Identification of candidate disease genes in patients with common variable immunodeficiency

Background: Common variable immunodeficiency (CVID), the most prevalent form of primary immunodeficiency (PID), is characterized by hypogammaglobulinemia and recurrent infections. Understanding protein-protein interaction (PPI) networks of CVID genes and identifying candidate CVID genes are critical steps in facilitating the early diagnosis of CVID. Here, the aim was to investigate PPI networks of CVID genes and identify candidate CVID genes using computation techniques. Methods: Network density and biological distance were used to study PPI data for CVID and PID genes obtained from the STRING database. Gene expression data of patients with CVID were obtained from the Gene Expression Omnibus, and then Pearson’s correlation coefficient, a PPI database, and Kyoto Encyclopedia of Genes and Genomes were used to identify candidate CVID genes. We then evaluated our predictions and identified differentially expressed CVID genes. Results: The majority of CVID genes are characterized by a high network density and small biological distance, whereas most PID genes are characterized by a low network density and large biological distance, indicating that CVID genes are more functionally similar to each other and closely interact with one other compared with PID genes. Subsequently, we identified 172 CVID candidate genes that have similar biological functions to known CVID genes, and eight genes were recently reported as CVID-related genes. MYC, a candidate gene, was down-regulated in CVID duodenal biopsies, but up-regulated in blood samples compared with levels in healthy controls. Conclusion: Our findings will aid in a better understanding of the complex of CVID genes, possibly further facilitating the early diagnosis of CVID.[Figure not available: see fulltext.]. © 2019, Higher Education Press and Springer-Verlag GmbH Germany, part of Springer Nature.This study was funded by the Act 211 Government of the Russian Federation (No. 02.A03.21.0006) and the IIP UB RAS project (No. AAAA-A18-118020590108-7)

APPLICATION OF DIFFERENT LABORATORY METHODS FOR ANTINUCLEAR AUTOANTIBODIES INVESTIGATION IN PATIENTS WITH AUTOIMMUNE CONNECTIVE TISSUE DISEASES

1222 patients with suspicion of different autoimmune connective tissue diseases are investigated. Antinuclear antibodies by indirect immunofluorescence reaction, by methods of ELISA and immunoblotting were determined. Laboratory tests results correlated with each other that testifies to satisfactory comparability of different laboratory methods. The most sensitive method for detection of antinuclear antibodies is indirect immunofluorescence. This is a preferable method for screening of autoimmune connective tissue diseases. At comparison of luminescence types in immunofluorescence test and results of immunoblotting was shown that for each type of a luminescence the set of antibody, revealed by immunoblotting, was characteristic. However, the same antibodies can be found in various types of fluorescence that complicates unequivocal interpretation of immunofluorescence test results. Antibodies to Ro-52 were most often found in all types of fluorescence, and also in the absence of that

A co-expression network for differentially expressed genes in bladder cancer and a risk score model for predicting survival

Background: Urothelial bladder cancer (BLCA) is one of the most common internal malignancies worldwide with poor prognosis. This study aims to explore effective prognostic biomarkers and construct a prognostic risk score model for patients with BLCA. Methods: Weighted gene co-expression network analysis (WGCNA) was used for identifying the co-expression module related to the pathological stage of BLCA based on the RNA-Seq data retrieved from The Cancer Genome Atlas database. Prognostic biomarkers screened by Cox proportional hazard regression model and random forest were used to construct a risk score model that can predict the prognosis of patients with BLCA. The GSE13507 dataset was used as the independent testing dataset to test the performance of the risk score model in predicting the prognosis of patients with BLCA. Results: WGCNA identified seven co-expression modules, in which the brown module consisted of 77 genes was most significantly correlated with the pathological stage of BLCA. Cox proportional hazard regression model and random forest identified TPST1 and P3H4 as prognostic biomarkers. Elevated TPST1 and P3H4 expressions were associated with the high pathological stage and worse survival. The risk score model based on the expression level of TPST1 and P3H4 outperformed pathological stage indicators and previously proposed prognostic models. Conclusion: The gene co-expression network-based study could provide additional insight into the tumorigenesis and progression of BLCA, and our proposed risk score model may aid physicians in the assessment of the prognosis of patients with BLCA

TRANSLATION INTO RUSSIAN OF THE CLASSIFICATION OF INBORN ERRORS OF IMMUNITY IN HUMANS UPDATED BY EXPERTS FROM A COMMITTEE ON CONGENITAL IMMUNITY ERRORS OF INTERNATIONAL UNION OF IMMUNOLOGICAL SOCIETIES (RUSSIAN VERSION 2019)

