antibiotics and immunity has been discussed in various aspects for more than a century. Empirical attempts to influence the immune system in order to enhance the fight against infections arose long before the “era of antibiotics” (E. Gener, E. Bering, V. Koley). Even the discoverer of penicillin, A. Fleming, began his bactericidal experiments with the study of lysozyme, one of the most important humoral factors of innate immunity. But with the advent of antibiotics, due to the absolute clarity of their mechanism and spectrum of action, as well as their unconditional effectiveness, immunotherapy for infections faded into the background and practically did not develop. Currently, the situation is beginning to change fundamentally due to the advent of the “era of antibiotic resistance”, and immunomodulatory therapy is becoming one of the real alternatives to anti-infective chemotherapy.In the “era of antibiotics,” the very ideology of using these drugs assumed the participation of the immune system in the processes of eliminating pathogens. It was believed that the task of an antibiotic (especially a bacteriostatic one) is to stop the uncontrolled proliferation of bacteria in order to enable the immune system to complete its removal from the body. In this regard, at the stage of preclinical studies, all modern antibiotics were tested for their effects on immunity before entering the market. The results of these studies varied. Some antibiotics, for example, macrolides, not only did not suppress the immune system, but also had some positive effect on immunocompetent cells. Tetracycline antibiotics, on the contrary, demonstrated moderate immunotoxicity. But in general, no direct negative effect of anti-infective antibiotics widely used in the clinic on the immune system was identified.
A completely different picture arises if we evaluate the indirect immunosuppressive effect of antibiotics (especially broad-spectrum antibiotics) from the perspective of the interaction of microbiota and MALT.
It has been repeatedly confirmed in experimental animal models and in humans in the clinic that antibiotics lead to changes in the microbiota. For example, clindamycin in the form of a 7-day course changes the species composition of commensals of the genus in humans for almost 2 years Bacteroides. A 5-day course of ciprofloxacin leads to a change in the microbiota in humans by almost 30%. It takes about a month to partially restore the microbiota after a course of ciprofloxacin; some types of commensals do not recover. Amoxicillin in therapeutic doses destroys Lactobacillus. Similar data on imbalance in the microbiota (dysbiosis) have been demonstrated for metronidazole, streptomycin, neomycin, vancomycin, tetracycline, ampicillin, cefoperazone
and their combinations.
Antibiotic-mediated changes in the microbiota can lead to two negative consequences.
Firstly, even incomplete (selective) suppression of normal flora by antibiotics - only a separate group of microorganisms - leads to their replacement by pathogens and an imbalance of the entire microbiota. The place of commensals after courses of antibacterial chemotherapy is taken by fungi, such as Candida albicans, and bacteria of the genera Proteus And Staphylococcus, and Clostridium difficile. In addition, with long courses of antibacterial therapy, there is a very high probability of the vacated space being colonized by antibiotic-resistant strains, which have an absolute advantage in this situation. A change in the composition of the microbiota obviously causes significant disturbances in the metabolic function of commensals with inhibition of the production of beneficial nutrients and the production of substances harmful to the host body (toxins). A classic clinical example of the consequences of microbiota imbalance after antibiotic administration is pseudomembranous colitis caused by intestinal colonization Clostridium difficile .
Secondly, changes in the quantity and composition of the microbiota during antibiotic therapy alter its interaction with the local immune system, as a result of which the activating and tolerogenic load of commensals at all levels of MALT protection is simultaneously reduced. In this case, two parallel
script:
At the epithelial level, a decrease in mucus production and a thinning of the “passive” barrier are observed. At the same time, the secretion of antimicrobial peptides decreases. In lamina propria dysregulation of T-cell adaptive immunity occurs, and, in particular, the production of interferon-γ (Th1) and IL-17 (Th17) decreases, and the number of IL-10-secreting Tregs decreases. An imbalance in T-helper responses type 1 and 17 causes an expansion of Th2 cells with a subsequent predominance of IgE-producing B lymphocytes (proallergic type) and a decrease in the production of protective sIgA. All these changes weaken the barrier function and create favorable conditions for the invasion of any microorganisms and the development of systemic infections, including antibiotic-resistant strains. In addition, the prerequisites are created for stimulating allergic inflammation.
