{"gene":"LTB","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2014,"finding":"T cell-derived lymphotoxin-beta (LTB) is required to maintain the structure and function of fibroblastic reticular cells (FRCs) in the spleen. In nude mice lacking T cells, splenic FRCs showed structural disorder and downregulated CCL19 and CCL21 expression, impairing T cell homing to the spleen. Transfusion of T cells from BALB/c mice restored FRC structure and function, but this rescue was blocked when the LTB receptor was occluded, demonstrating that T cell-derived LTB signals through its receptor on FRCs to maintain their architecture and chemokine output.","method":"T cell transfer into nude mice (T cell-deficient), LTB receptor blockade experiment, measurement of FRC marker (ER-TR7), CCL19/CCL21 expression, and T cell splenic homing assay","journal":"BMC immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean loss-of-function (nude mice) with defined cellular phenotype and receptor blockade rescue experiment, but single lab and single study","pmids":["25266629"],"is_preprint":false}],"current_model":"Lymphotoxin-beta (LTB/TNFSF3), expressed on T lymphocytes, signals through its receptor on splenic fibroblastic reticular cells (FRCs) to maintain FRC structural integrity and chemokine (CCL19/CCL21) expression, thereby supporting T cell homing to the spleen."},"narrative":{"mechanistic_narrative":"Lymphotoxin-beta (LTB) is a T cell-derived signal that maintains the structural and functional integrity of splenic fibroblastic reticular cells (FRCs) to support T cell homing [PMID:25266629]. In T cell-deficient nude mice, splenic FRCs show structural disorder and downregulated CCL19 and CCL21, and adoptive transfer of T cells restores FRC architecture and chemokine output; this rescue depends on LTB signaling through its receptor on FRCs, since receptor blockade abolishes it [PMID:25266629]. Beyond [PMID:25266629], no further mechanistic detail — including the downstream signaling pathway in FRCs — has been characterized in the available corpus.","teleology":[{"year":2014,"claim":"Established that T cells are not merely passengers in the spleen but actively maintain the stromal scaffold, by showing that T cell-derived LTB signals to FRCs to preserve their architecture and chemokine production.","evidence":"Adoptive T cell transfer into nude mice with LTB receptor blockade, scoring FRC marker ER-TR7, CCL19/CCL21 expression, and T cell splenic homing","pmids":["25266629"],"confidence":"Medium","gaps":["Single lab and single study without independent replication","Downstream FRC signaling pathway linking LTB receptor engagement to CCL19/CCL21 expression not defined","Direct biochemical demonstration of LTB binding to its FRC receptor not shown"]},{"year":null,"claim":"The intracellular signaling cascade in FRCs downstream of LTB receptor engagement, and the molecular form/partners of LTB on T cells, remain uncharacterized.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No identification of the FRC receptor or downstream effectors in this corpus","Role of LTB outside the splenic FRC/T cell context not addressed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q06643","full_name":"Lymphotoxin-beta","aliases":["Tumor necrosis factor C","TNF-C","Tumor necrosis factor ligand superfamily member 3"],"length_aa":244,"mass_kda":25.4,"function":"Cytokine that binds to LTBR/TNFRSF3 (PubMed:24248355). May play a specific role in immune response regulation. Provides the membrane anchor for the attachment of the heterotrimeric complex to the cell surface. Isoform 2 is probably non-functional","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q06643/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LTB","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LTB","total_profiled":1310},"omim":[{"mim_id":"610096","title":"T-CELL IMMUNOGLOBULIN AND MUCIN DOMAINS-CONTAINING PROTEIN 4; TIMD4","url":"https://www.omim.org/entry/610096"},{"mim_id":"607358","title":"AUTOIMMUNE REGULATOR; AIRE","url":"https://www.omim.org/entry/607358"},{"mim_id":"604655","title":"MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 14; MAP3K14","url":"https://www.omim.org/entry/604655"},{"mim_id":"604520","title":"TUMOR NECROSIS FACTOR LIGAND SUPERFAMILY, MEMBER 14; TNFSF14","url":"https://www.omim.org/entry/604520"},{"mim_id":"600979","title":"LYMPHOTOXIN B RECEPTOR; LTBR","url":"https://www.omim.org/entry/600979"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Centrosome","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":61.7},{"tissue":"lymphoid tissue","ntpm":220.1}],"url":"https://www.proteinatlas.org/search/LTB"},"hgnc":{"alias_symbol":["p33","TNFSF3"],"prev_symbol":["TNFC"]},"alphafold":{"accession":"Q06643","domains":[{"cath_id":"2.60.120.40","chopping":"88-241","consensus_level":"high","plddt":89.6747,"start":88,"end":241}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q06643","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q06643-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q06643-F1-predicted_aligned_error_v6.png","plddt_mean":77.