Publications by authors named "Tomohiro Morio"

283 Publications

Transplantation of human autologous synovial mesenchymal stem cells with trisomy 7 into the knee joint and 5 years of follow-up.

Stem Cells Transl Med 2021 Aug 3. Epub 2021 Aug 3.

Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

Mesenchymal stem cells (MSCs) can show trisomy 7; however, the safety of these cells has not been fully investigated. The purposes of this study were to determine the ratio of patients whose synovial MSCs were transplanted clinically, to intensively investigate MSCs with trisomy 7 from a safety perspective, and to follow up the patients for 5 years after transplantation. Synovial MSCs at passage 0 were transplanted into a knee for degenerative meniscus tears in 10 patients, and the patients were checked at 5 years. The synovial MSCs were evaluated at passages 0 to 15 by G-bands and digital karyotyping, and trisomy 7 was found in 3 of 10 patients. In those 3 patients, 5% to 10% of the synovial MSCs showed trisomy 7. The mRNA expressions of representative oncogenes and genes on chromosome 7 did not differ between MSCs with and without trisomy 7. Whole-genome sequencing and DNA methylation analysis showed similar results for MSCs with and without trisomy 7. Transplantation of human synovial MSCs with trisomy 7 into 8 mouse knees did not result in tumor formation under the skin or in the knees after 8 weeks in any mouse, whereas transplanted HT1080 cells formed tumors. In vitro chondrogenic potentials were similar between MSCs with and without trisomy 7. Five-year follow-ups revealed no serious adverse events in all 10 human patients, including 3 who had received MSCs with trisomy 7. Overall, our findings indicated that synovial MSCs with trisomy 7 were comparable with MSCs without trisomy 7 from a safety perspective.
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http://dx.doi.org/10.1002/sctm.20-0491DOI Listing
August 2021

PAX3/7-FOXO1 fusion-negative alveolar rhabdomyosarcoma in Schuurs-Hoeijmakers syndrome.

J Hum Genet 2021 Aug 2. Epub 2021 Aug 2.

Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

PAX3/7-FOXO1 fusion-negative alveolar rhabdomyosarcoma (ARMS) developed in a patient presenting with intellectual disability and dysmorphic facial features. Whole exome sequencing analysis of a germline sample identified a PACS1 c.607 C>T de novo variant and the patient was diagnosed with Schuurs-Hoeijmakers syndrome (SHS). SHS is a rare disease characterized by intellectual disability and dysmorphic facial features, among various physical abnormalities, due to PACS1 c.607 C>T de novo variant. Due to the rarity of the SHS, diagnosis based on phenotypic information is difficult. To date, there have been no previous reports describing malignancy associated with SHS. Comprehensive somatic mutation analysis revealed a unique pattern of genetic alterations in the PAX3/7-FOXO1 fusion-negative ARMS tumor, including mutations in the oncogene, HRAS; MYOD1, a molecule essential for muscle differentiation; and KMT2C and TET1, genes encoding factors involved in epigenetic regulation. Although the role of PACS1 in tumorigenesis is unclear, it is reported to function in apoptosis regulation. Our case suggests that PACS1 could have a novel role in oncogenesis.
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http://dx.doi.org/10.1038/s10038-021-00965-3DOI Listing
August 2021

Successful treatment of joint and fascial chronic graft-versus-host disease with baricitinib.

Rheumatology (Oxford) 2021 Jul 24. Epub 2021 Jul 24.

Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

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http://dx.doi.org/10.1093/rheumatology/keab599DOI Listing
July 2021

Inborn errors of IKAROS and AIOLOS.

Curr Opin Immunol 2021 Jul 12;72:239-248. Epub 2021 Jul 12.

Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan. Electronic address:

IKAROS is a pioneer protein of the IKZF family of transcription factors that plays an essential role in lymphocyte development. Recently, inborn errors of IKAROS have been identified in patients with B cell deficiency and hypogammaglobulinemia, and these patients often present with recurrent sinopulmonary infection. Autoimmunity and hematologic malignancies are other characteristic complications seen in the patients with IKAROS deficiency. Missense mutation involving asparagine at the 159th position results in combined immunodeficiency, often presenting with Pneumocystis jirovecii pneumonia. Inborn errors of AIOLOS, HELIOS, and PEGASUS have also been reported in patients with B cell deficiency, Evans syndrome, and hereditary thrombocytopenia, respectively. Here, we briefly review the phenotype and genotype of IKZF mutations, especially IKAROS.
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http://dx.doi.org/10.1016/j.coi.2021.06.010DOI Listing
July 2021

Hematopoietic Cell Transplantation Rescues Inflammatory Bowel Disease and Dysbiosis of Gut Microbiota in XIAP Deficiency.

J Allergy Clin Immunol Pract 2021 Jul 8. Epub 2021 Jul 8.

Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan. Electronic address:

Background: X-linked inhibitor of apoptosis protein (XIAP) deficiency is an infrequent inborn error of immunity that is often associated with refractory inflammatory bowel disease (IBD). The natural course of XIAP deficiency is typically associated with poor prognosis, and hematopoietic cell transplantation (HCT) is the only curative treatment.

Objective: To study (1) the effect of HCT on patients with XIAP deficiency undergoing HCT, (2) the status of XIAP deficiency-associated IBD after HCT, and (3) the gut microbiota of XIAP deficiency-associated IBD before and after HCT.

Methods: A nationwide survey of patients with XIAP deficiency was conducted. A spreadsheet questionnaire was collected from the physicians. Feces samples collected from the patients before and after HCT and their healthy family members were analyzed.

Results: Twenty-six patients with XIAP deficiency underwent HCT by the end of March 2020, and 22 patients (84.6%) survived. All the survivors underwent a fludarabine-based reduced-intensity condition regimen. Acute graft-versus-host disease was observed in 17 patients (65.4%). Nineteen patients experienced refractory IBD before undergoing HCT. IBD improved remarkably after HCT. After HCT, the colonoscopic and pathological symptoms were restored to normal, and the pediatric ulcerative colitis activity index improved significantly. Gut microbiota indicated dysbiosis before HCT; however, it was improved to resemble that of the healthy family members after HCT.

Conclusions: This study revealed that HCT has a favorable outcome for XIAP deficiency. HCT rescues gut inflammation and dysbiosis in patients with XIAP deficiency.
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http://dx.doi.org/10.1016/j.jaip.2021.05.045DOI Listing
July 2021

A variant in human AIOLOS impairs adaptive immunity by interfering with IKAROS.

Nat Immunol 2021 Jul 21;22(7):893-903. Epub 2021 Jun 21.

Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

In the present study, we report a human-inherited, impaired, adaptive immunity disorder, which predominantly manifested as a B cell differentiation defect, caused by a heterozygous IKZF3 missense variant, resulting in a glycine-to-arginine replacement within the DNA-binding domain of the encoded AIOLOS protein. Using mice that bear the corresponding variant and recapitulate the B and T cell phenotypes, we show that the mutant AIOLOS homodimers and AIOLOS-IKAROS heterodimers did not bind the canonical AIOLOS-IKAROS DNA sequence. In addition, homodimers and heterodimers containing one mutant AIOLOS bound to genomic regions lacking both canonical motifs. However, the removal of the dimerization capacity from mutant AIOLOS restored B cell development. Hence, the adaptive immunity defect is caused by the AIOLOS variant hijacking IKAROS function. Heterodimeric interference is a new mechanism of autosomal dominance that causes inborn errors of immunity by impairing protein function via the mutation of its heterodimeric partner.
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http://dx.doi.org/10.1038/s41590-021-00951-zDOI Listing
July 2021

Anti-nuclear matrix protein 2 antibody-positive inflammatory myopathies represent extensive myositis without dermatomyositis-specific rash.

Rheumatology (Oxford) 2021 Jun 21. Epub 2021 Jun 21.

Department of Dermatology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.

Objectives: Myositis-specific autoantibodies (MSAs) define distinct clinical subsets of idiopathic inflammatory myopathies (IIMs). The anti-nuclear matrix protein 2 (NXP2) antibody, a MSA detected in juvenile/adult IIMs, has been reported to be associated with a high risk of subcutaneous calcinosis, subcutaneous oedema, and internal malignancies. The study aimed to clarify the clinical features of anti-NXP2 antibody-positive IIMs in detail.

