Central tolerance and negative selection
Central tolerance is established in primary lymphoid organs: the thymus (for T cells) and the bone marrow (for B cells). The main mechanism at this stage is clonal deletion (elimination).
In the thymus, this process occurs at the double-positive thymocyte stage (CD4+CD8+). During this period, cells have low levels of anti-apoptotic factors and are extremely vulnerable. Medullary epithelial cells and dendritic cells present them with complexes of self-peptides and MHC molecules. If a T-cell receptor (TCR) binds to such an autoantigen with high affinity, the thymocyte receives an apoptotic signal and dies.
To prevent the immune system from attacking tissues of other organs (such as the thyroid gland), the medullary thymic epithelium expresses the AIRE (Autoimmune Regulator) gene. It triggers random ectopic expression of specific extrathymic antigens. Their presentation allows for the elimination of the vast majority of potentially dangerous autoaggressive clones.
Peripheral tolerance: anergy and editing
Because lymphocyte populations are constantly renewed and thymic selection is not 100% efficient, some autoreactive cells inevitably enter the bloodstream. Backup mechanisms exist in the periphery to control them.
- Anergy. This is a state of persistent functional unresponsiveness. It develops when a T lymphocyte recognizes its antigen but does not receive a second, costimulatory signal (interaction of CD28 with CD80/CD86 molecules on the antigen-presenting cell). The absence of costimulation blocks intracellular signaling pathways (specifically, the Ras-dependent branch of the MAP kinase cascade), and the cell loses its ability to become activated.
- Receptor editing. When an immature cell encounters an autoantigen, a lymphocyte rescue process may be triggered. In T cells, the expression of RAG genes resumes, and a secondary rearrangement of the TRAV gene of the TCR $\alpha$-chain occurs. As a result, the receptor changes its specificity, and the cell stops responding to self-tissues.
Role of regulatory T cells (Tregs)
Passive mechanisms of deletion and anergy are insufficient for reliable protection. The third critical echelon is dominant tolerance, mediated by natural regulatory T cells (Treg).
During development in the thymus, the affinity threshold for autoantigens required for cell death is higher in future Tregs than in conventional lymphocytes. Therefore, they evade negative selection and migrate to the periphery. Their phenotype is distinguished by the presence of CD4+, CD25hi, CTLA-4+ markers and the intracellular transcription factor FOXP3.
Migrating to lymph nodes, autospecific Tregs actively suppress effector T cells that have managed to escape deletion and anergy. Suppression occurs both via direct cell-to-cell contact and through the production of inhibitory cytokines — TGF-β and IL-10 (by Th3 and Tr1 cell types).
Ignorance and mucosal tolerance
Autotolerance can be maintained passively through ignorance. The immune system simply does not react to an antigen if its concentration is below a certain threshold or if it is hidden behind tight tissue barriers (in immunologically privileged organs). When barriers are damaged or during tumor growth (when protein concentration rises sharply), such ignorance is broken.
A special type of peripheral unresponsiveness is mucosal tolerance (e.g., oral tolerance or the historically described Felten paralysis phenomenon). The fate of antigens penetrating through the intestinal barrier and captured by dendritic cells is determined by the presence of PAMPs (pathogen-associated molecular patterns). If food molecules do not contain PAMPs, innate immune receptors are not activated, inflammatory cytokines are not released, and sustained tolerance is formed.
Briefly: answers to topical questions
Which intracellular signaling pathways are blocked during T-cell anergy development?
During T-cell anergy, intracellular signaling pathways associated with the MAPK cascade and kinase phosphorylation are blocked.
- MAPK cascade — its Ras-dependent branch is suppressed, which blocks the formation of ERK and c-Fos transcription factors.
- Tyrosine kinase (Lck) — its activity is attenuated.
- Kinase and adaptor protein (ZAP-70, LAT) — absence or reduction of their phosphorylation is observed.
The low-molecular-weight GTPase, p21ras factor, is also involved in this process.
Which human organs are considered immunologically privileged (barrier-protected)?
Immunologically privileged organs and tissues include:
- Brain and central nervous system.
- Eye structures: internal chambers of the eye, anterior chamber, cornea, vitreous body, retina, and lens.
- Testes, including the seminiferous tubules.
- Ovaries.
- Pregnant uterus and developing fetus.
- Hair follicles.
- Thyroid gland, including its follicles and colloid.
Immunologically privileged zones also include the intestinal mucosa and tumors; in these cases, the immune response is selectively limited or blocked.
How does receptor editing occur in immature B lymphocytes in the bone marrow?
The receptor editing process in immature B lymphocytes is triggered when they recognize autoantigens associated with bone marrow stromal cells.
- Resumption of expression — RAG1 and RAG2 genes are re-expressed.
- Secondary rearrangement — V gene rearrangement of light chains occurs (first κ genes, then λ genes).
- Successful editing — autoreactivity is lost, and the cell develops normally.
- Unsuccessful editing — if autoreactivity persists, the cell undergoes apoptosis.
What disease develops in case of a hereditary mutation in the FOXP3 gene?
A hereditary X-linked recessive mutation in the FOXP3 gene leads to IPEX syndrome (immune dysregulation, polyendocrinopathy, enteropathy, X-linked). The disease is associated with a defect in regulatory T-cell development and manifests with the following pathologies:
- Autoimmune processes — multiple endocrine gland involvement.
- Gastrointestinal involvement — severe enteropathy and intestinal lymphocyte hyperproliferation.
- Systemic disorders — cachexia, short stature, allergic and hematological manifestations.
The formula "D-B-I-R" helps remember the four pillars of autotolerance: Deletion (elimination in the thymus), Blockade (anergy without costimulation), Ignorance (isolation by barriers), Regulation (active suppression via Tregs).
Class and exam questions
Is negative selection in the thymus perfect?
No. The elimination mechanism is not 100% efficient, so isolated autospecific clones can enter the periphery, where they are restrained by other mechanisms.
What happens during mutations in the AIRE gene?
Failure of the AIRE gene to function properly disrupts negative selection in the thymus, which inevitably leads to fatal polyspecific autoimmune processes.
How is the presence of T-cell negative selection proven?
In transgenic experiments. Introducing receptor genes with known specificity into mouse embryos demonstrates that in the presence of the corresponding autoantigen in the thymus, total elimination of such T cells occurs.
Why don't we mount an immune response to food?
Food molecules do not contain PAMPs. Dendritic cells capturing them in the mucosa do not receive activating signals, leading to a systemic absence of immune response (oral tolerance).
What else to study on this topic
- Molecular mechanisms of anergy: the role of ZAP-70 and Lck kinases and the MAPK cascade.
- Experimental models demonstrating tolerance (H-Y antigen mice).
- Features of negative selection of B lymphocytes in the bone marrow.
- Routes of mucosal antigen entry and the function of M cells.
- Mechanisms of immune response suppression by Th3 and Tr1 cells (role of cytokines).
Master the entire topic in the "Immunology" course
This is a summary. The course covers everything tested in classes and exams.
- Complete study guide on "Autotolerance" and 723 more pages on the subject
- Assignments and quizzes after every topic — just like in a colloquium
- AI tutor answers questions on the topic anytime
- 23 video lessons on the subject
Other topics in the section "Immunity in defense and damage of the organism. Pathology of immunity"
Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.