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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.

Severe combined immunodeficiency (SCID) is effectively treated with hematopoietic cell transplantation (HCT), with overall survival approaching 90% in contemporary reports. However, survivors are at risk for developing late complications because of the variable durability of high-quality immune function, underlying genotype of SCID, comorbidities due to infections in the pretransplantation and post-transplantation periods, and use of conditioning before transplantation. An international group of transplantation experts was convened in 2016 to review the current knowledge of late effects seen in SCID patients after HCT and to develop recommendations for screening and monitoring for late effects. This report provides recommendations for screening and management of pediatric and adult SCID patients treated with HCT.

The molecular mechanisms involved colon cancer tumorigenesis and development of colon cancer remain unclear. The aim of this study is to explore the inhibitive effects of NM-3 on lymphatic vessel density and vascular endothelial growth factor of micrometastatic lesion of orthotopic implantated colon cancer in the severe combined immune deficiency (SCID) nude mice. Human colon cancer SW1116 cells were orthotopically implantated into the colon of the nude mice. Twenty-eight SCID nude mice were randomly divided into four groups (7 mice for each group) after one week feeding and then the nude mice were treated with carboplatin and NM-3 via intraperitoneal injection twice a week for 8 weeks. The mice were sacrificed after 8 weeks and the vascular endothelial growth factor-C (VEGF-C), VEGF-D, VEGF-R-3 and lymphatic vessel density (LVD) were analyzed using immunohistochemistry staining assay. LVD in NM-3 treated mice was significantly lower than that of control (normal saline treated) mice. The expression of VEGF-C, VEGF-D, and VEGF-R-3 and the expression of mRNA of VEGF-C, VEGF-D, and VEGF-R-3 in NM-3 treated mice were significantly lower than that of control mice. The NM-3 inhibited the growth of colon cancer in the SCID mice of orthotopic implantatation model, and this effect may be related to the inhibitive effects of NM-3 on the lymphangiogenesis and vascular endothelial growth factor in colon cancer. NM-3 and carboplatin played a synergistic role in inhibiting lymphangiogenesis of human colon cancer in SCID nude mice and the further investigation of molecular mechanisms involved in colon cancer metastasis will provide an important evidence for understanding of lymphangiogenesis of human colon cancer.

A successful gene therapy clinical trial that also encountered serious adverse effects has sparked extensive study and debate about the future directions for retrovirus-mediated interventions. Treatment of X-linked severe combined immunodeficiency with an oncoretrovirus harboring a normal copy of the gammac gene was applied in two clinical trials, essentially curing 13 of 16 infants, restoring a normal immune system without the need for additional immune-related therapies. Approximately 3 years after their gene therapy, tragically, 3 of these children, all from the same trial, developed leukemia as a result of this experimental treatment. The current understanding of the mechanism behind this leukemogenesis involves three critical and cooperating factors, i.e., viral integration, oncogene activation, and the function of the therapeutic gene. In this review, we will explore the causes of this unwanted event and some of the possibilities for reducing the risk of its reoccurrence.

Background The recombination-activating gene (RAG) 1/2 proteins play a critical role in the development of T and B cells by initiating the VDJ recombination process that leads to generation of a broad T-cell receptor (TCR) and B-cell receptor repertoire. Pathogenic mutations in the RAG1/2 genes result in various forms of primary immunodeficiency, ranging from T-B - severe combined immune deficiency to delayed-onset disease with granuloma formation, autoimmunity, or both. It is not clear what contributes to such heterogeneity of phenotypes. Objective We sought to investigate the molecular basis for phenotypic diversity presented in patients with various RAG1 mutations. Methods We have developed a flow cytometry-based assay that allows analysis of RAG recombination activity based on green fluorescent protein expression and have assessed the induction of the Ighc locus rearrangements in mouse Rag1-/- pro-B cells reconstituted with wild-type or mutant human RAG1 (hRAG1) using deep sequencing technology. Results Here we demonstrate correlation between defective recombination activity of hRAG1 mutant proteins and severity of the clinical and immunologic phenotype and provide insights on the molecular mechanisms accounting for such phenotypic diversity. Conclusions Using a sensitive assay to measure the RAG1 activity level of 79 mutations in a physiologic setting, we demonstrate correlation between recombination activity of RAG1 mutants and the severity of clinical presentation and show that RAG1 mutants can induce specific abnormalities of the VDJ recombination process. © 2013 American Academy of Allergy, Asthma & Immunology.

