Custom human endogenous retroviruses dedicated microarray identifies self-induced HERV-W family elements reactivated in testicular cancer upon methylation control.

Endogenous retroviruses (ERVs) are an inherited part of the eukaryotic genomes, and represent approximately 400,000 loci in the human genome. Human endogenous retroviruses (HERVs) can be divided into distinct families, composed of phylogenetically related but structurally heterogeneous elements. The majority of HERVs are silent in most physiological contexts, whereas a significant expression is observed in pathological contexts, such as cancers. Owing to their repetitive nature, few of the active HERV elements have been accurately identified. In addition, there are no criteria defining the active promoters among HERV long-terminal repeats (LTRs). Hence, it is difficult to understand the HERV (de)regulation mechanisms and their implication on the physiopathology of the host. We developed a microarray to specifically detect the LTR-containing transcripts from the HERV-H, HERV-E, HERV-W and HERV-K(HML-2) families. HERV transcriptome was analyzed in the placenta and seven normal/tumoral match-pair samples. We identified six HERV-W loci overexpressed in testicular cancer, including a usually placenta-restricted transcript of ERVWE1. For each locus, specific overexpression was confirmed by quantitative RT-PCR, and comparison of the activity of U3 versus U5 regions suggested a U3-promoted transcription coupled with 5'R initiation. The analysis of DNA from tumoral versus normal tissue revealed that hypomethylation of U3 promoters in tumors is a prerequisite for their activation.

Relationships of circulating CD4+ T cell subsets and cytokines with the risk of relapse in patients with Crohn's disease.

Background and aims: We aimed to analyze circulating CD4+ T cell subsets and cytokines during the course of Crohn's disease (CD). Methods and results: CD4+ T cell subsets, ultrasensitive C-reactive protein (usCRP), and various serum cytokines (IL-6, IL-8, IL-10, IL-13, IL-17A, IL-23, TNFα, IFNγ, and TGFß) were prospectively monitored every 3 months for 1 year, using multicolor flow cytometry and an ultrasensitive Erenna method in CD patients in remission at inclusion. Relapse occurred in 35 out of the 113 consecutive patients (31%). For patients in remission within 4 months prior to relapse and at the time of relapse, there was no significant difference in Th1, Th17, Treg, and double-positive CD4+ T cell subsets co-expressing either IFNγ and FOXP3, IL-17A and FOXP3, or IFNγ and IL-17A. On the contrary, in patients who remained in remission, the mean frequency and number of double-positive IL-17A+FOXP3+ CD4+ T cells and the level of usCRP were significantly higher (p ≤ 0.01) 1 to 4 months prior to relapse. At the time of relapse, only the IL-6 and usCRP levels were significantly higher (p ≤ 0.001) compared with those patients in remission. On multivariate analysis, a high number of double-positive IL-17A+FOXP3+ CD4+ T cells (≥1.4 cells/mm3) and elevated serum usCRP (≥3.44 mg/L) were two independent factors associated with risk of relapse. Conclusions: Detection of circulating double-positive FOXP3+IL-17A+ CD4+ T cell subsets supports that T cell plasticity may reflect the inflammatory context of Crohn's disease. Whether this subset contributes to the pathogenesis of CD relapse needs further studies.

Comparative methylation of ERVWE1/syncytin-1 and other human endogenous retrovirus LTRs in placenta tissues.

Human endogenous retroviruses (HERVs) are globally silent in somatic cells. However, some HERVs display high transcription in physiological conditions. In particular, ERVWE1, ERVFRDE1 and ERV3, three proviruses of distinct families, are highly transcribed in placenta and produce envelope proteins associated with placenta development. As silencing of repeated elements is thought to occur mainly by DNA methylation, we compared the methylation of ERVWE1 and related HERVs to appreciate whether HERV methylation relies upon the family, the integration site, the tissue, the long terminal repeat (LTR) function or the associated gene function. CpG methylation of HERV-W LTRs in placenta-associated tissues was heterogeneous but a joint epigenetic control was found for ERVWE1 5'LTR and its juxtaposed enhancer, a mammalian apparent LTR retrotransposon. Additionally, ERVWE1, ERVFRDE1 and ERV3 5'LTRs were all essentially hypomethylated in cytotrophoblasts during pregnancy, but showed distinct and stage-dependent methylation profiles. In non-cytotrophoblastic cells, they also exhibited different methylation profiles, compatible with their respective transcriptional activities. Comparative analyses of transcriptional activity and LTR methylation in cell lines further sustained a role for methylation in the control of functional LTRs. These results suggest that HERV methylation might not be family related but copy-specific, and related to the LTR function and the tissue. In particular, ERVWE1 and ERV3 could be developmentally epigenetically regulated HERVs.

Low levels of emotional awareness predict a better response to dermatological treatment in patients with psoriasis.

BACKGROUND: Personality and emotional factors are thought to influence the onset of psoriasis, the occurrence of relapses, and the sensitivity of this condition to dermatological treatments. OBJECTIVE: To explore the relationships between emotional disorders and emotional information processing in the one hand, and psoriasis severity and response to treatment on the other. METHODS: We recruited 93 patients through an article in the local press. These patients attended three consultations. We evaluated psoriasis severity by Psoriasis Area and Severity Index (PASI) score and response to treatment by change in PASI score from baseline to the 3-month visit. We screened for comorbid mental disorders, using the Mini International Neuropsychiatric Interview. We used the Hospital Anxiety and Depression Scale to assess anxiety and depressive symptoms. Alexithymia (difficulty in identifying and expressing emotions) was evaluated with the 26-item version of the Toronto Alexithymia Scale (TAS-26) and the ability to integrate and differentiate emotions (emotional awareness) was assessed with the Lane and Schwartz Levels of Emotional Awareness Scale (LEAS). RESULTS: Forty patients presented at least one psychiatric diagnosis and 33 were considered alexithymic (TAS > or =73). No psychological score was associated with baseline PASI score, which was higher in men and positively correlated with disease duration. Patients who considered their disease to be stress-reactive tended to have lower LEAS scores (p = 0.052). At the 3-month visit, PASI scores had significantly improved in the subset of patients (n = 67) presenting severe psoriasis at inclusion (PASI >2); emotional awareness and anxiety scores had also improved in these patients (p < 0.001), but dermatological and psychological changes were not statistically related. Dermatological improvement at 3 months with respect to baseline PASI was predicted by longer disease duration (>20 years) and lower baseline LEAS score (p = 0.044 and p = 0.021, respectively). CONCLUSION: This study demonstrates the value of assessing the ability of patients with psoriasis to process emotional information, as defined by emotional awareness. Patients with low LEAS scores appear to be more reactive to stress, but also to be more responsive to treatment, suggesting the activation of a particular stress physiology by negative affective states that are not experienced.