Methods: This multi-centre retrospective observational study on 76 anti-NXP2 antibody-positive patients. The antibody was detected via a serological assay using immunoprecipitation and western blotting. The patients were selected from 162 consecutive Japanese patients with IIMs.

Results: The cohort of anti-NXP2 antibody-positive IIMs included 29 juvenile patients and 47 adult patients. Twenty-seven (35.5%) patients presented with polymyositis phenotype without dermatomyositis-specific skin manifestations (heliotrope rash or Gottron sign/papules); this was more common in the adults than children (48.9% vs. 15.8%, P < 0.01). Nine (11.8%) patients had subcutaneous calcinosis, and 20 (26.3%) patients had subcutaneous oedema. In addition, the proportion of patients with muscle weakness extending to the distal limbs was high (36 patients [47.4%]) in this cohort. Adult patients had a higher prevalence of malignancy than the general population (age-standardised incidence ratio of malignancies: 22.4).

Conclusion: Anti-NXP2 antibody-positive IIMs, which include dermatomyositis sine dermatitis, are characterised by atypical skin manifestations and extensive muscular involvement.
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http://dx.doi.org/10.1093/rheumatology/keab518DOI Listing
June 2021

Heterozygous gain-of-function variants cause an autoinflammatory immunodeficiency.

Sci Immunol 2021 Jun;6(60)

Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.

Analysis of autoinflammatory and immunodeficiency disorders elucidates human immunity and fosters the development of targeted therapies. Oligoadenylate synthetase 1 is a type I interferon-induced, intracellular double-stranded RNA (dsRNA) sensor that generates 2'-5'-oligoadenylate to activate ribonuclease L (RNase L) as a means of antiviral defense. We identified four de novo heterozygous gain-of-function variants in six patients with a polymorphic autoinflammatory immunodeficiency characterized by recurrent fever, dermatitis, inflammatory bowel disease, pulmonary alveolar proteinosis, and hypogammaglobulinemia. To establish causality, we applied genetic, molecular dynamics simulation, biochemical, and cellular functional analyses in heterologous, autologous, and inducible pluripotent stem cell-derived macrophages and/or monocytes and B cells. We found that upon interferon-induced expression, OAS1 variant proteins displayed dsRNA-independent activity, which resulted in RNase L-mediated RNA cleavage, transcriptomic alteration, translational arrest, and dysfunction and apoptosis of monocytes, macrophages, and B cells. RNase L inhibition with curcumin modulated and allogeneic hematopoietic cell transplantation cured the disorder. Together, these data suggest that human OAS1 is a regulator of interferon-induced hyperinflammatory monocyte, macrophage, and B cell pathophysiology.
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http://dx.doi.org/10.1126/sciimmunol.abf9564DOI Listing
June 2021

Immunological abnormalities in patients with early-onset ataxia with ocular motor apraxia and hypoalbuminemia.

Clin Immunol 2021 Aug 9;229:108776. Epub 2021 Jun 9.

Department of Pediatrics, National Defense Medical College, Tokorozawa, Japan.

Early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH) is a neurodegenerative disorder caused by mutation in the aprataxin (APTX)-coding gene APTX, which is involved in DNA single-strand break repair (SSBR). The neurological abnormalities associated with EAOH are similar to those observed in patients with ataxia-telangiectasia. However, the immunological abnormalities in patients with EAOH have not been described. In this study, we report that EAOH patients have immunological abnormalities, including lymphopenia; decreased levels of CD4 T-cells, CD8 T-cells, and B-cells; hypogammaglobulinemia; low T-cell recombination excision circles and kappa-deleting element recombination circles; and oligoclonality of T-cell receptor β-chain variable repertoire. These immunological abnormalities vary among the EAOH patients. Additionally, mild radiosensitivity in the lymphocytes obtained from the patients with EAOH was demonstrated. These findings suggested that the immunological abnormalities and mild radiosensitivity evident in patients with EAOH could be probably caused by the DNA repair defects.
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http://dx.doi.org/10.1016/j.clim.2021.108776DOI Listing
August 2021

Therapeutic options for CTLA-4 insufficiency.

