central tolerance

**Definition:** Central tolerance = deletion or inactivation of self-reactive lymphocytes during development in primary (central) lymphoid organs. Contrasts with peripheral tolerance (anergy, Treg suppression, activation-induced cell death, immune privilege) which acts on mature lymphocytes in the periphery.

**T-cell central tolerance (thymus):** - Double-negative (CD4-/CD8-) thymocytes in the cortex rearrange TCR genes (RAG1/2), then become double-positive (CD4+/CD8+). - **Positive selection (cortex):** Cortical epithelial cells present self-peptide on MHC. Thymocytes must bind self-MHC with at least weak affinity; those that fail die by neglect. Determines MHC restriction: MHC II -> CD4+; MHC I -> CD8+. - **Negative selection (corticomedullary junction/medulla):** Medullary thymic epithelial cells (mTECs) and dendritic cells present self-antigens. Thymocytes binding with high affinity undergo apoptosis (involves Bim). Some self-reactive CD4+ cells are diverted to FoxP3+ regulatory T cells (nTregs). - **AIRE (autoimmune regulator):** Transcription factor in mTECs that drives expression of peripheral tissue-specific antigens (e.g., insulin, thyroglobulin) so that T cells reactive to them are deleted. Mutation -> **APS-1 (APECED):** chronic mucocutaneous candidiasis, hypoparathyroidism, adrenal insufficiency (autoimmune polyglandular syndrome type 1). - **FoxP3 mutation** -> IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked), a Treg defect (more a peripheral tolerance defect but a high-yield Treg association).

**B-cell central tolerance (bone marrow):** - Immature B cells expressing surface IgM encounter self-antigens in the bone marrow. - Strong binding to multivalent self-antigen leads to: (1) **receptor editing** (re-rearrangement of the light chain via RAG; first-line response), (2) **clonal deletion** (apoptosis) if editing fails, or (3) **anergy** if binding is weaker/soluble antigen. - Cells that escape are further regulated in the periphery.

**Clinical significance:** - Failure of central tolerance contributes to autoimmunity (APS-1; likely contributes to T1DM, MS, and others via polygenic risk, e.g., reduced thymic insulin expression with certain INS VNTR alleles). - Because central tolerance is incomplete (not all self-antigens are expressed in the thymus/bone marrow), peripheral tolerance is needed as a backup. - DiGeorge syndrome (22q11 deletion, thymic hypoplasia) -> T-cell deficiency; abnormal thymic selection may also increase autoimmunity risk. - Thymic selection is a classic exam topic: ~95% or more of thymocytes die in the thymus (by neglect or negative selection).

**High-yield mnemonic:** Positive selection = "Positive for MHC recognition" (cortex); Negative selection = "Negative for self-reactivity" (medulla). Central = "Control the generation" (thymus/marrow); Peripheral = "Policing the mature cells."