Severe combined immunodeficiency (SCID) syndromes are characterized by a block in T lymphocyte differentiation that is variably associated with abnormal development of other lymphocyte lineages (B and/or natural killer [NK] cells), leading to death early in life unless treated urgently by hematopoietic stem cell transplant. SCID comprises genotypically and phenotypically heterogeneous conditions, of which the genetic basis for approximately 85% of the underlying immunologic defects have been recently elucidated. A major obstacle in deciphering the pathogenesis of SCID syndromes is that different mutations in a single gene may give rise to distinct clinical conditions and that a similar clinical phenotype can result from mutations in different genes. Mutation analysis is now an important component of the complete evaluation of a patient with SCID since it has a dramatic impact on many aspects of this potentially life-threatening disease such as genetic counseling, prenatal diagnosis, modalities of treatment, and, eventually, prognosis. Dr Robert Good, one of the founders of modern immunology, described the SCID syndrome as "experiments of nature." By understanding the cellular and genetic basis of these immunodeficiency diseases and, eventually, normal immunity, we optimize the "bedside to research laboratory and back again" approach to medicine.

This study analyzes the hematopoietic cell transplantation experience in patients with immune deficiency at a single institution. The objective is to comprehensively evaluate the short-term and long-term outcomes with various preparative regimens, donor grafts, and ex vivo manipulations to identify transplantation approaches that most likely favor early donor immune competency without generating excessive toxicity. Clinical outcomes were evaluated in 52 consecutive patients with immune deficiencies. Thirty-seven of the 52 patients (71%) survived with attenuation of their underlying disease. The use of a melphalan-based reduced-intensity conditioning preparative regimen and immunomagnetic CD3(+) T cell depletion techniques (when T cell depletion was indicated) were associated with improved event-free survival. Survivors who received a preparative regimen other than a melphalan-based reduced-intensity regimen suffered from therapy-related morbidities or chronic/recurrent infections. Our findings indicate that melphalan-based reduced-intensity conditioning regimens and immunomagnetic CD3(+) T cell depletion limit therapy-related toxicity, and demonstrate promising results for the early establishment of donor immune competency.

Severe combined immunodeficiency (SCID) represents a rare group of primary immunodeficiency disorders (PIDs), with known or unknown genetic alterations. Here, we report a new interleukin 2 receptor, gamma chain (IL-2RG) mutation in an Iranian SCID newborn.The patient was a 6-day old boy with a family history of PID. The child was screened using a molecular-based analysis for the assessment of T cell receptor excision circles (TRECs) and kappa-deleting recombination excision circles (KRECs). Moreover, a complete immunological evaluation and gene sequencing was performed.Results showed undetectable TREC but a high level of KREC copy numbers. Flow cytometric data indicated low numbers of T and NK cells, but elevated number of B cells. A novel substitution in IL2RG: c.675 C>A, leading to p.225 Ser>Arg was found. Based on the functional analysis, the mutation is predicted to be damaging. The patient was diagnosed as a T B+ NK X-linked SCID.

Background While primary immunodeficiencies (PID has been recognized in the west for decades, recognition has been delayed in the third world. This study attempts to detail the spectrum of PID, the therapy provided, and constraints in the diagnosis and treatment in a middle income country such as Sri Lanka. Methods Nine hundred and forty two patients with recurrent infections and features suggestive of immune deficiency, referred from the entire country in a 4 year period, to the sole immunology unit in Sri Lanka were included. The following tests were performed. Full blood counts, serum Immunoglobulin and complement C3 and C4 levels, functional antibody levels, enumeration of lymphocyte subsets, in vitro and in vivo T cell functional assays,, nitroblue tetrazolium assay to diagnose chronic granulomatous disease, hair shaft assay to diagnose Griscelli syndrome. Sequencing of the common gamma chain to identify x linked severe combined immune deficiency, and X linked agammaglobulinemia was confirmed by assaying for Btk mutations by single sequence conformation polymorphism. HIV/AIDS was excluded in all patients. Results Seventy three patients were diagnosed with a primary immune deficiency. The majority (60.27%) had antibody deficiency. Common variable immune deficiency was the commonest (28.76%), followed by X linked agammaglobulinemia (XLA) (20.54%). Five patients had possible hyper IgM syndrome. Ten patients had severe combined immune deficiency (SCID), including 2 with x linked SCID, in addition to DiGeorge syndrome (2), ataxia telangiectasia (6), autosomal dominant hyper IgE syndrome (2), chronic granulomatous disease (4), leucocyte adhesion deficiency type 1 (2) and Griscelli syndrome (3). Patients with autoinflammatory, innate immune and complement defects could not be identified due to lack of facilities. Conclusions Antibody deficiency is the commonest PID, as in the west.IgA deficiency is rare. Autoinflammatory diseases, innate immune and complement deficiencies could not be identified due to lack of diagnostic facilities. Lack of awareness of PID among adult physicians result in delay in treatment of adult patients. While treatment of antibody deficiencies provided in state hospitals has extended life expectancy, there is no treatment available for severe T cell defects.