The cellular component of innate immunity, on the contrary, increases: the number of natural killer cells and macrophages increases. Cancellation of the suppressive effect of Treg, reduction in the concentration of polysaccharide A of B. fragilis, replacement of MAMP of the microbiota with PAMP of pathogens disrupts the tolerogen-activation balance of MALT and promotes sPRR-induced release of proinflammatory cytokines. Obviously, in this way the insufficiency of the protective functions of the epithelium and adaptive immunity is compensated, but at the same time, an inflammatory response occurs at the point of microbiota imbalance.
It should also be taken into account that all MALT compartments are closely interconnected due to selective homing, and an immune imbalance in one part of this subsystem will lead to disruption of the work of all others, which can result in the generalization of immunoinflammatory processes and the occurrence of chronic diseases. Microbiota disturbances have been shown to be closely associated with the development of immune-mediated diseases such as inflammatory bowel diseases (Crohn's disease and ulcerative colitis), rheumatoid arthritis, allergies, type 2 diabetes, and obesity.
To summarize this part of the review, it should be noted that recent data on the interaction of the microbiota and MALT, as well as the influence on this interaction of antibiotics, create a need to make adjustments to standard antimicrobial chemotherapy in order to eliminate the imbalance in the microbiota and/or (more importantly) maintaining MALT in “working” condition.
Options for overcoming antibiotic-induced immunosuppression
The topic of indirect microbiota-mediated immunosuppression as a result of antibiotic prescription is just beginning to become relevant for the medical professional community. But given its importance for a variety of areas of medicine and the growing problem of antibiotic resistance, we can expect numerous attempts to solve this problem in the near future. There is already some experience in this area.Fecal microbiota transplantation (FMT)
FMT involves collecting fecal matter from a donor, isolating microorganisms and introducing them to a patient with a disturbed microbiota. At the same time, the rectal route of administration is not optimal, since the donor microbiota does not enter the upper intestine. In this regard, special dosage forms for oral administration are being developed. Today it is believed that this method makes it possible to restore the microbiota of the gastrointestinal tract to the greatest extent. However, it has a number of significant disadvantages.The first problem is the selection of a donor from the point of view of the “normality” of the microbiota. In order to test the fecal microbiota, it is necessary to carry out its whole genome sequencing, and as already mentioned, the number of genes in the microbiota is 100 times greater than in the human genome. The second difficulty is the coincidence of the normal microbiota of the donor and recipient. Taking into account the fact that the intestinal microbiota is quite individual and is formed depending, among other things, on lifestyle and nutritional conditions, and also that in practice it is not possible to make a comparative analysis (the recipient’s microbiota has already been changed at the time of contacting the clinic), selection The donor will occur empirically (as a rule, these are close relatives), which reduces the safety of the method. The safety of FMT is also affected by the transplantation of live microorganisms into a patient with an imperfect mucosal barrier and impaired local immunity (MALT). This could potentially lead to infection and complication of the patient's condition. And finally, the patient’s consent to such a procedure is required.
Therefore, industrial scale-up of FMT is very problematic, and the procedure is today (and will obviously be used) as a last resort when it is impossible to destroy the pathogen by other means, for example, in the case of antibiotic-resistant strains. Currently, the effectiveness of FMT (80–100%) has been demonstrated in cases of infection Clostridium difficile as a measure to combat pseudomembranous colitis. It is possible to use FMT for inflammatory bowel diseases and after bone marrow transplantation, which is preceded by long courses of antibiotics.
Using Probiotics
The history of the targeted use of probiotics for the correction of microbiota begins in 1908 with the curdled milk of I. I. Mechnikov. At the present stage, significant progress has been observed in this area.Dozens of strains of probiotic microorganisms have been isolated, carefully characterized (genotyped) and standardized: Lactobacillus (plantarum, casei and bulgaricus); Streptococcus thermophilus, Saccharomyces boulardii, Escherichia coli Nissle 1917, Bifidobacterium spp. etc. . Their positive meta-
bolic, symbiotic and antipathogenic activity. Studies have been conducted on the immunomodulatory ability of some probiotics in relation to MALT. Finally, clinical studies have been conducted to demonstrate the effectiveness of certain probiotics in antibiotic-associated and infectious diarrhea, Clostridium difficile infection, Crohn's disease and ulcerative colitis, irritable bowel syndrome, necrotizing enterocolitis, and sepsis prevention.
