{"id":"ba9c7cea-fc49-5e19-a630-5a031c1d5f0f","stable_key":"availability:immune-redox-and-survival:1","predicate":"can_change","statement":"Selenium status can alter immune redox tone in a context-dependent manner.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"source_reported: Predominantly cell/animal; heterogeneous human observations and intervention findings are separate evidence categories.","direction":"context_dependent","is_public":true,"mechanism_event_id":"e117b167-7144-5bbc-87fc-4964b1511a37","mechanism_event_label":"Selenium status can alter immune redox tone in a context-dependent manner.","subject":{"id":"dc89d7e2-8f89-577b-838f-42bf5d8ec7c8","slug":"selenium","display_name":"Selenium","entity_type_key":"nutrient_element"},"object":{"id":"dae68856-224d-5be4-b643-4b7fecbb4a80","slug":"immune-redox-control","display_name":"Immune-cell redox control","entity_type_key":"cellular_process"},"evidence_count":2,"mechanism_event":{"id":"e117b167-7144-5bbc-87fc-4964b1511a37","stable_key":"availability:immune-redox-and-survival:1","event_type":"availability_dependent_change","label":"Selenium status can alter immune redox tone in a context-dependent manner.","description":"Selenium status changes in an immune context; GPX4 perturbation studies test specific downstream defenses. Much of the detailed mechanism comes from cell and animal models; human immune findings are heterogeneous.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"dc89d7e2-8f89-577b-838f-42bf5d8ec7c8","slug":"selenium","display_name":"Selenium","entity_type_key":"nutrient_element"},"role":"condition_input","stoichiometry":null,"state_label":"Selenium status changes in an immune context; GPX4 perturbation studies test specific downstream defenses.","sequence_order":0,"notes":""},{"entity":{"id":"dae68856-224d-5be4-b643-4b7fecbb4a80","slug":"immune-redox-control","display_name":"Immune-cell redox control","entity_type_key":"cellular_process"},"role":"affected_component","stoichiometry":null,"state_label":"Selenium status changes in an immune context; GPX4 perturbation studies test specific downstream defenses.","sequence_order":1,"notes":""}]},"contexts":[{"dimension":"availability_state","value_text":"Selenium status changes in an immune context; GPX4 perturbation studies test specific downstream defenses.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_scope","value_text":"Much of the detailed mechanism comes from cell and animal models; human immune findings are heterogeneous.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"A GPX4 knockout does not specify the response to dietary restriction. No single immune cascade explains every supplementation result, and no clinical immunity cutoff is inferred.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"trigger_kind","value_text":"nutrient_deficiency","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"91455f81-d0ce-53d1-8364-66af4c4bdce7","evidence_kind":"source_passage","locator":"lines 348-350","start_line":348,"end_line":350,"excerpt":"4.3 Immune system\n\nMuch of the detailed cell-by-cell mechanism comes from animal and cell models. These findings are biologically important but should not be converted directly into plasma cutoffs or guaranteed clinical outcomes.","model_system":"Supplied reference; verify the primary study and experimental context.","directness":"reported_statement","verification_status":"source_derived_draft","notes":"","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"c788c19c-884c-5233-92b1-0bd063d87741","stable_key":"deficiency","title":"Selenium deficiency: a mechanism-first reference","document_type":"user_supplied_reference","citation_label":"Supplied selenium deficiency reference","file_path":"X:\\metabolic-ledger\\source_material\\selenium-deficiency-reference.md","sha256":"a3f14bc3fa24c595dda830664523090a7b5bfa76e9dcf517f42f62212ceb767e","revision_id":"f8f97804-c1fb-56df-9c06-c02e36e2a5b8","review_status":"unverified_draft","notes":"Preserved verbatim. Reported study types are source labels, not independent verification."