Epigenetic Patterns Maintained in Early Caenorhabditis elegans Embryos Can Be Established by Gene Activity in the Parental Germ Cells

Epigenetic information, such as parental imprints, can be transmitted with genetic information from parent to offspring through the germ line. Recent reports show that histone modifications can be transmitted through sperm as a component of this information transfer. How the information that is transferred is established in the parent and maintained in the offspring is poorly understood. We previously described a form of imprinted X inactivation in Caenorhabditis elegans where dimethylation on histone 3 at lysine 4 (H3K4me2), a mark of active chromatin, is excluded from the paternal X chromosome (Xp) during spermatogenesis and persists through early cell divisions in the embryo. Based on the observation that the Xp (unlike the maternal X or any autosome) is largely transcriptionally inactive in the paternal germ line, we hypothesized that transcriptional activity in the parent germ line may influence epigenetic information inherited by and maintained in the embryo. We report that chromatin modifications and histone variant patterns assembled in the germ line can be retained in mature gametes. Furthermore, despite extensive chromatin remodeling events at fertilization, the modification patterns arriving with the gametes are largely retained in the early embryo. Using transgenes, we observe that expression in the parental germline correlates with differential chromatin assembly that is replicated and maintained in the early embryo. Expression in the adult germ cells also correlates with more robust expression in the somatic lineages of the offspring. These results suggest that differential expression in the parental germ lines may provide a potential mechanism for the establishment of parent-of-origin epigenomic content. This content can be maintained and may heritably affect gene expression in the offspring

Local recurrence in melanoma in situ: influence of sex, age, site of involvement and therapeutic modalities

Background Melanoma in situ (MIS) occurs on various body sites, in various age groups, and is managed by a variety of treatment modalities. Despite early treatment, recurrences may be encountered. Objectives To evaluate the influence of sex, age, body site and treatment modalities on recurrence rate in MIS. Methods Histologically confirmed cases of MIS from our dermatopathological database (n = 1351) from 1990 to 2000 were statistically analysed with respect to epidemiological characteristics, treatment modalities and outcome. Treatment modalities of the included MIS were evaluated by searching for data in the medical records and histopathological data sheets. Results There was a predominance of female patients (60.8%), and of involvement of the head and neck (53.4%). Total excision was performed in 95.9% of all patients; the remainder received cryotherapy, laser therapy or radiotherapy. In 265 patients, no data on definitive treatment were available. Alternatives to total excision were particularly performed in patients with advanced age and with lesions localized on the face. The mean +/- SD 5-year recurrence rate was 6.8 +/- 1.3% for surgically removed lesions, but was 31.3 +/- 8.5% for lesions treated by other modalities (log rank test: P < 0.0001). In a multivariate approach, mode of therapy and site of involvement, but not age, were significant prognostic variables (Cox proportional hazard model: P < 0.01). Conclusions In MIS, treatment modalities other than surgical excision may be used in certain situations, but carry a significantly increased risk of local recurrence

POS1265 DISTURBED CELLULAR IMMUNITY FOLLOWING mRNA VACCINATION AGAINST COVID-19 IN PATIENTS WITH B-CELL DEPLETING THERAPY

