Analysis of the association between CD40 and CD40 ligand polymorphisms and systemic sclerosis

Teruel, María; Simeón, Carmen P.; Broen, Jasper; Vonk, Madelon C.; Carreira, Patrícia; Camps, María Teresa; García-Portales, Rosa; Delgado-Frías, Esmeralda; Gallego, M.; Espinosa, Gerard; Beretta, Lorenzo; Airò, Paolo; Lunardi, Claudio; Riemekasten, Gabriela; Witte, Torsten; Krieg, Thomas; Kreuter, Alexander; Distler, Jörg H W; Hunzelmann, Nicolas; Koeleman, Bobby P. C.; Voskuyl, Alexandre E.; Schuerwegh, Annemie J.; Martín, Javier

doi:10.1186/ar3890

Cited by 11 publications

(7 citation statements)

References 31 publications

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“…We hypothesize that the lack of response in the number of cells secreting IgM to TCDD is due to a lesser degree of CD40L-mediated activation of the B cells from these individuals as the number of cells secreting IgM was significantly decreased in these donors. Differences in CD40L activation among our cohort of donors may be due to a plethora of reasons including polymorphisms within CD40 receptor gene, previous and present exposures, infections, inflammation, and many other factors of which we are unable to gather information due to the anonymity of blood donation (Blanco-Kelly et al, 2010;Jacobson et al, 2005;Orozco et al, 2010;Raychaudhuri et al, 2008;Teruel et al, 2012). Surprisingly, 2 of the 6 nonresponsive donors were deemed responsive in assaying the concentration of IgM secreted into the media (ie, ELISA).…”

Section: Discussionmentioning

confidence: 94%

The Influence of Human Interindividual Variability on the Low-Dose Region of Dose-Response Curve Induced by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin in Primary B Cells

Dornbos¹,

Crawford²,

Kaminski³

et al. 2016

Toxicol. Sci.

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The influence of interindividual variability is not typically assessed in traditional toxicological studies. Given that chemical exposures occur in heterogeneous populations, this knowledge gap has the potential to cause undue harm within the realms of public health and industrial and municipal finances. A recent report from the National Research Council (NRC) suggests that when accounting for interindividual variation in responses, traditionally assumed nonlinear dose-response relationships (DRRs) for noncancer-causing endpoints would better be explained with a linear relationship within the lowdose region. To address this knowledge gap and directly test the NRC's assumption, this study focused on assessing the DRR between 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD) exposure and immune suppression in a cohort of unique human donors. Human B cells were isolated from 51 individual donors and treated with logarithmically increasing concentrations of TCDD (0-30 nM TCDD). Two endpoints sensitive to TCDD were assessed: (1) number of IgM-secreting B cells and (2) quantity of IgM secreted. The results show that TCDD significantly suppressed both the number of IgM-secreting B cells and the quantity of IgM secreted (P < .05). Statistical model comparisons indicate that the low-dose region of the two DRRs is best explained with a nonlinear relationship. Rather than assuming low-dose linearity for all noncancer-causing DRRs, our study suggests the need to consider the specific mode of action of toxicants and pharmaceuticals during risk-management decision making.Key words: TCDD; AHR; human B cells; dose response; risk assessment; genetic variability.Understanding of the dose-response relationship (DRR) for any given chemical lies at the heart of risk assessment. Traditionally, data derived from lab-based toxicology studies are extrapolated in assessing the potential adverse health effects of chemicals in the human population. As traditional laboratory-based toxicology studies are performed on a small number of individuals or inbred mouse strains and as chemical exposures occur in a heterogeneous population of individuals, there lies a disconnect between lab-based toxicology and population-level risk assessment. Little is known regarding the degree of variability in a DRR within a heterogeneous population (Rhomberg, 2011).A recent report published by the National Research Council (NRC) suggested that interindividual variability within the human population would effectively linearize the low-dose region of DRRs for all noncancer-causing chemicals (NRC, 2009).

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Section: Discussionmentioning

confidence: 94%

The Influence of Human Interindividual Variability on the Low-Dose Region of Dose-Response Curve Induced by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin in Primary B Cells

Dornbos¹,

Crawford²,

Kaminski³

et al. 2016

Toxicol. Sci.

