Negative selection in the bone marrow
The fate of an immature B cell in the bone marrow directly depends on whether it recognizes the body's own antigens (autoantigens).
- No reaction. If the cell's receptors do not bind to autoantigens, it develops normally. The result is a fully functional cell in which IgM expression predominates over IgD.
- Binding to a soluble autoantigen. Leads to the induction of anergy, a state of functional unresponsiveness. Such cells are distinguished by a high density of IgD on the membrane.
- Binding to a cell-associated autoantigen. Triggers an attempt to "rescue" the receptor — BCR V-gene editing. If rearrangement is successful and autoreactivity disappears, the cell develops further. If affinity for own tissues persists, the B lymphocyte undergoes apoptosis or is sent to additional selection stages in peripheral organs.
Transitional stages in the periphery (T1–T3)
B lymphocytes leave the bone marrow immature. In the peripheral compartment, they go through transitional stages designated as T1, T2, and T3.
- T1 stage. Characterized by the phenotype IgM<sup>hi</sup>IgD<sup>-/lo</sup>CD23<sup>-</sup>CD21<sup>lo</sup>CD24<sup>hi</sup>. High expression of the CD24 marker indicates recent egress from the bone marrow. Positive selection takes place at this stage: cells receive a vital signal via the BCR (presumably without antigen participation).
- T2 and T3 stages. Cells acquire new markers (in T2: IgM<sup>hi</sup>IgD<sup>hi</sup>CD21<sup>int</sup>CD23<sup>+</sup>; in T3, IgM decreases). Survival here is regulated by a complex combination of signals from the BCR (now antigen-dependent) and BAFF receptors (BAFF-R, TAC-1, BCMA). These signals activate transcription factors of the NFκB family (classical p50RelA and alternative p52RelB), which is critical for clone viability.
Peripheral negative selection
In the periphery, autoreactive clones are destroyed autonomously, without the help of additional stromal cells. The central mechanism is a deficiency of survival signals.
At the T2 stage, B lymphocytes have very few receptors for the BAFF factor. If such a cell binds an autoantigen, it fails to receive a supportive signal from BAFF receptors and undergoes programmed cell death (apoptosis). An alternative, milder option is the induction of anergy (unresponsiveness), in which the cell's lifespan is drastically shortened, and it dies during natural pool turnover.
Cells that have successfully passed selection begin to express the chemokine receptor CXCR5. Following the CXCL13 (BLC) chemokine gradient, they migrate into lymphoid follicles. The transitional stage concludes: the density of BAFF/APRIL receptors normalizes, and now BCR binding to antigen leads not to death, but to activation and proliferation. This is how mature naive B lymphocytes are formed.
Main B-lymphocyte subpopulations
Mature cells are divided into subpopulations with stable functions and markers (most data obtained in mice).
- B2 cells (conventional). The main participants in the humoral immune response. They reside in the lymphoid follicles of the spleen, bone marrow, lymph nodes, and Peyer's patches. They constitute the bulk of circulating B cells.
- B1 cells. Localized in the abdominal and pleural serous cavities. They are able to migrate through the greater omentum into the intestinal mucosa, where they become potent IgA producers (up to 50% of all producers in this zone). They are scarce in the spleen (1–5%) and completely absent in mouse lymph nodes.
- Marginal zone B cells (MZB cells). Distinguished as a separate third subpopulation localized in specific zones of lymphoid organs.
Comparison: T- and B-lymphocyte selection
The selection processes of B and T cells have fundamental differences in localization and mechanisms.
| Characteristic | B lymphocytes | T lymphocytes |
|---|---|---|
| Localization | Bone marrow, spleen, lymph nodes | Thymus (subcapsular zone, cortex, medulla) |
| Helper cells | Bone marrow stroma (positive), autonomous (negative) | Cortical, medullary epithelial, and dendritic cells of the thymus |
| Essence of positive selection | Basic survival signal via BCR | Check for the ability to recognize MHC molecules |
| Essence of negative selection | BAFF reception deficiency upon recognition of autoantigen | Death upon too high affinity for autologous peptides |
Briefly: answers to topical questions
What differentiation CD markers distinguish the B1-lymphocyte subpopulation from B2 lymphocytes?
B1 and B2 lymphocyte subpopulations differ in the expression of membrane molecules CD5, CD11b, and CD23.
| Characteristic | B1 cells | B2 cells |
|---|---|---|
| CD5 | Present on B1a cells | Absent |
| CD11b | Present | — |
| CD23 | — | Present |
Additionally, B1 cells express costimulatory molecules CD80 and CD86, which provides them with the ability to function as antigen-presenting cells.
What is the molecular mechanism of BCR V-gene editing during autoreactivity?
Editing of B-cell receptor (BCR) V-genes is triggered by the reaction of an immature B cell with a cell-bound autoantigen.
The process is a gene rearrangement that has two possible outcomes:
- Successful editing — the cell loses autoreactivity, continues normal development, and matures into a functionally competent B cell.
- Unsuccessful editing — if the B lymphocyte retains autoreactivity after rearrangement, it undergoes apoptosis.
The detailed molecular mechanism is described in sources only using the example of T lymphocytes (re-expression of RAG genes and segment rearrangement).
What functions do marginal zone B cells (MZB cells) perform in the immune response?
Marginal zone B cells (MZB cells) participate in the humoral immune response to pathogens entering the bloodstream.
Their main functions and features:
- T-independent response — execute reactions against encapsulated pathogens.
- Interaction with T follicular helpers — ensured by strong expression of MHC-II molecules and costimulatory molecules.
- Antibody production — upon activation by antigens, they differentiate into short-lived antibody-secreting cells.
During an immune response, MZB cells do not undergo immunoglobulin class switching, so memory cells carry IgM on their surface.
Which specific bone marrow microenvironment cells provide positive selection of B lymphocytes?
Positive selection of B lymphocytes is provided by bone marrow stromal cells.
They deliver a signal through the B-cell receptor of immature B cells at the T1 stage. This process ensures lymphocyte survival and their subsequent egress into the peripheral pool. Presumably, this selection occurs without antigen participation.
Class and exam questions
What is the essence of positive and negative selection of B cells?
Positive selection (at the T1 stage) provides a basic survival signal via the B-cell receptor, permitting egress into the peripheral pool. Negative selection (at the T2 stage) eliminates autospecific cells due to a deficiency in BAFF reception in response to self-antigens.
What is BCR V-gene editing?
This is a rescue mechanism for an immature B cell in the bone marrow. If it binds to a cell-associated autoantigen, it attempts to rearrange its receptor to lose autoreactivity. If the attempt is unsuccessful, the cell undergoes apoptosis.
How do B1 lymphocytes differ from B2?
B2 cells are classical lymphocytes that provide a systemic humoral response and circulate throughout the body. B1 cells are localized predominantly in serous cavities and the intestine, where they act as the main producers of secretory IgA.
How do B-cells find their way into lymphoid follicles?
Cells that survive selection express the CXCR5 receptor. They move along the gradient of the specific chemokine CXCL13 (BLC), which directs them straight into the follicles.
What else to study on this topic
- Molecular mechanisms of BCR V-gene rearrangement and editing.
- Intracellular signaling: classical and alternative pathways of NFκB activation.
- The role of the BAFF receptor family in the pathogenesis of autoimmune diseases.
- Detailed characterization of β-selection of T lymphocytes in the subcapsular layer of the thymus.
- Differences between B1a and B1b cell subpopulations (under the expanded classification).
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