Dickkopf-3 Acts as a Modulator of B Cell Fate and Function

Ludwig, Julia; Federico, Giuseppina; Prokosch, Sandra; Küblbeck, Günter; Schmitt, Sabine; Klevenz, Alexandra; Gröne, Hermann Josef; Nitschke, Lars; Arnold, Bernd

doi:10.4049/jimmunol.1402160

Cited by 24 publications

(24 citation statements)

References 71 publications

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“…Although DKK3 is a relatively less-studied protein particularly in obstetrics, the highest DKK3 levels are found in organs classically considered as immune privileged, such as the embryo, placenta, and uterus [15, 36]. Importantly, recent reports demonstrated that DKK3 functions as a tissue-derived modulator of T-cell responses as well as a modulator of B-cell fate and maintenance [37, 38], suggesting that DKK3 may play an important role in the final common pathway of term and preterm parturition [39]. Therefore, DKK3 can be a potentially valuable target for diagnostic, prognostic, and therapeutic approaches to threatened preterm birth related to infectious and noninfectious etiologies; thus, this will be confirmed in the CVF, AF, and serum samples by further studies.…”

Section: Discussionmentioning

confidence: 99%

Non-invasive prediction of preterm birth in women with cervical insufficiency or an asymptomatic short cervix (≤25 mm) by measurement of biomarkers in the cervicovaginal fluid

et al. 2017

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ObjectiveTo determine whether various proteins in the cervicovaginal fluid (CVF) known to be involved in immune regulation, alone or in combination with clinical risk factors, can predict spontaneous preterm delivery (SPTD) in women with cervical insufficiency or a short cervix (≤25 mm).MethodsThis retrospective cohort study included 62 asymptomatic women with cervical insufficiency (n = 27) or an asymptomatic short cervix (n = 35) at 18–27 weeks. CVF swab samples were taken for assays of vitamin D binding protein (VDBP), interleukin (IL)-8, matrix metalloproteinases (MMP)-9, tissue inhibitor of metalloproteinases (TIMP)-1, and Dickkopf-related protein 3 (DKK3) before cervical examination, and maternal blood was collected for the determination of the C-reactive protein (CRP) level. The primary outcome measurement was SPTD at <32 weeks of gestation. Logistic regression analysis and receiver operating characteristic curves were used for the statistical analyses.ResultsThe rate of SPTD at <32 weeks was 40.3% (25/62). The CVF levels of VDBP, TIMP-1, and DKK3, but not IL-8 and MMP-9, were significantly higher in the women who had SPTD at <32 weeks than in those who did not deliver spontaneously at <32 weeks. The women who had SPTD at <32 weeks had a significantly more advanced cervical dilatation at presentation and a higher level of serum CRP. Using the stepwise regression analysis, a prediction model was developed by combining various proteins in the CVF and clinical factors, resulting in the inclusion of cervical dilatation, CVF VDBP, and use of corticosteroids (area under curve, 0.909).ConclusionsIn women with cervical insufficiency or a short cervix, VDBP, TIMP-1, and DKK3 in the CVF may be useful as non-invasive predictors of SPTD at <32 weeks. A combination of these markers and clinical factors appears to improve the predictability of SPTD compared with the markers alone.

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Section: Discussionmentioning

confidence: 99%

Non-invasive prediction of preterm birth in women with cervical insufficiency or an asymptomatic short cervix (≤25 mm) by measurement of biomarkers in the cervicovaginal fluid

et al. 2017

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“…We also found that DKK3 contributed to the immuno-suppressive microenvironment protecting transplanted, class-I mismatched embryoid bodies from T-cell-mediated rejection ( 21 ). DKK3 is also involved in regulating the composition of the B cell compartment ( 23 ). The development of B2 cells was impaired at the pre- and immature B cell stage in the absence of DKK3, resulting in decreased numbers of follicular B cells in adult DKK3-deficient mice.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, DKK3 limited B1 cell self-maintenance in the periphery, by decreasing the survival and proliferation of B1 cells. In addition, DKK3-deficient mice exhibited altered antibody responses and an increased secretion of the cytokine IL-10 ( 23 ).…”

Section: Introductionmentioning

confidence: 99%

Dickkopf-3 Contributes to the Regulation of Anti-Tumor Immune Responses by Mesenchymal Stem Cells

Tounsi

Shridhar

et al. 2015

Front. Immunol.

