Evolution of Highly Polymorphic T Cell Populations in Siblings with the Wiskott-Aldrich Syndrome

Population level evolutionary processes can occur within a single organism when the germ line contains a mutation that confers a cost at the level of the cell. Here we describe how multiple compensatory mutations arose through a within-individual evolutionary process in two brothers with the immune deficiency Wiskott-Aldrich Syndrome (WAS). As a result, both brothers have T lymphocyte populations that are highly polymorphic at the locus of the germ line defect, and no single allele achieves fixation. WASP, the gene product affected in this disease, is specific to white blood cells where it is responsible for regulating actin cytoskeleton dynamics in a wide range of cellular responses. The brothers inherited a rare allele predicted to result in truncated WASP lacking the carboxy-terminal VCA domains, the region that directly catalyzes actin filament generation. Although the brothers' T cell populations are highly polymorphic, all share a corrective effect relative to the inherited allele in that they restore the VCA domain. This indicates massive selection against the truncated germ line allele. No single somatic allele becomes fixed in the circulating T cell population of either brother, indicating that a regulated step in maturation of the affected cell lineage is severely compromised by the germ line allele. Based on the finding of multiple somatic mutations, the known maturation pathway for T-lineage cells and the known defects of T cells and precursor thymocytes in mice with truncated WASP, we hypothesize that the presence of truncated WASP (WASPΔVCA) confers an extreme disadvantage in early developing thymocytes, above and beyond the known cost of absence of full-length WASP, and that the disadvantage likely occurs through dominant negative competition of WASPΔVCA with N-WASP, a protein that otherwise partially compensates for WASP absence in developing thymocytes

ИССЛЕДОВАНИЕ АНТИГЕН-СТИМУЛИРОВАННОЙ ПРОДУКЦИИ υ-ИНТЕРФЕРОНА EX VIVO В ПЕРИФЕРИЧЕСКОЙ КРОВИ У БОЛЬНЫХ АКТИВНЫМ ТУБЕРКУЛЕЗОМ ЛЕГКИХ

Tuberculosis (TB) is one of the most significant problems in the Russian Health Care. Russia remains on the list of the 22 countries with a high TB incidence and on the third place in the world with a high prevalence of Drug Resistant TB [1]. It is urgently needed to develop new TB diagnostic methods as well as effective measures of the specific TB prevention, including a development of the novel vaccines, so we have to know better about the most immunogenic antigens of Mycobacterium Tuberculosis. We studied the Interferon-Q production in the whole blood after stimulating immune response with different proteins of Mycobacterium Tuberculosis in patients with active TB. The study results permitted us to evaluate the immunogenicity of the previously known proteins (Ag85a и ESAT-6) in comparison to the recently identified ones (Rv2957, Rv2958c и Rv0447), analyzing simultaneously their relation to tuberculin, as well as to antigens of the different viruses (Human Immunodeficiency Virus, Cytomegalovirus, Epstein-Barr Virus, Influenza Virus). Protein Rv2958c, unlike protein ESAT-6, showed the high immunogenicity in comparison to tuberculin. The expressed immunogenicity of protein Rv2958c might be indicated a possible greatest specificity of immune response to this antigen in TB patients. Meanwhile, bacillary tuberculosis was strongly associated with low immune response to this protein. Also we were found statistical differences in immune responses of patients to the different Mycobacterium Tuberculosis antigens depending on the drug sensitivity. In addition it was interesting to know about a significantly low immune response of patients with Drug Resistant TB to protein pp65 CMV.Туберкулез является одной из наиболее серьезных проблем российского здравоохранения. Россия остается в списке из 22 стран с высокой заболеваемостью туберкулезом и на 3-м месте в мире по распространенности лекарственно-устойчивых форм заболевания. Требуется разработка как новых методов диагностики, так и эффективных мер специфической профилактики, включая новые вакцины, для создания которых необходимо знание наиболее иммуногенных антигенов Mycobacterium tuberculosis. В данной работе исследовалась продукция интерферона-гамма в цельной крови пациентов с активным туберкулезом в ответ на антиген-стимуляцию различными белками Mycobacterium tuberculosis. Результаты исследования позволили дать оценку иммуногенности ранее изученных белков (Ag85a и ESAT -6) в сравнении с недавно идентифицированными белками (Rv 2957, Rv 2958c и Rv0447) с одновременным изучением их отношений к туберкулину и антигенам различных вирусов (вирус иммунодефицита человека, цитомегаловирус, вирус Эпштейна – Барр, вирус гриппа). Белок Rv2958c, в отличие от белка ESAT T-6, показал большую иммуногенность при сравнении с туберкуэффективлином. Выраженная иммуногенность белка Rv2958c может свидетельствовать о возможно большей специфичности иммунного ответа на этот антиген у больных туберкулезом. Между тем бактериовыделение было ассоциировано с достоверно низким иммунным ответом на данный белок. Также выявлены статистические различия в иммунореактивности пациентов к различным антигенам Mycobacterium tuberculosis в зависимости от наличия или отсутствия лекарственной устойчивости возбудителя. Представляет интерес достоверно низкая иммунореактивность пациентов с лекарственно-устойчивым туберкулезом в отношении белка pp65 CMV

Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis

Supported by F. Hoffmann–La Roche

Spinal muscular atrophy: a perspective outlook

Background. Recent decades have witnessed a leap in understanding the molecular genetic bases of spinal muscular atrophy for a considerable improvement in diagnosis and treatment of this disease and development of innovative therapies for correcting genetic deficiencies. Given scarcity of etiotropic therapies for spinal muscular atrophy, traditional effective approaches remain relevant to target pathophysiological mechanisms of the disease progression and demand further development and improvement.Objectives. Efficacy assessment of proactive therapy to spinal muscular atrophy based on electromyographic techniques using verifiable patient-specific functional scales.Methods. The study is designed as a prospective cohort study conducted at the Republican Clinical Centre for Neurorehabilitation. We used a 15-year monitoring data on 95 children (66 boys and 29 girls) with genetically confirmed proximal spinal muscular atrophy. Patients were divided in two cohorts. The main cohort (65 children) received personalised therapy based on a proactive comprehensive stepwise approach to isolate a stem pathological pattern with clinical and electromyographic data. The comparison cohort (30 children) received conventional symptomatic therapy, including neurometabolic, cholinotropic drugs, classical massage and physiotherapy. In the study design, functional capacities and electromyographic data were estimated in a standardised time scheme with reference points («baseline», «1 year», «3 years», «5 years»).Results. The proposed methodology for clinical and electromyographic data sampling at different points of the disease progression has yielded results. We registered a weaker pathological progression in the main cohort reflected by less pronounced motor deficiency and electromyographic pathology compared to the comparison group receiving conventional symptomatic therapy.Conclusion. Dynamic monitoring of clinical and neurological disorders using modern assessment scales and extended electromyography of morbid motor markers enables a personalised proactive clinically justified treatment to suppress complications and manifestation of pathology

Ways to Improve Speed GaAs-Transistor Schottky and Selective Doped Heterotranzystors for the Formation of Modern Microwave Circuits

There is no doubt that the use of technology with field-effect transistors on GaAs Schottky to form a high-speed LSI has a great future. No fewer prospects facing unique in its properties SLHT - technology for the design of modern LSI / VLSI. In the case of SLHT can satisfy three main technological criteria: performance, low power consumption and hichnist technological and manufacturing process of complex structures BI

Antigen induced production of υ-interferon ex vivo, in the peripheral blood of patients with active pulmonary tuberculosis

Tuberculosis (TB) is one of the most significant problems in the Russian Health Care. Russia remains on the list of the 22 countries with a high TB incidence and on the third place in the world with a high prevalence of Drug Resistant TB [1]. It is urgently needed to develop new TB diagnostic methods as well as effective measures of the specific TB prevention, including a development of the novel vaccines, so we have to know better about the most immunogenic antigens of Mycobacterium Tuberculosis. We studied the Interferon-Q production in the whole blood after stimulating immune response with different proteins of Mycobacterium Tuberculosis in patients with active TB. The study results permitted us to evaluate the immunogenicity of the previously known proteins (Ag85a и ESAT-6) in comparison to the recently identified ones (Rv2957, Rv2958c и Rv0447), analyzing simultaneously their relation to tuberculin, as well as to antigens of the different viruses (Human Immunodeficiency Virus, Cytomegalovirus, Epstein-Barr Virus, Influenza Virus). Protein Rv2958c, unlike protein ESAT-6, showed the high immunogenicity in comparison to tuberculin. The expressed immunogenicity of protein Rv2958c might be indicated a possible greatest specificity of immune response to this antigen in TB patients. Meanwhile, bacillary tuberculosis was strongly associated with low immune response to this protein. Also we were found statistical differences in immune responses of patients to the different Mycobacterium Tuberculosis antigens depending on the drug sensitivity. In addition it was interesting to know about a significantly low immune response of patients with Drug Resistant TB to protein pp65 CMV