Immunological indicators at children with autism spectrum disorders

Presents the results of a study on indicators of immunity 96 in children aged 3 to 11 years with autism spectrum disorders. The study of immunity by flow cytopfuorometry showed the highest number of leukocytes in peripheral blood is typical for children with delays in language development and autistic behavior, and for patients with Kanner syndrome increase in the absolute number of T-cytotoxic and limfocitopodobnye NK cells that may be indicative of immune activation. Of the results of the study of humoral immunity showed that in children with atypical autism IgA is higher but does not exceed the reference values. The data obtained can expand understanding of the nature of autism spectrum disorders involving the immune system, to objectify the condition of the nervous system, and enable the development of pathogenetic approaches to the treatment.Представлены результаты исследования показателей иммунитета у 96 пациентов в возрасте от 3 до 11 лет с РАС. Изучение клеточного иммунитета показало наибольшее количество лейкоцитов в периферической крови у детей с задержками развития речи и аутистическим поведением, у пациентов с синдромом Каннера повышение абсолютного количества Т-цитотоксических и лимфоцитоподобных NK клеток, что может свидетельствовать об активации иммунитета. В показателях гуморального иммунитета у детей с атипичным аутизмом IgA выше, но не выходит за пределы референсных значений. Полученные данные могут расширить представления о природе расстройств аутистического спектра, участие иммунной системы в данных нарушениях, объективизировать состояние нервной системы и позволят разработать патогенетические подходы в терапии

Mammalian sex determination—insights from humans and mice

Disorders of sex development (DSD) are congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical. Many of the genes required for gonad development have been identified by analysis of DSD patients. However, the use of knockout and transgenic mouse strains have contributed enormously to the study of gonad gene function and interactions within the development network. Although the genetic basis of mammalian sex determination and differentiation has advanced considerably in recent years, a majority of 46,XY gonadal dysgenesis patients still cannot be provided with an accurate diagnosis. Some of these unexplained DSD cases may be due to mutations in novel DSD genes or genomic rearrangements affecting regulatory regions that lead to atypical gene expression. Here, we review our current knowledge of mammalian sex determination drawing on insights from human DSD patients and mouse models

Safety and Immunogenicity of the GamTBvac, the Recombinant Subunit Tuberculosis Vaccine Candidate: A Phase II, Multi-Center, Double-Blind, Randomized, Placebo-Controlled Study

GamTBvac is a candidate tuberculosis vaccine with two fusion proteins, containing Ag85a, ESAT6, CFP10, and a dextran-binding domain (DBD). Phase II of a double-blind, randomized, multicenter, placebo-controlled study in parallel groups in healthy adults to evaluate the safety and immunogenicity of GamTBvac in 180 previously-vaccinated with Bacillus Calmette–Guérin vaccine (BCG) healthy volunteers without Mycobacterium tuberculosis (MTB) infection was conducted. The dose (0.5 mL) of either the study drug or a placebo was administered subcutaneously twice with an 8-week interval. At eight timepoints from 14 to 150 days, whole blood and sera were assayed. Antigen-specific T-cell responses were measured by an in-house interferon-gamma release assay (IGRA-test), the QuantiFERON (QTF) test, and intracellular cytokine staining (ICS). For antibody response detection, the bead-based multiplex immunoassay (MIA) was applied. The vaccine confirmed an acceptable safety profile previously shown in a first-in-human clinical study. After stimulation with both fusions, the highest median level of INF-γ was detected on day 21. The GamTBvac vaccine induced antigen-specific interferon-gamma release, Th1 cytokine-expressing CD4+ T-cells, and IgG responses and results support further clinical testing of GamTBvac

Expression and functional analysis of Dkk1 during early gonadal development

WNT signalling plays a central role in mammalian sex determination by promoting ovarian development and repressing aspects of testis development in the early gonad. Dickkopf homolog 1 (DKK1) is a WNT signalling antagonist that plays critical roles in multiple developmental systems by modulating WNT activity. Here, we examined the role of DKK1 in mouse sex determination and early gonadal development. Dkk1 mRNA was upregulated sex-specifically during testis differentiation, suggesting that DKK1 could repress WNT signalling in the developing testis. However, we observed overtly normal testis development in Dkk1-null XY gonads, and found no significant upregulation of Axin2 or Sp5 that would indicate increased canonical WNT signalling. Nor did we find significant differences in expression of key markers of testis and ovarian development. We propose that DKK1 may play a protective role that is not unmasked by loss-of-function in the absence of other stressors. Copyright (C) 2011 S. Karger AG, Base

The complex genetics of hypoplastic left heart syndrome.

Congenital heart disease (CHD) affects up to 1% of live births. Although a genetic etiology is indicated by an increased recurrence risk, sporadic occurrence suggests that CHD genetics is complex. Here, we show that hypoplastic left heart syndrome (HLHS), a severe CHD, is multigenic and genetically heterogeneous. Using mouse forward genetics, we report what is, to our knowledge, the first isolation of HLHS mutant mice and identification of genes causing HLHS. Mutations from seven HLHS mouse lines showed multigenic enrichment in ten human chromosome regions linked to HLHS. Mutations in Sap130 and Pcdha9, genes not previously associated with CHD, were validated by CRISPR-Cas9 genome editing in mice as being digenic causes of HLHS. We also identified one subject with HLHS with SAP130 and PCDHA13 mutations. Mouse and zebrafish modeling showed that Sap130 mediates left ventricular hypoplasia, whereas Pcdha9 increases penetrance of aortic valve abnormalities, both signature HLHS defects. These findings show that HLHS can arise genetically in a combinatorial fashion, thus providing a new paradigm for the complex genetics of CHD. Nat Genet 2017 Jul; 49(7):1152-59