J Allergy Clin Immunol 2021 Jun 7. Epub 2021 Jun 7.

The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania.

Background: Heterozygous germline mutations in cytotoxic T lymphocyte-associated antigen-4 (CTLA4) impair the immunomodulatory function of regulatory T cells. Affected individuals are prone to life-threatening autoimmune and lymphoproliferative complications. A number of therapeutic options are currently being used with variable effectiveness.

Objective: Our aim was to characterize the responsiveness of patients with CTLA-4 insufficiency to specific therapies and provide recommendations for the diagnostic workup and therapy at an organ-specific level.

Methods: Clinical features, laboratory findings, and response to treatment were reviewed retrospectively in an international cohort of 173 carriers of CTLA4 mutation. Patients were followed between 2014 and 2020 for a total of 2624 months from diagnosis. Clinical manifestations were grouped on the basis of organ-specific involvement. Medication use and response were recorded and evaluated.

Results: Among the 173 CTLA4 mutation carriers, 123 (71%) had been treated for immune complications. Abatacept, rituximab, sirolimus, and corticosteroids ameliorated disease severity, especially in cases of cytopenias and lymphocytic organ infiltration of the gut, lungs, and central nervous system. Immunoglobulin replacement was effective in prevention of infection. Only 4 of 16 patients (25%) with cytopenia who underwent splenectomy had a sustained clinical response. Cure was achieved with stem cell transplantation in 13 of 18 patients (72%). As a result of the aforementioned methods, organ-specific treatment pathways were developed.

Conclusion: Systemic immunosuppressants and abatacept may provide partial control but require ongoing administration. Allogeneic hematopoietic stem cell transplantation offers a possible cure for patients with CTLA-4 insufficiency.
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http://dx.doi.org/10.1016/j.jaci.2021.04.039DOI Listing
June 2021

Inborn errors of immunity-recent advances in research on the pathogenesis.

Inflamm Regen 2021 Mar 25;41(1). Epub 2021 Mar 25.

Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.

Primary immunodeficiency (PID) is a genetic disorder with a defect of one of the important components of our immune system. Classical PID has been recognized as a disorder with loss of function of the immune system. Recent studies have unveiled disorders with immune dysfunction with autoimmunity, autoinflammation, allergy, or predisposition to malignancy. Some of them were caused by an augmented immune function or a defect in immune regulation. With this background, the term inborn errors of immunity (IEI) is now used to refer to PID in the International Union of Immunological Societies (IUIS) classification. More than 400 responsible genes have been identified in patients with IEI so far, and importantly, many of them identified lately were caused by a heterologous mutation. Moreover, the onset is not necessarily in childhood, and we started seeing more and more IEI patients diagnosed in adulthood in the clinical settings. Recent advances in genetic analysis, including whole-exome analysis, whole-genome analysis, and RNA-seq have contributed to the identification of the disease-causing gene mutation. We also started to find heterogeneity of phenotype even in the patients with the same mutation in the same family, leading us to wonder if modifier gene or epigenetic modification is involved in the pathogenesis. In contrast, we accumulated many cases suggesting genetic heterogeneity is associated with phenotypic homogeneity. It has thus become difficult to deduce a responsible gene only from the phenotype in a certain type of IEI. Current curative therapy for IEI includes hematopoietic cell transplantation and gene therapy. Other curative therapeutic modalities have been long waited and are to be introduced in the future. These include a small molecule that inhibits the gain-of-function of the molecule- and genome-editing technology. Research on IEI will surely lead to a better understanding of other immune-related disorders including rheumatic diseases and atopic disorders.
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http://dx.doi.org/10.1186/s41232-021-00159-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992775PMC
March 2021

Safety and tolerability of IgPro10 in Japanese primary immunodeficiency patients: a registrational study.

Int J Hematol 2021 Jun 18;113(6):921-929. Epub 2021 Mar 18.