We present to Russian-speaking audience a translation and commentary on the classification of inborn errors of immunity presented at the end of 2019 by the Committee on Congenital Immunity Errors at the International Union of Immunological Societies (IUIS). Inborn errors of immunity, or, as they were called earlier, primary immunodeficiencies, is a rapidly expanding class of diseases that includes the most diverse congenital pathologies which can manifest at any age by heterogenous symptomes. Clinical masks characterize these diseases, hence the time from the onset of clinical disorder to the final diagnosis may take many years. A doctor of any specialty encounters these patients, and the molecular mechanisms of pathology concern different organs and systems of the patients. The classification consists of ten tables covering more than 400 syndromes and their corresponding genes, or associated chromosomal abnormalities. This is a tool, which allows navigating a wide variety of different primary immunodeficiencies, autoimmune and autoinflammatory syndromes, complement defects, and bone marrow failure syndromes. We hope that, due to translation, current knowledge about these various diseases will become more close and available to the Russian-speaking audience. © 2021, RSI © 2021, РНОИ

ROLE OF INNATE ERRORS OF IMMUNITY IN THE GROUP OF CHILDREN WITH FATAL OUTCOMES DURING THE FIRST YEAR OF LIFE

In the modern world, inborn errors of immunity (IEIs), or primary immunodeficiencies (PIDs), are among of the main causes of childhood disability and mortality, determining the demographic state of mankind not only at present, but also in the future. In the Sverdlovsk Region over the past 5 years, there were about 30% of children who died from severe combined primary immunodeficiency. This retrospective study is devoted to the study of the nosological profile of mortality in the children with immune-dependent disorders in the Sverdlovsk Region, as well as to assess information significance of extrachromosomal circular DNA molecules (TREC and KREC) analysis. Some anamnestic data on the course of prenatal period in the current and previous pregnancies were considered the signs of suggested diagnosis of primary immunodeficiencies, i.e., threats of pregnancy loss at the early terms, documented cases of early childhood death, persistent viral and bacterial infections in the mother, complicated course of pregnancy in the mother, as well as some clinical manifestations, including fungal-bacterial sepsis, generalized viral infection, repair disorders, reduced physiological tolerance accompanied by autoimmune organ damage and uncontrolled systemic inflammation. The study demonstrated a wide range of nosological entities of innate errors of immunity in the structure of early childhood mortality, including both classical forms of primary immunodeficiencies and the disorders not directly related to innate errors of immunity, but those showing phenotypically pronounced immunodeficiency and their immediate role in statistical deviations. Among the main criteria that may presume possible presence of an immune-dependent pathology in the early neonatal period we considered the molecular markers of naive T and B cells (TREC and KREC, respectively) revealed in 70% of the cases studied, with, at least, one of these indexes found to be reduced. It is important to understand that primary immunodeficiencies are not as rare as previously thought. Therefore, it is necessary to carry out timely and high-quality diagnostics, in order to avoid unavoidable deaths. © 2022, RSI

Oral manifestations of primary immunodeficiencies

To understand the current state of the issue of dental manifestations of primary immunodeficiencies, foreign literature on the problem has been analyzed. The article describes the dental manifestations of many primary immunodeficiencies, which can be both secondary and major symptoms. The article presents the data on the following syndromes: severe combined immunodeficiency, hyper IgE, Wiskott - Aldrich, DiGeorge, deficiency of STIM1 and ORAI1, NEMO deficiency and IκBα deficiency, common variable immunodeficiency, X-linked agammaglobulinemia, hyper IgM, selective IgA deficiency, autoimmune lymphoproliferative syndrome, autoimmune polyendocrine syndrome type 1, Chediak - Higashi syndrome, CD70 deficiency, severe congenital neutropenia syndromes, leukocyte adhesion deficiency, localized aggressive periodontitis, Papillon - Lefevre syndrome, chronic mucocutaneous candidiasis, Marshall syndrome, hyper IgD syndrome, Aicardi - Goutières syndrome type 7, cherubism syndrome, CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature), PAPA (pyogenic arthritis, pyoderma gangrenosum and acne), chronic recurrent multifocal osteomyelitis, periodontal Ehlers - Danlos syndrome, and C1 inhibitor deficiency. The role of secretory immunoglobulins of salivary fluid is described. © 2019 Siberian State Medical University. All rights reserved.Ural Branch, Russian Academy of Sciences, UB RAS: АААА-А18-118020590108-7Sourse of financing. The study was supported by the state order of the Institute of Immunology and Physiology of the Ural Branch of the Russian Academy of Sciences (topic No. АААА-А18-118020590108-7) as well as by the decree of the Russian Federation Government No. 211, contract No. 02.A03.21.0006

Predicting the Most Deleterious Missense Nonsynonymous Single-Nucleotide Polymorphisms of Hennekam Syndrome-Causing CCBE1 Gene, in Silico Analysis