}},{"id":"51069af2-cb26-5d81-8fd9-c73ec2453b4e","evidence_kind":"source_passage","locator":"lines 394-394","start_line":394,"end_line":394,"excerpt":"A useful summary is: selenium status can alter immune redox tone and cell survival, but no single immune-cell cascade explains all reported supplementation effects.","model_system":"Supplied reference; verify the primary study and experimental context.","directness":"reported_statement","verification_status":"source_derived_draft","notes":"","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"c788c19c-884c-5233-92b1-0bd063d87741","stable_key":"deficiency","title":"Selenium deficiency: a mechanism-first reference","document_type":"user_supplied_reference","citation_label":"Supplied selenium deficiency reference","file_path":"X:\\metabolic-ledger\\source_material\\selenium-deficiency-reference.md","sha256":"a3f14bc3fa24c595dda830664523090a7b5bfa76e9dcf517f42f62212ceb767e","revision_id":"f8f97804-c1fb-56df-9c06-c02e36e2a5b8","review_status":"unverified_draft","notes":"Preserved verbatim. Reported study types are source labels, not independent verification."}}],"relations":[],"conflicts":[],"corrections":[{"id":"97c1d4e9-b4c5-5a64-95ce-f9dc60e9d1c0","title":"GPX4 dependence differs between B-cell subsets and Tfh cells","kind":"contradiction","status":"corrected","why":"B-cell-specific deletion preserved measured B2/germinal-center responses while harming B1/MZ; a Tfh phenotype cannot be assigned to germinal-center B cells.","resolution":"Separate lineage-specific findings; do not infer nutritional deletion of an immune compartment in humans.","created_at":"2026-09-17 07:19:34","record_type":"correction","display_label":"Correction history","record_url":"/corrections/97c1d4e9-b4c5-5a64-95ce-f9dc60e9d1c0","literature_review":{"revision_id":"80984e03-5f0f-5877-8094-afef7637444e","start_line":1630,"end_line":1636,"papers":[{"paper_key":"muri-b-2019","title":"B1 and Marginal Zone B Cells but Not Follicular B2 Cells Require Gpx4 to Prevent Lipid Peroxidation and Ferroptosis","url":"https://pubmed.ncbi.nlm.nih.gov/31775041/","doi":"10.1016/j.celrep.2019.10.070","year":2019,"model":"Mouse B-cell-specific Gpx4 deletion","summary":"B1/MZ vulnerable; measured follicular B2 and germinal-center responses preserved."},{"paper_key":"yao-2021","title":"Selenium-GPX4 axis protects follicular helper T cells from ferroptosis","url":"https://www.nature.com/articles/s41590-021-00996-0","doi":"10.1038/s41590-021-00996-0","year":2021,"model":"Mouse T-cell/Tfh experiments and young-adult influenza vaccination study","summary":"Narrow Tfh protection mechanism; use corrected article, author correction DOI 10.1038/s41590-024-01949-z is metadata/FACS correction, not retraction."}]},"sides":[{"conflict_id":"97c1d4e9-b4c5-5a64-95ce-f9dc60e9d1c0","ordinal":0,"label":"Original preserved statement","revision_id":"fbed30e0-1c0d-5b83-8a1f-2867fbe8a5b5","start_line":137,"end_line":137,"quote":"| **Germinal center B**                     | lost → no affinity maturation                                              | vitamin E                            |","claim_id":null,"source_key":"immune","source_title":"Selenium in immune cells","claim_ids":[]},{"conflict_id":"97c1d4e9-b4c5-5a64-95ce-f9dc60e9d1c0","ordinal":1,"label":"Original preserved statement","revision_id":"fbed30e0-1c0d-5b83-8a1f-2867fbe8a5b5","start_line":158,"end_line":158,"quote":"**Selenium deficiency silently deletes an entire arm of innate humoral immunity**, and nothing in a standard immune workup would show it.","claim_id":null,"source_key":"immune","source_title":"Selenium in immune cells","claim_ids":[]},{"conflict_id":"97c1d4e9-b4c5-5a64-95ce-f9dc60e9d1c0","ordinal":2,"label":"Original preserved statement","revision_id":"f8f97804-c1fb-56df-9c06-c02e36e2a5b8","start_line":350,"end_line":394,"quote":"Much of the detailed cell-by-cell mechanism comes from animal and cell models. These findings are biologically important but should not be converted directly into plasma cutoffs or guaranteed clinical outcomes.