-
Frontiers in Immunology 2023Recombination activating genes () 1 and 2 defects are the most frequent form of severe combined immunodeficiency (SCID). Patients with residual RAG activity have a...
INTRODUCTION
Recombination activating genes () 1 and 2 defects are the most frequent form of severe combined immunodeficiency (SCID). Patients with residual RAG activity have a spectrum of clinical manifestations ranging from Omenn syndrome to delayed-onset combined immunodeficiency, often associated with granulomas and/or autoimmunity (CID-G/AI). Lentiviral vector (LV) gene therapy (GT) has been proposed as an alternative treatment to the standard hematopoietic stem cell transplant and a clinical trial for RAG1 SCID patients recently started. However, GT in patients with hypomorphic RAG mutations poses additional risks, because of the residual endogenous RAG1 expression and the general state of immune dysregulation and associated inflammation.
METHODS
In this study, we assessed the efficacy of GT in 2 hypomorphic Rag1 murine models (Rag1 and Rag1), exploiting the same LV used in the clinical trial encoding RAG1 under control of the MND promoter.
RESULTS AND DISCUSSION
Starting 6 weeks after transplant, GT-treated mice showed a decrease in proportion of myeloid cells and a concomitant increase of B, T and total white blood cells. However, counts remained lower than in mice transplanted with WT Lin- cells. At euthanasia, we observed a general redistribution of immune subsets in tissues, with the appearance of mature recirculating B cells in the bone marrow. In the thymus, we demonstrated correction of the block at double negative stage, with a modest improvement in the cortical/medullary ratio. Analysis of antigenspecific IgM and IgG serum levels after challenge showed an amelioration of antibody responses, suggesting that the partial immune correction could confer a clinical benefit. Notably, no overt signs of autoimmunity were detected, with B-cell activating factor decreasing to normal levels and autoantibodies remaining stable after GT. On the other hand, thymic enlargement was frequently observed, although not due to vector integration and insertional mutagenesis. In conclusion, our work shows that GT could partially alleviate the combined immunodeficiency of hypomorphic RAG1 patients and that extensive efficacy and safety studies with alternative models are required before commencing RAG gene therapy in thesehighly complex patients.
Topics: Humans; Mice; Animals; Homeodomain Proteins; Immunologic Deficiency Syndromes; B-Lymphocytes; Severe Combined Immunodeficiency; Genetic Therapy; Immunoproteins; Mutation
PubMed: 38022635
DOI: 10.3389/fimmu.2023.1268620 -
Cureus Oct 2023Severe combined immunodeficiency (SCID) is a rare condition with very high mortality. SCID is mainly caused by the multiple mutations of genes affecting the entire... (Review)
Review
Severe combined immunodeficiency (SCID) is a rare condition with very high mortality. SCID is mainly caused by the multiple mutations of genes affecting the entire immune cells. Children with this disease are born with an impaired immune system. The child appears healthy but the consequences of the impaired immune system lead to various secondary infections such as meningeal infections and respiratory infections further leading to consolidation, diarrhea, inflammation of skin and other systemic diseases. Severe combined immunodeficiency is also known as "bubble boy disease" or "living in the bubble" syndrome, as in early days for treatment the physicians decided to completely isolate them until they got the perfect match for the bone marrow transplantation. It is one of the pediatric emergencies and is to be treated as soon as possible. SCID involves multiple genes which leads to makes diagnosis of the disease cumbersome. In early years many infants were diagnosed almost after half a year and in severe conditions which led to the decrease in the survival rate of the children. But now due to advanced newborn screening modalities and other monitoring systems it can be diagnosed as early as within three months of age. The various treatment modalities include hematopoietic stem cell transplantation, gene therapy, enzyme replacement therapy and chemotherapy. This narrative review article describes about the severe combined immunodeficiency and its newer treatment modalities.
PubMed: 38022338
DOI: 10.7759/cureus.47759 -
Journal of Korean Medical Science Nov 2023Combined malonic and methylmalonic aciduria is a rare genetic disorder caused by biallelic variants that results in impaired protein and fat metabolism and the...