However, none of the probitics can completely reproduce the composition of the normal flora, and therefore are not able to restore the normal balance of the intestinal microbiota. In addition, the mechanisms of positive effects on the host organism differ between probiotics, and the “optimal” probiotic that combines them all has not yet been found. Another obstacle to the widespread use of probiotics in the clinic is that, with the exception of the post-Soviet space and certain countries of Eastern Europe, they are not registered as medicines, i.e., prescribing them by doctors, and even for severe infections, is not possible. Moreover, even in the most civilized countries, food products (the main source of probiotics in the USA and Europe) have different standardization requirements than medications. In conclusion, as with FMT, administering live microorganisms in probiotics to patients with a compromised mucosal barrier is unsafe. Especially when some manufacturers of probiotic preparations claim that these microorganisms are resistant to all known antibiotics and therefore can be taken simultaneously with anti-infective chemotherapy.
MAMPs and their minimal biologically active fragments (MBAFs)
Taking into account the above-mentioned disadvantages of FMT and probiotics, the question arises: is it possible to replace living microorganisms that form the microbiota with their components, at least in terms of maintaining the immunological balance in barrier tissues? This would make it possible to protect the host organism from invasion of pathogenic microorganisms during the course of antimicrobial chemotherapy and after it, up to the restoration of the microbiota.Before answering this question, we should answer another: what is the immunomodulatory principle of the microbiota? Perhaps these are symbiotic microorganisms themselves. But then they must constantly penetrate the mucous barrier and come into contact with the epithelium and even pass through the epithelial layer into lamina propria to stimulate innate immune cells. However, this process is completely unsafe for the macroorganism, since commensals, in the absence of restraining factors, can cause infection of the host.
An alternative answer to the question posed is the assumption that MALT stimulation occurs due to the constant destruction of normal flora microorganisms and the release of MAMPs from them, which diffuse through the mucous layer, contact the epithelium and are delivered to the lamina propria dendritic cells and/or M cells.
Let's try to consider this possibility using the example of PG as one of the main sources of immunoregulatory fragments that maintain the “tone” of the immune system in barrier tissues. Firstly, PG is included as the main component in both Gram(+) and Gram(-) bacteria, i.e. its total mass fraction in the microbiota should be greater than other components. Secondly, PG is broken down into minor units: muramyl dipeptides (MDP) and meso-diaminopimelic acid derivatives (meso-DAP) by lysozyme, which is constantly present on the surface of mucous membranes in high concentrations (1 mg/ml). In other words, the process of partial biodegradation of PG must occur continuously somewhere on the border between the liquid and dense sublayer of the mucous layer. And thirdly, for PG components, in addition to PRR from the Toll family (TLR-2), there are 2 more specific cytoplasmic receptors from the NOD family: NOD-1 and NOD-2. In this case, NOD-1 is expressed predominantly on epithelial cells and, connecting with its ligand meso-DAP, triggers a bidirectional signal (formation of the mucous layer and activation of the immune system). NOD-2 is predominantly present on innate immune cells (phagocytes, dendritic cells), and when it interacts with its ligand MDP, direct activation of the regulatory and effector potential of these cells occurs. These facts suggest that PG fragments are one of the main (but, of course, not the only) regulators that maintain mucosal immunity in a sensitized state and readiness to respond to the penetration of foreign agents. In addition, normally, PG fragments and antibodies to them are found in the systemic circulation, which indicates their formation in the mucous layer and the ability to penetrate the epithelium.
Several dozen studies conducted in gnotobionts or experimental animals treated with long courses of broad-spectrum antibiotics confirm that MAMPs (PG, LPS, flagellin, commensal DNA) or their fragments, when administered orally or rectally, are capable of imitating the effect of microbiota on MALT and systemic immunity.
Acting through sPRR, MAMPs and their fragments stimulate the synthesis of the main component of mucus - mucin and antimicrobial peptides by epithelial cells, promote the development of isolated lymphatic follicles in lamina propria, restore the T-cell adaptive immune response and antibody synthesis. At the systemic level, MAMP fragments penetrate the bone marrow and perform neutrophil priming, as well as increasing their bactericidal activity. By activating the adaptive immune response in the gut, MAMP
and their fragments enhance protection against influenza virus in the lungs, thereby demonstrating MALT-specific transfer of immunity from one floor of barrier tissues to another (homing).
