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Front Pediatr. 2022 Oct 5;10:1017195. doi: 10.3389/fped.2022.1017195. eCollection 2022.

ABSTRACT

C3 is a crucial protein of the complement system. Congenital C3 deficiency is extremely rare and manifests through recurrent, severe infections and should always be considered as a differential diagnosis of recurrent pyogenic infections. We report a case of a patient with a novel C3 gene mutation, responsible for complete C3 deficiency with impaired complement system activation and recurrent infections.

PMID:36299691 | PMC:PMC9589888 | DOI:10.3389/fped.2022.1017195

Viruses. 2022 Sep 30;14(10):2157. doi: 10.3390/v14102157.

ABSTRACT

Selective gene delivery to a cell type of interest utilizing targeted lentiviral vectors (LVs) is an efficient and safe strategy for cell and gene therapy applications, including chimeric antigen receptor (CAR)-T cell therapy. LVs pseudotyped with measles virus envelope proteins (MV-LVs) have been retargeted by ablating binding to natural receptors while fusing to a single-chain antibody specific for the antigen of choice. However, the broad application of MV-LVs is hampered by the laborious LV engineering required for every new target. Here, we report the first versatile targeting system for MV-LVs that solely requires mixing with biotinylated adapter molecules to enable selective gene transfer. The analysis of the selectivity in mixed cell populations revealed transduction efficiencies below the detection limit in the absence of an adapter and up to 5000-fold on-to-off-target ratios. Flexibility was confirmed by transducing cell lines and primary cells applying seven different adapter specificities in total. Furthermore, adapter mixtures were applied to generate CAR-T cells with varying CD4/CD8-ratios in a single transduction step. In summary, a selective and flexible targeting system was established that may serve to improve the safety and efficacy of cellular therapies. Compatibility with a wide range of readily available biotinylated molecules provides an ideal technology for a variety of applications.

PMID:36298713 | DOI:10.3390/v14102157

Genes (Basel). 2022 Oct 20;13(10):1912. doi: 10.3390/genes13101912.

ABSTRACT

Dominant negative mutations in the STAT3 gene account for autosomal dominant hyper-IgE syndrome (AD-HIES). Patients typically present high IgE serum levels, recurrent infections, and soft tissue abnormalities. While current therapies focus on alleviating the symptoms, hematopoietic stem cell transplantation (HSCT) has recently been proposed as a strategy to treat the immunological defect and stabilize the disease, especially in cases with severe lung infections. However, because of the potentially severe side effects associated with allogeneic HSCT, this has been considered only for a few patients. Autologous HSCT represents a safer alternative but it requires the removal of the dominant negative mutation in the patients’ cells prior to transplantation. Here, we developed allele-specific CRISPR-Cas9 nucleases to selectively disrupt five of the most common STAT3 dominant negative alleles. When tested ex vivo in patient-derived hematopoietic cells, allele-specific disruption frequencies varied in an allele-dependent fashion and reached up to 62% of alleles harboring the V637M mutation without detectable alterations in the healthy STAT3 allele. However, assessment of the gene expression profiles of the STAT3 downstream target genes revealed that, upon activation of those edited patient cells, mono-allelic STAT3 expression (functional haploinsufficiency) is not able to sufficiently restore STAT3-dependent signaling in edited T cells cultured in vitro. Moreover, the stochastic mutagenesis induced by the repair of the nuclease-induced DNA break could further contribute to dominant negative effects. In summary, our results advocate for precise genome editing strategies rather than allele-specific gene disruption to correct the underlying mutations in AD-HIES.

PMID:36292796 | DOI:10.3390/genes13101912

Genes (Basel). 2022 Oct 19;13(10):1900. doi: 10.3390/genes13101900.

ABSTRACT

BACKGROUND: Inborn errors of immunity (IEIs) are comprised of heterogeneous groups of genetic disorders affecting immune function. In this report, a 17-month-old Malay patient suspected of having Hyper IgM syndrome, a type of IEIs, was described. However, the diagnosis of Hyper IgM syndrome was excluded by the normal functional studies and the mild features of ectodermal dysplasia observed from a further clinical phenotype inspection.

METHODS: Whole-exome sequencing (WES) was performed to unravel the causative mutation in this patient.

