Altered immunoglobulin profiles in children with Tourette syndrome

Background

Post-infectious autoimmunity and immune deficiency have been implicated in the pathogenesis of Tourette syndrome (TS). We asked here whether B cell immunity of patients with TS differs from healthy subjects.

Methods

In two independent cross-sectional samples, we compared serum levels of IgG1, IgG2, IgG3, IgG4, IgM, IgA, and IgE in 21 patients with TS from Yale University (17 males, 4 females, 8-16 years) versus 21 healthy controls (13 males, 8 females, 7-17 years); and in 53 patients with TS from Groningen University (45 males, 8 females, 6-18 years) versus 53 healthy controls (22 males, 31 females, 6-18 years), respectively. We also investigated correlations between Ig concentrations and symptom severity. In 13 additional patients (9 males, 4 females, age range 9-14), we established Ig profiles at time points before, during, and after symptom exacerbations.

Results

IgG3 levels were significantly lower in Yale patients compared to healthy children (medians 0.28 versus 0.49 mg/ml, p = .04), while levels of IgG2, IgG4, and IgM in patients were lower at trend-level significance (p ? .10). Decreased IgG3 (medians 0.45 versus 0.52 mg/ml; p = .05) and IgM (medians 0.30 versus 0.38 mg/ml; p = .04) levels were replicated in the Groningen patients. Ig levels did not correlate with symptom severity. There was a trend-level elevation of IgG1 during symptom exacerbations (p = .09).

Conclusion

These pilot data indicate that at least some patients with TS have decreased serum IgG3, and possibly also IgM levels, though only few subjects had fully expressed Ig immunodeficiency. Whether these changes are related to TS pathogenesis needs to be investigated.     

Prevention of recurrent postpartum depression a reasonable option?

Clinical Dilemma: A 27-year-old woman is in the 32nd week of her second pregnancy. After her first childbirth she suffered from postpartum depression (PPD) and was successfully treated with an antidepressant. Since then she has been asymptomatic. Now she asks for consultation whether she should be treated preventively for depression after her upcoming childbirth.     

Methylation-mediated silencing and tumour suppressive function of <Emphasis Type="Italic">hsa-miR-124</Emphasis> in cervical cancer

Background  

A substantial number of microRNAs (miRNAs) is subject to epigenetic silencing in cancer. Although epigenetic silencing of tumour suppressor genes is an important feature of cervical cancer, little is known about epigenetic silencing of miRNAs. Since DNA methylation-based silencing of hsa-miR-124 occurs in various human cancers, we studied the frequency and functional effects of hsa-miR-124 methylation in cervical carcinogenesis.     

Methylation marker analysis and HPV16/18 genotyping in high-risk HPV positive self-sampled specimens to identify women with high grade CIN or cervical cancer

Objectives

Methylation marker analysis using bi-marker panel MAL/miR-124-2 is a promising triage test for identifying cervical (pre)cancer in high-risk human papillomavirus (hrHPV) positive women. Bi-marker panel MAL/miR-124-2 can be applied directly on self-sampled cervico-vaginal material and its sensitivity is non-inferior to that of cytology, yet at the cost of more colposcopy referrals. Our objective was to increase specificity of MAL/miR-124-2 methylation analysis by varying the assay thresholds and adding HPV16/18 genotyping.

Methods

1019 hrHPV-positive women were selected from a randomized controlled self-sampling trial (PROHTECT-3; 33–63 years, n = 46,001) and nine triage strategies with methylation testing of MAL/miR-124-2 and HPV16/18 genotyping were evaluated. The methylation assay threshold was set at four different predefined levels which correspond with clinical specificities for end-point cervical intra-epithelial grade 3 or worse (CIN3 +) of 50%, 60%, 70%, and 80%.

Results

The CIN3 + sensitivity of methylation analysis decreased (73.5 to 44.9%) while specificity increased (47.2 to 83.4%) when increasing the assay threshold. CIN3 + sensitivity and specificity of HPV16/18 genotyping were 68.0% and 65.6%, respectively. Combined methylation analysis at threshold-80 and HPV16/18 genotyping yielded similar CIN3 + sensitivity as that of methylation only at threshold-50 (77.6%) with an increased specificity (54.8%).

Conclusions

Combined triage by MAL/miR-124-2 methylation analysis with threshold-80 and HPV16/18 genotyping reaches high CIN3 + sensitivity with increased specificity to identify women with cervical (pre)cancer among HPV self-sample positive women. The combined strategy is attractive as it is fully molecular and identifies women at the highest risk of cervical (pre)cancer because of strongly elevated methylation levels and/or HPV16/18 positivity.     

CADM1 and MAL promoter methylation levels in hrHPV‐positive cervical scrapes increase proportional to degree and duration of underlying cervical disease

Combined detection of cell adhesion molecule 1 (CADM1) and T‐lymphocyte maturation‐associated protein (MAL) promoter methylation in cervical scrapes is a promising triage strategy for high‐risk human papillomavirus (hrHPV)‐positive women. Here, CADM1 and MAL DNA methylation levels were analysed in cervical scrapes of hrHPV‐positive women with no underlying high‐grade disease, high‐grade cervical intraepithelial neoplasia (CIN) and cervical cancer. CADM1 and MAL methylation levels in scrapes were first related to CIN‐grade of the corresponding biopsy and second to CIN‐grade stratified by the presence of ‘normal’ or ‘abnormal’ cytology as present in the accompanying scrape preceding the cervical biopsy. The scrapes included 167 women with ≤CIN1, 54 with CIN2/3 and 44 with carcinoma. In a separate series of hrHPV‐positive scrapes of women with CIN2/3 (n = 48), methylation levels were related to duration of preceding hrHPV infection (PHI; <5 and ≥5 years). Methylation levels were determined by quantitative methylation‐specific PCR and normal cytology scrapes of hrHPV‐positive women with histologically ≤CIN1 served as reference. CADM1 and MAL methylation levels increased proportional to severity of the underlying lesion, showing an increase of 5.3‐ and 6.2‐fold in CIN2/3, respectively, and 143.5‐ and 454.9‐fold in carcinomas, respectively, compared to the reference. Methylation levels were also elevated in CIN2/3 with a longer duration of PHI (i.e. 11.5‐ and 13.6‐fold, respectively). Moreover, per histological category, methylation levels were higher in accompanying scrapes with abnormal cytology than in scrapes with normal cytology. Concluding, CADM1 and MAL promoter methylation levels in hrHPV‐positive cervical scrapes are related to the degree and duration of underlying cervical disease and markedly increased in cervical cancer.