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IMF-094-01-0001-en	Why must developing lymphocytes undergo selection before joining the mature repertoire?	Random gene rearrangement inevitably creates nonfunctional and self-reactive receptors, so cells must be tested for function and danger before release.	Integrated Medical Foundations; chapter 94, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: f8a9954105d008d33f50f5572645e32bfe8c3ff23aa3dfd2d5a7e1ea0c3ad37c; editorial review pending	imf lang::en chapter::094 module::094-01 review::pending
IMF-094-01-0002-en	How do RAG1/RAG2 and non-homologous end joining divide the work of antigen-receptor gene recombination?	RAG1 and RAG2 cut at recombination-signal sequences obeying the 12/23 rule, and non-homologous end joining then repairs the selected ends.	Integrated Medical Foundations; chapter 94, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: f8a9954105d008d33f50f5572645e32bfe8c3ff23aa3dfd2d5a7e1ea0c3ad37c; editorial review pending	imf lang::en chapter::094 module::094-01 review::pending
IMF-094-01-0003-en	Why does junctional diversity add more variety than segment choice, and why does it make checkpoints necessary?	Hairpin opening, nucleotide deletion, palindromic additions and TdT additions alter coding junctions, but many rearrangements end out of frame, so development needs repeated attempts and checkpoints.	Integrated Medical Foundations; chapter 94, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: f8a9954105d008d33f50f5572645e32bfe8c3ff23aa3dfd2d5a7e1ea0c3ad37c; editorial review pending	imf lang::en chapter::094 module::094-01 review::pending
IMF-094-01-0004-en	What does pre-B-cell receptor signalling accomplish once a productive mu heavy chain forms?	The mu chain pairs with surrogate light chain, and the signal drives proliferation, heavy-chain allelic exclusion and then light-chain rearrangement.	Integrated Medical Foundations; chapter 94, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: f8a9954105d008d33f50f5572645e32bfe8c3ff23aa3dfd2d5a7e1ea0c3ad37c; editorial review pending	imf lang::en chapter::094 module::094-01 review::pending
IMF-094-01-0005-en	What three fates can an immature B cell take if its receptor strongly recognises self?	It can rearrange its light chain again through receptor editing, become anergic, or be deleted.	Integrated Medical Foundations; chapter 94, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: f8a9954105d008d33f50f5572645e32bfe8c3ff23aa3dfd2d5a7e1ea0c3ad37c; editorial review pending	imf lang::en chapter::094 module::094-01 review::pending
IMF-094-01-0006-en	How do follicular B cells differ from marginal-zone and B-1-like cells in role and repertoire?	Follicular B cells recirculate and support T-dependent responses, whereas marginal-zone and B-1-like cells respond rapidly to blood-borne or repetitive antigens with more restricted repertoires.	Integrated Medical Foundations; chapter 94, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: f8a9954105d008d33f50f5572645e32bfe8c3ff23aa3dfd2d5a7e1ea0c3ad37c; editorial review pending	imf lang::en chapter::094 module::094-01 review::pending
IMF-094-01-0007-en	What happens to double-positive thymocytes that cannot bind self peptide-MHC on cortical thymic epithelium sufficiently?	They die by neglect, because survival in the cortex requires adequate recognition of self peptide-MHC complexes.	Integrated Medical Foundations; chapter 94, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: f8a9954105d008d33f50f5572645e32bfe8c3ff23aa3dfd2d5a7e1ea0c3ad37c; editorial review pending	imf lang::en chapter::094 module::094-01 review::pending
IMF-094-01-0008-en	How does positive selection create MHC restriction and set CD4 versus CD8 lineage?	It preserves cells that recognise self MHC, so mature T cells see foreign peptide only on inherited self molecules; class I recognition favours CD8 and class II favours CD4.	Integrated Medical Foundations; chapter 94, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: f8a9954105d008d33f50f5572645e32bfe8c3ff23aa3dfd2d5a7e1ea0c3ad37c; editorial review pending	imf lang::en chapter::094 module::094-01 review::pending