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LTB","jax_strain_url":"https://www.jax.org/strain/search?query=LTB"},"sequence":{"accession":"Q06643","fasta_url":"https://rest.uniprot.org/uniprotkb/Q06643.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q06643/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q06643"}},"corpus_meta":[{"pmid":"9682399","id":"PMC_9682399","title":"Edible vaccine protects mice against Escherichia coli heat-labile enterotoxin (LT): potatoes expressing a synthetic LT-B gene.","date":"1998","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/9682399","citation_count":217,"is_preprint":false},{"pmid":"29042026","id":"PMC_29042026","title":"Identification, signaling, and functions of LTB4 receptors.","date":"2017","source":"Seminars in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29042026","citation_count":79,"is_preprint":false},{"pmid":"12437079","id":"PMC_12437079","title":"A functional antigen in a practical crop: LT-B producing maize protects mice against Escherichia coli heat labile enterotoxin (LT) and cholera toxin (CT).","date":"2002","source":"Transgenic research","url":"https://pubmed.ncbi.nlm.nih.gov/12437079","citation_count":76,"is_preprint":false},{"pmid":"11257419","id":"PMC_11257419","title":"Oral immunisation of naive and primed animals with transgenic potato tubers expressing LT-B.","date":"2001","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/11257419","citation_count":73,"is_preprint":false},{"pmid":"11600420","id":"PMC_11600420","title":"Effects of IL-8, Gro-alpha, and LTB(4) on the adhesive kinetics of LFA-1 and Mac-1 on human neutrophils.","date":"2001","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/11600420","citation_count":60,"is_preprint":false},{"pmid":"11003605","id":"PMC_11003605","title":"15(S)-HETE modulates LTB(4) production and neutrophil chemotaxis in chronic bronchitis.","date":"2000","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/11003605","citation_count":58,"is_preprint":false},{"pmid":"19958557","id":"PMC_19958557","title":"Recombinant porcine rotavirus VP4 and VP4-LTB expressed in Lactobacillus casei induced mucosal and systemic antibody responses in mice.","date":"2009","source":"BMC microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/19958557","citation_count":45,"is_preprint":false},{"pmid":"16856209","id":"PMC_16856209","title":"Neutrophil recruitment in immunized mice depends on MIP-2 inducing the sequential release of MIP-1alpha, TNF-alpha and LTB(4).","date":"2006","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/16856209","citation_count":43,"is_preprint":false},{"pmid":"23306362","id":"PMC_23306362","title":"Clinical trial to evaluate safety and immunogenicity of an oral inactivated enterotoxigenic Escherichia coli prototype vaccine containing CFA/I overexpressing bacteria and recombinantly produced LTB/CTB hybrid protein.","date":"2013","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/23306362","citation_count":43,"is_preprint":false},{"pmid":"29042029","id":"PMC_29042029","title":"LTB4 and BLT1 in inflammatory arthritis.","date":"2017","source":"Seminars in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29042029","citation_count":42,"is_preprint":false},{"pmid":"27860074","id":"PMC_27860074","title":"Immunogenicity of recombinant Lactobacillus casei-expressing F4 (K88) fimbrial adhesin FaeG in conjunction with a heat-labile enterotoxin A (LTAK63) and heat-labile enterotoxin B (LTB) of enterotoxigenic Escherichia coli as an oral adjuvant in mice.","date":"2016","source":"Journal of applied microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/27860074","citation_count":39,"is_preprint":false},{"pmid":"21447051","id":"PMC_21447051","title":"Plastid expression of a double-pentameric vaccine candidate containing human papillomavirus-16 L1 antigen fused with LTB as adjuvant: transplastomic plants show pleiotropic phenotypes.","date":"2011","source":"Plant biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/21447051","citation_count":39,"is_preprint":false},{"pmid":"19586628","id":"PMC_19586628","title":"Participation of 5-lipoxygenase-derived LTB(4) in 4-hydroxynonenal-enhanced MMP-2 production in vascular smooth muscle cells.","date":"2009","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/19586628","citation_count":38,"is_preprint":false},{"pmid":"8719215","id":"PMC_8719215","title":"A genetic hybrid of the Campylobacter jejuni flaA gene with LT-B of Escherichia coli and assessment of the efficacy of the hybrid protein as an oral chicken vaccine.","date":"1995","source":"Avian diseases","url":"https://pubmed.ncbi.nlm.nih.gov/8719215","citation_count":37,"is_preprint":false},{"pmid":"16464614","id":"PMC_16464614","title":"Improved uptake of plant-derived LTB-linked proteins in carp gut and induction of specific humoral immune responses upon infeed delivery.","date":"2006","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/16464614","citation_count":36,"is_preprint":false},{"pmid":"31666208","id":"PMC_31666208","title":"Eicosanoid pathway on host resistance and inflammation during Mycobacterium tuberculosis infection is comprised by LTB4 reduction but not PGE2 increment.","date":"2019","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/31666208","citation_count":35,"is_preprint":false},{"pmid":"23675482","id":"PMC_23675482","title":"Mucosal and systemic immune responses to Mycobacterium tuberculosis antigen 85A following its co-delivery with CpG, MPLA or LTB to the lungs in mice.