Combined malonic and methylmalonic aciduria is a rare genetic disorder caused by biallelic variants that results in impaired protein and fat metabolism and the accumulation of malonic and methylmalonic acids. A 52-day-old infant with a fever and a history of possible meningitis during the neonatal period was hospitalized. Multiple lesions of necrotizing lymphadenitis with abscesses in the left inguinal area were treated by incision and drainage along with appropriate antibiotic therapy, which revealed a methicillin-resistant infection. At 6 months of age, the patient was admitted with anal abscesses. Due to the increased suspicion of primary immunodeficiency disease, genetic testing was conducted, which revealed biallelic variants inherited from both parents. Urine organic acid analysis revealed elevated levels of malonic and methylmalonic acids. At 29 months, the patient showed normal growth and development without any dietary modifications. He had occasional colds, but severe bacterial infections were absent. The prognosis suggests a benign disease course. Here, we present the first reported case of compound heterozygote variants in Korea.
Topics: Infant; Infant, Newborn; Male; Humans; Abscess; Methicillin-Resistant Staphylococcus aureus; Methylmalonic Acid; Primary Immunodeficiency Diseases
PubMed: 37987109
DOI: 10.3346/jkms.2023.38.e387 -
Frontiers in Cellular and Infection... 2023is a protozoan parasite and one of the leading causes of gastroenteritis in the world, primarily affecting very young children and immunocompromised patients. While...
is a protozoan parasite and one of the leading causes of gastroenteritis in the world, primarily affecting very young children and immunocompromised patients. While infection is usually self-limiting, it can become chronic and even lethal in these vulnerable populations, in whom treatments are generally ineffective, due to their acting in concert with a functioning immune system. Here, we describe a case of chronic cryptosporidiosis in a European child with severe CD40L immunodeficiency infected with of the IIa20G1 subgenotype, a lineage which has thus far only ever been described in the Middle East. After years of on-off treatment with conventional and non-conventional anti-parasitic drugs failed to clear parasitosis, we performed targeted metagenomics to observe the bacterial composition of the patient's gut microbiota (GM), and to evaluate fecal microbiota transplantation (FMT) as a potential treatment option. We found that infection led to significant shifts in GM bacterial composition in our patient, with consequent shifts in predicted intestinal functional signatures consistent with a state of persistent inflammation. This, combined with the patient's poor prognosis and increasing parasitic burden despite many rounds of anti-parasitic drug treatments, made the patient a potential candidate for an experimental FMT procedure. Unfortunately, given the many comorbidities that were precipitated by the patient's immunodeficiency and chronic infection, FMT was postponed in favor of more urgently necessary liver and bone marrow transplants. Tragically, after the first liver transplant failed, the patient lost his life before undergoing FMT and a second liver transplant. With this case report, we present the first description of how cryptosporidiosis can shape the gut microbiota of a pediatric patient with severe immunodeficiency. Finally, we discuss how both our results and the current scientific literature suggest that GM modulations, either by probiotics or FMT, can become novel treatment options for chronic infection and its consequent complications, especially in those patients who do not respond to the currently available anti-parasitic therapies.
Topics: Animals; Humans; Child; Child, Preschool; Cryptosporidiosis; CD40 Ligand; Gastrointestinal Microbiome; Cryptosporidium; Intestines; Immunologic Deficiency Syndromes; Parasites; Cryptosporidium parvum; Bacteria; Propionibacterium acnes
PubMed: 37965266
DOI: 10.3389/fcimb.2023.1281440 -
Stem Cell Research & Therapy Nov 2023A non-invasive imaging technology that can monitor cell viability, retention, distribution, and interaction with host tissue after transplantation is needed for...
BACKGROUND
A non-invasive imaging technology that can monitor cell viability, retention, distribution, and interaction with host tissue after transplantation is needed for optimizing and translating stem cell-based therapies. Current cell imaging approaches are limited in sensitivity or specificity, or both, for in vivo cell tracking. The objective of this study was to apply a novel ferritin-based magnetic resonance imaging (MRI) platform to longitudinal tracking of human embryonic stem cells (hESCs) in vivo.