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“…To screen for the maximum number of polymorphisms potentially involved in CD40L protein expression or reported to be associated with immune disorders or inflammation32454864, PCR was performed with eleven primer pairs with corresponding annealing temperatures (Table 3, Supplementary Data S1 for PCR protocols). To promote stable heteroduplex formation, PCR products were denatured for 5 min at 96°C, and then gradually cooled at a rate of 0.5°C per 10 sec over 150 cycles.…”

Section: Methodsmentioning

confidence: 99%

Are polymorphisms of the immunoregulatory factor CD40LG implicated in acute transfusion reactions?

Aloui

Sut

Prigent

et al. 2014

Sci Rep

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The CD40 ligand (CD40L/CD154), a member of TNF superfamily, is notably expressed on activated CD4+ T-cells and stimulated platelets. CD40L is linked to a variety of pathologies and to acute transfusion reactions (ATR). Mutations in this gene (CD40LG) lead to X-linked hyper-IgM syndrome. Some CD40LG polymorphisms are associated with variable protein expression. The rationale behind this study is that CD40L protein has been observed to be involved in ATR. We wondered whether genetic polymorphisms are implicated. We investigated genetic diversity in the CD40LG using DHPLC and capillary electrophoresis for screening and genotyping (n = 485 French and Tunisian blood donors). We identified significant difference in the CD40LG linkage pattern between the two populations. Variant minor alleles were significantly over-represented in Tunisian donors (P<0.0001 to 0.0270). We found higher heterogeneity in the Tunisian, including three novel low frequency variants. As there was not a particular pattern of CD40LG in single apheresis donors whose platelet components induced an ATR, we discuss how this information may be useful for future disease association studies on CD40LG.

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“…Buck and colleagues have been found neither significant differences between patients with multiple sclerosis and SNP of the CD40 (C/T21) gene variant (53). In another study it has been demonstrated that CD40 (rs1883832, rs4810485, and rs1535045)/CD154 (rs3092952, and rs3092920) SNPs has not any role in the susceptibility to systemic sclerosis (54). Here we have shown that among CD40/ CD154 gene variants, CD40 rs1883832 is associated with susceptibility to migraine in Iranian population.…”

Section: Discussionmentioning

confidence: 96%

Investigation of association between CD40 current gene variants (rs4810485, rs1883832 and rs3765459) and serum CD154 protein levels in Iranian migraineurs

Ramroodi¹,

Saboori²,

Sanadgol³

2018

Cell Mol Biol (Noisy-le-grand)

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Migraine is a chronic neurological disease described by recurrent moderate to severe headaches often in association with neuro-inflammation. As cytokines are affect the immune response and migraine exacerbation, the current study aimed to investigate the possible associations between CD40 polymorphisms and level of soluble CD154 protein with migraine. In a prospective case-control study, we studied blood samples of 190 patients with migraine (migraineurs) and 200 healthy controls (HCs) from southeast Iran. Genotyping for the CD40 (rs4810485-intron, rs1883832-5´-UTR, and rs3765459-intron) gene variants were executed using PCR-RFLP and soluble CD154 protein levels were measured via ELISA method. Among CD40 gene variants, rs1883832 (TC genotype) was significantly associated with migraine (P = 0.007, OR = 2.326, 95% CI = 1.258-4.303). No significant associations observed between the rs4810485 and rs3765459 SNPs with migraine. The most frequent genotypes for CD40 were GG in rs4810485 (51.5%) and rs3765459 (62.1%) as well as TC in rs1883832 (53.7%). There was no statistically relationship between these gene variants and different subclasses of migraine. Concentration of soluble CD40L among patients with rs1883832 (TC genotype) were significantly (P = 0.027, OR = 0.417, CI = 0.192-0.906) higher in compared to healthy controls. Our findings showed that in CD40 rs1883832, TC genotype may have a role in migraine susceptibility. Therefore, it suggested that in addition to other factors, CD40 rs1883832 (TC genotype) genetic variation may also play a critical role in the etiology of migraine.

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Analysis of the association between CD40 and CD40 ligand polymorphisms and systemic sclerosis

Cited by 11 publications

References 31 publications

The Influence of Human Interindividual Variability on the Low-Dose Region of Dose-Response Curve Induced by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin in Primary B Cells

The Influence of Human Interindividual Variability on the Low-Dose Region of Dose-Response Curve Induced by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin in Primary B Cells

Are polymorphisms of the immunoregulatory factor CD40LG implicated in acute transfusion reactions?

Investigation of association between CD40 current gene variants (rs4810485, rs1883832 and rs3765459) and serum CD154 protein levels in Iranian migraineurs

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