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23675482","citation_count":34,"is_preprint":false},{"pmid":"11688989","id":"PMC_11688989","title":"Identification of dual cyclooxygenase-eicosanoid oxidoreductase inhibitors: NSAIDs that inhibit PG-LX reductase/LTB(4) dehydrogenase.","date":"2001","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11688989","citation_count":33,"is_preprint":false},{"pmid":"18475433","id":"PMC_18475433","title":"Cytokine gene regulation by PGE(2), LTB(4) and PAF.","date":"1992","source":"Mediators of inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/18475433","citation_count":33,"is_preprint":false},{"pmid":"28965882","id":"PMC_28965882","title":"The inhibition of 5-Lipoxygenase (5-LO) products leukotriene B4 (LTB4) and cysteinyl leukotrienes (cysLTs) modulates the inflammatory response and improves cutaneous wound healing.","date":"2017","source":"Clinical immunology (Orlando, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/28965882","citation_count":32,"is_preprint":false},{"pmid":"15618162","id":"PMC_15618162","title":"Construction and characterization of bivalent Shigella flexneri 2a vaccine strains SC608(pCFAI) and SC608(pCFAI/LTB) that express antigens from enterotoxigenic Escherichia coli.","date":"2005","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/15618162","citation_count":32,"is_preprint":false},{"pmid":"30158177","id":"PMC_30158177","title":"The LTB4-BLT1 axis regulates the polarized trafficking of chemoattractant GPCRs during neutrophil chemotaxis.","date":"2018","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/30158177","citation_count":29,"is_preprint":false},{"pmid":"24909331","id":"PMC_24909331","title":"Immune responses of a chimaeric protein vaccine containing Mycoplasma hyopneumoniae antigens and LTB against experimental M. hyopneumoniae infection in pigs.","date":"2014","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/24909331","citation_count":29,"is_preprint":false},{"pmid":"33847026","id":"PMC_33847026","title":"Oral multivalent epitope vaccine, based on UreB, HpaA, CAT, and LTB, for prevention and treatment of Helicobacter pylori infection in C57BL / 6 mice.","date":"2021","source":"Helicobacter","url":"https://pubmed.ncbi.nlm.nih.gov/33847026","citation_count":29,"is_preprint":false},{"pmid":"25091529","id":"PMC_25091529","title":"Local and systemic immune responses induced by a recombinant chimeric protein containing Mycoplasma hyopneumoniae antigens fused to the B subunit of Escherichia coli heat-labile enterotoxin LTB.","date":"2014","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/25091529","citation_count":29,"is_preprint":false},{"pmid":"34417262","id":"PMC_34417262","title":"LTB4-Driven Inflammation and Increased Expression of ALOX5/ACE2 During Severe COVID-19 in Individuals With Diabetes.","date":"2021","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/34417262","citation_count":28,"is_preprint":false},{"pmid":"17310334","id":"PMC_17310334","title":"Expression of Escherichia coli heat-labile enterotoxin b subunit (LTB) in carrot (Daucus carota L.).","date":"2007","source":"Plant cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/17310334","citation_count":28,"is_preprint":false},{"pmid":"30676680","id":"PMC_30676680","title":"20-Hydroxy- and 20-carboxy-leukotriene (LT) B4 downregulate LTB4 -mediated responses of human neutrophils and eosinophils.","date":"2019","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/30676680","citation_count":27,"is_preprint":false},{"pmid":"28303931","id":"PMC_28303931","title":"The development of novel LTA4H modulators to selectively target LTB4 generation.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28303931","citation_count":26,"is_preprint":false},{"pmid":"12121145","id":"PMC_12121145","title":"99mTc-Labeling of a hydrazinonicotinamide-conjugated LTB(4) receptor antagonist useful for imaging infection and inflammation.","date":"2002","source":"Bioconjugate chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12121145","citation_count":26,"is_preprint":false},{"pmid":"28811215","id":"PMC_28811215","title":"Molecular mechanisms underlying protection against H9N2 influenza virus challenge in mice by recombinant Lactobacillus plantarum with surface displayed HA2-LTB.","date":"2017","source":"Journal of biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/28811215","citation_count":26,"is_preprint":false},{"pmid":"10430706","id":"PMC_10430706","title":"LTB(4)-induced nasal gland serous cell secretion mediated by neutrophil elastase.","date":"1999","source":"American journal of respiratory and critical care medicine","url":"https://pubmed.ncbi.nlm.nih.gov/10430706","citation_count":24,"is_preprint":false},{"pmid":"28827365","id":"PMC_28827365","title":"Capturing LTA4 hydrolase in action: Insights to the chemistry and dynamics of chemotactic LTB4 synthesis.