BackgroundImmunocompromised patients are considered high-risk and prioritized for vaccination against COVID-19 (1). Furthermore, vaccination-induced CD4 and CD8 T-cell responses have been suggested to have a protective role in COVID-19 (2). If T-cell responses are diminished after vaccination in immunocompromised individuals is not known to date.ObjectivesTo investigate cellular immunity following mRNA vaccination against COVID-19 in healthy individuals and patients undergoing B-cell depletion therapy.MethodsIn this interim analysis of the CoVVac study (NCT04858607), we analyzed T-cell responses in autoimmune patients treated with B-cell depleting therapy (BD, n=41) and age-matched healthy controls (HCs, n=50) 3-4 weeks after the second dose of mRNA vaccination against COVID-19. Therefore, we isolated PBMCs and stimulated them with a peptide pool covering the spike protein in vitro. Reactive CD4 and CD8 T-cells were determined by staining for IFNg, TNFa, IL-2 and GzmB by flow cytometry. Anti-SARS-CoV-2 antibody assays targeting the receptor-binding domain (RBD) or trimeric S protein (TSP) were performed to elucidate concomitant B-cell responses.ResultsWe observed significant alterations in anti-SARS-CoV-2 antibody responses in our cohort, the frequency of IFNg+ and IL-2+ CD4 and CD8 T-cells was similar in BD patients and controls. On the other hand, TNFa+ CD4 T-cells were significantly enriched in healthy controls versus BD patients (p=0.017) and correlated significantly with antibody titres (p=0.003). Similarly, GzmB+ CD8 T-cells were significantly diminished in our patient cohort (p&lt;0.001) and also showed a significant correlation with antibody titres (p&lt;0.001). Overall, the frequency of GzmB+ CD8 T-cells correlated very well with reactivity of T-cell subsets for other cytokines. This effect, however, is lost in the BD cohort. No difference was observed in the frequency of TNFa+ CD8 T-cells between the groups.Only 21 (42%) healthy individuals and 14 (34%) patients showed reactive T-cells for all the cytokines tested. This observation is mainly explained by a lack of cytokine production of CD8 T-cells in 26 (52%) HCs and 27 (66%) BD patients. In turn, 22 (44%) HCs and 17 (42%) patients didn’t show any IL-2 producing CD8 cells. Of note, only 2 (4%) of HCs showed no GzmB+ CD8 T-cells whereas the number increased to 15 (37%) of BD individuals (p&lt;0.001). In contrast, 42 (84%) HCs as well as 32 (78%) of patients showed production of all IFNg, TNFa and IL-2 in CD4 T-cells.ConclusionOur data suggest that most patients with B-cell depleting therapy are able to mount T-cell responses similar to those of healthy individuals while a minority of these patients did not show complete immunity against SARS CoV-2. Further analyses are needed to better understand a possible link of B-cell depletion therapy and CD8 T-cell responses.References[1]Shields AM, Burns SO, Savic S, Richter AG; UK PIN COVID-19 Consortium. COVID-19 in patients with primary and secondary immunodeficiency: The United Kingdom experience. J Allergy Clin Immunol. 2021 Mar;147(3):870-875.e1.[2]Angyal, A., Longet, S., Chalk, J., 2022. T-cell and antibody responses to first BNT162b2 vaccine dose in previously infected and SARS-CoV-2-naive UK health-care workers: a multicentre prospective cohort study. The Lancet Microbe 3Disclosure of InterestsNone declared</jats:sec

Outcomes associated with different vaccines in individuals with bipolar disorder and impact on the current COVID-19 pandemic- a systematic review.

Bipolar disorder (BD) might be associated with higher infection rates of coronavirus disease (COVID-19) which in turn could result in worsening the clinical course and outcome. This may be due to a high prevalence of somatic comorbidities and an increased risk of delays in and poorer treatment of somatic disease in patients with severe mental illness in general. Vaccination is the most important public health intervention to tackle the ongoing pandemic. We undertook a systematic review regarding the data on vaccinations in individuals with BD. Proportion of prevalence rates, efficacy and specific side effects of vaccinations and in individuals with BD were searched. Results show that only five studies have investigated vaccinations in individuals with BD, which substantially limits the interpretation of overall findings. Studies on antibody production after vaccinations in BD are very limited and results are inconsistent. Also, the evidence-based science on side effects of vaccinations in individuals with BD so far is poor

Outcomes associated with different vaccines in individuals with bipolar disorder and impact on the current COVID-19 pandemic- a systematic review

Bipolar disorder (BD) might be associated with higher infection rates of coronavirus disease (COVID-19) which in turn could result in worsening the clinical course and outcome. This may be due to a high prevalence of somatic comorbidities and an increased risk of delays in and poorer treatment of somatic disease in patients with severe mental illness in general. Vaccination is the most important public health intervention to tackle the ongoing pandemic. We undertook a systematic review regarding the data on vaccinations in individuals with BD. Proportion of prevalence rates, efficacy and specific side effects of vaccinations and in individuals with BD were searched. Results show that only five studies have investigated vaccinations in individuals with BD, which substantially limits the interpretation of overall findings. Studies on antibody production after vaccinations in BD are very limited and results are inconsistent. Also, the evidence-based science on side effects of vaccinations in individuals with BD so far is poor