Classification and Structure of Thymic Peptides
Thymus hormones are represented by several groups of polypeptide molecules isolated from thymic extracts.
- Thymulin. Historical name: thymic humoral factor (FTS). It is a nonapeptide (9 amino acid residues) with a molecular weight of 847 Da. Its molecular structure is highly conserved and identical in various mammals. In the blood, it circulates bound to a large carrier protein (40–50 kDa). Interestingly, the structural gene of this hormone has not yet been identified. Upon thymectomy, thymulin completely disappears from the bloodstream, as there are no other sources of its synthesis.
- Thymosins. A group of factors discovered by A. Goldstein in 1967. The most studied is $\alpha_1$-thymosin (28 amino acids, molecular weight 3108 Da). It is not synthesized de novo, but cleaved from a larger intracellular protein — prothymosin $\alpha$ (113 residues), which is widespread in the body and responsible for chromatin remodeling. Processing occurs with the participation of lysosomal asparaginyl endopeptidase.
- Thymopoietins (I and II). Molecules consisting of 49 amino acids, differing by only three residues (at positions 1, 2, and 43). Thymopoietin I has a greater effect on neuromuscular transmission, while thymopoietin II affects T cells. In modern medicine and research, instead of whole molecules, thymopentin is used — a synthetic active pentapeptide (a segment of five amino acids from 32 to 36).
- Thymic humoral factor. A complex preparation whose active fraction is the synthesized $\gamma_2$ peptide. It is normally absent in circulating blood, but is actively used in clinical practice for the treatment of tumors and hepatitis B.
Secretion Mechanisms and Biological Role
The synthesis of thymulin, $\alpha_1$-thymosin, and thymopoietins is carried out by the same subcapsular and medullary epithelial cells. These cells also express ganglioside GQ and produce neuropeptides. Hormones are released into the blood via calcium-dependent exocytosis.
Upon entering the peripheral blood, thymic hormones act on specific targets outside the thymus gland. Their main target is recent thymic "graduates" (T lymphocytes that have already entered the periphery but have not yet become fully mature naive T cells).
Key biological effects:
- Enhanced synthesis of interleukin-2 (IL-2) by activated T cells.
- Increased expression of IL-2 receptors.
- Stimulation of natural killer (NK cell) activity.
- Mediated effect on macrophages, B lymphocytes, and dendritic cells (proven for $\alpha_1$-thymosin).
Key rule: these factors on their own are not capable of initiating the process of T-lymphocyte differentiation. They merely induce the expression of maturity markers on the surface of progenitor cells.
Age Dynamics and Clinical Significance
The level of thymic hormones in human blood undergoes significant age-related changes. Using thymulin as an example, a clear dynamic can be traced:
- Peak concentration is observed in childhood (5–10 years).
- Decrease becomes pronounced by the age of 36.
- Stabilization at a minimum occurs by the age of 80.
It is precisely this age-related deficiency of thymic hormones that causes the decline in T-cell activity in elderly people (primarily, their ability to produce IL-2 is reduced).
To correct such age-related disorders, as well as to treat induced immunodeficiency states, synthetic analogues of thymic hormones are successfully used (e.g., synthetic thymopentin). In addition, thymic hormones do not work in isolation—their bidirectional connection with the hypothalamic-pituitary-gonadal axis and other endocrine glands has been proven.
Briefly: answers to topical questions
What pharmacological drugs based on thymus extracts and their synthetic analogues exist?
There are natural complex thymus preparations and synthetic peptide analogues.
Natural preparations include:
- Thymalin is a complex preparation obtained by acetic acid extraction.
- Thymosin is a complex preparation obtained by a modified method of obtaining thymosin fraction 5.
Synthetic analogues include:
- Thymogen (L-Glu-L-Trp) is a dipeptide, alpha-glutamyl-tryptophan.
- Thymodepressin is a dimer of D-isomers of the same amino acids connected via a gamma-bond.
- Bestim is a dimer of D-Glu and L-Trp connected via a gamma-bond.
- Neogen is a trimeric peptide: a leucine residue is added to the N-terminus of the L-dimer identical to thymogen.
- Imunofan is a synthetic hexapeptide created on the basis of the active fragment of thymopoietin.
- Thymopentin is a synthetic active pentapeptide corresponding to residues 32–36 of thymopoietins.
Which intracellular signaling pathways are activated in lymphocytes upon the action of thymus hormones?
The action of thymus hormones in lymphocytes is mediated through effects on the cyclic nucleotide system. In particular, changes in the intracellular cAMP level regulate cell activity: its increase leads to the attenuation of T-lymphocyte functions, which is analogous to the state of thymus hormone deficiency. Other specific intracellular signaling cascades activated directly by thymus hormones are not described in the literature.
To remember that thymopentin is an artificial analogue of thymopoietin, pay attention to word roots: the thymopoietin molecule is quite long (49 residues), whereas clinical practice uses a short PENTapeptide (5 residues)—thymopentin.
Class and exam questions
Are thymus hormones capable of directly inducing T-lymphocyte differentiation?
No, they are not capable. Their main action consists in inducing the expression of mature T-cell markers on the surface of already existing precursors.
Where does $\alpha_1$-thymosin come from in the body?
It is formed by the cleavage of the N-terminal fragment from the intracellular protein prothymosin $\alpha$ with the participation of lysosomal asparaginyl endopeptidase. This process is active in the thymus, but has also been detected in the nervous system.
Do all thymus hormones disappear from the blood after the removal of the thymus gland?
No. Following thymectomy, only thymulin completely disappears from circulation. The levels of $\alpha_1$-thymosin and thymopoietins may decrease, but do not always drop to zero.
What else to study on this topic
- Mechanisms of apoptosis and necrosis of immune system cells
- The role of apoptosis in T-lymphocyte selection
- Intracellular functions of prothymosin $\alpha$ in chromatin remodeling
- Interaction of the thymus with the hypothalamic-pituitary-gonadal axis
- Clinical application of synthetic thymus peptides (TGF$\gamma_2$, thymogen)
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