At the body level, muramyl dipeptide, through its NOD-2 receptor, protects the intestines from inflammation. LPS and lipoteichoic acid can replace commensals in protecting experimental animals from chemically induced colitis. Flagellin, LPS or commensal DNA prevent post-antibiotic colonization of the intestine Clostridium difficile, Encephalitozoon cuniculi or vancomycin-resistant enterococci.
Thus, the answer to the question asked at the beginning of this section is most likely positive: MAMPs or their fragments may well imitate the immunomodulatory activity of living commensals. Although more targeted research is needed to fully understand which patterns and at what dose will be most effective and safe.
What is the practical significance of this conclusion? This is the creation of new drugs to accompany antibiotic therapy and overcome post-antibiotic dysbiosis based on MAMPs and their fragments. At the same time, MAMPs are not a very promising object from the point of view of pharmaceutical technology. Most of them are high-molecular compounds with a very complex structure. The process of isolating and standardizing them is quite expensive. The species of the pattern should also be taken into account - many PAMPs, unlike MAPMs, are pyrogenic and toxic. In addition, these compounds in the body must be subjected to additional processing in order to be able to pass through the mucous layer to the epithelium and lamina propria.
An alternative is to create drugs based on MAMP fragments that retain the ability to bind to sPRR and have fully or partially the same biological activity. These minimal biologically active fragments (MBAFs) should not be species specific and have a fairly simple structure, which allows them to be obtained by chemical synthesis.
One of these MBAFs, glucosaminylmuramyl dipeptide (GMDP), is already presented on the drug market in the post-Soviet space in the form of a drug Lycopid.
GMDP is a semi-synthetic derivative of muramyl dipeptide (MDP), which is an MBAF PG. GMDP is a selective ligand (agonist) of the NOD-2 receptor, through whose signaling pathways it activates innate immune cells.
Over more than 20 years of clinical use, GMDP has been repeatedly studied in infectious processes in combination with antibiotics and other anti-infective agents. These studies demonstrated the therapeutic benefit of this combination (reduction in the severity and duration of the disease) against the background of normalization of systemic immunity. However, until the research results presented in this review appeared, GMDP was not considered as a MALT modulator and a possible candidate that mimics the immunomodulatory activity of microbiota in barrier tissues.
Conclusion
Thanks to the deciphering of the mechanisms of barrier immunity (MALT) and the discovery of signaling receptors of innate immunity (sPRR), it was possible to describe in detail how the body's main anti-infective defense is carried out at the local level. The study of microbiota and its interaction with MALT has fundamentally changed the understanding of the functioning of the immune system, especially under normal conditions, with intact barriers and the absence of aggression from pathogenic microorganisms. It turned out that the immunity of border tissues must be in a state of constant “smoldering” activation, and exit from this state (both with a minus and a plus sign) is accompanied by severe consequences for the body. In the first case, these are immunodeficiency states and the inability to stop the invasion of pathogens or the progression of tumors. In the second - the development of local and systemic immunoinflammatory diseases, including ulcerative colitis, diabetes and allergies. Finally, taken together, studies of MALT and microbiota have allowed us to take a fresh look at modern etiotropic anti-infective therapy, formulate an idea of indirect antibiotic-mediated immunodeficiency, and develop a new ideology for the clinical use of these important drugs.Literature
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This system is represented by accumulations of lymphocytes in the mucous membranes of the gastrointestinal tract, bronchi, genitourinary tract, excretory ducts of the mammary and salivary glands. Lymphocytes can form single or group lymphoid nodules (tonsils, appendix, group lymph nodes or Peyer's patches of the intestine). Lymphatic nodules provide local immune protection to these organs.
Common to all these areas are the location of lymphocytes in the loose fibrous connective tissue of the membranes covered with epithelium, the formation of antibodies related to IgA. Antigen-stimulated B lymphocytes and their descendants plasma cells participate in the formation of IgA. As well as epithelial cells of the membranes, which produce the secretory component IgAs. The assembly of immunoglobulin molecules occurs in the mucus on the surface of epithelial cells, where they provide local antibacterial and antiviral protection. T-lymphocytes located in the nodules carry out cellular immune reactions and regulate the activity of B-lymphocytes.