Hennekam lymphangiectasia-lymphedema syndrome has been linked to single-nucleotide polymorphisms in the CCBE1 (collagen and calcium-binding EGF domains 1) gene. Several bioinformatics methods were used to find the most dangerous nsSNPs that could affect CCBE1 structure and function. Using state-of-the-art in silico tools, this study examined the most pathogenic nonsynonymous single-nucleotide polymorphisms (nsSNPs) that disrupt the CCBE1 protein and extracellular matrix remodeling and migration. Our results indicate that seven nsSNPs, rs115982879, rs149792489, rs374941368, rs121908254, rs149531418, rs121908251, and rs372499913, are deleterious in the CCBE1 gene, four (G330E, C102S, C174R, and G107D) of which are the highly deleterious, two of them (G330E and G107D) have never been seen reported in the context of Hennekam syndrome. Twelve missense SNPs, rs199902030, rs267605221, rs37517418, rs80008675, rs116596858, rs116675104, rs121908252, rs147974432, rs147681552, rs192224843, rs139059968, and rs148498685, are found to revert into stop codons. Structural homology-based methods and sequence homology-based tools revealed that 8.8% of the nsSNPs are pathogenic. SIFT, PolyPhen2, M-CAP, CADD, FATHMM-MKL, DANN, PANTHER, Mutation Taster, LRT, and SNAP2 had a significant score for identifying deleterious nsSNPs. The importance of rs374941368 and rs200149541 in the prediction of post-translation changes was highlighted because it impacts a possible phosphorylation site. Gene-gene interactions revealed CCBE1's association with other genes, showing its role in a number of pathways and coexpressions. The top 16 deleterious nsSNPs found in this research should be investigated further in the future while researching diseases caused CCBE1 gene specifically HS. The FT web server predicted amino acid residues involved in the ligand-binding site of the CCBE1 protein, and two of the substitutions (R167W and T153N) were found to be involved. These highly deleterious nsSNPs can be used as marker pathogenic variants in the mutational diagnosis of the HS syndrome, and this research also offers potential insights that will aid in the development of precision medicines. CCBE1 proteins from Hennekam syndrome patients should be tested in animal models for this purpose. © 2021 Khyber Shinwari et al.The work was carried out within the framework of state research at the Institute of Immunology and Physiology of the Ural Branch of the Russian Academy of Sciences, project number AAAA-A21-121012090091-6

Неонатальный скрининг на тяжелую комбинированную иммунную недостаточность в России: прекрасное дале ко или завтрашняя реальность?

Mass screening of newborns in Russia for five hereditary diseases does not meet the requirements of the world community for the neonatal screening program. Success in the development of laboratory diagnostic technologies and active introduction of achievements in genetics and molecular biology into medical practice allow for the revision of the list of nosologies included in the national neonatal screening program by replacing the disease or adding new nosologies. The article discusses the possibility of including genetic testing for severe combined immune deficiency in the Newborn Screening Program in Russia. The results from a retrospective study of markers of naive T- and B-lymphocytes (TREC and KREC) in the group of children with immuno-dependent pathology developed in the first year of life are discussed. © 2017 Voprosy Sovremennoi Pediatrii - Current Pediatrics. All rights reserved

Molecular diagnostics of primary immunodeficiencies in Sverdlovsk region

The article presents the results of the work performed by the laboratory of molecular diagnostics at the Medical Center “Health Care of Mother and Child” for the diagnosis of primary immunodeficiency in Sverdlovsk region over 5 years. The laboratory was organized in 2009 to verify the diagnosis of monogenic hereditary diseases included in the Neonatal Screening Program in the Russian Federation, e.g., phenylketonuria, cystic fibrosis, classical galactosemia. Over time, the range of diagnosed nosologies expanded, and since 2014, the laboratory has included in studies of a new group of disorders, i.e., congenital errors of immunity. Every year the Regional Registry of patients with primary immunodeficiencies (PIDs) replenished by 20 to 70 persons, thus comprising 15 to 43% of the entire Russian Registry for these conditions. As of 03/01/2020, the registry of patients with a clinical diagnosis of “primary immunodeficiency” consisted of 526 people, more than half of them (275) being children under 18 years of age. According to the expert calculations, the frequency of detected PID cases in the Sverdlovsk region is 1:10 480 inhabitants, which indicates not only high level of the existing clinical immunology service, but also the high expected frequency of PID in the region. Until 2014, verification of the “primary immunodeficiency” diagnosis in the patients from Sverdlovsk region was traditionally carried out in Moscow clinics (Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow Research Centre for Medical Genetics). Over 6 years of cooperation between regional immunological service with the medical genetic center, 47 children received molecular genetic confirmation of the diagnosis of congenital immunity errors at the laboratory of Regional Medical Center “Health Care of Mother and Child”. The authors present the data of Regional Registry of patients, classified into nosological forms of immune-dependent pathology and provide a detailed description of diagnostic procedures for the patients with various PIDs. A deletion of chromosome 22 (Di Giorgi syndrome) was found in 43 people, mutations in the Btk gene (X-linked agammaglobulinemia) were revealed in 7 patients and 6 members of their families, Nijmegen syndrome was confirmed in 1 child, a familial case of ADA-deficiency, difficult for diagnostics, was decided. The results of the study encourage the authors for further expansion of the spectrum of detectable disorders diagnosis, and give a hope that development of regional laboratories at this level may improve the diagnostic algorithm for PID diagnostic procedures in Russia, i.e., from prenatal and neonatal screening to the development of gene therapy for certain forms of immune-dependent disorders