\n\nImmune component\n\nExperimental finding\n\nEvidence level\n\nT-cell subsets\n\nGPX4-dependent control of lipid peroxidation can affect survival and differentiation\n\nCell/animal\n\nCD8 effector responses\n\nRedox and lipid-peroxidation defenses can affect expansion/function\n\nCell/animal\n\nB-cell compartments\n\nSelenium-dependent redox systems can influence antibody responses\n\nMostly animal; some human supplementation data\n\nNeutrophils\n\nOxidative-burst biology creates high antioxidant demand\n\nCell/animal\n\nNK activity\n\nSelenium status has been associated with altered activity in some studies\n\nHuman/animal, heterogeneous\n\nMacrophage / inflammasome signaling\n\nThioredoxin, TXNIP, lipid peroxide and eicosanoid pathways provide plausible mechanisms\n\nCell/animal\n\nA useful summary is: selenium status can alter immune redox tone and cell survival, but no single immune-cell cascade explains all reported supplementation effects.","claim_id":null,"source_key":"deficiency","source_title":"Selenium deficiency: a mechanism-first reference","claim_ids":[]},{"conflict_id":"97c1d4e9-b4c5-5a64-95ce-f9dc60e9d1c0","ordinal":3,"label":"Literature correction and experimental limits","revision_id":"80984e03-5f0f-5877-8094-afef7637444e","start_line":1630,"end_line":1636,"quote":"## GPX4 dependence differs between B-cell subsets and Tfh cells\n\nB-cell-specific deletion preserved measured B2/germinal-center responses while harming B1/MZ; a Tfh phenotype cannot be assigned to germinal-center B cells.\n\nSeparate lineage-specific findings; do not infer nutritional deletion of an immune compartment in humans.\nPrimary reference: [B1 and Marginal Zone B Cells but Not Follicular B2 Cells Require Gpx4 to Prevent Lipid Peroxidation and Ferroptosis](https://pubmed.ncbi.nlm.nih.gov/31775041/)\nPrimary reference: [Selenium-GPX4 axis protects follicular helper T cells from ferroptosis](https://www.nature.com/articles/s41590-021-00996-0)","claim_id":null,"source_key":"selenium-research-2026-09-17","source_title":"Selenium: literature corrections and mechanism additions","claim_ids":[]}]},{"id":"34f4e373-09c8-5971-b0c3-2fefbfa43b73","title":"GPX4–Tfh protection does not explain every vaccine association","kind":"qualification","status":"qualified","why":"Mouse mechanism and young-adult influenza results do not establish one threshold mediating every vaccine response; IL-2 can oppose Tfh differentiation.","resolution":"Keep candidate mechanism and corrected article; retain later rejection of one cascade and independent IL-2/STAT5/Blimp-1 branch.","created_at":"2026-09-17 07:19:34","record_type":"qualification","display_label":"Source qualification","record_url":"/corrections/34f4e373-09c8-5971-b0c3-2fefbfa43b73","literature_review":{"revision_id":"80984e03-5f0f-5877-8094-afef7637444e","start_line":1638,"end_line":1644,"papers":[{"paper_key":"yao-2021","title":"Selenium-GPX4 axis protects follicular helper T cells from ferroptosis","url":"https://www.nature.com/articles/s41590-021-00996-0","doi":"10.1038/s41590-021-00996-0","year":2021,"model":"Mouse T-cell/Tfh experiments and young-adult influenza vaccination study","summary":"Narrow Tfh protection mechanism; use corrected article, author correction DOI 10.1038/s41590-024-01949-z is metadata/FACS correction, not retraction."},{"paper_key":"johnston-2012-stat5-tfh","title":"STAT5 is a potent negative regulator of TFH cell differentiation","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC3281266/","doi":"10.1084/jem.20111174","year":2012,"model":"Mouse LCMV infection, transferred antigen-specific CD4 cells and genetic perturbations","summary":"Tests IL-2/STAT5 suppression of Tfh differentiation and its dependence on Blimp-1."}]},"sides":[{"conflict_id":"34f4e373-09c8-5971-b0c3-2fefbfa43b73","ordinal":0,"label":"Original preserved statement","revision_id":"fbed30e0-1c0d-5b83-8a1f-2867fbe8a5b5","start_line":152,"end_line":152,"quote":"**Tfh are the selenium-sensitive bottleneck of the humoral response.** Selenium supplementation increases Tfh numbers and antibody titers. Every \"selenium improves antibody response to vaccination\" epidemiology paper is downstream of **one lipid peroxidation threshold in one T cell subset.**","claim_id":null,"source_key":"immune","source_title":"Selenium in immune cells","claim_ids":[]},{"conflict_id":"34f4e373-09c8-5971-b0c3-2fefbfa43b73","ordinal":1,"label":"Original preserved statement","revision_id":"f8f97804-c1fb-56df-9c06-c02e36e2a5b8","start_line":394,"end_line":394,"quote":"A useful summary is: selenium status can alter immune redox tone and cell survival, but no single immune-cell cascade explains all reported supplementation effects.","claim_id":null,"source_key":"deficiency","source_title":"Selenium deficiency: a mechanism-first reference","claim_ids":[]},{"conflict_id":"34f4e373-09c8-5971-b0c3-2fefbfa43b73","ordinal":2,"label":"Literature correction and experimental limits","revision_id":"80984e03-5f0f-5877-8094-afef7637444e","start_line":1638,"end_line":1644,"quote":"## GPX4–Tfh protection does not explain every vaccine association\n\nMouse mechanism and young-adult influenza results do not establish one threshold mediating every vaccine response; IL-2 can oppose Tfh differentiation.