METHODS
Human embryonic stem cells (hESCs) were genetically modified to stably overexpress ferritin using the CRISPR-Cas9 system. Cellular toxicity associated with ferritin overexpression and manganese (Mn) supplementation were assessed based on cell viability, proliferation, and metabolic activity. Ferritin-overexpressing hESCs were characterized based on stem cell pluripotency and cardiac-lineage differentiation capability. Cells were supplemented with Mn and imaged in vitro as cell pellets on a preclinical 3 T MR scanner. T1-weighted images and T1 relaxation times were analyzed to assess contrast. For in vivo study, three million cells were injected into the leg muscle of non-obese diabetic severe combined immunodeficiency (NOD SCID) mice. Mn was administrated subcutaneously. T1-weighted sequences and T1 mapping were used to image the animals for longitudinal in vivo cell tracking. Cell survival, proliferation, and teratoma formation were non-invasively monitored by MRI. Histological analysis was used to validate MRI results.
RESULTS
Ferritin-overexpressing hESCs labeled with 0.1 mM MnCl provided significant T1-induced bright contrast on in vitro MRI, with no adverse effect on cell viability, proliferation, pluripotency, and differentiation into cardiomyocytes. Transplanted hESCs displayed significant bright contrast on MRI 24 h after Mn administration, with contrast persisting for 5 days. Bright contrast was recalled at 4-6 weeks with early teratoma outgrowth.
CONCLUSIONS
The bright-ferritin platform provides the first demonstration of longitudinal cell tracking with signal recall, opening a window on the massive cell death that hESCs undergo in the weeks following transplantation before the surviving cell fraction proliferates to form teratomas.
Topics: Mice; Animals; Humans; Human Embryonic Stem Cells; Ferritins; Mice, SCID; Magnetic Resonance Imaging; Embryonic Stem Cells; Teratoma
PubMed: 37964388
DOI: 10.1186/s13287-023-03565-4 -
Pediatric Annals Nov 2023
Topics: Infant, Newborn; Humans; Severe Combined Immunodeficiency; Immunologic Deficiency Syndromes; Neonatal Screening
PubMed: 37935399
DOI: 10.3928/19382359-20231004-01 -
The Journal of Allergy and Clinical... Feb 2024To date, fewer than 20 patients have been identified as having germline biallelic mutations in the coronin-1A gene () and its protein with clinical features of combined...
BACKGROUND
To date, fewer than 20 patients have been identified as having germline biallelic mutations in the coronin-1A gene () and its protein with clinical features of combined immunodeficiency characterized by T-cell lymphopenia ranging from the severe phenotype to the mild phenotype, recurrent infections, and lymphoproliferative disorders. However, the effects of CORO1A protein disruption on actin-dependent functions in primary cells have not been fully delineated.
OBJECTIVE
We sought to characterize the underlying defects of actin-dependent cellular functions in a female patient with combined immunodeficiency caused by a novel missense variant in the gene in combination with a heterozygous microdeletion of chromosome 16p11.2 and also to provide evidence of the pathogenicity of this gene mutation.
METHODS
To identify the genetic defect, next-generation sequencing followed by Sanger confirmation and array comparative genomic hybridization were performed. Western blot and quantitative PCR tests were used to assess the effects on the protein. Flow cytometry and live microscopy were performed to investigate cellular motility and immune cell counts and function.
RESULTS
We demonstrated that the hemizygous variant c.19C>T, p. A7C induces significant decreases in cellular levels of the CORO1A protein while leaving mRNA concentrations unaffected. The observed mutation resulted in impaired natural killer cell cytotoxicity and platelet calcium signaling. In addition, primary granulocytes and mesenchymal cells showed significant defects in motility.
CONCLUSION
Collectively, we added new data about the gene as a key player in actin cytoskeleton dynamics and cell signaling. Our findings expand the clinical spectrum regarding CORO1A protein deficiency and confirm the importance of a personalized therapeutic approach for each patient.
