Physiology of the thymus gland (thymus)

The thymus gland has long been considered an endocrine organ, although numerous observations have shown that it is more likely an object of hormonal influences than a source of specific hormones. However, in recent years, a number of active substances have been isolated from the thymus gland that have an effect primarily on immune processes in the body.

In humans, the thymus is located behind the sternum, reaching the aortic arch from below. It consists of two closely adjacent lobes covered with a connective tissue capsule, from which septa extend, dividing the organ into separate lobes. In each of them, a cortex and a medulla are distinguished. At birth, the thymus mass is 10-15 g. Subsequently, it increases, reaching a maximum at the onset of puberty (30-40 g), and then decreases (age-related involution of the thymus). In a number of cases of sudden death, a large thymus was found at autopsy. The combination of this with a loose ("lymphatic") physique has long given reason to talk about the existence of a special thymic-lymphatic status, which supposedly causes an extremely high susceptibility of the body to adverse effects. At present, the thymic-lymphatic status is not given such great importance and even doubts are expressed about its very existence. Indeed, in cases of violent death, the size of the thymus is usually as large as in the supposed thymic-lymphatic status. On the other hand, obvious hyperplasia of the thymus, which occurs, for example, in malignant myasthenia, as a rule does not lead to sudden death. Physiological involution of the gland consists in the gradual disappearance of characteristic cellular elements from it with their replacement by adipocytes and fibrous tissue. Acute involution of the thymus gland, usually associated with stress, is also observed.

The thymus cortex is represented by small lymphocytes and a small number of reticuloendothelial cells. The ratio of these elements is approximately 100:1. The medulla contains the so-called Hassall's corpuscles - clusters of epithelial cells surrounding lymphocytes and eosinophils. However, the former are approximately 20 times less numerous in the medulla than the latter. The latter have villi and contain PAS-positive material resembling thyroid colloid. Electron microscopic studies reveal in these cells a rough endoplasmic reticulum, a well-developed lamellar complex (Golgi apparatus) and granules, the contents of which may have hormonal activity. There is no consensus regarding the structure of the vessel walls in the thymus gland (i.e. the presence of a histohematic barrier in this organ). Arteries pass only in the thymus cortex, while veins pass in the medulla. Mitoses are found almost exclusively in lymphocytes of the cortex of the thymus gland.

Based on the structural features of this organ, it is believed that it serves as an important source of lymphocytes in the body, but, unlike other similar structures, does not directly participate in immune reactions. Cystic formations present in the thymus, the cells of the walls of which have secretory properties, may reflect the endocrine function of this organ.

In phylo- and ontogenesis, a clear connection can be traced between the appearance and development of the thymus, on the one hand, and the emergence of the body's immunological reactivity, on the other. Therefore, the main role of the thymus is seen in the regulation of immunological processes. The lymphopoietic activity of this organ is closely related to this function. Differentiation of various subpopulations of T-lymphocytes occurs in the thymus gland, which have helper, suppressor, and killer effects. In recent years, it has been shown that the immunoregulatory and lymphopoietic functions of the thymus are carried out due to the secretion of humoral factors. Epithelial cells of the medulla apparently have secretory activity. The role of the thymus in the body is clearly visible in the example of pathological conditions that develop with insufficiency of its functions or in its absence.

The table shows some hypothetical dependencies of clinical syndromes on the activity of the thymus gland, but there are no indications of a number of its other proven functions. However, even in this form it gives an idea of the diversity and importance of the physiological activity of the thymus.

Functions of the thymus gland and syndromes caused by their disruption

Functions	Syndromes
Development of immunocompetence Restoration of immunocompetence Maintenance of immunocompetence Regulation of the peripheral lymphoid system Production of bone marrow stimulating factor Production of hypoglycemic factor Permeability factor production Production of neuromuscular transmission inhibitory factor	Immune deficiency syndrome Autoimmune diseases Neoplasia Lymphoid proliferation Thymoma, agammaglobulinemia with erythrocyte aplasia Hypoglycemia in leukemia Delayed hypersensitivity Malignant myasthenia

Neonatal thymectomy of animals (especially rodents) leads to the development of the so-called wasting syndrome - growth retardation, depletion of lymphoid tissue, hypogammaglobulinemia, dystrophic changes in the skin with hair loss, atrophy of the subcutaneous fat tissue and, finally, early death. In addition to purely immunological causes of this syndrome, a role in its genesis may be played by a disruption in the interaction of some thymus factors with the somatotropic function of the pituitary gland. Similar changes develop in mutant rodent lines with a congenital absence of the thymus gland (mutant atimia) bred by inbreeding. Such animals may completely lack T-lymphocytes, cell-mediated immunity does not manifest, and they die much earlier than normal individuals of a given species. Congenital hypoplasia and aplasia of the thymus in humans are characterized by generalized lymphoid depletion and hypertrophy of peripheral lymphoid structures. There is suppression of the synthesis of immunoglobulins and cellular immunity. Usually, children with such pathology do not survive to 1 year. Treatment of patients with a normal thymus preparation (thymosin) improves their condition, which is accompanied by an increase in the number of T-lymphocytes in the blood.