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28827365","citation_count":23,"is_preprint":false},{"pmid":"22053005","id":"PMC_22053005","title":"Construction of Bifidobacterium infantis as a live oral vaccine that expresses antigens of the major fimbrial subunit (CfaB) and the B subunit of heat-labile enterotoxin (LTB) from enterotoxigenic Escherichia coli.","date":"2011","source":"Microbiology (Reading, England)","url":"https://pubmed.ncbi.nlm.nih.gov/22053005","citation_count":23,"is_preprint":false},{"pmid":"21085949","id":"PMC_21085949","title":"Protection of mice against enterotoxigenic E. coli by immunization with a polyvalent enterotoxin comprising a combination of LTB, STa, and STb.","date":"2010","source":"Applied microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/21085949","citation_count":22,"is_preprint":false},{"pmid":"29696149","id":"PMC_29696149","title":"Anti-Inflammatory Benefits of Antibiotics: Tylvalosin Induces Apoptosis of Porcine Neutrophils and Macrophages, Promotes Efferocytosis, and Inhibits Pro-Inflammatory CXCL-8, IL1α, and LTB4 Production, While Inducing the Release of Pro-Resolving Lipoxin A4 and Resolvin D1.","date":"2018","source":"Frontiers in veterinary science","url":"https://pubmed.ncbi.nlm.nih.gov/29696149","citation_count":21,"is_preprint":false},{"pmid":"7973462","id":"PMC_7973462","title":"Identification of the site of uptake of the E. coli heat-labile enterotoxin, LTB.","date":"1994","source":"Scandinavian journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/7973462","citation_count":21,"is_preprint":false},{"pmid":"27942840","id":"PMC_27942840","title":"Expression of an immunogenic LTB-based chimeric protein targeting Zaire ebolavirus epitopes from GP1 in plant cells.","date":"2016","source":"Plant cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27942840","citation_count":20,"is_preprint":false},{"pmid":"28053185","id":"PMC_28053185","title":"Macrophage LTB4 drives efficient phagocytosis of Borrelia burgdorferi via BLT1 or BLT2.","date":"2017","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/28053185","citation_count":19,"is_preprint":false},{"pmid":"35201443","id":"PMC_35201443","title":"New immunological potential markers for triple negative breast cancer: IL18R1, CD53, TRIM, Jaw1, LTB, PTPRCAP.","date":"2021","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35201443","citation_count":19,"is_preprint":false},{"pmid":"16145550","id":"PMC_16145550","title":"Expression of Escherichia coli heat-labile enterotoxin B subunit (LTB) in Saccharomyces cerevisiae.","date":"2005","source":"Journal of microbiology (Seoul, Korea)","url":"https://pubmed.ncbi.nlm.nih.gov/16145550","citation_count":18,"is_preprint":false},{"pmid":"22843747","id":"PMC_22843747","title":"TAK1 contributes to the enhanced responsiveness of LTB(4)-treated neutrophils to Toll-like receptor ligands.","date":"2012","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/22843747","citation_count":18,"is_preprint":false},{"pmid":"25266629","id":"PMC_25266629","title":"T lymphocytes maintain structure and function of fibroblastic reticular cells via lymphotoxin (LT)-B.","date":"2014","source":"BMC immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25266629","citation_count":18,"is_preprint":false},{"pmid":"29894720","id":"PMC_29894720","title":"LTB4 and PGE2 modulate the release of MIP-1α and IL-1β by cells stimulated with Bothrops snake venoms.","date":"2018","source":"Toxicon : official journal of the International Society on Toxinology","url":"https://pubmed.ncbi.nlm.nih.gov/29894720","citation_count":17,"is_preprint":false},{"pmid":"21318355","id":"PMC_21318355","title":"Immunogenicity of nuclear-encoded LTB:ST fusion protein from Escherichia coli expressed in tobacco plants.","date":"2011","source":"Plant cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/21318355","citation_count":17,"is_preprint":false},{"pmid":"27832917","id":"PMC_27832917","title":"Immune response characterization and vaccine potential of a recombinant chimera comprising B-cell epitope of Aeromonas hydrophila outer membrane protein C and LTB.","date":"2016","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/27832917","citation_count":17,"is_preprint":false},{"pmid":"11606320","id":"PMC_11606320","title":"Pharmacological comparison of LTB(4)-induced NADPH oxidase activation in adherent and non-adherent guinea-pig eosinophils.","date":"2001","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/11606320","citation_count":17,"is_preprint":false},{"pmid":"26724200","id":"PMC_26724200","title":"Recombinant baculovirus vaccine containing multiple M2e and adjuvant LTB induces T cell dependent, cross-clade protection against H5N1 influenza virus in mice.","date":"2015","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/26724200","citation_count":16,"is_preprint":false},{"pmid":"32361084","id":"PMC_32361084","title":"RvE1 uses the LTB4 receptor BLT1 to increase [Ca2+]i and stimulate mucin secretion in cultured rat and human conjunctival goblet cells.","date":"2020","source":"The ocular surface","url":"https://pubmed.ncbi.nlm.nih.gov/32361084","citation_count":15,"is_preprint":false},{"pmid":"31740445","id":"PMC_31740445","title":"LTB4 and 5-oxo-ETE from extracellular vesicles stimulate