Immunological Tolerance

 Immunological Tolerance

Immune tolerance or immunological tolerance is the process by which the immune system does not attack an antigen. It can be either natural or self-tolerance, in which the body does not mount an immune response to self-antigens, or induced tolerance, in which tolerance to external antigens can be created by manipulating the immune system through the administration of antigen according to certain regimens.

Self-tolerance is the immune system's inability to mount an attack against autologous (host) antigens.  This serves as the critical boundary between self and non-self. When these regulatory checks fail, the immune system targets the body's own tissues, directly causing autoimmune disease.

Induced tolerance is created therapeutically or experimentally to silence harmful immunological reactions against specific antigens while leaving the rest of the immune system fully functional.

Antigens that induce tolerance are called tolerogens. Whether an encounter leads to immunity or tolerance depends on the antigen's structure, concentration, route of entry, co-stimulatory context, and the maturation stage of the encountering lymphocyte.   Immunological tolerance is not failure to recognise an antigen.  It is an active response to a particular epitope and is specific, as an immune response.  Both B cells and T cells can be made tolerant, but T cell tolerance is more important than B cell tolerance because B cells cannot make antibodies to most antigens without the help of T cells.

Immunological Tolerance occurs in three forms: central tolerance, Peripheral tolerance and acquired tolerance.

1. Central Tolerance

Central tolerance occurs during early lymphocyte development within primary lymphoid organs, the thymus for T lymphocytes and the bone marrow for B lymphocytes.

T-Cell Central Tolerance (in Thymus)

• Positive Selection (Cortex) - Immature double-positive (CD4+ CD8+) thymocytes interact with self-peptide–MHC complexes on cortical thymic epithelial cells. Cells with weak-to-moderate affinity receive survival signals and commit to either single-positive CD4+ or CD8+ lineages. Cells with no affinity undergo death by neglect.
• Negative Selection (Medulla) - Single-positive thymocytes interact with medullary thymic epithelial cells and dendritic cells. High-affinity binding to self-antigen–MHC triggers apoptosis (clonal deletion).  antigen-presenting cells in the medulla of the thymus express a gene, AIRE, that encodes a transcription factor that turns on the expression of hundreds of tissue-specific genes encoding various proteins such as insulin, thyroglobulin, and retinal proteins.
• Generation of tTregs: tTreg (Thymus-Derived Regulatory T Cell), is a specialized subset of regulatory T lymphocytes that develops and matures within the thymus to actively enforce immunological self-tolerance.  During negative selection, while clones with excessively high affinity for self-peptide–MHC complexes are deleted by apoptosis, thymocytes that recognize self-antigens with an intermediate-to-high affinity receive survival and differentiation signals to develop into the regulatory T-cell lineage. Their self-reactivity ensures that they are physically present at the site of self-antigens, where their inhibitory machinery neutralizes any conventional autoreactive T cells that escaped clonal deletion.

B-Cell Central Tolerance (in Bone Marrow)

Immature B cells expressing surface  encounter multivalent self-antigens in the bone marrow stroma. One of four fates follows:

• Receptor Editing: Strong cross-linking of surface  induces re arrangement of autoreactive light chain so that a non-autoreactive antibody results.
• Clonal Deletion: If receptor editing fails to eliminate high-affinity self-reactivity, the cell undergoes apoptotic death.
• Anergy: Exposure to soluble, self-antigens downregulates surface  and uncouples signal transduction, rendering the cell functionally inactive.
• Ignorance: Low-affinity self-antigens are ignored, the cells exit to the periphery without deletion because the antigen is either undetectable or inaccessible.

2. Peripheral Tolerance

Since some self-antigens are absent in primary lymphoid organs, and lower-affinity self-reactive clones escape, central tolerance is incomplete.  So secondary lymphoid tissues and peripheral sites enforce peripheral tolerance. 

B cells with a potential for attacking self can be kept under control by the absence of the T-helper cells.  T-cell tolerance is probably the most important mechanism for maintaining B-cell tolerance.