The consequences of thymus removal in adults are much less demonstrative, and such consequences become apparent after a fairly long time. In operated mice, the "graft versus host" reaction is reduced. Immune deficiency in such conditions can only be observed by a slowdown in the restoration of the population of long-lived immunocompetent cells, reduced by, for example, X-ray irradiation.

A number of autoimmune diseases, in which antibodies to antigens of the body's own tissues appear in the blood, are associated with factors produced by the thymus. Among such diseases, the most attention is drawn to malignant myasthenia, accompanied by pronounced changes in the thymus gland (autoimmune thymitis). A factor (thymine) has been isolated from the normal thymus, which slows down the transmission of nerve impulses to muscle cells. Its hypersecretion may underlie the development of malignant myasthenia. In addition, thymus factors (or their deficiency), by affecting immunocompetent cells, can promote the production of "clone-prohibited" lymphocyte antibodies directed against acetylcholine receptors and other antigens of muscle cells.

There are other data indicating the hormonal activity of the thymus gland. Age-related dynamics of the thymus size have long suggested its participation in the regulation of the body's growth. However, although substances influencing growth have been isolated from the thymus tissue, their presence has also been found in other tissues. Nevertheless, it has been shown that after thymectomy, the growth effects of somatotropic hormone are significantly weakened. Direct evidence of the systemic production of thymic factors was provided by experiments with transplantation of the thymus gland, enclosed in fine-pored diffusion chambers. This operation contributed to the elimination or mitigation of the symptoms of thymectomy.

At present, many (more than 20) substances with biological activity in various test systems have been isolated from thymus tissue. Most of them have not been studied well. In some cases, it is not even known whether they are really different compounds or differ only in the extraction method. Substances produced in the thymus include polypeptides (thymosin fraction-5, thymopoietin, thymus factor of the blood, active thymus factor - AFT-6, thymarin) with a molecular weight of 900-14,000 daltons and other factors that exhibit different activities in relation to the expression of T-cell markers, the abolition of wasting syndrome, the restoration of the T-lymphocyte population in athymic mice, the stimulation of DNA synthesis, tumor growth and other phenomena. In a number of cases, the amino acid sequence of such factors (for example, the thymus factor of the blood), the localization of the active part of the molecule, and even the mechanism of their action (through cAMP and prostaglandins) have been established. Thus, thymopoietin is a single-chain peptide consisting of 49 amino acid residues. It induces differentiation of prothymocytes into immunologically competent T cells with full expression of surface antigens. The effect of the native thymopoietin molecule is reproduced by a synthetic pentapeptide containing the amino acid sequence from the 32nd to the 36th residue. When administered intravenously, it can alleviate the manifestations of rheumatoid arthritis.

Alpha1-thymosin, isolated from bovine thymus extract, contains 28 amino acid residues. It is currently obtained by genetic engineering. When injected into athymic dwarf mice, lymphocyte proliferation is observed, the body growth rate increases, and the ability to reject allografts is restored. Of clinical interest are data on the beneficial effect of thymosin injections in children with hereditary forms of immunodeficiency, as well as in patients with lymphopenia after radiation or chemotherapy for malignant tumors.

A more detailed description of the relevant factors is given in immunology manuals, since they mainly control immunological reactions. At the same time, there is data that allows the thymus gland to be included in the more traditional system of endocrine regulation in the body. These data indicate a relationship between the thymus and the activity of other endocrine glands. Thus, antiserum to pituitary tissue causes thymus atrophy in newborn mice. On the contrary, antilymphocyte serum causes degranulation of acidophilic cells of the anterior pituitary gland, in which growth hormone is synthesized. Neonatal thymectomy also leads to similar changes in the pituitary gland. In adult rats, removal of the gland leads to an increase in the level of growth hormone in the blood. The content of TSH also increases. Thymectomy causes an increase in the mass of the adrenal glands with a decrease in the content of ascorbic acid and cholesterol in them, which serves as a sign of an increase in the secretory activity of the adrenal cortex. An increase in the level of corticosteroids (especially aldosterone) in the blood of thymectomized animals has also been found. Data on the influence of these substances (as well as sex hormones) on the condition of the thymus gland are well known. With regard to the effect of thymus factors on the function of other endocrine glands, the results of experimental studies are less certain; clinical data also do not provide clear indications of the presence of corresponding interactions.

Among the metabolic effects of thymectomy and thymosin, it is worth noting the increase in the level of triglycerides in the serum of thymectomized animals and its normalization under the influence of thymosin.

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