neutrophils in granulomatosis with polyangiitis.","date":"2019","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/31740445","citation_count":15,"is_preprint":false},{"pmid":"19462253","id":"PMC_19462253","title":"Enhancement of mucosal immune response against the M2eHBc+ antigen in mice with the fusion expression products of LTB and M2eHBc+ through mucosal immunization route.","date":"2009","source":"Veterinary research communications","url":"https://pubmed.ncbi.nlm.nih.gov/19462253","citation_count":15,"is_preprint":false},{"pmid":"30172635","id":"PMC_30172635","title":"Inclusion of membrane-anchored LTB or flagellin protein in H5N1 virus-like particles enhances protective responses following intramuscular and oral immunization of mice.","date":"2018","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/30172635","citation_count":15,"is_preprint":false},{"pmid":"29415034","id":"PMC_29415034","title":"Molecular characterization of the recombinant protein RmLTI-BmCG-LTB: Protective immunity against Rhipicephalus (Boophilus) microplus.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29415034","citation_count":15,"is_preprint":false},{"pmid":"33923272","id":"PMC_33923272","title":"The Kinetics of Lymphatic Dysfunction and Leukocyte Expansion in the Draining Lymph Node during LTB4 Antagonism in a Mouse Model of Lymphedema.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33923272","citation_count":15,"is_preprint":false},{"pmid":"29358130","id":"PMC_29358130","title":"Ononitol monohydrate enhances PRDM16 & UCP-1 expression, mitochondrial biogenesis and insulin sensitivity via STAT6 and LTB4R in maturing adipocytes.","date":"2018","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/29358130","citation_count":14,"is_preprint":false},{"pmid":"31360201","id":"PMC_31360201","title":"Urotensin II promotes secretion of LTB4 through 5-lipoxygenase via the UT-ROS-Akt pathway in RAW264.7 macrophages.","date":"2019","source":"Archives of medical science : AMS","url":"https://pubmed.ncbi.nlm.nih.gov/31360201","citation_count":13,"is_preprint":false},{"pmid":"31843518","id":"PMC_31843518","title":"Using carrot cells as biofactories and oral delivery vehicles of LTB-Syn: A low-cost vaccine candidate against synucleinopathies.","date":"2019","source":"Journal of biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/31843518","citation_count":13,"is_preprint":false},{"pmid":"29354854","id":"PMC_29354854","title":"Immunological features and efficacy of the recombinant subunit vaccine LTB-EMY162 against Echinococcus multilocularis metacestode.","date":"2018","source":"Applied microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/29354854","citation_count":12,"is_preprint":false},{"pmid":"37531900","id":"PMC_37531900","title":"Blocking LTB4 signaling-mediated TAMs recruitment by Rhizoma Coptidis sensitizes lung cancer to immunotherapy.","date":"2023","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37531900","citation_count":12,"is_preprint":false},{"pmid":"27733309","id":"PMC_27733309","title":"Construction and immunogenic properties of a chimeric protein comprising CfaE, CfaB and LTB against Enterotoxigenic Escherichia coli.","date":"2016","source":"Biologicals : journal of the International Association of Biological Standardization","url":"https://pubmed.ncbi.nlm.nih.gov/27733309","citation_count":11,"is_preprint":false},{"pmid":"24389278","id":"PMC_24389278","title":"A CssA, CssB and LTB chimeric protein induces protection against Enterotoxigenic Escherichia coli.","date":"2014","source":"The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases","url":"https://pubmed.ncbi.nlm.nih.gov/24389278","citation_count":11,"is_preprint":false},{"pmid":"15948247","id":"PMC_15948247","title":"Construction of a novel Shigella live-vector strain co-expressing CS3 and LTB/STm of enterotoxigenic E.coli.","date":"2005","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/15948247","citation_count":11,"is_preprint":false},{"pmid":"34153721","id":"PMC_34153721","title":"Immunization with recombinant Erns-LTB fusion protein elicits protective immune responses against bovine viral diarrhea virus.","date":"2021","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34153721","citation_count":10,"is_preprint":false},{"pmid":"18814842","id":"PMC_18814842","title":"Secretory and GM1 receptor binding role of N-terminal region of LTB in Vibrio cholerae.","date":"2008","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/18814842","citation_count":10,"is_preprint":false},{"pmid":"29859938","id":"PMC_29859938","title":"BLT1-mediated O-GlcNAcylation is required for NOX2-dependent migration, exocytotic degranulation and IL-8 release of human mast cell induced by Trichomonas vaginalis-secreted LTB4.","date":"2018","source":"Microbes and infection","url":"https://pubmed.ncbi.nlm.nih.gov/29859938","citation_count":10,"is_preprint":false},{"pmid":"28543534","id":"PMC_28543534","title":"A Chimeric protein of CFA/I, CS6 subunits and LTB/STa toxoid protects immunized mice against enterotoxigenic Escherichia coli.","date":"2017","source":"Microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28543534","citation_count":10,"is_preprint":false},{"pmid":"23040995","id":"PMC_23040995","title":"Nanoparticulated