RESULTS: The variant analysis demonstrated a novel missense mutation in NFKBIA (NM_020529:c.94A > T,NP_065390:p.Ser32Cys) and was predicted as damaging by in silico prediction tools. The NFKBIA gene encodes for IκBα, a member of nuclear factor kappa B (NF-κB) inhibitors, playing an important role in regulating NF-κB activity. The mutation occurred at the six degrons (Asp31-Ser36) in IκBα which were evolutionarily conserved across several species. Prediction analysis suggested that the substitution of Ser32Cys may cause a loss of the phosphorylation site at residue 32 and a gain of the sumoylation site at residue 38, resulting in the alteration of post-translational modifications of IκBα required for NF-κB activation.

CONCLUSION: Our analysis hints that the post-translational modification in the NFKBIA Ser32Cys mutant would alter the signaling pathway of NF-κB. Our findings support the usefulness of WES in diagnosing IEIs and suggest the role of post-translational modification of IκBα.

PMID:36292785 | DOI:10.3390/genes13101900

Diagnostics (Basel). 2022 Oct 7;12(10):2423. doi: 10.3390/diagnostics12102423.

ABSTRACT

Predominantly antibody deficiencies are the most frequent type of primary immunodeficiency (PID). Diagnosis requires evaluation of the immune function by distinguishing the presence or absence of a response against polysaccharide antigens. Salmonella enterica serovar Typhi-based vaccines have proved to be a suitable tool. We studied a group of patients with suspicion of primary immunodeficiency and classified them by final diagnosis. We analyzed the vaccination response to S. Typhi and other immune biomarkers and clinical data. The aim of this study was to classify patients regarding the intensity of their immune response measured as the difference between specific immunoglobulin G levels before and after vaccination and antibody levels in the post-vaccination sample in order to improve clinical decisions regarding follow up and treatment of immunodeficiency patients. We established four groups of response: Non responders (NR), Low responders (LR), Intermediate responders (IR), and High responders (HR), where we found differences in IgG, IgG1, IgG2, IgG4, IgA, IgA1, IgA2, and IgM, and where the finally achieved diagnosis was also different and corresponding to the level of vaccination response.

PMID:36292112 | DOI:10.3390/diagnostics12102423

Children (Basel). 2022 Oct 7;9(10):1534. doi: 10.3390/children9101534.

ABSTRACT

Idiopathic CD4 Lymphopenia is a heterogeneous condition, recognized in the late 20th century, with a wide spectrum of presentations, requiring a high index of suspicion to avoid misdiagnosing the condition. This case highlights the diversity in its clinical presentations in the context of an autosomal dominant pattern of inheritance. We are reporting a case of a nine-year-old child, initially labelled by her primary treating hospital as primary ciliary dyskinesia after presenting with chronic cough, purulent nasal discharge, and recurrent chest infections. She was referred to our facility, a tertiary center, as her condition marginally improved. After the patient has undergone a comprehensive diagnostic workup, including a gene study, she was found to be carrying a mutation known to cause idiopathic CD4 lymphopenia. Extended work up of her family showed that two of her siblings have inherited an autosomal dominant mutation from their mother who had a milder form of the disease. This condition is an extremely rare condition in children, which can be easily mislabeled. Thus, healthcare providers should avoid labeling certain long-standing diseases unless the diagnosis has been established. We encourage leveraging the use of the latest revolutionary genetic testing techniques to confirm the diagnosis of such puzzling cases.

PMID:36291470 | DOI:10.3390/children9101534

Biomedicines. 2022 Oct 14;10(10):2570. doi: 10.3390/biomedicines10102570.

ABSTRACT

Nitric oxide (NO), a signaling molecule, regulates multiple biological functions, including a variety of physiological and pathological processes. In this regard, NO participates in cutaneous inflammations, modulation of mitochondrial functions, vascular diseases, COVID-19, neurologic diseases, and obesity. It also mediates changes in the skeletal muscle function. Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder characterized by the malfunction of phagocytes caused by mutations in some of the genes encoding subunits of the superoxide-generating phagocyte NADPH (NOX). The literature consulted shows that there is a relationship between the production of NO and the NADPH oxidase system, which regulates the persistence of NO in the medium. Nevertheless, the underlying mechanisms of the effects of NO on CGD remain unknown. In this paper, we briefly review the regulatory role of NO in CGD and its potential underlying mechanisms.

PMID:36289832 | DOI:10.3390/biomedicines10102570

Ter Arkh. 2021 Dec 15;93(12):1522-1527. doi: 10.26442/00403660.2021.12.201176.

