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Open Access Green as soon as Postprint is submitted to ZB.
Features of isoforms of human soluble TACI.
J. Immunol. 211, 199-208 (2023)
The BAFF/APRIL-system with the two cytokines BAFF and APRIL and their three receptors, transmembrane activator and CAML interactor (TACI), BAFF receptor, and B-cell maturation Ag, is important for B cell maintenance. The BAFF/APRIL system is a therapeutic target in B cell-derived malignancies and autoimmune diseases. However, unexpected outcomes of clinical trials with atacicept (TACI-Fc) underline our incomplete understanding of this system. Shedding of the three receptors is one important regulatory element. In humans, TACI exists in two isoforms generated through alternative splicing in their extracellular portion: TACI-long (l) has two cysteine-rich domains, whereas TACI-short (s) lacks the first low-affinity one. In this study, we discriminated soluble (s) forms of TACI-l and TACI-s with newly generated mAbs and found that both were spontaneously released from activated human B cells, with a predominance of sTACI-l. Furthermore, sTACI-l was also the dominant isoform in human serum. Vaccination with the mRNA vaccine from BioNTech does not significantly affect the serum levels of sTACI-l. Both TACI-s and TACI-l were shed by a disintegrin and metalloproteinase domain-containing protein 10. TACI-l and TACI-s formed homo- and hetero-oligomers in soluble and membrane-bound forms. Both sTACI-l and sTACI-s acted as decoy receptors for BAFF, but only sTACI-l also efficiently inhibited APRIL. Dimerization of sTACI-l enhanced its decoy functions only slightly. Together, we extend our knowledge of the complexity of the BAFF/APRIL system by identifying and characterizing the two soluble isoforms of TACI.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Common Variable Immunodeficiency; Crystal-structure; Receptor; April; Baff; Bcma; Immunoregulator; Therapy; Antigen; System
ISSN (print) / ISBN
0022-1767
e-ISSN
1550-6606
Journal
Journal of Immunology
Quellenangaben
Volume: 211,
Issue: 2,
Pages: 199-208
Publisher
American Association of Immunologists
Publishing Place
9650 Rockville Pike, Bethesda, Md 20814 Usa
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
CF Monoclonal Antibodies (CF-MAB)
Grants
Deutsche Forschungsgemeinschaft research fellowship
Swiss National Science Foundation
Munich Cluster for Systems Neurology (SyNergy)
Else-Kroner Fresenius Stiftung
Gemeinnutzige Hertie Stiftung
Novartis Pharma
Merck
Deutsche Forschungsgemeinschaft
Swiss National Science Foundation
Munich Cluster for Systems Neurology (SyNergy)
Else-Kroner Fresenius Stiftung
Gemeinnutzige Hertie Stiftung
Novartis Pharma
Merck
Deutsche Forschungsgemeinschaft