The unified (diffuse) immune system of the mucous membranes in the English literature is designated by the abbreviation MALT - mucous associated lymphatic tissue.
74. Characteristics of the endocrine system. Features of the structure of the endocrine glands. Epiphysis Structure, functions.
Endocrine regulation is one of several types regulatory influences, among which are:
· autocrine regulation (within one cell or cells of one type);
· paracrine regulation (short-distance, - on neighboring cells);
endocrine (mediated by hormones circulating in the blood);
· nervous regulation.
Along with the term “endocrine regulation”, the term “neuro-humoral regulation” is often used, emphasizing the close relationship between the nervous and endocrine systems.
Common to nerve and endocrine cells is the production of humoral regulatory factors. Endocrine cells synthesize hormones and release them into the blood, and neurons synthesize neurotransmitters (most of which are neuroamines): norepinephrine, serotinin and others, released into synaptic clefts. The hypothalamus contains secretory neurons that combine the properties of nerve and endocrine cells. They have the ability to form both neuroamines and oligopeptide hormones. The production of hormones by endocrine organs is regulated by the nervous system.
Classification of endocrine structures
· I. Central regulatory formations of the endocrine system:
o hypothalamus (neurosecretory nuclei);
o pituitary gland (adenohypophysis and neurohypophysis);
· II. Peripheral endocrine glands:
o thyroid gland;
o parathyroid glands;
o adrenal glands (cortex and medulla).
· III. Organs that combine endocrine and non-endocrine functions:
o gonads (sex glands - testes and ovaries);
o placenta;
o pancreas.
· IV. Single hormone-producing cells, apudocytes.
As in any system, its central and peripheral links have direct and feedback connections. Hormones produced in peripheral endocrine formations can have a regulatory effect on the activity of the central units.
One of the structural features of endocrine organs is the abundance of vessels in them, especially sinusoidal type hemocapillaries and lymphocapillaries, which receive secreted hormones.
Pineal gland
The pineal gland is the upper appendage of the brain, or the pineal body (corpus pineale), involved in the regulation of cyclic processes in the body.
The pineal gland develops as a protrusion of the roof of the third ventricle of the diencephalon. The pineal gland reaches its maximum development in children under 7 years of age.
The structure of the pineal gland
Outside, the epiphysis is surrounded by a thin connective tissue capsule, from which branching septa extend into the gland, forming its stroma and dividing its parenchyma into lobules. In adults, dense layered formations are detected in the stroma - epiphyseal nodules, or brain sand.
In the parenchyma there are two types of cells - secreting pinealocytes and supporting glial, or interstitial cells. Pinealocytes are located in the central part of the lobules. They are somewhat larger than supporting neuroglial cells. Long processes extend from the body of the pinealocyte, branching like dendrites, which intertwine with the processes of glial cells. The processes of pinealocytes are directed to the fenestrated capillaries and come into contact with them. Among pinealocytes, light and dark cells are distinguished.
Glial cells predominate at the periphery of the lobules. Their processes are directed to the interlobular connective tissue septa, forming a kind of marginal border of the lobule. These cells perform mainly a supporting function.
Pineal gland hormones:
Melatonin- photoperiodic hormone, - is released mainly at night, because its secretion is inhibited by impulses coming from the retina. Melatonin is synthesized by pinealocytes from serotonin; it inhibits the secretion of GnRH by the hypothalamus and gonadotropins of the anterior pituitary gland. When the function of the pineal gland is impaired in childhood, premature puberty is observed.
In addition to melatonin, the inhibitory effect on sexual functions is also determined by other pineal gland hormones - arginine-vasotocin, antigonadotropin.
Adrenoglomerulotropin pineal gland stimulates the formation of aldosterone in the adrenal glands.
Pinealocytes produce several dozen regulatory peptides. Of these, the most important are arginine-vasotocin, thyroliberin, luliberin and even thyrotropin.