IMF-094-01-0009-en	Why do AIRE and FEZF2 matter for deleting thymocytes reactive to pancreatic or endocrine proteins?	They drive medullary expression of tissue-restricted proteins, exposing thymocytes to antigens normally found elsewhere so strongly self-reactive cells can be deleted or diverted into the regulatory lineage.	Integrated Medical Foundations; chapter 94, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: f8a9954105d008d33f50f5572645e32bfe8c3ff23aa3dfd2d5a7e1ea0c3ad37c; editorial review pending	imf lang::en chapter::094 module::094-01 review::pending
IMF-094-01-0010-en	What does autoimmune polyendocrine syndrome from AIRE deficiency teach, and why are peripheral mechanisms still indispensable?	Central tolerance depends on ectopic self-antigen display; even when intact, not every self epitope is shown at the right concentration or modification, so thymic selection is incomplete.	Integrated Medical Foundations; chapter 94, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: f8a9954105d008d33f50f5572645e32bfe8c3ff23aa3dfd2d5a7e1ea0c3ad37c; editorial review pending	imf lang::en chapter::094 module::094-01 review::pending
IMF-094-01-0011-en	Why can hypomorphic RAG variants cause autoimmunity while complete RAG deficiency causes severe combined immunodeficiency?	Loss of recombination blocks both B and T cells, whereas partial activity permits limited oligoclonal cells that can be accompanied by autoimmunity.	Integrated Medical Foundations; chapter 94, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: f8a9954105d008d33f50f5572645e32bfe8c3ff23aa3dfd2d5a7e1ea0c3ad37c; editorial review pending	imf lang::en chapter::094 module::094-01 review::pending
IMF-094-01-0012-en	Why does antigen recognition by a naive T cell in resting tissue usually fail to cause activation, and when can this safeguard fail?	Without CD28 costimulation the cell becomes anergic, dies or turns regulatory, but infection near self antigens can supply bystander signals.	Integrated Medical Foundations; chapter 94, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: f8a9954105d008d33f50f5572645e32bfe8c3ff23aa3dfd2d5a7e1ea0c3ad37c; editorial review pending	imf lang::en chapter::094 module::094-01 review::pending
IMF-094-01-0013-en	What distinguishes anergy from clonal deletion as peripheral T-cell tolerance?	Anergy is a durable hyporesponsive state from unbalanced signalling, altered transcription, metabolic restriction and inhibitory molecules; deletion removes the cell by apoptosis after repeated or strong self recognition.	Integrated Medical Foundations; chapter 94, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: f8a9954105d008d33f50f5572645e32bfe8c3ff23aa3dfd2d5a7e1ea0c3ad37c; editorial review pending	imf lang::en chapter::094 module::094-01 review::pending
IMF-094-01-0014-en	By what mechanisms do FOXP3 regulatory T cells suppress other responses?	They consume interleukin 2, express CTLA4, produce interleukin 10 and TGF-beta, and modify antigen-presenting cells.	Integrated Medical Foundations; chapter 94, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: f8a9954105d008d33f50f5572645e32bfe8c3ff23aa3dfd2d5a7e1ea0c3ad37c; editorial review pending	imf lang::en chapter::094 module::094-01 review::pending
IMF-094-01-0015-en	Why does a normal regulatory T-cell count not prove that regulation is working?	Function also depends on stability, tissue homing, antigen specificity and the inflammatory environment, not quantity alone.	Integrated Medical Foundations; chapter 94, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: f8a9954105d008d33f50f5572645e32bfe8c3ff23aa3dfd2d5a7e1ea0c3ad37c; editorial review pending	imf lang::en chapter::094 module::094-01 review::pending
IMF-094-01-0016-en	How do CTLA4 and PD1 restrain T cells by different mechanisms?	CTLA4 outcompetes CD28 for B7 ligands with high affinity and strips them from antigen-presenting cells; PD1 recruits inhibitory phosphatases when engaged by ligands in tissues and chronic inflammation.	Integrated Medical Foundations; chapter 94, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: f8a9954105d008d33f50f5572645e32bfe8c3ff23aa3dfd2d5a7e1ea0c3ad37c; editorial review pending	imf lang::en chapter::094 module::094-01 review::pending
