Immunological tolerance mechanism and types
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Immunological Tolerance: Mechanisms and Types
Immunological tolerance is the state of specific unresponsiveness to an antigen. When directed at self-antigens, it prevents autoimmunity. When it fails, autoimmune disease results. The core principle: lymphocytes with randomly generated receptors inevitably include self-reactive clones, so mechanisms must exist to delete or silence them.
Historical Background
In the mid-1940s, John Owen observed that dizygotic twin cattle sharing placental circulation were chimeric (they had each other's red cells). Frank Macfarlane Burnet and Frank Fenner then proposed that antigens encountered during immunological immaturity suppress future responses to that antigen. Peter Medawar confirmed this experimentally - neonatal injection of CBA cells into newborn A-strain mice prevented adult rejection of CBA skin grafts. This work earned Burnet and Medawar the Nobel Prize and established the concept of "acquired immunological tolerance."
Key principle: antigen persistence is required to maintain tolerance. With living cells (chimerism), tolerance is long-lived. With soluble proteins, tolerance wanes as the antigen is cleared.
- Roitt's Essential Immunology, p. 322
Overview of Types
Tolerance is broadly classified by the anatomical site where it is induced:
| Type | Site | Cells Affected |
|---|---|---|
| Central tolerance | Thymus (T cells), Bone marrow (B cells) | Immature, developing lymphocytes |
| Peripheral tolerance | Secondary lymphoid organs, tissues | Mature, naive lymphocytes that escaped central deletion |
1. Central Tolerance
T-Cell Central Tolerance (Thymus)
Developing T cells in the thymus undergo negative selection: if an immature T cell recognizes self-peptides presented by thymic MHC with high affinity, it is deleted by apoptosis. This is the most potent mechanism - it eliminates self-reactive clones before they reach the periphery.
A key molecular player is AIRE (Autoimmune Regulator), a transcription factor in thymic medullary epithelial cells that drives expression of peripheral tissue antigens (e.g., insulin, thyroglobulin) within the thymus itself. This allows deletion of T cells reactive to antigens they would normally only encounter outside the thymus. Mutations in AIRE cause Autoimmune Polyglandular Syndrome (APS-1/APECED), in which self-reactive T cells escape deletion and attack endocrine and other tissues.
- Robbins & Kumar Basic Pathology, p. 174-175
- Goldman-Cecil Medicine, p. 354
B-Cell Central Tolerance (Bone Marrow)
Immature B cells encountering self-antigens in the bone marrow undergo:
- Clonal deletion - death of strongly self-reactive cells
- Receptor editing - secondary V-gene rearrangement produces a new light chain with different specificity, "editing out" the autoreactivity. If heavy + light chain transgenes encoding a high-affinity anti-DNA antibody are introduced into a mouse, the cells undergo genetic reshuffling until a combination is achieved that no longer binds DNA.
Whether deletion or anergy results from self-antigen encounter depends primarily on receptor cross-linking: membrane-expressed antigen (rich cross-linking) → deletion; soluble antigen (poor cross-linking) → anergy.
- Roitt's Essential Immunology, pp. 326-329
2. Peripheral Tolerance
Central tolerance is imperfect - some self-reactive lymphocytes escape into the periphery (especially for antigens not expressed in thymus/bone marrow). Peripheral tolerance mechanisms keep these cells in check.
2a. Clonal Anergy
T-cell activation requires two signals:
- TCR engagement with MHC-peptide (Signal 1)
- Co-stimulation via CD28 binding to B7 (Signal 2)
When antigen is presented by immature or resting APCs that lack co-stimulatory molecules, Signal 1 is delivered without Signal 2. This renders the T cell anergic - functionally unresponsive even if later stimulated properly. Anergy is a transient, actively maintained state.
Similarly, B cells can become anergic - the transgenic anti-lysozyme model showed B cells with abundant surface IgM that could bind antigen but could not be activated. They "see" the antigen but cannot respond.
- Goldman-Cecil Medicine, p. 354
- Roitt's Essential Immunology, p. 327
2b. Peripheral Clonal Deletion (Activation-Induced Cell Death)
Hyperstimulation of T cells (e.g., by very high antigen doses and high IL-2 concentrations) preferentially activates pro-apoptotic pathways, causing elimination of the responding clone. This is distinct from central thymic deletion.
Activated lymphocytes co-express the death receptor Fas and its ligand (FasL). Fas-FasL engagement triggers apoptosis. Mutations in FAS cause Autoimmune Lymphoproliferative Syndrome (ALPS), characterized by lymphoproliferation and multiple autoantibodies.
