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