heat-stable (STa) and heat-labile B subunit (LTB) recombinant toxin improves vaccine protection against enterotoxigenic Escherichia coli challenge in mouse.","date":"2012","source":"Journal of bioscience and bioengineering","url":"https://pubmed.ncbi.nlm.nih.gov/23040995","citation_count":10,"is_preprint":false},{"pmid":"21029472","id":"PMC_21029472","title":"A study of the TNF/LTA/LTB locus and susceptibility to severe malaria in highland papuan children and adults.","date":"2010","source":"Malaria journal","url":"https://pubmed.ncbi.nlm.nih.gov/21029472","citation_count":10,"is_preprint":false},{"pmid":"8069576","id":"PMC_8069576","title":"Intestinal tissue distribution and epithelial transport of the oral immunogen LTB, the B subunit of E. coli heat-labile enterotoxin.","date":"1993","source":"Journal of drug targeting","url":"https://pubmed.ncbi.nlm.nih.gov/8069576","citation_count":10,"is_preprint":false},{"pmid":"31010302","id":"PMC_31010302","title":"Bexarotene Exerts Protective Effects Through Modulation of the Cerebral Vascular Smooth Muscle Cell Phenotypic Transformation by Regulating PPARγ/FLAP/LTB4 After Subarachnoid Hemorrhage in Rats.","date":"2019","source":"Cell transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/31010302","citation_count":10,"is_preprint":false},{"pmid":"36298624","id":"PMC_36298624","title":"Production and Purification of LTB-RBD: A Potential Antigen for Mucosal Vaccine Development against SARS-CoV-2.","date":"2022","source":"Vaccines","url":"https://pubmed.ncbi.nlm.nih.gov/36298624","citation_count":9,"is_preprint":false},{"pmid":"35090823","id":"PMC_35090823","title":"Serum levels of novel anti-inflammatory cytokine Interleukin-38 in diabetes patients infected with latent tuberculosis (DM-LTB-3).","date":"2022","source":"Journal of diabetes and its complications","url":"https://pubmed.ncbi.nlm.nih.gov/35090823","citation_count":9,"is_preprint":false},{"pmid":"31057373","id":"PMC_31057373","title":"Paradoxical Effect of LTB4 on the Regulation of Stress-Induced Corticosterone Production.","date":"2019","source":"Frontiers in behavioral neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/31057373","citation_count":9,"is_preprint":false},{"pmid":"35832818","id":"PMC_35832818","title":"Unique Reciprocal Association Seen Between Latent Tuberculosis Infection and Diabetes Is Due to Immunoendocrine Modulation (DM-LTB-1).","date":"2022","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/35832818","citation_count":9,"is_preprint":false},{"pmid":"24750381","id":"PMC_24750381","title":"Chicken egg yolk immunoglobulin (IgY) developed against fusion protein LTB-STa-STb neutralizes the toxicity of Escherichia coli heat-stable enterotoxins.","date":"2014","source":"Journal of applied microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/24750381","citation_count":9,"is_preprint":false},{"pmid":"11311748","id":"PMC_11311748","title":"10-Phenylbutyryl-substituted anthracenones as inhibitors of keratinocyte growth and LTB(4) biosynthesis.","date":"2001","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11311748","citation_count":9,"is_preprint":false},{"pmid":"20722054","id":"PMC_20722054","title":"Blockade of LTB(4) /BLT(1) pathway improves CD8(+) T-cell-mediated colitis.","date":"2010","source":"Inflammatory bowel diseases","url":"https://pubmed.ncbi.nlm.nih.gov/20722054","citation_count":8,"is_preprint":false},{"pmid":"34372508","id":"PMC_34372508","title":"Oral Immunization with Lactobacillus casei Expressing the Porcine Circovirus Type 2 Cap and LTB Induces Mucosal and Systemic Antibody Responses in Mice.","date":"2021","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/34372508","citation_count":8,"is_preprint":false},{"pmid":"20219579","id":"PMC_20219579","title":"Mineral trioxide aggregate stimulates macrophages and mast cells to release neutrophil chemotactic factors: role of IL-1beta, MIP-2 and LTB(4).","date":"2010","source":"Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics","url":"https://pubmed.ncbi.nlm.nih.gov/20219579","citation_count":8,"is_preprint":false},{"pmid":"33159884","id":"PMC_33159884","title":"Leukotriene B4 and Its Receptor in Experimental Autoimmune Uveitis and in Human Retinal Tissues: Clinical Severity and LTB4 Dependence of Retinal Th17 Cells.","date":"2020","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/33159884","citation_count":8,"is_preprint":false},{"pmid":"8873387","id":"PMC_8873387","title":"Construction, purification and immunogenicity of antigen-antibody-LTB complexes.","date":"1996","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/8873387","citation_count":8,"is_preprint":false},{"pmid":"31300915","id":"PMC_31300915","title":"Immunization with recombinant fusion of LTB and linear epitope (40-62) of epsilon toxin elicits protective immune response against the epsilon toxin of Clostridium perfringens type D.","date":"2019","source":"AMB Express","url":"https://pubmed.ncbi.nlm.nih.gov/31300915","citation_count":8,"is_preprint":false},{"pmid":"28315001","id":"PMC_28315001","title":"LTB-Syn: a recombinant immunogen for the development of plant-made vaccines