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Frontiers in Pediatrics 2023Bare lymphocyte syndrome type II (BLS II) is a rare form of severe combined immunodeficiency caused by mutations in the gene, which regulates major histocompatibility...
BACKGROUND
Bare lymphocyte syndrome type II (BLS II) is a rare form of severe combined immunodeficiency caused by mutations in the gene, which regulates major histocompatibility complex class II (MHC II) expression.
OBJECTIVE
We report the case of a Saudi boy with a novel mutation in the gene who presented with acute and late meningoencephalomyelitis, resulting in severe neurodevelopmental regression.
METHODS
We reviewed the patient's clinical and laboratory data obtained from medical records and performed a literature search on BLS II.
RESULTS
The patient presented with acute meningoencephalomyelitis confirmed by MRI findings and was later found to carry a homozygous pathogenic variant in the gene p.(Leu473Hisfs*15). The patient had no MCH II expression, confirming the genetic diagnosis of autosomal recessive BLS II. Surprisingly, the patient's prior clinical history was unremarkable for significant infections or autoimmunity.
CONCLUSIONS
We report a case with a novel gene mutation presenting atypically with a late and isolated severe infection. Isolated severe meningoencephalomyelitis may be a manifestation of primary immunodeficiency.
PubMed: 37842025
DOI: 10.3389/fped.2023.1269396 -
Acta Pharmacologica Sinica Feb 2024Lysophosphatidic acid (LPA) is a bioactive phospholipid mediator that has been found to ameliorate nonsteroidal anti-inflammatory drug (NSAID)-induced gastric injury by...
Lysophosphatidic acid (LPA) is a bioactive phospholipid mediator that has been found to ameliorate nonsteroidal anti-inflammatory drug (NSAID)-induced gastric injury by acting on lysophosphatidic acid type 2 receptor (LPAR2). In this study, we investigated whether LPAR2 signaling was implicated in the development of NSAID-induced small intestinal injury (enteropathy), another major complication of NSAID use. Wild-type (WT) and Lpar2 deficient (Lpar2) mice were treated with a single, large dose (20 or 30 mg/kg, i.g.) of indomethacin (IND). The mice were euthanized at 6 or 24 h after IND treatment. We showed that IND-induced mucosal enteropathy and neutrophil recruitment occurred much earlier (at 6 h after IND treatment) in Lpar2 mice compared to WT mice, but the tissue levels of inflammatory mediators (IL-1β, TNF-α, inducible COX-2, CAMP) remained at much lower levels. Administration of a selective LPAR2 agonist DBIBB (1, 10 mg/kg, i.g., twice at 24 h and 30 min before IND treatment) dose-dependently reduced mucosal injury and neutrophil activation in enteropathy, but it also enhanced IND-induced elevation of several proinflammatory chemokines and cytokines. By assessing caspase-3 activation, we found significantly increased intestinal apoptosis in IND-treated Lpar2 mice, but it was attenuated after DBIBB administration, especially in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. Finally, we showed that IND treatment reduced the plasma activity and expression of autotaxin (ATX), the main LPA-producing enzyme, and also reduced the intestinal expression of Lpar2 mRNA, which preceded the development of mucosal damage. We conclude that LPAR2 has a dual role in NSAID enteropathy, as it contributes to the maintenance of mucosal integrity after NSAID exposure, but also orchestrates the inflammatory responses associated with ulceration. Our study suggests that IND-induced inhibition of the ATX-LPAR2 axis is an early event in the pathogenesis of enteropathy.
Topics: Mice; Animals; Receptors, Lysophosphatidic Acid; Mice, Inbred NOD; Mice, SCID; Anti-Inflammatory Agents, Non-Steroidal; Indomethacin; Intestinal Diseases; Diabetes Mellitus, Type 2; Lysophospholipids
PubMed: 37816857
DOI: 10.1038/s41401-023-01175-7 -
Experimental Hematology Dec 2023Acute myeloid leukemia (AML) is one of the deadliest hematologic malignancies, and its targeted therapy has developed slowly. The molecular mechanism of the...
Acute myeloid leukemia (AML) is one of the deadliest hematologic malignancies, and its targeted therapy has developed slowly. The molecular mechanism of the pathophysiology of the disease remains to be clarified. The aim of our study was to probe the specific regulatory mechanism of miR-455-3p in AML. This study measured the levels of miR-455-3p and ubinuclein-2 (UBN2) in AML cell lines, evaluated cell viability with CCK-8, used flow cytometry to estimate the cell cycle and apoptosis, detected cell apoptosis and autophagy-related protein levels by Western blotting, and added 50 μM chloroquine (CQ) to evaluate the relationship between autophagy and AML. In animal experiments, HL-60 cells were injected into male non-obese diabetic/severe combined immunodeficiency disease (NOD/SCID) mice through the tail vein to determine survival time and observe the degree of liver and spleen damage in the mice. miR-455-3p was prominently reduced in the peripheral blood and AML cell lines, and UBN2 showed high expression. The transfected miR-455-3p mimic effectively restrained the activity of AML cells, whereas overexpression of UBN2 or the addition of the autophagy inhibitor CQ reversed the effect of miR-455-3p. The interaction between UBN2 and peroxisome proliferator-activated receptor alpha (PPARα) was confirmed by coimmunoprecipitation, and overexpression of PPARα reversed the promoting effect of UBN2 knockdown on apoptosis and autophagy in AML cells. In conclusion, miR-455-3p mediates PPARα protein expression through UBN2, exacerbating AML cell apoptosis and autophagy. This study found that miR-455-3p plays an important role in AML cell apoptosis and autophagy, which may provide novel insights for the treatment of AML diseases.
