B lymphocytes: overproduction and negative selection
The bone marrow is the birthplace and maturation site of the humoral arm of the immune system. Interestingly, it produces a colossal excess of B lymphocytes—significantly more than actually required to renew the cellular population (for example, in mice this figure reaches 20–50 million cells).
The vast majority of these cells are destined to die within the organ. Massive elimination occurs at two key stages:
- During immunoglobulin gene rearrangement.
- At the stage of immature B cells during negative selection. This mechanism is critically important: it destroys autospecific clones capable of attacking the body's own tissues.
T cells in the bone marrow: unusual phenotype
Unlike B cells, T lymphocytes in the bone marrow are represented exclusively by mature forms that have migrated here from the systemic circulation.
The T-cell population in the bone marrow has unique characteristics:
- Predominant phenotype: About 60% of all CD3+ cells are unusual lymphocytes with the `CD3+CD4-CD8-` profile. They resemble hepatic T cells, but are not completely identical to them. It is believed that these cells undergo extrathymic development.
- Conventional T cells: Among monopositive lymphocytes, cytotoxic CD8+ cells predominate over helper CD4+ cells.
- Subpopulation ratio: The CD4+/CD8+ ratio in the bone marrow is 0.5–1.0. For comparison, in peripheral blood this figure is 1.5–2.0. This difference is explained by the fact that these subpopulations have varying capacities for migration into bone marrow tissue.
In addition, the functional status of the organ strongly depends on external factors. During stress responses accompanied by a surge of glucocorticoids, the influx of T cells (including immature thymocytes) from the bloodstream into the bone marrow increases manifold.
Thymus (Thymus): discovery and anatomy
The thymus is located behind the manubrium of the sternum. In humans, as in most mammals, this organ consists of two lobes.
For a long time, the role of the thymus remained a mystery to medicine, as its removal in adult patients did not lead to pronounced severe consequences. The breakthrough occurred in 1961 thanks to the research of J.F.A. Miller (J.F.A.P. Miller). He experimentally proved that the removal of the thymus in newborns critically disrupts the development of most lymphocytes. This discovery led to the understanding of lymphocyte heterogeneity and the identification of a special population of thymus-dependent cells—T lymphocytes, which mature specifically in this organ.
Histological structure of the thymus
The thymus is a lymphoepithelial organ with a characteristic three-layered organization: connective tissue stroma, epithelial reticulum, and lymphoid component. The organ is covered on the outside by a dense connective tissue capsule.
Organ architectonics:
- Cortex (cortical substance): Includes the outer (subcapsular) layer, deep cortex, and corticomedullary junction. Interlobular septa extend from the capsule inward, dividing only the cortex into lobules.
- Medulla (medullary substance): Is not divided into lobules and represents a single continuous structure.
- Corticomedullary junction: Acts as the "gateway" of the organ—this is precisely where blood vessels and nerve fibers enter and exit.
The blood supply to the organ is rather poor, which is why the thymus is often called the "pale organ." The main functional structures of the vascular bed are postcapillary venules. Progenitor cells penetrate into the organ through their walls, while fully mature T lymphocytes leave it.
Thymus cells have different origins. Epithelial elements and most of the stroma develop locally (local origin), whereas lymphocytes originate in the bone marrow and migrate into the gland to undergo "education".
Briefly: answers to topical questions
What hormones are produced by thymic epithelial cells?
Thymic epithelial cells produce peptide hormones related to neuropeptides. The main hormones secreted by subcapsular and medullary cells of the thymic epithelium include:
- Thymulin — a zinc-binding nonapeptide, also known as thymic humoral factor; exhibits activity only in a complex with zinc ions.
- Thymosins — a group of polypeptide factors, primarily α1-thymosin, which is the N-terminal fragment of prothymosin α.
- Thymopoietins — peptide factors that induce the expression of mature T-lymphocyte markers on the surface of their precursors.
Thymulin, α1-thymosin, and thymopoietin are produced by the same secretory cells of the thymic epithelium.
What stages of maturation do T lymphocytes go through in the thymus?
During maturation in the thymus, T lymphocytes pass through several consecutive stages of differentiation. The main stages include:
- Common lymphoid progenitor (CLP) — the earliest stage of development.
- Double-negative thymocytes (DN1–DN4) — cells with the CD4-CD8- phenotype undergoing rearrangement of cell receptor genes.
- Immature single-positive cells (ISP) — a transitional stage before the formation of double-positive cells.
- Double-positive thymocytes (DP) — cells with the CD4+CD8+ phenotype undergoing positive and negative selection processes.
- Single-positive cells (SP) — mature cells with the CD4+CD8- or CD4-CD8+ phenotype.
What specific structures are located in the medulla of the thymus?
Specific morphological structures—Hassall's corpuscles, as well as specialized blood vessels—are located in the medulla of the thymus.
- Hassall's corpuscles — multilayered squamous formations consisting of concentric layers of partially keratinized epithelioreticulocytes. Non-viable keratinized cells are located in their center. They secrete cytokines and serve as an absolute morphological marker of the medulla.
- High endothelial postcapillary venules — vessels through the walls of which recirculating T lymphocytes enter or leave the bloodstream.
Class and exam questions
Why is the bone marrow classified as both a central and a peripheral organ?
The bone marrow combines the functions of a central organ, since new cells (B lymphocytes) develop in it, and a peripheral organ, since mature lymphocytes (T cells) actively migrate into it from the bloodstream.
What happens to the majority of B lymphocytes in the bone marrow?
They undergo massive cell death during immunoglobulin gene rearrangement and at the negative selection stage to prevent autospecific clones from entering the blood.
What is the structural feature of the thymic lobules?
Connective tissue septa extending from the capsule divide exclusively the cortical substance into lobules; the medulla of the thymus remains undivided.
Through which vessels do cells enter and leave the thymus?
Cell transport is carried out through postcapillary venules located in the region of the corticomedullary junction.
What else to study on this topic
- Mechanisms of immunoglobulin gene rearrangement
- The process of B-lymphocyte negative selection
- Extrathymic T-cell development
- Cellular composition of the thymic cortex and medulla
- Mechanisms of lymphocyte migration through postcapillary venules
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