against synucleinopathies.","date":"2017","source":"Planta","url":"https://pubmed.ncbi.nlm.nih.gov/28315001","citation_count":8,"is_preprint":false},{"pmid":"9014300","id":"PMC_9014300","title":"Immunogenicity of a fusion protein linking the beta subunit carboxyl terminal peptide (CTP) of human chorionic gonadotropin to the B subunit of Escherichia coli heat-labile enterotoxin (LTB).","date":"1996","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/9014300","citation_count":8,"is_preprint":false},{"pmid":"34540066","id":"PMC_34540066","title":"Total serum IL-6 and TNF-C levels in children with bronchopneumonia following treatment with methylprednisolone in combination with azithromycin.","date":"2021","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/34540066","citation_count":8,"is_preprint":false},{"pmid":"34918307","id":"PMC_34918307","title":"Establishment of the Carrot-Made LTB-Syn Antigen Cell Line in Shake Flask and Airlift Bioreactor Cultures.","date":"2021","source":"Planta medica","url":"https://pubmed.ncbi.nlm.nih.gov/34918307","citation_count":7,"is_preprint":false},{"pmid":"29922433","id":"PMC_29922433","title":"An LTB-entrapped protein in PLGA nanoparticles preserves against enterotoxin of enterotoxigenic Escherichia coli.","date":"2018","source":"Iranian journal of basic medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29922433","citation_count":7,"is_preprint":false},{"pmid":"15309718","id":"PMC_15309718","title":"Construction of prokaryotic expression system of ltB-ureB fusion gene and identification of the recombinant protein immunity and adjuvanticity.","date":"2004","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/15309718","citation_count":7,"is_preprint":false},{"pmid":"30996830","id":"PMC_30996830","title":"Vaccine potential of LenA and LcpA proteins of Leptospira interrogans in combination with Escherichia coli heat-labile enterotoxin, B subunit (LTB).","date":"2019","source":"Iranian journal of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/30996830","citation_count":7,"is_preprint":false},{"pmid":"9382733","id":"PMC_9382733","title":"Epitope analysis of the CS3 fimbrial subunit of human enterotoxigenic Escherichia coli and the construction of novel CS3::ST and CS3::LT-B immunogens.","date":"1997","source":"Behring Institute Mitteilungen","url":"https://pubmed.ncbi.nlm.nih.gov/9382733","citation_count":7,"is_preprint":false},{"pmid":"12890398","id":"PMC_12890398","title":"Highly efficient expression, purification of recombinant LTB protein and its activity against mucosal immunoadjuvant by nasal immunization.","date":"2003","source":"Chinese medical journal","url":"https://pubmed.ncbi.nlm.nih.gov/12890398","citation_count":6,"is_preprint":false},{"pmid":"40476513","id":"PMC_40476513","title":"Development of an oral gut-targeted rabies virus-like particles (RVLPs) vaccine with mucosal immune adjuvant LTB via delivering of localized-release microparticles.","date":"2025","source":"Emerging microbes & infections","url":"https://pubmed.ncbi.nlm.nih.gov/40476513","citation_count":6,"is_preprint":false},{"pmid":"36940784","id":"PMC_36940784","title":"Immunization effect of recombinant Lactobacillus casei displaying Aeromonas veronii Aha1 with an LTB adjuvant in carp.","date":"2023","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36940784","citation_count":6,"is_preprint":false},{"pmid":"29460309","id":"PMC_29460309","title":"Entrapment of LTB protein in alginate nanoparticles protects against Enterotoxigenic Escherichia coli.","date":"2018","source":"APMIS : acta pathologica, microbiologica, et immunologica Scandinavica","url":"https://pubmed.ncbi.nlm.nih.gov/29460309","citation_count":6,"is_preprint":false},{"pmid":"40199055","id":"PMC_40199055","title":"LTB4 is converted into a potent human neutrophil NADPH oxidase activator via a receptor transactivation mechanism in which the BLT1 receptor activates the free fatty acid receptor 2.","date":"2025","source":"Prostaglandins, leukotrienes, and essential fatty acids","url":"https://pubmed.ncbi.nlm.nih.gov/40199055","citation_count":6,"is_preprint":false},{"pmid":"10685030","id":"PMC_10685030","title":"LTA(4)-derived 5-oxo-eicosatetraenoic acid: pH-dependent formation and interaction with the LTB(4) receptor of human polymorphonuclear leukocytes.","date":"2000","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/10685030","citation_count":6,"is_preprint":false},{"pmid":"36674760","id":"PMC_36674760","title":"Both LTA and LTB Subunits Are Equally Important to Heat-Labile Enterotoxin (LT)-Enhanced Bacterial Adherence.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36674760","citation_count":5,"is_preprint":false},{"pmid":"36319730","id":"PMC_36319730","title":"Blockade of the BLT1-LTB4 axis does not affect mast cell migration towards advanced atherosclerotic lesions in LDLr-/- mice.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/36319730","citation_count":5,"is_preprint":false},{"pmid":"28296951","id":"PMC_28296951","title":"In-silico design, expression, and purification of novel chimeric Escherichia coli O157:H7 OmpA fused to LTB protein in Escherichia coli.