·       Negative Selection in the Peripheral Immune System - AIRE is also active in some APC in the organs of the peripheral immune system (lymph nodes and spleen). So any potentially autoreactive T cells that failed to be eliminated in the thymus are deleted here.

·       Lack of Costimulation is a primary mechanism of peripheral tolerance that prevents mature, self-reactive T cells from attacking healthy tissues when they encounter self-antigens outside the thymus. T-cell activation strictly requires two signals: Signal 1 (TCR recognition of peptide-MHC) and Signal 2 (co-stimulation via CD28 binding B7 on mature APCs). Lack of co-stimulation leads to prolonged, antigen-specific hypo responsiveness.

·       Failure to Encounter Self Antigens - Some tissues are hidden behind anatomical barriers that keep T cells from reaching them. Examples of such "privileged sites" are Interior of the eye, testes and brain.  Mechanical damage can breach the barrier and an autoimmune reaction follow.

·       Receipt of Death Signals - Some cells of the body express FasL.  Activated T cells always express Fas.  When they encounter these cells, binding of Fas to FasL triggers T cell death by apoptosis.

• Control by Regulatory T Cells - Regulatory T cells, suppresses the activity of other T cells.

3. Induced or acquired tolerance

This is the deliberate manipulation of the immune system to establish antigen-specific unresponsiveness toward external or non-self antigens.

• Acquired tolerance against such allergens - In allergic individuals, the immune system fails to maintain natural tolerance toward harmless environmental antigens (allergens).  There will be hypersensitivity response towards such allergens. Inducing acquired tolerance against such allergens help such individuals.  Inducing Tolerance can be done by allergen immunotherapy or desensitization.  Clinically, tolerance is induced by administering tiny, gradually escalating doses of the allergen over an extended period.
• Transplant Tolerance: Inducing tolerance to allografts allows the transplant to survive long-term without continuous immunosuppressive drugs. This graft tolerance is typically established when donor cells fail to deliver costimulatory second signals to host T cells, and it is maintained by the persistence and survival of donor cells within the recipient.
• Tolerance of the Fetus: The human fetus functions immunologically as an allograft expressing paternal antigens, yet the maternal immune system actively refrains from rejecting it throughout gestation. This is due to anatomical sequestration, absence of costimulatory second signals, enforcement by regulatory t cells, etc.

Factors determining the induction, extent, and duration of tolerance

1. Competence of the immune system - tolerance develops much more readily in animals with immature immune systems (neonates) or in adults whose immune competence has been compromised by irradiation, immunosuppressive drugs, or thoracic duct drainage.

2. Molecular characteristics of the antigen - polymeric or aggregated molecules induce immunity, whereas monomeric or deaggregated forms induce tolerance. Polymeric salmonella adelaide flagellin (104 kda) is highly immunogenic, but its monomeric form (4 kda) is tolerogenic at high doses, and a smaller 1.8 kda fragment induces tolerance even at low doses.  Also, chemical modifications can convert an immunogen into a tolerogen.

3. Dose of the antigen – high concentration of antigen induces tolerance, subimmunogenic amounts administered over prolonged periods induces tolerance.  In general, intermediate doses stimulate an active immune response, whereas both low and high extremes drive tolerance. 

4. Route of administration - intravenous and intraperitoneal dose induce tolerance, mucosal exposure via feeding regularly induce tolerance, subcutaneous route induced active immunity.

5. Persistence of the antigen - sustained tolerance requires the physical persistence and accessibility of the tolerogen to continuously neutralize newly emerging naive t and b cells.

6. Termination of tolerance - the tolerant state is not permanent and gradually wanes over time.

7. Genetic susceptibility - tolerance induction is genetically controlled.  Balb/c mice exhibit genetic resistance to tolerance induction

8. Costimulatory signals -  the lack of signal 2 (cd28 binding to b7 on apcs) determines whether a t cell undergoes anergy/apoptosis or activation.