- Robbins & Kumar Basic Pathology, p. 176
2c. Suppression by Regulatory T Cells (Tregs)
Tregs are CD4+ T cells (~5-10% of circulating CD4 cells) defined by expression of the master transcription factor FoxP3. They arise in two ways:
- Thymic Tregs (tTregs): Selected in the thymus from potentially self-reactive T cells that bind self-peptide/MHC with high affinity
- Peripheral Tregs (pTregs): Induced in the periphery from naive CD4 T cells, especially at mucosal surfaces
Mechanisms of Treg suppression:
- CTLA-4 competition - Tregs constitutively express CTLA-4, which outcompetes CD28 for B7 ligands on APCs (CTLA-4 has higher affinity for B7). Tregs can physically strip B7 from APC surfaces, depriving conventional T cells of co-stimulation.
- IL-2 sequestration - Tregs constitutively express the high-affinity IL-2Rα chain (CD25), consuming IL-2 and starving naive/activated T cells of this essential growth factor.
- Immunosuppressive cytokines - Tregs secrete IL-10, TGF-β, and IL-35, which suppress TH1 and TH2 effector functions.
Loss-of-function mutations in FOXP3 cause IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked) - a fatal multi-organ autoimmune disease, illustrating the indispensable role of Tregs. Mutations in CTLA4, IL-2Rα, IL-10, or IL-10R also impair Treg function and cause autoimmunity.
- Janeway's Immunobiology 10e, pp. 406-407
- Robbins & Kumar Basic Pathology, p. 175-176
2d. Inhibitory Receptors
Activated T cells express CTLA-4 and PD-1 (programmed cell death 1), both of which suppress ongoing T-cell activation - they function as checkpoints. B cells express FcγRIIB and CD22, which deliver inhibitory signals to prevent B-cell activation.
This is clinically relevant: cancer immunotherapy with anti-PD-1/anti-CTLA-4 checkpoint inhibitors (e.g., nivolumab, ipilimumab) releases this brake and can cause immune-related adverse events (autoimmune side effects).
- Robbins & Kumar Basic Pathology, p. 176
2e. Clonal Ignorance
Some self-reactive lymphocytes remain in the periphery but are functionally unresponsive because the relevant antigen is physically inaccessible (sequestered). Examples include antigens in the eye (aqueous humor), testis, or CNS. If these antigens are released (e.g., after trauma), tolerance may break and autoimmunity can occur (e.g., sympathetic ophthalmia).
- Goldman-Cecil Medicine, p. 354
2f. Tolerance via Lack of T-Cell Help
T cells are more readily tolerized than B cells by circulating self-proteins. A self-reactive B cell may survive but be functionally "helpless" because the T helper cells needed to assist it are already tolerant to that antigen. This operates especially for proteins present at intermediate concentrations (e.g., thyroglobulin tolerizes T cells but not B cells at physiological concentrations).
- Roitt's Essential Immunology, p. 327
Summary Table
| Mechanism | Type | Cell | Key Molecules |
|---|---|---|---|
| Negative selection (clonal deletion) | Central | T and B cells | AIRE, MHC, TCR/BCR |
| Receptor editing | Central | B cells | RAG-1/2, light chain loci |
| Clonal anergy | Peripheral | T and B cells | B7, CD28, costimulation |
| Activation-induced cell death | Peripheral | T cells | Fas, FasL |
| Treg suppression | Peripheral | CD4+ Tregs on T and B | FoxP3, CTLA-4, IL-10, TGF-β, PD-1 |
| Inhibitory receptors | Peripheral | T cells, B cells | PD-1, CTLA-4, FcγRIIB, CD22 |
| Clonal ignorance | Peripheral | T and B cells | Sequestered antigens |
| Lack of T-cell help | Peripheral | B cells | Carrier-hapten tolerance |
Clinical Consequences of Tolerance Failure
| Mechanism Disrupted | Disease |
|---|---|
| AIRE mutations | Autoimmune Polyglandular Syndrome (APS-1) |
| FoxP3 mutations | IPEX syndrome |
| Fas mutations | ALPS (Autoimmune Lymphoproliferative Syndrome) |
| PD-1/CTLA-4 blockade | Drug-induced autoimmunity (cancer therapy side effects) |
| General failure | SLE, rheumatoid arthritis, type 1 diabetes, MS |
Sources:
- Roitt's Essential Immunology (Essentials), pp. 321-329
- Robbins & Kumar Basic Pathology, pp. 174-176
- Janeway's Immunobiology 10e, pp. 406-407
- Goldman-Cecil Medicine, pp. 353-354
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