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Polymorphic variants of LIGHT (TNF superfamily-14) alter receptor avidity and bioavailability

(2010) JOURNAL OF IMMUNOLOGY. 185(3). p.1949-1958
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Abstract
The TNF superfamily member homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed by T lymphocytes (LIGHT) [ TNF superfamily (SF)-14], is a key cytokine that activates T cells and dendritic cells and is implicated as a mediator of inflammatory, metabolic, and malignant diseases. LIGHT engages the lymphotoxin-beta receptor (LT beta R) and HVEM (TNFRSF14), but is competitively limited in activating these receptors by soluble decoy receptor-3 (DcR3; TNFRSF6B). Two variants in the human LIGHT alter the protein at E214K (rs344560) in the receptor-binding domain and S32L (rs2291667) in the cytosolic domain; however, the functional impact of these polymorphisms is unknown. A neutralizing Ab failed to bind the LIGHT-214K variant, indicating this position as a part of the receptor-binding region. Relative to the predominant reference variant S32/E214, the other variants showed altered avidity with LT beta R and less with HVEM. Heterotrimers of the LIGHT variants decreased binding avidity to DcR3 and minimized the inhibitory effect of DcR3 toward LT beta R-induced activation of NF-kappa B. In patients with immune-mediated inflammatory diseases, such as rheumatoid arthritis, DcR3 protein levels were significantly elevated. Immunohistochemistry revealed synoviocytes as a significant source of DcR3 production, and DcR3 hyperexpression is controlled by posttranscriptional mechanisms. The increased potential for LT beta R signaling, coupled with increased bioavailability due to lower DcR3 avidity, provides a mechanism of how polymorphic variants in LIGHT could contribute to the pathogenesis of inflammatory diseases.
Keywords
T-CELL-ACTIVATION, LYMPHOTOXIN-BETA-RECEPTOR, HERPESVIRUS ENTRY MEDIATOR, SYSTEMIC-LUPUS-ERYTHEMATOSUS, DECOY RECEPTOR-3, HEPATOCELLULAR-CARCINOMA, RHEUMATOID-ARTHRITIS, EXPRESSION, LYMPHOCYTE-ACTIVATION, APOPTOSIS

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Chicago
Cheung, Timothy C, Ken Coppieters, Hideki Sanjo, Lisa M Oborne, Paula S Norris, Amy Coddington, Steven W Granger, Dirk Elewaut, and Carl F Ware. 2010. “Polymorphic Variants of LIGHT (TNF Superfamily-14) Alter Receptor Avidity and Bioavailability.” Journal of Immunology 185 (3): 1949–1958.
APA
Cheung, T. C., Coppieters, K., Sanjo, H., Oborne, L. M., Norris, P. S., Coddington, A., Granger, S. W., et al. (2010). Polymorphic variants of LIGHT (TNF superfamily-14) alter receptor avidity and bioavailability. JOURNAL OF IMMUNOLOGY, 185(3), 1949–1958.
Vancouver
1.
Cheung TC, Coppieters K, Sanjo H, Oborne LM, Norris PS, Coddington A, et al. Polymorphic variants of LIGHT (TNF superfamily-14) alter receptor avidity and bioavailability. JOURNAL OF IMMUNOLOGY. 2010;185(3):1949–58.
MLA
Cheung, Timothy C, Ken Coppieters, Hideki Sanjo, et al. “Polymorphic Variants of LIGHT (TNF Superfamily-14) Alter Receptor Avidity and Bioavailability.” JOURNAL OF IMMUNOLOGY 185.3 (2010): 1949–1958. Print.
@article{1096147,
  abstract     = {The TNF superfamily member homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed by T lymphocytes (LIGHT) [ TNF superfamily (SF)-14], is a key cytokine that activates T cells and dendritic cells and is implicated as a mediator of inflammatory, metabolic, and malignant diseases. LIGHT engages the lymphotoxin-beta receptor (LT beta R) and HVEM (TNFRSF14), but is competitively limited in activating these receptors by soluble decoy receptor-3 (DcR3; TNFRSF6B). Two variants in the human LIGHT alter the protein at E214K (rs344560) in the receptor-binding domain and S32L (rs2291667) in the cytosolic domain; however, the functional impact of these polymorphisms is unknown. A neutralizing Ab failed to bind the LIGHT-214K variant, indicating this position as a part of the receptor-binding region. Relative to the predominant reference variant S32/E214, the other variants showed altered avidity with LT beta R and less with HVEM. Heterotrimers of the LIGHT variants decreased binding avidity to DcR3 and minimized the inhibitory effect of DcR3 toward LT beta R-induced activation of NF-kappa B. In patients with immune-mediated inflammatory diseases, such as rheumatoid arthritis, DcR3 protein levels were significantly elevated. Immunohistochemistry revealed synoviocytes as a significant source of DcR3 production, and DcR3 hyperexpression is controlled by posttranscriptional mechanisms. The increased potential for LT beta R signaling, coupled with increased bioavailability due to lower DcR3 avidity, provides a mechanism of how polymorphic variants in LIGHT could contribute to the pathogenesis of inflammatory diseases.},
  author       = {Cheung, Timothy C and Coppieters, Ken and Sanjo, Hideki and Oborne, Lisa M and Norris, Paula S and Coddington, Amy and Granger, Steven W and Elewaut, Dirk and Ware, Carl F},
  issn         = {0022-1767},
  journal      = {JOURNAL OF IMMUNOLOGY},
  keyword      = {T-CELL-ACTIVATION,LYMPHOTOXIN-BETA-RECEPTOR,HERPESVIRUS ENTRY MEDIATOR,SYSTEMIC-LUPUS-ERYTHEMATOSUS,DECOY RECEPTOR-3,HEPATOCELLULAR-CARCINOMA,RHEUMATOID-ARTHRITIS,EXPRESSION,LYMPHOCYTE-ACTIVATION,APOPTOSIS},
  language     = {eng},
  number       = {3},
  pages        = {1949--1958},
  title        = {Polymorphic variants of LIGHT (TNF superfamily-14) alter receptor avidity and bioavailability},
  url          = {http://dx.doi.org/10.4049/jimmunol.1001159},
  volume       = {185},
  year         = {2010},
}

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