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

Janzi, Magdalena; Kull, Inger; Wickman, Magnus; Hammarström, Lennart

doi:10.1038/gene.2011.55

Cited by 24 publications

(19 citation statements)

References 36 publications

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“…It is thought that TACI plays a key role in B cell activation and differentiation into plasma cells. In a recent study, rare mutations in TNFRSF13B were associated with asthma symptoms in Swedish children 67 . Moreover, BAFF expression in alveolar macrophages was inversely correlated with lung function in COPD patients 68 .…”

Section: Discussionmentioning

confidence: 96%

Genome-wide association study of lung function phenotypes in a founder population

Yao

Han

et al. 2014

Journal of Allergy and Clinical Immunology

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Background Lung function is a long-term predictor of mortality and morbidity. Objective We sought to identify single nucleotide polymorphisms (SNPs) associated with lung function. Methods We performed a genome-wide association study (GWAS) of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC in 1,144 Hutterites aged 6–89 years, who are members of a founder population of European descent. We performed least absolute shrinkage and selection operation (LASSO) regression to select the minimum set of SNPs that best predict FEV1/FVC in the Hutterites and used the GRAIL algorithm to mine the Gene Ontology database for evidence of functional connections between genes near the predictive SNPs. Results Our GWAS identified significant associations between FEV1/FVC and SNPs at the THSD4-UACA-TLE3 locus on chromosome 15q23 (P = 5.7x10−8 ~ 3.4x10−9). Nine SNPs at or near four additional loci had P-values < 10−5 with FEV1/FVC. There were only two SNPs with P-values < 10−5 for FEV1 or FVC. We found nominal levels of significance with SNPs at 9 of the 27 previously reported loci associated with lung function measures. Among a predictive set of 80 SNPs, six loci were identified that had a significant degree of functional connectivity (GRAIL P < 0.05), including three clusters of β-defensin genes, two chemokine genes (CCL18 and CXCL12), and TNFRSF13B. Conclusion This study identifies genome-wide significant associations and replicates results of previous GWAS. Multimarker modeling implicated for the first time common variation in genes involved in anti-microbial immunity in airway mucosa influences lung function.

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Section: Discussionmentioning

confidence: 96%

Genome-wide association study of lung function phenotypes in a founder population

Yao

Han

et al. 2014

Journal of Allergy and Clinical Immunology

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“…141,142 A recent study showed that Swedish children with TNFRSF13B mutations had a 2.5-fold increased risk of asthma at 4 years, independent of IgE levels. 143 Although further studies are needed to determine the exact mechanisms underlying this association, the study findings highlight potential humoral immune dysfunctions in patients with asthma.…”

Section: Potential Mechanisms Underlying the Association Between Atopmentioning

confidence: 88%

Risks for infection in patients with asthma (or other atopic conditions): Is asthma more than a chronic airway disease?

Juhn¹

2014

Journal of Allergy and Clinical Immunology

123

124

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Most of the research effort regarding asthma has been devoted to its causes, therapy, and prognosis. There is also evidence that the presence of asthma can influence patients’ susceptibility to infections, yet research in this aspect of asthma has been limited. There is additional debate in this field, with current literature tending to view the increased risk of infection among atopic patients as due to opportunistic infections secondary to airway inflammation, especially in severe atopic diseases. Other evidence, however, suggests that such risk and its underlying immune dysfunction may be a phenotypic or clinical feature of atopic conditions. This review argues that 1) improved understanding of the effects of asthma or other atopic conditions on the risk of microbial infections will bring important and new perspectives to clinical practice, research, and public health concerning atopic conditions and that 2) research efforts into the causes and effects of asthma must be juxtaposed because they are likely to guide each other.

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“…Likewise, APRIL deficiency results in enhanced Th2 response and increased lung inflammation in an asthma model (42). The fact that pediatric CVID patients with tnfrsf13b mutations are prone to asthma development may be another indication of a requirement for functional TACI to maintain the M1 phenotype (43).…”

Section: Discussionmentioning

confidence: 99%

TACI deficiency leads to alternatively activated macrophage phenotype and susceptibility toLeishmaniainfection

Allman

Dey

Liu

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The TNF family member, transmembrane activator and calciummodulator and cyclophilin ligand interactor (TACI), is a key molecule for plasma cell maintenance and is required in infections where protection depends on antibody response. Here, we report that compared with WT mouse, TACI KO Μϕs expressed lower levels of Toll-like receptors (TLRs), CD14, myeloid differentiation primary response protein 88, and adaptor protein Toll/IL-1 receptor domaincontaining adapter-inducing IFN-β and responded poorly to TLR agonists. Analysis of Μϕ phenotype revealed that, in the absence of TACI, Μϕs adapt the alternatively activated (M2) phenotype. Steady-state expression levels for M2 markers IL-4Rα, CD206, CCL22, IL-10, Arg1, IL1RN, and FIZZ1 were significantly higher in TACI KO Μϕ than in WT cells. Confirming their M2 phenotype, TACI-KO Mϕs were unable to control Leishmania major infection in vitro, and intradermal inoculation of Leishmania resulted in a more severe manifestation of disease than in the resistant C57BL/6 strain. Transfer of WT Μϕs to TACI KO mice was sufficient to significantly reduce disease severity. TACI is likely to influence Mϕ phenotype by mediating B cell-activating factor belonging to the TNF family (BAFF) and a proliferation inducing ligand (APRIL) signals because both these ligands down-regulated M2 markers in WT but not in TACI-deficient Μϕs. Moreover, treatment of Μϕs with BAFF or APRIL enhanced the clearance of Leishmania from cells only when TACI is expressed. These findings may have implications for understanding the shortcomings of host response in newborns where TACI expression is reduced and in combined variable immunodeficiency patients where TACI signaling is ablated.T ransmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) is a member of the TNF family molecules (1). It is a receptor for B-cell activating factor (BAFF) and a proliferation inducing ligand (APRIL). Although BAFF and APRIL share a second receptor, B-cell maturation antigen (BCMA), BAFF-R only binds to BAFF, and heparan sulfate proteoglycans only engage APRIL. TACI is primarily expressed on mature B cells and mediates signals for Ig isotype switch and secretion (2). Studies in TACI KO mice (3), combined variable immune deficient (CVID) patients with mutations in TACI gene tnfrsf13b (4), and newborns who express severely reduced B-cell TACI (5) all point to its pivotal role in determining antibody (Ab) development against T cell-independent type 2 (TI-2) antigens. In contrast to earlier publications (3), more recent reports showed diminished sustainment of plasma cells in response to T cell-dependent (TD) antigens in TACI KO mice (6). Interestingly, Tsuji et al. reported that despite impaired plasma cell survival and reduced Ab response to TD antigens, TACI KO mice manifest enhanced clearance of the enteric pathogen Citrobacter rodentium, presumably due to generation of higher avidity of Abs in the absence of TACI (7). Whereas TACI is well established as a B-cell receptor, its involvement in innate i...

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

Cited by 24 publications

References 36 publications

Genome-wide association study of lung function phenotypes in a founder population

Genome-wide association study of lung function phenotypes in a founder population

Risks for infection in patients with asthma (or other atopic conditions): Is asthma more than a chronic airway disease?

TACI deficiency leads to alternatively activated macrophage phenotype and susceptibility toLeishmaniainfection

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