Publications by authors named "Yoko Mizoguchi"

Purpose: Transcription factor 3 (TCF3) encodes 2 transcription factors generated by alternative splicing, E12 and E47, which contribute to early lymphocyte differentiation. In humans, autosomal dominant (AD) E47 transcription factor deficiency is an inborn error of immunity characterized by B-cell deficiency and agammaglobulinemia. Only the recurrent de novo p.

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  • Blinatumomab is a bispecific T-cell engager specifically targeting CD3 and CD19, primarily used for treating relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
  • While it shows effectiveness in treatment, it can lead to serious side effects, including cytokine release syndrome and various neurological complications.
  • A case study involving a pediatric patient demonstrated that blinatumomab can cause rare encephalopathy, which began with uncontrollable seizures and progressed to cerebral infarction, resulting in prolonged paralysis and significant brain damage.
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The human bone marrow (BM) niche sustains hematopoiesis throughout life. We present a method for generating complex BM-like organoids (BMOs) from human induced pluripotent stem cells (iPSCs). BMOs consist of key cell types that self-organize into spatially defined three-dimensional structures mimicking cellular, structural and molecular characteristics of the hematopoietic microenvironment.

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Purpose: Inborn errors of the IL-17A/F-responsive pathway lead to chronic mucocutaneous candidiasis (CMC) as a predominant clinical phenotype, without other significant clinical manifestations apart from mucocutaneous staphylococcal diseases. Among inborn errors affecting IL-17-dependent immunity, autosomal recessive (AR) IL-17RC deficiency is a rare disease with only three kindreds described to date. The lack of an in vitro functional evaluation system of IL17RC variants renders its diagnosis difficult.

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Germline human heterozygous STAT1 gain-of-function (GOF) variants were first discovered a common cause of chronic mucocutaneous candidiasis (CMC) in 2011. Since then, numerous STAT1 GOF variants have been identified. A variety of clinical phenotypes, including fungal, viral, and bacterial infections, endocrine disorders, autoimmunity, malignancy, and aneurysms, have recently been revealed for STAT1 GOF variants, which has led to the expansion of the clinical spectrum associated with STAT1 GOF.

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  • Early prophylaxis alone is not sufficient to prevent joint disease in most pediatric patients with hemophilia, as indicated by recent studies.
  • A study evaluated the incidence of acute joint disease in 48 children with hemophilia over five years, finding that joint disease increased with age, particularly affecting those beyond high school age.
  • Patients regularly followed by specialized hemophilia treatment centers had a significantly lower incidence of joint disease, highlighting the importance of routine check-ups and comprehensive care in managing joint health.
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  • A seven-year-old Japanese girl with chronic mucocutaneous candidiasis (CMC) was studied due to a rare genetic condition linked to her immune response, specifically involving IL-17A/F pathways, which caused her to have persistent fungal infections.
  • Genetic analysis revealed a novel duplication variant causing a premature stop codon in the IL-17RC gene, leading to a loss of its function and confirming its role in the patient's clinical symptoms.
  • A new evaluation system was developed to assess genetic variants, helping to differentiate between harmful mutations and neutral variations, which can assist in diagnosing similar cases of AR IL-17RC deficiency in the future.
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  • * Six patients from five families with heterozygous RELA mutations showed additional autoimmune and autoinflammatory symptoms, all linked to mutations creating a premature stop codon in the RELA gene.
  • * The patients' cells express truncated RelA proteins that negatively affect normal function, leading to increased production of type I/III interferons and an associated novel condition characterized by excessive IFN production and immune dysregulation.
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Advances in next-generation sequencing technology have identified many genes responsible for inborn errors of immunity (IEI). However, there is still room for improvement in the efficiency of genetic diagnosis. Recently, RNA sequencing and proteomics using peripheral blood mononuclear cells (PBMCs) have gained attention, but only some studies have integrated these analyses in IEI.

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  • - The study highlights how the reduced effectiveness of antibodies against mutated SARS-CoV-2 spike RBD can lead to breakthrough infections from Omicron variants, showing the need for effective neutralizing antibodies.
  • - Researchers analyzed a powerful antibody called NCV2SG48 from long-term COVID-19 patients, which shows strong activity against multiple Omicron variants as well as other strains.
  • - The antibody’s effectiveness is attributed to its unique structure and extensive binding capabilities, allowing it to neutralize various variants; this suggests that targeting specific B cells could improve immunity against evolving SARS-CoV-2 strains.
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Mitochondrial metabolism is critical in hematopoietic stem cell maintenance and differentiation. Here, we present a step-by-step protocol to efficiently differentiate human induced pluripotent stem cells into myeloid progenitors by a robust feeder- and serum-free system. Furthermore, we provide a protocol to subsequently assess mitochondrial function in iPSC-derived myeloid progenitors.

