--- module: 094-01 language: en chapter: 94 title: "Immune Development, Tolerance, Hypersensitivity, and Immunological Methods" module_title: "Lymphocyte development, receptor diversification, central tolerance, and peripheral restraint" source_sha256: f8a9954105d008d33f50f5572645e32bfe8c3ff23aa3dfd2d5a7e1ea0c3ad37c --- # Lymphocyte development and tolerance ## Why tolerance must be active ### Huge receptor repertoire made before exposure ### Random rearrangement makes useless and self-reactive receptors #### Developing lymphocytes undergo selection ### Survivors held by costimulation, anergy, regulatory cells ### Tolerance actively maintained throughout life ## Receptor gene recombination ### Stem cells in marrow give lymphoid progenitors #### B cells in marrow, T precursors to thymus ### V, D, J and constant segments #### Heavy and TCR beta use V, D and J #### Light and TCR alpha use V and J ### RAG1 and RAG2 cut at signal sequences, 12/23 rule ### Non-homologous end joining repairs ends ### Junctional diversity exceeds combinatorial choice #### Hairpin opening, deletion, palindromic and TdT additions ### Out-of-frame rearrangements need checkpoints ## B-cell development ### Heavy chain rearranges first ### Pre-B-cell receptor with surrogate light chain #### Proliferation, allelic exclusion, light-chain rearrangement ### Kappa or lambda light chain forms surface IgM ### Strong self recognition: editing, anergy, deletion ### Mature naive cells coexpress IgM and IgD #### Need BAFF survival signals ### Follicular cells support T-dependent responses ### Marginal-zone and B-1-like cells respond rapidly ## Thymic selection ### Double-negative precursors enter cortex ### TCR beta and pre-T receptor signalling ### Insufficient binding: death by neglect ### Positive selection keeps self-MHC recognisers #### Class I favours CD8, class II favours CD4 #### Creates MHC restriction ### Medulla presents broad self antigens #### AIRE and FEZF2 drive tissue-restricted proteins #### Strong self-reactivity: deletion or regulatory lineage ## Central tolerance defects ### AIRE deficiency: autoimmune polyendocrine syndrome #### Chronic mucocutaneous candidiasis #### Shows dependence on ectopic antigen display ### Thymic selection incomplete, periphery indispensable ### RAG deficiency can cause SCID #### Hypomorphic variants: oligoclonal cells, autoimmunity ### Artemis defects add radiation sensitivity ### Fetal repertoires have less junctional diversity ## Peripheral T-cell restraint ### No CD28 costimulation: anergy, apoptosis, regulation ### Inflammation licenses dendritic cells #### Infection near self antigens gives bystander signals ### Anergy: durable hyporesponsive state ### Deletion after repeated or strong self recognition ### Limited survival cytokines constrain clone size ### Regulatory T cells: CD4, high CD25, FOXP3 #### Consume IL-2, CTLA4, IL-10, TGF-beta #### FOXP3 deficiency causes IPEX #### Quantity alone does not prove function ### CTLA4 competes with CD28 for B7 ### PD1 recruits inhibitory phosphatases #### Blockade causes organ-specific inflammation ## B-cell and clearance restraint ### Autoreactive B cells silent without T-cell help ### TLR signals or poor nuclear clearance bypass restraint ### Complement and Fc receptors clear debris #### Early classical deficiency: lupus-like disease ### Necrosis or infection exposes cryptic epitopes ## Breaking tolerance ### Immune privilege is relative #### Barriers, limited drainage, inhibitory ligands #### Injury releases sequestered antigens ### Molecular mimicry: microbial and self cross-react ### Epitope spreading to neighbouring determinants ### Bystander activation without cross-reactivity ### Genes plus environmental and stochastic events #### HLA alleles shape peptide presentation #### Autoantibody may precede disease, not sufficient ## Tolerance as trade-off and across life ### Stringent deletion would leave pathogen gaps ### Autoimmunity is a predictable cost of diversity ### Ageing reduces naive output, raises inflammation ### Pregnancy shows context-specific tolerance #### Decidual regulatory cells, trophoblast HLA, uterine NK ### Phenotype reveals the failed checkpoint