IMF-094-01-0017-en	What do germline checkpoint insufficiency and therapeutic checkpoint blockade have in common clinically?	Both remove restraint on activation: germline insufficiency can cause lymphoproliferation and autoimmunity, and blockade can cause organ-specific inflammatory toxicities.	Integrated Medical Foundations; chapter 94, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: f8a9954105d008d33f50f5572645e32bfe8c3ff23aa3dfd2d5a7e1ea0c3ad37c; editorial review pending	imf lang::en chapter::094 module::094-01 review::pending
IMF-094-01-0018-en	Why can autoreactive B cells survive yet remain harmless, and what bypasses this restraint?	They stay silent without cognate T-cell help; Toll-like-receptor activation or defective clearance of nuclear material can bypass this, especially for receptors binding DNA- or RNA-containing complexes.	Integrated Medical Foundations; chapter 94, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: f8a9954105d008d33f50f5572645e32bfe8c3ff23aa3dfd2d5a7e1ea0c3ad37c; editorial review pending	imf lang::en chapter::094 module::094-01 review::pending
IMF-094-01-0019-en	Why do early classical complement deficiencies predispose to lupus-like disease?	Apoptotic debris and immune complexes are cleared less well, so debris persists and B-cell handling of self material changes.	Integrated Medical Foundations; chapter 94, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: f8a9954105d008d33f50f5572645e32bfe8c3ff23aa3dfd2d5a7e1ea0c3ad37c; editorial review pending	imf lang::en chapter::094 module::094-01 review::pending
IMF-094-01-0020-en	Why is immune privilege in the eye, brain, testis and placenta described as relative rather than absolute?	Barriers, limited lymphatic drainage and local inhibitory signals only limit inflammation; injury can release sequestered antigens and infection can trigger lasting immune access.	Integrated Medical Foundations; chapter 94, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: f8a9954105d008d33f50f5572645e32bfe8c3ff23aa3dfd2d5a7e1ea0c3ad37c; editorial review pending	imf lang::en chapter::094 module::094-01 review::pending
IMF-094-01-0021-en	What distinguishes molecular mimicry, epitope spreading and bystander activation as routes to lost tolerance?	Mimicry is cross-reaction between microbial and self epitopes; spreading extends a response to neighbouring determinants during tissue damage; bystander activation supplies cytokines and costimulation without receptor cross-reactivity.	Integrated Medical Foundations; chapter 94, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: f8a9954105d008d33f50f5572645e32bfe8c3ff23aa3dfd2d5a7e1ea0c3ad37c; editorial review pending	imf lang::en chapter::094 module::094-01 review::pending
IMF-094-01-0022-en	An autoantibody is found years before any disease. Why does that not mean it causes the disease by itself?	Autoimmunity usually needs genetic susceptibility plus environmental and stochastic events, so an autoantibody can precede disease without being sufficient.	Integrated Medical Foundations; chapter 94, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: f8a9954105d008d33f50f5572645e32bfe8c3ff23aa3dfd2d5a7e1ea0c3ad37c; editorial review pending	imf lang::en chapter::094 module::094-01 review::pending
IMF-094-01-0023-en	Why is autoimmunity described as a predictable cost of a diverse repertoire rather than a simple failure to identify self?	Stringent deletion would leave gaps in pathogen recognition, so some self-reactive clones are kept because weak self recognition supports survival or their receptors also see microbes.	Integrated Medical Foundations; chapter 94, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: f8a9954105d008d33f50f5572645e32bfe8c3ff23aa3dfd2d5a7e1ea0c3ad37c; editorial review pending	imf lang::en chapter::094 module::094-01 review::pending
IMF-094-01-0024-en	How does pregnancy illustrate context-specific rather than global tolerance?	Maternal antimicrobial defence is preserved while decidual regulatory cells, trophoblast HLA expression, uterine NK cells and local metabolic signals limit destructive responses at the interface.	Integrated Medical Foundations; chapter 94, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: f8a9954105d008d33f50f5572645e32bfe8c3ff23aa3dfd2d5a7e1ea0c3ad37c; editorial review pending	imf lang::en chapter::094 module::094-01 review::pending