The Effects of Cyclosporin A on V(D)J Recombination Activity

Döbbeling, Udo

doi:10.1046/j.1365-3083.1997.d01-426.x

Cited by 4 publications

(3 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In fact, one of the variants identified in our metaanalysis (rs116100695, p.Arg486Trp [c.1456T>G], MAF ¼ 0.3%, beta HGB ¼ À0.242 g/dl, p HGB ¼ 1.2 3 10 À5 ) is a frequent cause of PK deficiency in Italian and Spanish subjects. 48,49 This variant was confirmed in the replication cohorts (p replication ¼ 0.039; Table S7). Two additional PKLR rare missense variants contribute to the gene-based association statistic with HGB and HCT: rs61755431 (p.Arg569Gln [c.1706G>A], MAF ¼ 0.2%, beta HGB ¼ À0.179 g/dl, p HGB ¼ 0.006) and rs8177988 (p.Val506Ile [c.1516G>A], MAF ¼ 0.6%, beta HGB ¼ þ0.116 g/dl, p HGB ¼ 0.003).…”

Section: Gene-based Association Testingmentioning

confidence: 62%

Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits

Chami

Chen

Slater

et al. 2016

The American Journal of Human Genetics

View full text Add to dashboard Cite

Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.

show abstract

Section: Gene-based Association Testingmentioning

confidence: 62%

Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits

Chami

Chen

Slater

et al. 2016

The American Journal of Human Genetics

View full text Add to dashboard Cite

show abstract

“…B-cell responses to CsA in vivo and in vitro is reported to block TI-2 stimulation, 16,36 Furthermore, B-1 cell differentiation following stimulation with TI-2 Ags can be blocked by CsA treatment. 18 Since CsA suppresses the action of the nuclear factor, which is required for V(D)J recombination in precursor B cells, 37,38 it might selectively affect precursors of B-1 cells. However, it may not affect well-differentiated B-1 cells or B cells that are actively producing Abs because these cells no longer require V(D)J recombination.…”

Section: Elimination Of B Cells Responding To Group a Carbohydrates 4571mentioning

confidence: 99%

The persistent elimination of B cells responding to blood group A carbohydrates by synthetic group A carbohydrates and B-1 cell differentiation blockade: novel concept in preventing antibody-mediated rejection in ABO-incompatible transplantation

Irei

Ohdan

Zhou

et al. 2007

Blood

View full text Add to dashboard Cite

We demonstrated a novel strategy for specific and persistent inhibition of antibody (Ab) production against blood group A or B carbohydrate determinants necessary for successful ABO-incompatible transplantation. Similar to human blood group O or B individuals, mice have naturally occurring Abs against human blood group A carbohydrates in their sera. B cells with receptors for A carbohydrates in mice belonging to the CD5+CD11b+B-1a subset have phenotypic properties similar to those of human B cells. These cells could be temporarily eliminated by injecting synthetic A carbohydrates (GalNAcα1–3, Fucα1–2Gal) conjugated to bovine serum albumin (A-BSA) and anti-BSA Abs. In mice that received the injection of A-BSA/anti-BSA Abs, the serum levels of anti-A IgM were reduced, but immunization with human A erythrocytes resulted in increased serum levels of anti-A Abs. When combined with cyclosporin A (CsA) treatment, which blocks B-1a cell differentiation, and treatment with A-BSA/anti-BSA Abs, the serum levels of anti-A Abs were persistently undetectable in the mice even after the immunization. B cells with receptors for A carbohydrates were markedly reduced in these mice. These results are consistent with the hypotheses that treatment with A-BSA/anti-BSA Abs temporarily depletes B cells responding to A determinants, and CsA treatment prevents the replenishment of these cells.

show abstract

“…It is well known that one of the mechanisms of corticosteroid action is mediated by blocking the induction of NF-kB [37,38], while CsA's action is mediated by blocking the induction of NF-AT [39]. In this regard, recent studies have demonstrated that CsA has direct effect on B cell proliferation and V(D)J recombination [40][41][42]. We propose that the mechanism of corticosteroid-and CsA-regulated B7 molecules on B cells is mediated through the inhibition of CD40-induced NF-kB or NF-AT signalling pathway.…”

Section: Discussionmentioning

confidence: 99%

The modulation of B7.2 and B7.1 on B cells by immunosuppressive agents

Jirapongsananuruk

Leung

1999

Clinical and Experimental Immunology

View full text Add to dashboard Cite

Several recent studies demonstrate that B7.2, but not B7.1, play an important role in allergic inflammation and IgE production. Agents that down-regulate B7.2 may therefore be of benefit for the treatment of Th2-driven allergic diseases. Our current study was carried out to investigate the effect of immunosuppressive agents, cyclosporin A (CsA) and dexamethasone, on B7.2 and B7.1 expression on B cells stimulated with the superantigen, toxic shock syndrome toxin-1 (TSST-1). The analysis of B7.2 and B7.1 on the same cells by flow cytometry demonstrated that TSST-1 up-regulated B7.2+B7.1- but not B7.1+B7.2- on B cells in a dose-dependent fashion. CsA and dexamethasone significantly down-regulated B7.2+B7.1- but up-regulated B7.2-B7.1+ B cells in the presence or absence of TSST-1 (100 ng/ml). Interestingly, the combination of CsA and dexamethasone was much more potent in the inhibition of B7.2 expression than either of these agents alone. As CD40 is known to up-regulate B7.2 expression on B cells, the mechanism of B7.2 down-regulation by CsA and dexamethasone was further studied by investigating the effect of these agents on CD40 expression on B cells. TSST-1 significantly increased CD40 expression on B cells. However, the addition of CsA or dexamethasone significantly down-regulated CD40 expression. Anti-CD40 MoAb significantly reversed the effects of CsA or dexamethasone on B7.2 and B7.1 expression, suggesting that T cell engagement of CD40 plays a role in the mechanisms by which CsA and dexamethasone acts on B cells. These data demonstrate the modulatory effect of CsA and dexamethasone on B7.2 and B7.1 expression on B cells and the potential role of CD40 in mediating this effect.

show abstract

The Effects of Cyclosporin A on V(D)J Recombination Activity

Cited by 4 publications

References 36 publications

Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits

Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits

The persistent elimination of B cells responding to blood group A carbohydrates by synthetic group A carbohydrates and B-1 cell differentiation blockade: novel concept in preventing antibody-mediated rejection in ABO-incompatible transplantation

The modulation of B7.2 and B7.1 on B cells by immunosuppressive agents

Contact Info

Product

Resources

About