The formation of oligopeptide hormones together with neuroamines (serotonin and melatonin) demonstrates that pineal cells of the pineal gland belong to the APUD system.
In humans, the pineal gland reaches its maximum development by 5-6 years of life, after which, despite its continued functioning, its age-related involution begins. A certain number of pinealocytes undergo atrophy, and the stroma grows, and in it the deposition of nodules increases - phosphate and carbonate salts in the form of layered balls - the so-called. brain sand.
75. Pituitary gland. Structure, functions. Connection between the pituitary gland and hypothalamus.
Pituitary
The pituitary gland, the lower appendage of the brain, is also the central organ of the endocrine system. It regulates the activity of a number of endocrine glands and serves as a site for the release of hypothalamic hormones (vasopressin and oxytocin).
The pituitary gland consists of two parts, different in origin, structure and function: the adenohypophysis and the neurohypophysis.
IN adenohypophysis distinguish the anterior lobe, intermediate lobe and tuberal part. The adenohypophysis develops from the pituitary recess lining the upper part of the oral cavity. Hormone-producing cells of the adenohypophysis are epithelial and have ectodermal origin (from the epithelium of the oral bay).
IN neurohypophysis distinguish between the posterior lobe, stalk and infundibulum. The neurohypophysis is formed as a protrusion of the diencephalon, i.e. has a neuroectodermal origin.
The pituitary gland is covered by a capsule of dense fibrous tissue. Its stroma is represented by very thin layers of connective tissue associated with a network of reticular fibers, which in the adenohypophysis surrounds strands of epithelial cells and small vessels.
The anterior lobe of the pituitary gland is formed by branched epithelial strands - trabeculae, forming a relatively dense network. The spaces between the trabeculae are filled with loose fibrous connective tissue and sinusoidal capillaries entwining the trabeculae.
Endocrinocytes, located along the periphery of trabeculae, contain secretory granules in their cytoplasm that intensively perceive dyes. These are chromophilic endocrinocytes. Other cells occupying the middle of the trabecula have unclear boundaries, and their cytoplasm is weakly stained - these are chromophobe endocrinocytes.
Chromophilic endocrinocytes are divided into acidophilic and basophilic according to the staining of their secretory granules.
Acidophilic endocrinocytes are represented by two types of cells.
The first type of acidophilic cells is somatotropes- produce somatotropic hormone (GH), or growth hormone; the action of this hormone is mediated by special proteins - somatomedins.
The second type of acidophilic cells is lactotropes- produce lactotropic hormone (LTH), or prolactin, which stimulates the development of mammary glands and lactation.
Basophilic cells of the adenohypophysis are represented by three types of cells (gonadotropes, thyrotropes and corticotropes).
The first type of basophilic cells is gonadotropes- produce two gonadotropic hormones - follicle-stimulating and luteinizing:
· follicle-stimulating hormone (FSH) stimulates the growth of ovarian follicles and spermatogenesis;
· luteinizing hormone (LH) promotes the secretion of female and male sex hormones and the formation of the corpus luteum.
The second type of basophilic cells is thyrotropes- produce thyroid-stimulating hormone (TSH), which stimulates the activity of the thyroid gland.
The third type of basophilic cells is corticotropes- produce adrenocorticotropic hormone (ACTH), which stimulates the activity of the adrenal cortex.
Most cells of the adenohypophysis are chromophobic. Unlike the described chromophilic cells, chromophobe cells poorly perceive dyes and do not contain distinct secretory granules.
Chromophobic cells are heterogeneous, they include:
· chromophilic cells - after excretion of secretion granules;
poorly differentiated cambial elements;
· so-called follicular stellate cells.
The middle (intermediate) lobe of the pituitary gland is represented by a narrow strip of epithelium. Endocrinocytes of the intermediate lobe are capable of producing melanocyte-stimulating hormone (MSH), and lipotropic hormone (LPG) that enhances lipid metabolism.