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Mesenchymal stem cells (MSCs) are known to limit immune responses in vivo by multiple soluble factors. Dickkopf-3 (DKK3), a secreted glycoprotein, has recently been identified as a novel immune modulator. Since DKK3 has been reported to be produced by MSCs, we investigated whether DKK3 contributes to the immune suppression of anti-tumor responses by MSCs. Whereas wild-type MSCs inhibited immune responses against two different transplantation tumors, DKK3-deficient MSCs did not affect the rejection process. Increased CD8+ T cell and reduced M2-type macrophages infiltration was observed in tumors inoculated together with DKK3-deficient MSCs. Thus, DKK3 could alter the composition of the tumor stroma, thereby supporting the MSCs-mediated suppression of immune responses against these tumor transplants.

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“…RYBP appears to be a key actor maintaining B-2 progenitors as the dominant adult B lymphocyte precursors, and it also inhibits B-1P expansion. A number of genes in mouse mutant or transgenic lines have been associated with increased numbers of mature B-1 cells (39,(45)(46)(47)(48), but to our knowledge, only Rybp has been involved in targeting adult B-1P expansion.…”

Section: Discussionmentioning

confidence: 99%

Role of Polycomb RYBP in Maintaining the B-1-to-B-2 B-Cell Lineage Switch in Adult Hematopoiesis

Calés

Pavón

Starowicz

et al. 2016

Molecular and Cellular Biology

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dPolycomb chromatin modifiers regulate hematopoietic pluripotent stem and progenitor cell self-renewal and expansion. Polycomb complex redundancy and biochemical heterogeneity complicate the unraveling of the functional contributions of distinct components. We have studied the hematopoietic activity of RYBP, a direct interactor and proposed modulator of RING1A/ RING1B-dependent histone H2A monoubiquitylation (H2AUb). Using a mouse model to conditionally inactivate Rybp in adult hematopoiesis, we have found that RYBP deletion results in a reversion of B-1-to-B-2 B-cell progenitor ratios, i.e., of the innate (predominantly fetal) to acquired (mostly adult) immunity precursors. Increased numbers of B-1 progenitors correlated with a loss of pre-proB cells, the B-2 progenitors. RYBP-deficient stem and progenitor cell populations (LKS) and isolated common lymphoid progenitors (CLP) gave rise to increased numbers of B-1 progenitors in vitro. Rybp inactivation, however, did not result in changes of global H2AUb and did not interact genetically with Ring1A or Ring1B deletions. These results show that a sustained regulation of the B-1-to-B-2 switch is needed throughout adult life and that RYBP plays an important role in keeping B-2 dominance, most likely independently of its Polycomb affiliation. RING1 and YY1 binding protein (RYBP) is a component of a subset of type I Polycomb repressive complexes (PRC1), chromatin regulators endowed with histone H2A monoubiquitylating activity (recently reviewed in references 1 and 2). RYBP contacts the C-terminal region of RING1B and its paralog, RING1A (3), heterodimeric RING-type E3 ubiquitin ligases that modify lysine 119 of histone H2A (H2AUb) (4, 5). Canonical PRC1 assemblies are characterized by the presence of both chromobox-containing subunits and oligomerizing SAM motif subunits, PHC proteins (6, 7). Noncanonical PRC1 complexes, on the other hand, contain RYBP or its paralog, YY1-associated factor (YAF1), instead of chromobox proteins (6, 7), as their association with RING1 proteins is mutually exclusive (8). PRC1 association with chromatin not only modifies H2A but also promotes compaction, a structural alteration that usually correlates with transcriptionally repressed states (6, 9-11). PRC1 is recruited to chromatin through PRC2-induced H3K27me3-dependent and -independent mechanisms (6,7,12). In vitro, RYBP-PRC1 is more efficient at histone monoubiquitylation than canonical PRC1 complexes (6), an observation consistent with in vivo evidence showing decreased levels of global H2AUb upon short-hairpin downregulation of RYBP (6, 7, 13). However, the relative contributions to the H2A modification of RYBP-or chromobox-containing PRC1 complexes still are controversial (6,14), possibly because of cell type variations.In the mouse, genetic analysis of PRC1 functions in differentiation often has focused on the hematopoietic compartment (summarized in references 15 and 16) as one of the best known hierarchies of related cell lineages (17). Most defects in PRC1 mutant lines pertain to...

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Dickkopf-3 Acts as a Modulator of B Cell Fate and Function

Cited by 24 publications

References 71 publications

Non-invasive prediction of preterm birth in women with cervical insufficiency or an asymptomatic short cervix (≤25 mm) by measurement of biomarkers in the cervicovaginal fluid

Non-invasive prediction of preterm birth in women with cervical insufficiency or an asymptomatic short cervix (≤25 mm) by measurement of biomarkers in the cervicovaginal fluid

Dickkopf-3 Contributes to the Regulation of Anti-Tumor Immune Responses by Mesenchymal Stem Cells

Role of Polycomb RYBP in Maintaining the B-1-to-B-2 B-Cell Lineage Switch in Adult Hematopoiesis

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