Topics: Animals; Male; Mice; Apoptosis; Autophagy; Cell Line, Tumor; Cell Proliferation; Leukemia, Myeloid, Acute; Mice, Inbred NOD; Mice, SCID; MicroRNAs; PPAR alpha; Transcription Factors
PubMed: 37805161
DOI: 10.1016/j.exphem.2023.09.007 -
Science Advances Oct 2023Lentiviral vector (LV)-based gene therapy holds promise for a broad range of diseases. Analyzing more than 280,000 vector integration sites (VISs) in 273 samples from 10...
Lentiviral vector (LV)-based gene therapy holds promise for a broad range of diseases. Analyzing more than 280,000 vector integration sites (VISs) in 273 samples from 10 patients with X-linked severe combined immunodeficiency (SCID-X1), we discovered shared LV integrome signatures in 9 of 10 patients in relation to the genomics, epigenomics, and 3D structure of the human genome. VISs were enriched in the nuclear subcompartment A1 and integrated into super-enhancers close to nuclear pore complexes. These signatures were validated in T cells transduced with an LV encoding a CD19-specific chimeric antigen receptor. Intriguingly, the one patient whose VISs deviated from the identified integrome signatures had a distinct clinical course. Comparison of LV and gamma retrovirus integromes regarding their 3D genome signatures identified differences that might explain the lower risk of insertional mutagenesis in LV-based gene therapy. Our findings suggest that LV integrome signatures, shaped by common features such as genome organization, may affect the efficacy of LV-based cellular therapies.
Topics: Humans; Genetic Vectors; Genetic Therapy; Retroviridae; X-Linked Combined Immunodeficiency Diseases; T-Lymphocytes
PubMed: 37801507
DOI: 10.1126/sciadv.adg9959 -
The Journal of Allergy and Clinical... Nov 2023We describe the case of a 10-month-old boy with vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities...
We describe the case of a 10-month-old boy with vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities (VACTERL) association and athymia who developed Omenn syndrome.
PubMed: 37781660
DOI: 10.1016/j.jacig.2023.100153 -
Frontiers in Immunology 2023This report illustrates a case that would have been missed in the most common screening algorithms used worldwide in newborn screening (NBS) for severe combined...
This report illustrates a case that would have been missed in the most common screening algorithms used worldwide in newborn screening (NBS) for severe combined immunodeficiency (SCID). Our patient presented with a clinical picture that suggested a severe inborn error of immunity (IEI). The 6-month-old baby had normal T-cell receptor excision circle (TREC) levels but no measurable level of kappa-deleting recombination excision circles (KRECs) in the NBS sample. A mutation (c.476A>G, p.Asn159Ser) was found. The clinical picture, immunologic workup, and genetic result were consistent with -related combined immunodeficiency (CID). Our patient had symptomatic treatment and underwent allogeneic hematopoietic cell transplantation (HCT). -related CID is a rare, serious, and early-onset disease; this case provides further insights into the phenotype, including KREC status.
Topics: Infant, Newborn; Infant; Humans; Severe Combined Immunodeficiency; Phenotype; Neonatal Screening; Ikaros Transcription Factor
PubMed: 37771582
DOI: 10.3389/fimmu.2023.1257581 -
Pathogens (Basel, Switzerland) Sep 2023A 35-year-old man with a late-onset combined immunodeficiency (LOCID) variant of common variable immunodeficiency, severe plaque psoriasis, psoriatic arthritis, and...
A 35-year-old man with a late-onset combined immunodeficiency (LOCID) variant of common variable immunodeficiency, severe plaque psoriasis, psoriatic arthritis, and Crohn's disease was attended in the Regional Hospital of Presidente Prudente and HC-FMUSP, São Paulo, Brazil. Anti-IL-12/IL-23 (ustekinumab) monoclonal antibody was prescribed due to the failure of other treatments (phototherapy, oral acitretin) for psoriasis and a Psoriasis Area Severity Index >10. We evaluated the impact of treatment with ustekinumab on severe infectious diseases in a patient with uncontrolled psoriasis and LOCID followed for 8 years. Four quarterly doses of ustekinumab 90 mg and human immunoglobulin replacement (10,000 mg at 28-day intervals) were administered. Immunophenotyping, cultures of lymphocytes, genetic sequencing, and whole exome sequencing were performed to investigate the primary immunodeficiency. Normal lymphocyte proliferation; pathogenic variants in genetic sequencing, and clinically significant variants in the whole exome for primary immunodeficiencies were not detected. The main infections before and after treatment with ustekinumab were chronic sinusitis and gastroenteritis. The patient was infected with COVID-19, dengue (twice) and influenza and was hospitalized three times for intravenous antibiotic therapy. Ustekinumab did not influence the susceptibility of the patient with LOCID to severe infections and significantly improved psoriasis, psoriatic arthritis, and Crohn's disease.