PubMed: 37915722
DOI: 10.1016/j.jacig.2023.100172 -
Frontiers in Oncology 2023Hypomorphic mutations of cause an atypical severe combined immunodeficiency (SCID), and Epstein-Barr virus (EBV)-related colon lymphoma is a rare complication.
INTRODUCTION
Hypomorphic mutations of cause an atypical severe combined immunodeficiency (SCID), and Epstein-Barr virus (EBV)-related colon lymphoma is a rare complication.
CASE PRESENTATION
A teenage boy presented with colon EBV-related colon lymphoma, plantar warts, and a history of recurrent pneumonia. His peripheral blood lymphocyte count and serum level of immunoglobulin (Ig) G were normal, but he exhibited a TBNK immunophenotype. Genetic analysis by whole exome sequencing revealed compound heterozygous mutations of (NM_001033855.3), including a novel paternal splicing donor mutation (c.109 + 2T>C) in intron 1, and a maternal c.1147C>T (p.R383X) nonsense mutation in exon 13. Based on his clinical features and genetic results, the diagnosis of atypical SCID with colon lymphoma was established. Our review shows that seven patients, including our patient, have been reported to develop lymphoma, all with hypomorphic mutations. Among these cases, six had EBV-related B-cell lineage lymphoma, and one had Hodgkin lymphoma with EBV reactivation. Unfortunately, all of the patients died.
CONCLUSION
Recognizing the radiosensitivity of the disease is critical for the prognosis. Hematopoietic stem cell transplantation before being infected with EBV is an optimal treatment.
PubMed: 37901335
DOI: 10.3389/fonc.2023.1282678 -
Allergologie Select 2023Hymenoptera venom (HV) is injected into the skin during a sting by Hymenoptera such as bees or wasps. Some components of HV are potential allergens and can cause large...
Diagnosis and treatment of Hymenoptera venom allergy: S2k Guideline of the German Society of Allergology and Clinical Immunology (DGAKI) in collaboration with the Arbeitsgemeinschaft für Berufs- und Umweltdermatologie e.V. (ABD), the Medical Association of German Allergologists (AeDA), the German...
Hymenoptera venom (HV) is injected into the skin during a sting by Hymenoptera such as bees or wasps. Some components of HV are potential allergens and can cause large local and/or systemic allergic reactions (SAR) in sensitized individuals. During their lifetime, ~ 3% of the general population will develop SAR following a Hymenoptera sting. This guideline presents the diagnostic and therapeutic approach to SAR following Hymenoptera stings. Symptomatic therapy is usually required after a severe local reaction, but specific diagnosis or allergen immunotherapy (AIT) with HV (VIT) is not necessary. When taking a patient's medical history after SAR, clinicians should discuss possible risk factors for more frequent stings and more severe anaphylactic reactions. The most important risk factors for more severe SAR are mast cell disease and, especially in children, uncontrolled asthma. Therefore, if the SAR extends beyond the skin (according to the Ring and Messmer classification: grade > I), the baseline serum tryptase concentration shall be measured and the skin shall be examined for possible mastocytosis. The medical history should also include questions specific to asthma symptoms. To demonstrate sensitization to HV, allergists shall determine concentrations of specific IgE antibodies (sIgE) to bee and/or vespid venoms, their constituents and other venoms as appropriate. If the results are negative less than 2 weeks after the sting, the tests shall be repeated (at least 4 - 6 weeks after the sting). If only sIgE to the total venom extracts have been determined, if there is double sensitization, or if the results are implausible, allergists shall determine sIgE to the different venom components. Skin testing may be omitted if in-vitro methods have provided a definitive diagnosis. If neither laboratory diagnosis nor skin testing has led to conclusive results, additional cellular testing can be performed. Therapy for HV allergy includes prophylaxis of reexposure, patient self treatment measures (including use of rescue medication) in the event of re-stings, and VIT. Following a grade I SAR and in the absence of other risk factors for repeated sting exposure or more severe anaphylaxis, it is not necessary to prescribe an adrenaline auto-injector (AAI) or to administer VIT. Under certain conditions, VIT can be administered even in the presence of previous grade I anaphylaxis, e.g., if there are additional risk factors or if quality of life would be reduced without