CSL Behring LLC, King of Prussia, PA, USA.

Studies investigating the safety of IgPro10 (Privigen, CSL Behring, King of Prussia, PA, USA) in Japanese patients with primary immunodeficiency (PID) are lacking. This study evaluated safety and tolerability of IgPro10 in Japanese patients with PID. In this prospective, open-label, single-arm, registrational study for Japan, IgPro10 was administered intravenously at pre-study doses of 138-556 mg/kg body weight per 3-/4-weekly dosing cycle for up to 4 months. Frequency and intensity of adverse events (AEs), their relationship to IgPro10 and AE rate per infusion (AERI) were evaluated. Of 11 enrolled patients, 10 completed the study. The median (range) total duration of exposure was 16.14 (4.1-16.3) weeks. Eight patients reported 19 AEs, none severe (based on maximum severity), giving an AERI of 0.442. One AE was deemed related to IgPro10 treatment. Three patients experienced temporally associated AEs. No serious AEs or deaths were reported. Nine patients (90%) who completed the study tolerated flow rates of ≥ 8 mg/kg/min; 5 tolerated 12 mg/kg/min (7.2 mL/kg/h), translating into a threefold decrease in mean infusion time. IgPro10 was well tolerated at a flow rate of up to 12 mg/kg/min. Safety and tolerability findings were consistent with previously reported studies in non-Japanese patients with PID.
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http://dx.doi.org/10.1007/s12185-021-03106-wDOI Listing
June 2021

Correction to: Helicobacter cinaedi-Associated Refractory Cellulitis in Patients with X-Linked Agammaglobulinemia.

J Clin Immunol 2021 May;41(4):847

Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

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http://dx.doi.org/10.1007/s10875-021-01015-5DOI Listing
May 2021

Utility of novel T-cell-specific extracellular vesicles in monitoring and evaluation of acute GVHD.

Int J Hematol 2021 Jun 8;113(6):910-920. Epub 2021 Mar 8.

Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, 113-8519, Japan.

We have recently reported a new method for detecting T-cell-derived extracellular vesicles (EVs), CD3CD4EVs,CD3CD8EVs, and CD3HLA-DREVs. In our previous study, CD3HLA-DREVs were released profusely by CD8T cells, only moderately by T helper1 (Th1) CD4T cells, and very little from Th2 CD4T cells in vitro. EVs were measured sequentially in patients undergoing hematopoietic stem cell transplantation (HSCT), and their relationship to GVHD was investigated in comparison with other conventional biomarkers. We analyzed peripheral blood samples from 20 patients (13 children and 7 adults) who underwent HSCT at Tokyo Medical and Dental University Hospital. CD3CD4EV and CD3CD8EV levels specifically correlated with the CD4 and CD8T lymphocyte counts, respectively. CD3CD8EVs and CD3HLA-DREVs increased in GVHD and reflected the persistence of GVHD more specifically than soluble IL-2 receptor (sIL-2R). In engraftment syndrome, sIL-2R was markedly elevated, but CD3HLA-DREVs were not. Furthermore, ferritin and sIL-2R markedly increased in hemophagocytic syndrome (HPS) that developed before engraftment; however, the change in CD3HLA-DREVs was marginal. CD3CD4, CD3CD8, and CD3HLA-DREVs efficiently reflect the cell-mediated immune response, and CD3CD8EVs and CD3HLA-DREVs are more useful than other conventional biomarkers, such as sIL-2R, for monitoring and evaluation of acute GVHD.
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http://dx.doi.org/10.1007/s12185-021-03113-xDOI Listing
June 2021

The Ever-Increasing Array of Novel Inborn Errors of Immunity: an Interim Update by the IUIS Committee.

J Clin Immunol 2021 Apr 18;41(3):666-679. Epub 2021 Feb 18.

Department of Immunology and Microbiology, Laboratory for Inborn Errors of Immunity, Department of Pediatrics, University Hospitals Leuven and KU Leuven, 3000, Leuven, Belgium.