PubMed: 37764964
DOI: 10.3390/pathogens12091156 -
Biomedicines Sep 2023The hyperinflammatory response caused by SARS-CoV-2 infection contributes to its severity, and many critically ill patients show features of cytokine storm (CS)...
The hyperinflammatory response caused by SARS-CoV-2 infection contributes to its severity, and many critically ill patients show features of cytokine storm (CS) syndrome. We investigated, by next-generation sequencing, 24 causative genes of primary immunodeficiencies whose defect predisposes to CS. We studied two cohorts with extreme phenotypes of SARS-CoV-2 infection: critical/severe hyperinflammatory patients (H-P) and asymptomatic patients (AM-risk-P) with a high risk (older age) to severe COVID-19. To explore inborn errors of the immunity, we investigated the presence of pathogenic or rare variants, and to identify COVID-19 severity-associated markers, we compared the allele frequencies of common genetic polymorphisms between our two cohorts. We found: 1 H-P carries the likely pathogenic variant c.887-2 A>C in the gene and 5 H-P carries variants in the gene, whose role in the pathogenicity of the familial Mediterranean fever (FMF) disease is controversial. The common polymorphism analysis showed three potential risk biomarkers for developing the hyperinflammatory response: the homozygous haplotype rs1231123A/A-rs1231122A/A in gene, the p.Phe8Ser variant, and the p.Val181Met variant. The combined analysis showed an increased risk of developing severe COVID-19 in patients that had at least one of our genetic risk markers (odds ratio (OR) = 6.2 (95% CI) (2.430-16.20)).
PubMed: 37760989
DOI: 10.3390/biomedicines11092548 -
EClinicalMedicine Oct 2023Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of SARS-CoV-2 infection. It remains unclear how MIS-C phenotypes vary across SARS-CoV-2...
BACKGROUND
Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of SARS-CoV-2 infection. It remains unclear how MIS-C phenotypes vary across SARS-CoV-2 variants. We aimed to investigate clinical characteristics and outcomes of MIS-C across SARS-CoV-2 eras.
METHODS
We performed a multicentre observational retrospective study including seven paediatric hospitals in four countries (France, Spain, U.K., and U.S.). All consecutive confirmed patients with MIS-C hospitalised between February 1st, 2020, and May 31st, 2022, were included. Electronic Health Records (EHR) data were used to calculate pooled risk differences (RD) and effect sizes (ES) at site level, using as reference. Meta-analysis was used to pool data across sites.
FINDINGS
Of 598 patients with MIS-C (61% male, 39% female; mean age 9.7 years [SD 4.5]), 383 (64%) were admitted in the era, 111 (19%) in the era, and 104 (17%) in the era. Compared with patients admitted in the era, those admitted in the era were younger (ES -1.18 years [95% CI -2.05, -0.32]), had fewer respiratory symptoms (RD -0.15 [95% CI -0.33, -0.04]), less frequent non-cardiogenic shock or systemic inflammatory response syndrome (SIRS) (RD -0.35 [95% CI -0.64, -0.07]), lower lymphocyte count (ES -0.16 × 10/uL [95% CI -0.30, -0.01]), lower C-reactive protein (ES -28.5 mg/L [95% CI -46.3, -10.7]), and lower troponin (ES -0.14 ng/mL [95% CI -0.26, -0.03]). Patients admitted in the versus eras were younger (ES -1.6 years [95% CI -2.5, -0.8]), had less frequent SIRS (RD -0.18 [95% CI -0.30, -0.05]), lower lymphocyte count (ES -0.39 × 10/uL [95% CI -0.52, -0.25]), lower troponin (ES -0.16 ng/mL [95% CI -0.30, -0.01]) and less frequently received anticoagulation therapy (RD -0.19 [95% CI -0.37, -0.04]). Length of hospitalization was shorter in the versus eras (-1.3 days [95% CI -2.3, -0.4]).
INTERPRETATION
Our study suggested that MIS-C clinical phenotypes varied across SARS-CoV-2 eras, with patients in and eras being younger and less sick. EHR data can be effectively leveraged to identify rare complications of pandemic diseases and their variation over time.
FUNDING
None.
PubMed: 37745025
DOI: 10.1016/j.eclinm.2023.102212