VIT. Physicians should be aware of the contraindications to VIT, although they can be overridden in justified individual cases after weighing benefits and risks. The use of β-blockers and ACE inhibitors is not a contraindication to VIT. Patients should be informed about possible interactions. For VIT, the venom extract shall be used that, according to the patient's history and the results of the allergy diagnostics, was the trigger of the disease. If, in the case of double sensitization and an unclear history regarding the trigger, it is not possible to determine the culprit venom even with additional diagnostic procedures, VIT shall be performed with both venom extracts. The standard maintenance dose of VIT is 100 µg HV. In adult patients with bee venom allergy and an increased risk of sting exposure or particularly severe anaphylaxis, a maintenance dose of 200 µg can be considered from the start of VIT. Administration of a non-sedating H1-blocking antihistamine can be considered to reduce side effects. The maintenance dose should be given at 4-weekly intervals during the first year and, following the manufacturer's instructions, every 5 - 6 weeks from the second year, depending on the preparation used; if a depot preparation is used, the interval can be extended to 8 weeks from the third year onwards. If significant recurrent systemic reactions occur during VIT, clinicians shall identify and as possible eliminate co-factors that promote these reactions. If this is not possible or if there are no such co-factors, if prophylactic administration of an H1-blocking antihistamine is not effective, and if a higher dose of VIT has not led to tolerability of VIT, physicians should should consider additional treatment with an anti IgE antibody such as omalizumab as off lable use. For practical reasons, only a small number of patients are able to undergo sting challenge tests to check the success of the therapy, which requires in-hospital monitoring and emergency standby. To perform such a provocation test, patients must have tolerated VIT at the planned maintenance dose. In the event of treatment failure while on treatment with an ACE inhibitor, physicians should consider discontinuing the ACE inhibitor. In the absence of tolerance induction, physicians shall increase the maintenance dose (200 µg to a maximum of 400 µg in adults, maximum of 200 µg HV in children). If increasing the maintenance dose does not provide adequate protection and there are risk factors for a severe anaphylactic reaction, physicians should consider a co-medication based on an anti-IgE antibody (omalizumab; off-label use) during the insect flight season. In patients without specific risk factors, VIT can be discontinued after 3 - 5 years if maintenance therapy has been tolerated without recurrent anaphylactic events. Prolonged or permanent VIT can be considered in patients with mastocytosis, a history of cardiovascular or respiratory arrest due to Hymenoptera sting (severity grade IV), or other specific constellations associated with an increased individual risk of recurrent and/or severe SAR (e.g., hereditary α-tryptasemia). In cases of strongly increased, unavoidable insect exposure, adults may receive VIT until the end of intense contact. The prescription of an AAI can be omitted in patients with a history of SAR grade I and II when the maintenance dose of VIT has been reached and tolerated, provided that there are no additional risk factors. The same holds true once the VIT has been terminated after the regular treatment period. Patients with a history of SAR grade ≥ III reaction, or grade II reaction combined with additional factors that increase the risk of non response or repeated severe sting reactions, should carry an emergency kit, including an AAI, during VIT and after regular termination of the VIT.
PubMed: 37854067
DOI: 10.5414/ALX02430E -
Cureus Sep 2023Severe combined immunodeficiency (SCID) is an inborn error of immunity invariably resulting in mortality in infancy until managed by hematopoietic stem cell transplant...
Severe combined immunodeficiency (SCID) is an inborn error of immunity invariably resulting in mortality in infancy until managed by hematopoietic stem cell transplant (HSCT). We present an unusual case of SCID with a rare mutation involving the non-homologous end-joining 1 (NHEJ1) gene, where a haploidentical HSCT was carried out with modified conditioning and graft versus host prophylaxis regimen using proteasome inhibitor bortezomib with a successful outcome.
PubMed: 37842439
DOI: 10.7759/cureus.45159