Paper I
Question
Immunological tolerance
Answer
Immunological tolerance is the state of specific unresponsiveness of the immune system towards a particular antigen — most importantly, towards the body’s own (self) antigens — achieved through active mechanisms that eliminate or inactivate self-reactive lymphocytes, preventing autoimmune disease.
Central tolerance: occurs during lymphocyte development in the primary lymphoid organs.
- T cells (thymus): developing T cells undergo negative selection — thymocytes whose T-cell receptors bind self-peptide-MHC complexes with high affinity are induced to undergo apoptosis (clonal deletion); the AIRE gene promotes expression of a wide range of tissue-specific self-antigens in the thymus to allow this screening.
- B cells (bone marrow): self-reactive B cells encountering self-antigen during development undergo clonal deletion, or receptor editing (rearranging their light-chain genes to produce a new, non-self-reactive receptor).
Peripheral tolerance: mechanisms controlling self-reactive lymphocytes that escape central tolerance and enter the periphery.
- Anergy — functional inactivation of a lymphocyte that recognizes antigen without adequate co-stimulation (the “second signal,” e.g., CD28-B7 interaction for T cells), rendering it unresponsive on subsequent encounter.
- Regulatory T cells (Tregs) — a specialized CD4+CD25+FoxP3+ T-cell subset that actively suppresses the activation of other self-reactive lymphocytes.
- Clonal deletion (peripheral) — activation-induced cell death of self-reactive lymphocytes on repeated/excessive antigen encounter.
- Immune ignorance — self-antigens sequestered in immunologically privileged sites (e.g., eye, testis, CNS) that lymphocytes never physically encounter under normal conditions.
Clinical significance: breakdown of self-tolerance underlies autoimmune disease; understanding tolerance mechanisms is also central to preventing graft rejection and to developing antigen-specific immunotherapies.