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  • * Researchers analyze neutrophils from patients with known genetic variations, identifying key differences in their protein composition (proteome).
  • * Experiments using human stem cells and zebrafish models show that SRP deficiency disrupts important cellular processes needed for proper neutrophil development.
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  • High expression of the transcription factor T-bet is linked to a unique type of B cell called "age-associated B cells" (ABCs) in mice, and T-bet deficiency can lead to fewer ABCs and weakened immune responses.
  • A patient with T-bet deficiency showed normal overall immune responses but had an unusual pattern of antibody class switching and distinct B cell characteristics, similar to ABCs in mice.
  • T-bet plays a crucial role in the development of a specific subset of human B cells, impacting their differentiation and genetic programming, while being less critical for maintaining long-term effective humoral immunity.
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  • A study evaluated the prevalence of autoantibodies (aAbs) and neutralizing autoantibodies (naAbs) to type I interferons in Japanese COVID-19 patients and a healthy control group.
  • Among uninfected individuals in the general Japanese population, only 0.087% had aAbs, whereas 10.6% of critically ill patients had naAbs.
  • The presence of naAbs was significantly linked to critical illness, older age, and male sex, indicating a greater risk for severe COVID-19 in those with pre-existing naAbs.
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The relevance of molecular mechanisms governing mitochondrial proteostasis to the differentiation and function of hematopoietic and immune cells is largely elusive. Through dissection of the network of proteins related to HCLS1-associated protein X-1, we defined a potentially novel functional CLPB/HAX1/(PRKD2)/HSP27 axis with critical importance for the differentiation of neutrophil granulocytes and, thus, elucidated molecular and metabolic mechanisms underlying congenital neutropenia in patients with HAX1 deficiency as well as bi- and monoallelic mutations in CLPB. As shown by stable isotope labeling by amino acids in cell culture (SILAC) proteomics, CLPB and HAX1 control the balance of mitochondrial protein synthesis and persistence crucial for proper mitochondrial function.

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  • The study investigates the prevalence of autoantibodies (aAbs) and neutralizing autoantibodies (naAbs) to type I interferons (IFNs) among Japanese individuals, noting a rare occurrence in the general population but higher rates in older adults and critically ill COVID-19 patients.
  • Out of 3,456 healthy Japanese controls, only 0.087% had aAbs, while in the 627 COVID-19 patients studied, naAbs were significantly present in 10.6% of critical cases and in lower percentages for severe cases.
  • Results show that older COVID-19 patients (especially men) had higher naAb prevalence, suggesting a link between pre-existing naAbs and increased risk for severe
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Background: Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by a selective predisposition to infections caused by intracellular pathogens, such as mycobacteria, due to impaired IFN-γ immunity. To date, 18 different genes associated with MSMD have been reported.

Objectives: This review describes recent discoveries, a 2020-2021 update, in MSMD through the introduction of three novel genetic disorders, namely, AR IFN-γ, T-bet, and ZNFX1 complete deficiency, as well as molecular mechanisms underlying multifocal osteomyelitis in patients with this condition.

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  • * The study investigated how impaired IFN-γ responses in specific deficiencies (AD IFN-γR1 and AD STAT1) lead to increased osteoclast differentiation and activity, using various laboratory techniques.
  • * Results indicated that individuals with AD IFN-γR1 and AD STAT1 deficiencies have heightened osteoclast numbers due to reduced inhibition from IFN-γ, which may contribute to excessive bone resorption in areas of infection.
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Signal transducer and activator of transcription 1 (STAT1) is a latent cytoplasmic transcription factor that is activated by multiple stimuli, including type I, II, and III interferons and interleukin-27. Inborn errors of human STAT1 immunity underlie 4 distinct disorders: autosomal recessive (AR) complete STAT1 deficiency, AR partial STAT1 deficiency, autosomal dominant (AD) STAT1 deficiency, and AD STAT1 gain-of-function. Each disease presents distinct clinical manifestations, excluding the difference in two AR STAT1 deficiencies, which are mainly explained by severity.

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  • CARD9 deficiency is an autosomal recessive condition that significantly increases the risk of invasive fungal diseases, particularly from Candida and Trichophyton species, and symptoms often become apparent in adulthood, though it can occur earlier.* -
  • A study identified specific CARD9 mutations in a 4-year-old patient suffering from severe fungal infection (Exophiala dermatitidis), while his siblings, sharing the same mutations, remained asymptomatic despite also having cellular abnormalities in their immune response.* -
  • The findings suggest that individuals who appear healthy but have a family history of CARD9 deficiency should be evaluated, as detecting immune cell dysfunction can help diagnose the condition even in asymptomatic relatives.*
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Vacuolar protein sorting 45 homolog (VPS45), a member of the Sec1/Munc18 (SM) family, has been implicated in the regulation of endosomal trafficking. VPS45 deficiency in human patients results in congenital neutropenia, bone marrow fibrosis, and extramedullary renal hematopoiesis. Detailed mechanisms of the VPS45 function are unknown.

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IRAK4 deficiency is an inborn error of immunity predisposing patients to invasive pyogenic infections. Currently, there is no established simple assay that enables precise characterization of IRAK4 mutant alleles in isolation. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune condition that is characterized by psychiatric symptoms, involuntary movement, seizures, autonomic dysfunction, and central hypoventilation.

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Autosomal recessive (AR) complete signal transducer and activator of transcription 1 (STAT1) deficiency is an extremely rare primary immunodeficiency that causes life-threatening mycobacterial and viral infections. Only seven patients from five unrelated families with this disorder have been so far reported. All causal STAT1 mutations reported are exonic and homozygous.

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