\n\nKeep candidate mechanism and corrected article; retain later rejection of one cascade and independent IL-2/STAT5/Blimp-1 branch.\nPrimary reference: [Selenium-GPX4 axis protects follicular helper T cells from ferroptosis](https://www.nature.com/articles/s41590-021-00996-0)\nPrimary reference: [STAT5 is a potent negative regulator of TFH cell differentiation](https://pmc.ncbi.nlm.nih.gov/articles/PMC3281266/)","claim_id":null,"source_key":"selenium-research-2026-09-17","source_title":"Selenium: literature corrections and mechanism additions","claim_ids":[]}]},{"id":"c4c894cb-324f-54d9-8f8d-d82fad4c8442","title":"TXNIP–NLRP3 is not a universal selenium-controlled switch","kind":"context_difference","status":"qualified","why":"TXNIP involvement in one setting coexists with Txnip-independent macrophage IL-1beta requiring Trx1 in another.","resolution":"Record stimulus, lineage and perturbation; do not automatically reverse TrxR1 loss into increased IL-1beta.","created_at":"2026-09-17 07:19:34","record_type":"qualification","display_label":"Source qualification","record_url":"/corrections/c4c894cb-324f-54d9-8f8d-d82fad4c8442","literature_review":{"revision_id":"80984e03-5f0f-5877-8094-afef7637444e","start_line":1646,"end_line":1652,"papers":[{"paper_key":"zhou-2010","title":"Thioredoxin-interacting protein links oxidative stress to inflammasome activation","url":"https://pubmed.ncbi.nlm.nih.gov/20023662/","doi":"10.1038/ni.1831","year":2010,"model":"Cellular and mouse metabolic/oxidative-stress models","summary":"Supports context-specific TXNIP/NLRP3 link."},{"paper_key":"muri-2020","title":"Thioredoxin-1 distinctly promotes NF-kB target DNA binding and NLRP3 inflammasome activation independently of Txnip","url":"https://elifesciences.org/articles/53627","doi":"10.7554/eLife.53627","year":2020,"model":"Mouse macrophage gene perturbation/inflammasome experiments","summary":"Txnip-independent IL-1beta production can require Trx1 control of excessive ROS."}]},"sides":[{"conflict_id":"c4c894cb-324f-54d9-8f8d-d82fad4c8442","ordinal":0,"label":"Original preserved statement","revision_id":"fbed30e0-1c0d-5b83-8a1f-2867fbe8a5b5","start_line":244,"end_line":248,"quote":"TrxR1 (SELENOENZYME) keeps Trx1 reduced → keeps TXNIP sequestered → NLRP3 OFF\n\n```\n\n**Selenium deficiency → oxidized Trx1 → TXNIP released → IL-1β.** One selenoenzyme standing between redox state and the master inflammatory cytokine.","claim_id":null,"source_key":"immune","source_title":"Selenium in immune cells","claim_ids":[]},{"conflict_id":"c4c894cb-324f-54d9-8f8d-d82fad4c8442","ordinal":1,"label":"Original preserved statement","revision_id":"f8f97804-c1fb-56df-9c06-c02e36e2a5b8","start_line":388,"end_line":394,"quote":"Macrophage / inflammasome signaling\n\nThioredoxin, TXNIP, lipid peroxide and eicosanoid pathways provide plausible mechanisms\n\nCell/animal\n\nA useful summary is: selenium status can alter immune redox tone and cell survival, but no single immune-cell cascade explains all reported supplementation effects.","claim_id":null,"source_key":"deficiency","source_title":"Selenium deficiency: a mechanism-first reference","claim_ids":[]},{"conflict_id":"c4c894cb-324f-54d9-8f8d-d82fad4c8442","ordinal":2,"label":"Literature correction and experimental limits","revision_id":"80984e03-5f0f-5877-8094-afef7637444e","start_line":1646,"end_line":1652,"quote":"## TXNIP–NLRP3 is not a universal selenium-controlled switch\n\nTXNIP involvement in one setting coexists with Txnip-independent macrophage IL-1beta requiring Trx1 in another.\n\nRecord stimulus, lineage and perturbation; do not automatically reverse TrxR1 loss into increased IL-1beta.\nPrimary reference: [Thioredoxin-interacting protein links oxidative stress to inflammasome activation](https://pubmed.ncbi.nlm.nih.gov/20023662/)\nPrimary reference: [Thioredoxin-1 distinctly promotes NF-kB target DNA binding and NLRP3 inflammasome activation independently of Txnip](https://elifesciences.org/articles/53627)","claim_id":null,"source_key":"selenium-research-2026-09-17","source_title":"Selenium: literature corrections and mechanism additions","claim_ids":[]}]}],"research":null}