Dominant-negative effect of the heterozygous C104R TACI mutation in common variable immunodeficiency (CVID)

Garibyan, Lilit; Lobito, Adrian A.; Siegel, Richard M.; Call, Matthew E.; Wucherpfennig, Kai W.; Geha, Raif S.

doi:10.1172/jci31023

Cited by 85 publications

(86 citation statements)

References 30 publications

(44 reference statements)

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“…Baseline cytoplasmic p65 staining was noted for cells containing both short and long TACI isoforms, reflecting a basal activation state noted previously for TACI-expressing cells in the absence of ligands. 26 However, p65 staining was significantly more intense for A20 cells transduced with the short TACI isoform (P 5 .02). After incubation with rhAPRIL, the p65 signal was further enhanced and was even more increased for cells transduced with the short isoform, as confirmed by quantitation of p65 fluorescence ( Figure 3B).…”

Section: Differential Downstream P65 Nuclear Translocation In Taci Ismentioning

confidence: 88%

Differential induction of plasma cells by isoforms of human TACI

García-Carmona

Cols

Ting

et al. 2015

Blood

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Key Points• Activation of TACI on B cells leads to proliferation, isotype switch, and B-cell survival.• Human TACI is produced in 2 isoforms; only the short form is a potent inducer of plasmacell differentiation.Subjects with common variable immune deficiency may have mutations in transmembrane activator calcium modulator and cyclophilin ligand interactor (TACI). Unlike the murine gene, human TACI undergoes alternative messenger (m)RNA splicing to produce isoforms with 1 or 2 ligand-binding domains. Because both isoforms are found in human B cells, we compared their functions in transduced murine B and human pre-B cells.Although murine cells and pre-B cells transduced with the long TACI isoform retained surface CD19 and immunoglobulin G, cells transduced with the short TACI isoform completely lost these B-cell characteristics. Expression of the short TACI isoform produced intense nuclear factor kB activation, nuclear p65 translocation, and colocalization with myeloid differentiation factor 88 and calcium-modulating cyclophilin ligand. The short TACI-transduced cells became larger and CD138 positive, demonstrated upregulated BLIMP1 and XBP1 mRNA, and acquired the morphology of plasma cells. In contrast, cells bearing the long isoform had significantly less BLIMP1 and XBP1 mRNA and, for human pre-B cells, remained CD138 negative. Although human B cells express both isoforms, the short isoform predominates in CD27 1 B cells, toll-like receptor 9-activated peripheral B cells, and splenic marginal zone B cells. Although the transcriptional controls for alternative splicing of isoforms remain unknown, differential signals via isoforms may control plasma-cell generation in humans.

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Section: Differential Downstream P65 Nuclear Translocation In Taci Ismentioning

confidence: 88%

Differential induction of plasma cells by isoforms of human TACI

García-Carmona

Cols

Ting

et al. 2015

Blood

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“…TACI has an extracellular domain containing two cysteine-rich domains (CRDs), each with different functions. The first CRD is involved in the assembly of TACI into multimeric complexes, 20 the second CRD is involved in the binding of APRIL and BAFF. The C104R and the A181E mutation are the two most commonly seen variants in CVID patients.…”

Section: Discussionmentioning

confidence: 99%

Rare mutations in TNFRSF13B increase the risk of asthma symptoms in Swedish children

et al. 2011

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TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) mutations seem to be associated with autoimmunity and common variable immunodeficiency in humans. Because of its role in immune responses, we investigated the association between TACI mutations and infection proneness/asthma symptoms in children. A total of 2372 children were genotyped for TACI mutations (I87N, C104R, S144X, A181E, R202H and ins204A). Serum IgA, IgG and specific IgE levels were determined in children with mutations. Data on parentally reported allergic diseases and infections were collected. In all, 55 individuals with TACI mutations were identified. Children with TACI mutations had a 2-fold increased risk of wheeze at 2 and 4 years of age and a 2.5-fold increased risk of asthma was seen at 4 years of age. None of the children with mutations suffered from IgA deficiency (o0.07 g l À1 ). No significant differences in serum IgG levels or specific IgE were found. Common variants in asthma susceptibility genes may account for up to 40% of cases of childhood-onset asthma, indicating a high contribution, compared with other common disorders. The role of rare variants/mutations in the pathogenesis of asthma is less clear. We conclude that mutations in TACI are the contributing factors for asthma symptoms in Swedish children, although the mechanisms still remain elusive.

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“…The eight haplotypes mentioned above accounted for 89% of control chromosomes and for 91 and 84% of IgAD and CVID chromosomes, respectively. Cases with CVID showed another nonrare haplotype (h27) carrying the supposed pathogenic replacement change C104R, 24 with a higher but not significantly different frequency with respect to the control sample (3.25 vs 1.04%; Fisher's exact test, P ¼ 0.25). Rare haplotypes accounted for 7% of analyzed chromosomes in the control sample, whereas their frequency rose to 9% in cases with IgAD and 11% in cases with CVID.…”

Section: Polymorphic Variationmentioning

confidence: 93%

An evolutionary approach to the medical implications of the tumor necrosis factor receptor superfamily member 13B (TNFRSF13B) gene

et al. 2009

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Coding variants in tumor necrosis factor receptor superfamily member 13B (TNFRSF13B) have been implicated in common variable immunodeficiency (CVID), but the functional effects of such mutations in relation to the development of the disease have not been entirely established. To examine the potential contribution of TNFRSF13B variants to CVID, we have applied an evolutionary approach by sequencing its coding region in 451 individuals belonging to 26 worldwide populations, in addition to controls, patients with CVID and selective IgA deficiency (IgAD) from Italy. The low level of geographical structure for the observed genetic diversity and the several neutrality tests performed confirm the absence of recent population-specific selective pressures, suggesting that TNFRSF13B may be involved also in innate immune functions, rather than in adaptive immunity only. A slight excess of rare derived alleles was found in patients with CVID, and thus some of these variants may contribute to the disease, implying that CVID probably fits the rare variants rather than the common disease/common variant paradigm. This also confirms the previous suggestion that TNFRSF13B defects alone do not cause CVID and that such an extremely heterogeneous immunodeficiency might be more likely related to additional, still unknown environmental and genetic factors.

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Dominant-negative effect of the heterozygous C104R TACI mutation in common variable immunodeficiency (CVID)

Cited by 85 publications

References 30 publications

Differential induction of plasma cells by isoforms of human TACI

Differential induction of plasma cells by isoforms of human TACI

Rare mutations in TNFRSF13B increase the risk of asthma symptoms in Swedish children

An evolutionary approach to the medical implications of the tumor necrosis factor receptor superfamily member 13B (TNFRSF13B) gene

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