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28296951","citation_count":5,"is_preprint":false},{"pmid":"27618897","id":"PMC_27618897","title":"Quantitative Proteomic Analysis of Escherichia coli Heat-Labile Toxin B Subunit (LTB) with Enterovirus 71 (EV71) Subunit VP1.","date":"2016","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/27618897","citation_count":5,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":54207,"output_tokens":874,"usd":0.087865,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6676,"output_tokens":908,"usd":0.02804,"stage2_stop_reason":"end_turn"},"total_usd":0.115905,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify which papers are about the human gene LTB (lymphotoxin beta, TNFSF3/TNFC) versus the E. coli heat-labile enterotoxin B subunit (also abbreviated \"LTB\"). The vast majority of papers (>90) are about the bacterial E. coli LTB, which is a completely different protein. I need to filter carefully.\n\nThe human LTB gene (TNFSF3/TNFC) encodes lymphotoxin-beta, a TNF superfamily member involved in lymphoid organogenesis and lymphocyte biology. Let me identify papers actually about this protein:\n\n- Paper [43]: \"T lymphocytes maintain structure and function of fibroblastic reticular cells via lymphotoxin (LT)-B\" — this is clearly about the human/mammalian LTB (TNFSF3).\n- Paper [68]: \"A study of the TNF/LTA/LTB locus and susceptibility to severe malaria\" — this is a genetic association study, no mechanistic experiment.\n- Papers [2], [5], [6], [8], [10], [13], [16], [18], [19], [20], [22], [26], [28], [29], [32], [33], [36], [39], [42], [44], [47], [49], [50], [54], [56], [59], [65], [73], [77], [79], [80], [95], [96], [97], [98] — these are all about leukotriene B4 (LTB4), a lipid mediator, NOT the protein LTB/TNFSF3.\n- All remaining papers are about E. coli LT-B subunit vaccine work.\n\nOnly paper [43] describes mechanistic findings about the canonical human LTB (lymphotoxin-beta/TNFSF3) protein.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"T cell-derived lymphotoxin-beta (LTB) is required to maintain the structure and function of fibroblastic reticular cells (FRCs) in the spleen. In nude mice lacking T cells, splenic FRCs showed structural disorder and downregulated CCL19 and CCL21 expression, impairing T cell homing to the spleen. Transfusion of T cells from BALB/c mice restored FRC structure and function, but this rescue was blocked when the LTB receptor was occluded, demonstrating that T cell-derived LTB signals through its receptor on FRCs to maintain their architecture and chemokine output.\",\n      \"method\": \"T cell transfer into nude mice (T cell-deficient), LTB receptor blockade experiment, measurement of FRC marker (ER-TR7), CCL19/CCL21 expression, and T cell splenic homing assay\",\n      \"journal\": \"BMC immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean loss-of-function (nude mice) with defined cellular phenotype and receptor blockade rescue experiment, but single lab and single study\",\n      \"pmids\": [\"25266629\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Lymphotoxin-beta (LTB/TNFSF3), expressed on T lymphocytes, signals through its receptor on splenic fibroblastic reticular cells (FRCs) to maintain FRC structural integrity and chemokine (CCL19/CCL21) expression, thereby supporting T cell homing to the spleen.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Lymphotoxin-beta (LTB) is a T cell-derived signal that maintains the structural and functional integrity of splenic fibroblastic reticular cells (FRCs) to support T cell homing [#0]. In T cell-deficient nude mice, splenic FRCs show structural disorder and downregulated CCL19 and CCL21, and adoptive transfer of T cells restores FRC architecture and chemokine output; this rescue depends on LTB signaling through its receptor on FRCs, since receptor blockade abolishes it [#0]. Beyond [#0], no further mechanistic detail — including the downstream signaling pathway in FRCs — has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established that T cells are not merely passengers in the spleen but actively maintain the stromal scaffold, by showing that T cell-derived LTB signals to FRCs to preserve their architecture and chemokine production.\",\n      \"evidence\": \"Adoptive T cell transfer into nude mice with LTB receptor blockade, scoring FRC marker ER-TR7, CCL19/CCL21 expression, and T cell splenic homing\",\n      \"pmids\": [\"25266629\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab and single study without independent replication\",\n        \"Downstream FRC signaling pathway linking LTB receptor engagement to CCL19/CCL21 expression not defined\",\n        \"Direct biochemical demonstration of LTB binding to its FRC receptor not shown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The intracellular signaling cascade in FRCs downstream of LTB receptor engagement, and the molecular form/partners of LTB on T cells, remain uncharacterized.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No identification of the FRC receptor or downstream effectors in this corpus\",\n        \"Role of LTB outside the splenic FRC/T cell context not addressed\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}