RUSSIAN IMMUNOLOGICAL JOURNAL, 2008, volume 2(11), no. 1, p. 3-19
CELLULAR BASIS OF MUCOSAL IMMUNITY
© 2008 A.A. Yarilin
Institute of Immunology FMBA, Moscow, Russia Received: 12/04/07 Accepted: 12/18/07
The structure and general patterns of functioning of the mucosal part of the immune system are considered. Data are presented on the sections of the immune system associated with mucous membranes (MALT), the characteristics of epithelial and lymphoid cells, and the structure of lymphoid tissue of the mucous membranes. The main stages of the development of the immune response in the mucous membranes are traced, including the transport of antigen by dendritic cells to the lymph nodes, the implementation of the central link of the immune response and the subsequent migration of effector cells into the mucous membranes, caused by the expression of the necessary adhesion molecules and receptors for chemokines produced in the mucous membranes. The features of the effector phase of mucosal immunity are characterized - the predominance of a cytotoxic and Ig2-dependent humoral immune response with the predominant synthesis of IgA antibodies secreted into the lumen of the tracts. The features of the secondary response in the mucous membranes, caused by the high content of memory cells activated by local antigen-presenting cells, are considered. The idea of mucous membranes as the main place of “familiarization” of the body with foreign antigens is presented, in which a choice is made between the development of an immune response or anergy to these antigens and the formation of a fund of memory cells to environmental antigens.
Key words: mucosal immunity, Peyer's patches, M cells
INTRODUCTION
The mucous membranes are the main area of contact of the body with environmental antigens. Contrary to traditional ideas, it turned out that foreign substances enter the body not only as a result of disruption of barriers, but also as a result of active transport carried out by specialized cells of the mucous membranes. This gives new meaning to the long-held belief that the mucous membranes are not a passive barrier and that they should be fully considered as an active part of the immune system. The study of mucosal immunity is still in the process of formation, but already now “mucosal immunology” requires a revision of traditional ideas about the structure and functioning of the immune system, based on the study of “classical” lymphoid organs, such as lymph nodes and the spleen. This process of “embedding” knowledge about mucosal immunity into immunology
recent years, as evidenced by numerous reviews, including in Russian.
1. STRUCTURE AND CELLULAR COMPOSITION OF THE MUCOSAAL DIVISION OF THE IMMUNE SYSTEM
The mucosal department of the immune system includes immunologically significant structures, which include the epithelial layer of mucous membranes and the subepithelial space - the lamina propria, containing free lymphocytes and structured lymphoid tissue of several varieties, as well as lymph nodes draining these tissue segments. The listed structures form the morphofunctional unit of the mucosal department of the immune system (Fig. 1). The complex of such areas of barrier tissues, which necessarily contain structured lymphoid formations, is united by the concept of “mucosa-associated lymphoid tissue” - MALT (MALT - from mucosa-associated lymphoid tissue). MALT has a presence in the intestines (GALT - gut-associated lymphoid tissue), nasopharynx (NALT - nasopharynx-associated lymphoid
is being intensively and successfully implemented in
Address: 115478 Moscow, Kashirskoe shosse, 24, building 2, Institute of Immunology. Email: ayarilin [email protected]
Epithelium
Regional lymph nodes
Rice. 1. Structure of the local segment of the mucosal immune system
tissue), bronchi (BALT - bronchus-associated lymphoid tissue), as well as in the conjunctiva, Eustachian and fallopian tubes, ducts of the exocrine glands - salivary, lacrimal, etc. , but is absent in the urogenital tract. The MALT departments scattered in the mucous membranes are interconnected due to the common origin of immunocytes and the recycling of lymphoid cells, which allows us to speak of a unified mucosal immune system (CMIS - Common mucosal immune system). In addition to the mucosal one, several other compartments are distinguished in the barrier tissues - intravascular, interstitial, intraluminal, which we will not consider in this review.
1.1. Lymphoid structures of mucous membranes
There are several types of lymphoid structures of the mucous membranes - Peyer's patches and their analogues in the colon, tonsils, isolated follicles, cryptopatches, appendix. The basis of the structure of all these formations is the lymphoid follicle, surrounded by a T-zone, developed to a greater or lesser extent. On the luminal side, these structures are lined with follicular epithelium. The difference between the follicular epithelium and the surrounding columnar epithelium is the absence of a brush border and mucus-producing goblet cells. Epithelial cells of the mucous membranes, even in a resting state, secrete bactericidal peptides (defensins, cathelicitins) and cytokines (for example, transforming growth factor - TGFP). In addition, they are ex-
press TL receptors (TLR2, TLR3, TLR4), which recognize molecular structures (patterns) associated with pathogens - PAMP. On their surface there are receptors for a number of inflammatory cytokines (IL-1, TNFa, interferons), MHC molecules, adhesion molecules (CD58, CD44, ICAM-1). This provides the possibility of epithelial cells being involved in inflammation and immune processes under the influence of pathogens.