The most recent updated classification of inborn errors of immunity/primary immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee, was published in January 2020. Within days of completing this report, it was already out of date, evidenced by the frequent publication of genetic variants proposed to cause novel inborn errors of immunity. As the next formal report from the IUIS Expert Committee will not be published until 2022, we felt it important to provide the community with a brief update of recent contributions to the field of inborn errors of immunity. Herein, we highlight studies that have identified 26 additional monogenic gene defects that reach the threshold to represent novel causes of immune defects.
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http://dx.doi.org/10.1007/s10875-021-00980-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889474PMC
April 2021

Marked clinical heterogeneity in congenital hyperinsulinism due to a novel homozygous ABCC8 mutation.

Clin Endocrinol (Oxf) 2021 Jun 14;94(6):940-948. Epub 2021 Mar 14.

Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.

Background: The most severe forms of congenital hyperinsulinism (CHI) are caused by inactivating mutations of two KATP channel genes, KCNJ11 and ABCC8. Unresponsiveness to diazoxide and need for subtotal pancreatectomy can usually be predicted by genetic form, particularly biallelic mutations in KATP channel genes. A few reports indicated marked clinical heterogeneity in siblings with identical biallelic mutations in ABCC8. The clinical heterogeneity in biallelic KATP CHI was speculated to be caused by epigenetic and environmental factors or related to differences in splicing factor machinery.

Objective: To elucidate the clinical pathophysiology, especially heterogeneity, among three cases with CHI caused by a homogenous novel mutation.

Patients And Methods: We report a case series that includes two siblings and one unrelated individual with CHI caused by a homogenous 1-bp deletion around the splice acceptor site at the exon 35 mutation of ABCC8, which exhibited markedly distinct phenotypes. To assess the effect of the mutation on splicing, we performed digital droplet polymerase chain reaction (ddPCR) on normal pancreas tissue and a patient's lymphocytes.

Results: ddPCR of ABCC8 cDNA revealed that expression of exon 35 and its upstream and downstream regions did not differ. These data suggested that clinical heterogeneity may not be caused by differences in splicing factor machinery.

Conclusion: The phenotypic variation in homozygotes could not be explained by splicing abnormalities. Though early genetic diagnosis of KATP CHI could contribute to selecting appropriate therapeutic options, more deliberate selection of therapeutic options in diffuse CHI due to biallelic ABCC8 mutations may be required.
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http://dx.doi.org/10.1111/cen.14443DOI Listing
June 2021

Inherited CARD9 Deficiency in a Child with Invasive Disease Due to Exophiala dermatitidis and Two Older but Asymptomatic Siblings.

J Clin Immunol 2021 Jul 8;41(5):975-986. Epub 2021 Feb 8.

Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Science, Hiroshima, Japan.

Purpose: Autosomal recessive CARD9 deficiency predisposes patients to invasive fungal disease. Candida and Trichophyton species are major causes of fungal disease in these patients. Other CARD9-deficient patients display invasive diseases caused by other fungi, such as Exophiala spp. The clinical penetrance of CARD9 deficiency regarding fungal disease is surprisingly not complete until adulthood, though the age remains unclear. Moreover, the immunological features of genetically confirmed yet asymptomatic individuals with CARD9 deficiency have not been reported.

Methods: Identification of CARD9 mutations by gene panel sequencing and characterization of the cellular phenotype by quantitative PCR, immunoblot, luciferase reporter, and cytometric bead array assays were performed.

Results: Gene panel sequencing identified compound heterozygous CARD9 variants, c.1118G>C (p.R373P) and c.586A>G (p.K196E), in a 4-year-old patient with multiple cerebral lesions and systemic lymphadenopathy due to Exophiala dermatitidis. The p.R373P is a known disease-causing variant, whereas the p.K196E is a private variant. Although the patient's siblings, a 10-year-old brother and an 8-year-old sister, were also compound heterozygous, they have been asymptomatic to date. Normal CARD9 mRNA and protein expression were found in the patient's CD14 monocytes. However, these cells exhibited markedly impaired pro-inflammatory cytokine production in response to fungal stimulation. Monocytes from both asymptomatic siblings displayed the same cellular phenotype.

