Disease relevance of TNFRSF13B

• Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans [1].
• Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival [2].
• Search on chromosome 17 centromere reveals TNFRSF13B as a susceptibility gene for intracranial aneurysm: a preliminary study [3].
• TACI is mutant in common variable immunodeficiency and IgA deficiency [4].
• TACI(-/-) mice develop fatal autoimmune glomerulonephritis, proteinurea, and elevated levels of circulating autoantibodies [5].

High impact information on TNFRSF13B

• Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency [6].
• Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency [7].
• TNFRSF13B mutations cosegregated with the phenotype of CVID or IgAD in family members of four index individuals that we studied [4].
• The tumor necrosis factor receptor family member TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor) mediates isotype switching in B cells [4].
• We found that 4 of 19 unrelated individuals with common variable immunodeficiency (CVID) and 1 of 16 individuals with IgA deficiency (IgAD) had a missense mutation in one allele of TNFRSF13B (encoding TACI) [4].

Chemical compound and disease context of TNFRSF13B

• S. pneumoniae is a common pathogen responsible from pulmonary infections and impaired antibody response to polysaccharide antigens is seen in patients with IgG2 and IgA deficiency as well as patients with CVID and WAS [8].

Biological context of TNFRSF13B

• APRIL and TALL-I and receptors BCMA and TACI: system for regulating humoral immunity [9].
• However, another form of TACI exists wherein the N-terminal CRD is removed by alternative splicing [10].
• The level of TACI gene expression in myeloma cells is associated with a signature of microenvironment dependence versus a plasmablastic signature [11].
• These results demonstrate the critical requirement for TACI in regulating B cell homeostasis [5].
• Loss of TACI causes fatal lymphoproliferation and autoimmunity, establishing TACI as an inhibitory BLyS receptor [5].

Anatomical context of TNFRSF13B

• Thus, APRIL-TALL-I and BCMA-TACI form a two ligands-two receptors pathway involved in stimulation of B and T cell function [9].
• Both ligands can bind the two members of the TNF receptor family, namely the transmembrane activator and calcium modulator cyclophilin ligand interactor (TACI), as well as B-cell maturation antigen (BCMA) [12].
• BAFF-R expression increased initially and then decreased with a corresponding induction of TACI and BCMA expression during differentiation to plasma cells (PCs) [13].
• Cross-linking of this lymphocyte-specific protein, designated TACI (transmembrane activator and CAML-interactor), on the surface of transfected Jurkat cells with TACI-specific antibodies led to activation of the transcription factors NF-AT, AP-1, and NFkappaB [14].
• Unlike their putative germinal center B-cell precursors, HRS cells lacked BAFF-R, but expressed TACI and BCMA, a phenotype similar to that of plasmacytoid B cells [15].

Associations of TNFRSF13B with chemical compounds

• Soluble TACI extracellular domain protein specifically blocks TALL-1-mediated B cell proliferation without affecting CD40- or lipopolysaccharide-mediated B cell proliferation in vitro [16].
• TACI binding appears to require heparan sulfate posttranslational modifications of syndecan-2, because free heparin or pretreatment with heparitinase blocked the interaction [17].
• The human Taci gene (Transmembrane Activator and CAML Interactor) encodes a recently discovered member of the Tumor Necrosis Factor Receptor family [18].
• We recommend that all CVID patients with evidence of an enteropathy be screened for vitamin E deficiency, as early detection and consequent treatment may prevent, halt or reverse the neurological sequelae [19].
• The Cu(II) complex of the ligand all-cis-2,4,6-triamino-1,3,5-trihydroxycyclohexane (TACI) is a very efficient catalyst of the cleavage of plasmid DNA in the absence of any added cofactor [20].

Physical interactions of TNFRSF13B

• Expression of TACI in HEK293T cells confers on the cells the ability to bind BLyS with subnanomolar affinity [21].
• Syndecan-2 bound TACI but bound neither BAFF-R nor BCMA [17].

Regulatory relationships of TNFRSF13B

• Importantly, BAFF-R and CD40 enhanced B cell responsiveness to TACI-mediated suppression [22].
• TACI-induced activation of NF-AT was specifically blocked by a dominant-negative CAML mutant, thus implicating CAML as a signaling intermediate [14].
• This is the first identification of ligands that selectively activate TACI without simultaneously triggering BCMA or BAFF-R [17].
• B cells from individuals with TACI mutations did not produce IgG and IgA in response to the TACI ligand a proliferation-inducing ligand (APRIL), probably reflecting impaired isotype switching [23].
• In support of this notion, mouse TACI was found to activate NFAT, NFkB, and AP1 transcription factors in a transient transfection assay [18].

Other interactions of TNFRSF13B

• TACI expression is a good indicator of a BAFF-binding receptor [11].
• BLyS and APRIL are capable of signaling through TACI to mediate NF-kappaB responses in HEK293 cells [21].
• By yeast two-hybrid screening of a B cell library with TACI intracellular domain, we identified that, like many other TNFR family members, TACI intracellular domain interacts with TNFR-associated factor (TRAF)2, 5, and 6 [16].
• Thus, the recent discovery of deletions in the ICOS, BAFF-R and TACI genes leading to disturbances in late B cell differentiation and hypogammaglobulinaemia underline the potential impact of targeting these molecules for therapeutic strategies in autoimmune disorders [24].

Analytical, diagnostic and therapeutic context of TNFRSF13B

• Molecular cloning and functional characterization of murine transmembrane activator and CAML interactor (TACI) with chromosomal localization in human and mouse [18].
• The Taci gene was localized to human Chromosome (Chr) 17p11 by fluorescence in situ hybridization [18].
• We have investigated the effects of a new omega-conotoxin, CVID (AM-336), and compared them with omega-conotoxin GVIA (SNX-124), omega-conotoxin MVIIA (SNX-111) and morphine in a spinal nerve ligation model of neuropathic pain in the rat [25].
• In this study, a profound alteration of the T cell receptor repertoire was noted, especially in CD8(+) T cells, in CVID patients when compared to a control group [26].

References