The most specific component of the follicular epithelium are M-cells (from the English microfold). Microfolds, which give these cells their name, replace them with microvilli. M cells lack the mucus layer that covers other epithelial cells of the mucous membranes. The M cell marker is the European snail (Ulex europeus) lectin type I receptor, UEAR1. These cells cover a significant part of the surface of the MALT lymphoid structures (about 10% of the surface of Peyer's patches). They are bell-shaped, the concave part of which faces the lymphoid follicles (Fig. 2). The M-cells are directly adjacent to the dome (cathedral) of lymphoid structures - the space in which T- and B-lymphocytes are located - mainly memory cells. Somewhat deeper, along with these cells, there are macrophages and CD1^+ dendritic cells of three types - CD11p + CD8-, CD11p-CD8+ and CD11P-CD8-. The main feature of M-cells is the ability to actively transport antigenic material, including microbial bodies, from the lumen of the tracts into the lymphoid structures. The mechanism of transport is not yet clear, but it is not related to MHC-dependent processing of antigens by antigen-presenting cells (although M cells express MHC class II molecules).
Among the types of lymphoid formations listed above, MALT Peyer's patches are the most developed, approaching the degree of complexity, as well as the structure and cellular composition of the lymph nodes. In mice they are localized in the small intestine (in a mouse there are 8-12 plaques). They are based on 5 - 7 follicles containing germinal centers, which are absent only in sterile animals. The T-zone surrounding the follicles takes up less space; the T/B ratio in Peyer's patches is 0.2. In T-zones, CD4+ T-lymphocytes predominate (CD4+/CD8+ ratio is 5). At the points of contact between follicles and T-zones, there are areas occupied by cells of both types. Colon plaques in mice have a similar structure, but are smaller than Peyer's patches and are contained in smaller quantities. In humans, on the contrary, Peyer's patches are found in greater quantities in the large intestine than in the small intestine. Both types of plaques develop in humans at the 14th week of embryonic development (in mice - postnatally); their size and cellularity increase after birth. The development of Peyer's patches (as well as lymph nodes) is determined by the migration of special cells - LTIC (Lymphoid tissue inducer cells), which have the CD4+CD45+CD8-CD3- phenotype, express the membrane lymphotoxin CTa1R2 and the receptor for IL-7. The interaction of LTA1P2 with the LTP receptor of stromal cells induces the ability of the latter to secrete chemokines that attract T and B cells (CCL19, CCL21, CXCL13), as well as IL-7, which ensures their survival.
Isolated follicles are similar in structure to the follicles of other organs - lymph nodes, spleen and Peyer's patches. The small intestine of a mouse contains 150 - 300 isolated follicles; their size is 15 times smaller than Peyer's patches. One structure of this type may contain 1 - 2 follicles. The T-zones in them are poorly developed. As in the follicles of Peyer's patches, they always contain germinal centers (unlike the follicles of lymph nodes, in which germinal centers appear when the node is involved in the immune response). B cells predominate in isolated follicles (70%), T cells account for 10-13% (with a CD4+/CD8+ ratio of 3). More than 10% of cells are lymphoid precursors
parents (c-kit+IL-7R+), about 10% are CD11c+ dendritic cells. Isolated follicles are absent in newborns and are induced in the postnatal period with the participation of microflora.
Cryptopatches are accumulations of lymphoid cells in the lamina propria between the crypts, described in mice in 1996; they have not been found in humans. In the small intestine their content is higher (about 1500) than in the large intestine. Each cryptoplaque contains up to 1000 cells. At the periphery of the plaque there are dendritic cells (20 - 30% of the total number of cells), in the center there are lymphocytes. Among them, only 2% are mature T and B cells. The remaining lymphoid cells have the phenotype of young T-cells CD3-TCR-CD44 + c-kit+IL-7R+. It was assumed that these are the precursors of T-lymphocytes that differentiate
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