Structural and Functional Thymic Biomarkers Are Involved in the Pathogenesis of Thymic Epithelial Tumors: An Overview
Abstract
:1. Introduction
2. A Short Overview of Thymic Development and Cellular Types
3. Immunodeficiency as a Clue to Understanding Thymic Development and Functions
4. Selected Developmental and Functional Genes in the Thymus
4.1. On the Role of Foxn1
4.2. CD205 Is Foxn1-Related
4.3. Notch1
4.4. Keratins: Not Only Structural Components of TEC
4.5. AIRE
4.6. Compartment Specific Antibodies
4.7. Thymic Tuft Cells and POU2F3
5. On the Role of Developmental and Functional Genes in Thymic Epithelial Tumors (TET)
5.1. Foxn1 and CD205 in TET
5.2. Notch
5.3. Keratins
5.4. AIRE
5.5. Compartment-Specific Antibodies
5.6. A TUFT Cell Signature in TET?
6. Targeted Therapies in TET: A Short Overview of Current Available Experimental and Clinical Data and of Perspectives Advances
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Biomarker | Foxn1 Foxn1 (gene) | CD205 (Protein) Ly75 (Gene) | Notch1 | Aire Aire (Gene) | β5tProteasome Psmb11 (Gene) | Claudins (in mTEC Cld3/4) | Keratins |
---|---|---|---|---|---|---|---|
Chromosome involved/gene name | In humans: 17q11.2 | Humans: chromosome 2 | Humans: 9q34 | 21q22.3 | In vertebrates: Chrom. 1 and 11; in humans chrom 14 | Cld3/Cld4 on chrom 7q11; Cld5 on chrom22q11 | Different chrom.according to CK |
Mol. biology | forkhead box gene family of TF | integral MB protein belonging to family of C-type multilecitin | TransMB receptor | TF | Multi-subunit protease complex | TransMB protein large family (more than 27 members) | CK5/14: primary CK of basal cells; CK8/18 primary CK of simple epithelium |
Cellular localization by IHC/IF * | Nuclear expression (scattered EC) | Coarse granular cytoplasmic with membranous accentuation | Nuclear expression | Nuclear | cTEC (expression dependent on Foxn1) | TEC scattered in medulla Cld5 in endothelium | All TEC CK19+; CK14+ in subcapsular TEC, mTEC and HCs; CK8/18+ in mTEC and HCs; CK10+ only in HCs |
Target cells/functions | Thymic cTEC and mTEC | Mature cTEC for positive selection of T lymphocytes; DC subpopulations | Regulator of TECP and mTEC fate during fetal thymus development; Notch1 signaling required for T-cell | mTEChigh; eTACs | It produces in cTEC unique Class I binding peptides supporting positive selection of CD8+ cells | Involved in Tight-Junctions(TJ); | CK8/18 and 19 stain cTEC CK5/14 stain mTEC; K5 and K8 stain TEC at the CMJ (By IF *) |
Target genes/cells in thymus | CCL25, CXCL12, Dll4; Psmb11 encoding β5tProteasome | Involved in positive selection of thymocytes in the C; in generation of cTEC and AIRE+ mTEC | Commitment of thymus progenitors; it promotes establishment/expansion of the mTEPC pool | It acts in a multi-molecular complex | Mature cTEC | embryonic Cld3,4hi TEC maintain functional mTEC regeneration; assure lifelong central T cell tolerance | Different TEC subpop. Foxn1 always needed to maintain the 3D-thymic structure. |
Human diseases/mice models | In AR Foxn1 deficit: Nude SCID phenotype. Several MDM with different Foxn1 alleles associated to different phenotypes. | CD205-deficient (Ly75−/−) and Ly75+/− MDM available; moreover isolated CD205 + CD40− TEC formed RTOC consisting of cortical and medullary thymic regions | loss-of-function and gain of function models (Notch loss of function results in mTEC hypoplasia, while its gain of function leads to TEPC maturation arrest) | Autoimm. polyendocrinopathy candidiasis ectodermal dysplasia (APECED; later APS1) | β5t-deficient mice displayed an altered TCR repertoire, and were functionally defective in IR; PSMB11 polymorphisms altered the CD8 T cell repertoire | Knockout models; “Cld-pathies” associated to some members of the family; some cancers | MDM: Examples: Rac1 deleted K14+ embryonic cells showed failure in thymic organogenesis; Rac1 deleted post-natal K14 + TEC showed thymic atrophy |
Experimental and/or clinical findings | In Homoz. Mutations congenital universal alopecia, nail dystrophy; severe T-cell ID; life-threatening infections; thymic aplasia | CD205-targeted Ag administration resulted in successful vaccination against HIV gag-antigens and cancer antigens in MDM | Extrathymic disease: Multiple human disorders: developmental syndromes and adult onset diseases | Genetically engineered Aire deficient mice show severe autoimm disease manifestations | PSMB11 polymorphisms associated with a higher risk of an AID in humans (Sjögren’s disease); SNV in human β5t gene caused no severe health problems in homozygous individuals | Cld3/4 were found highly upregulated in multiple cancers and possible target of therapies; Cld3/4 are surface receptors for Clostridium perfringens enterotoxin in gut | In the K5CrexRac1flox/flox transgenic mouse, most mice showed athymia/few other showed remnants of M-C architecture |
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Gallo, E.; Ramieri, M.T.; Marino, M. Structural and Functional Thymic Biomarkers Are Involved in the Pathogenesis of Thymic Epithelial Tumors: An Overview. Immuno 2022, 2, 408-429. https://doi.org/10.3390/immuno2020025
Gallo E, Ramieri MT, Marino M. Structural and Functional Thymic Biomarkers Are Involved in the Pathogenesis of Thymic Epithelial Tumors: An Overview. Immuno. 2022; 2(2):408-429. https://doi.org/10.3390/immuno2020025
Chicago/Turabian StyleGallo, Enzo, Maria Teresa Ramieri, and Mirella Marino. 2022. "Structural and Functional Thymic Biomarkers Are Involved in the Pathogenesis of Thymic Epithelial Tumors: An Overview" Immuno 2, no. 2: 408-429. https://doi.org/10.3390/immuno2020025