ABSTRACT

Common variable immunodeficiency (CVID) is one form of the primary immunodeficiencies (PIDs). CVID is characterized by variable clinical manifestations. Genetic alteration is a cause of the disease in many cases. In the current paper we described Patient N of 45 years old, who have been suffering from frequent various infections and therefore attended an immunologist and clinical geneticist. Immunoglobulins (Ig) A, M, and G deficiency was found in the patient. As a result of medical genetic counselling primary immunodeficiency has been suggested as a diagnosis. Further molecular genetic testing using clinical exome sequencing (Next Generation Sequencing method) revealed a likely-pathogenic variant c.204dupA (p.Leu69ThrfsX12, rs72553875) of TNFRSF13B gene in the patient. The gene variant was found in homozygous state. According to the international medical literature and genomic databases TNFRSF13B gene mutations lead to the CVID development and in some patients are characterized by isolated IgA deficiency and in the other group of patients can lead to decrease of IgA, IgM, and IgG. The patient had a family history of cancer and autoimmune inflammatory bowel disease (erosive-ulcerative enterocolitis). Moreover, one sibling of the patient died at the age of 3 weeks from complications of toxoplasmosis infection. The other sibling of 51 years old have been also suffering from recurrent infectious diseases. Thus, the genetic cause of the disease was identified in the proband. It has been shown that homozygosity for variant c.204dupA of TNFRSF13B gene is characterized by the deficiency of all three classes of Ig. Medical genetic counselling and modern molecular genetic methods application is an important step in management of people with signs of immunodeficiency. Such approach helps to make a diagnosis to the patient, to find an exact molecular reason of the condition, to use effective treatment, and to perform preventive measures in patient`s family.

PMID:36286682 | DOI:10.26442/00403660.2021.12.201176

Rev Esp Quimioter. 2022 Oct;35 Suppl 3:63-66. doi: 10.37201/req/s03.14.2022. Epub 2022 Oct 24.

ABSTRACT

Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency (PID) in general population. PID are genetic diseases that share a dysfunction in the immune system entailing a greater risk of both chronic and recurrent infections. These patients can also develop chronic gastrointestinal infections caused by norovirus with persistent viral dissemination, which can be detected months after primoinfection. Additionally, a proportion of CVID patients show a typical severe enteropathy presenting with recurrent diarrhoea, intestinal malabsorption, inflammatory lesions, and villous atrophy. Some studies have related this enteropathy with chronic intestinal infection caused by norovirus.

PMID:36285861 | DOI:10.37201/req/s03.14.2022

Clin Infect Dis. 2022 Oct 26:ciac842. doi: 10.1093/cid/ciac842. Online ahead of print.

ABSTRACT

BACKGROUND: Primary immunodeficiencies (PIDs) in adults are mainly revealed by recurrent and/or severe bacterial infections. The objective of this study was to evaluate a systematic research strategy of PIDs in adults with unexplained bacterial infections, with a special focus on specific polysaccharide antibody deficiency (SPAD).

MATERIALS/METHODS: In this prospective multicenter study, inclusion criteria were recurrent benign upper and lower respiratory tract infections (RTIs) for at least two years (group 1), at least one upper or lower RTI requiring hospitalization (group 2), and/or at least one invasive infection documented with encapsulated bacteria (group 3). Main exclusion criteria were all local and general conditions that could explain infections. If no PID diagnosis was made, response to polysaccharide antigens was assessed using a pneumococcal polysaccharide vaccine.

RESULTS: From March 2015 to March 2020, 118 patients were included (37 males, median age of 41 years): 73, 17, and 28 in groups 1, 2, and 3, respectively. Forty-seven PIDs were diagnosed, giving an estimated frequency of 39.8% (95% IC [30.4; 48.8]). SPAD was the most frequent diagnosis by far (n = 37/47, 78.7%), and was made in 23, 5, and 9 patients from groups 1 to 3, respectively. All SPAD patients received conjugate vaccines, and according to their infectious history, were on surveillance or treated with preventive antibiotics (n = 6) and/or with immunoglobulins replacement therapy (n = 10), the latter being dramatically efficient in all cases.

CONCLUSIONS: Considering its high prevalence among adults with unexplained recurrent and/or severe bacterial infections, SPAD should be screened in those patients.

PMID:36285530 | DOI:10.1093/cid/ciac842