Conclusions: CARD9 deficiency should be considered in previously healthy patients with invasive Exophiala dermatitidis disease. Asymptomatic relatives of all ages should be tested for CARD9 deficiency. Detecting cellular defects in asymptomatic individuals is useful for diagnosing CARD9 deficiency.
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http://dx.doi.org/10.1007/s10875-021-00988-7DOI Listing
July 2021

Detailed analysis of Japanese patients with adenosine deaminase 2 deficiency reveals characteristic elevation of type II interferon signature and STAT1 hyperactivation.

J Allergy Clin Immunol 2021 Jan 30. Epub 2021 Jan 30.

Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan.

Background: Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive inflammatory disease caused by loss-of-function mutations in both alleles of the ADA2 gene. Most patients with DADA2 exhibit systemic vasculopathy consistent with polyarteritis nodosa, but large phenotypic variability has been reported, and the pathogenesis of DADA2 remains unclear.

Objectives: This study sought to assess the clinical and genetic characteristics of Japanese patients with DADA2 and to gain insight into the pathogenesis of DADA2 by multi-omics analysis.

Methods: Clinical and genetic data were collected from 8 Japanese patients with DADA2 diagnosed between 2016 and 2019. ADA2 variants in this cohort were functionally analyzed by in vitro overexpression analysis. PBMCs from 4 patients with DADA2 were subjected to transcriptome and proteome analyses. Patient samples were collected before and after introduction of anti- TNF-α therapies. Transcriptome data were compared with those of normal controls and patients with other autoinflammatory diseases.

Results: Five novel ADA2 variants were identified in these 8 patients and were confirmed pathogenic by in vitro analysis. Anti-TNF-α therapy controlled inflammation in all 8 patients. Transcriptome and proteome analyses showed that upregulation of type II interferon signaling was characteristic of DADA2. Network analysis identified STAT1 as a key regulator and a hub molecule in DADA2 pathogenesis, a finding supported by the hyperactivation of STAT1 in patients' monocytes and B cells after IFN-γ stimulation.

Conclusions: Type II interferon signaling and STAT1 are associated with the pathogenesis of DADA2.
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http://dx.doi.org/10.1016/j.jaci.2021.01.018DOI Listing
January 2021

Hematopoietic Cell Transplantation with Reduced Intensity Conditioning Using Fludarabine/Busulfan or Fludarabine/Melphalan for Primary Immunodeficiency Diseases.

J Clin Immunol 2021 Jul 1;41(5):944-957. Epub 2021 Feb 1.

Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

Purpose: The purpose of our study was to compare the safety and efficacy of hematopoietic cell transplantation (HCT) using fludarabine (Flu)-based reduced intensity conditioning (RIC) with busulfan (BU) or melphalan (Mel) for primary immunodeficiency diseases (PID).

Methods: We retrospectively analyzed transplant outcome, including engraftment, chimerism, immune reconstitution, and complications in 15 patients with severe combined immunodeficiency (SCID) and 27 patients with non-SCID PID. The patients underwent Flu-based RIC-HCT with BU (FluBU: 7 SCID, 16 non-SCID) or Mel (FluMel: 8 SCID, 11 non-SCID). The targeted low-dose BU with therapeutic drug monitoring was set to 30 mg hour/L for SCID.

Results: The 2-year overall survival of all patients was 79.6% and that of patients with SCID in the FluBU and FluMel groups was 100% and 62.5%, respectively. In the FluBU group, all seven patients achieved engraftment, good immune reconstitution, and long-term survival. All five patients receiving umbilical cord blood transplantation achieved complete or high-level mixed chimerism and sufficient specific IgG production. In the FluMel group, six of eight patients achieved complete or high-level mixed chimerism. Viral reactivation or new viral infection occurred in one FluBU group patient and four FluMel group patients. In the non-SCID group, 10 of 11 patients (91%) who received FluMel achieved complete or high-level mixed chimerism but had variable outcomes. Patients with WAS (2/2 patients), NEMO deficiency (2/2 patients), and X-linked hyper IgM syndrome (2/3 patients) who received FluBU achieved complete or high-level mixed chimerism and long-term survival.

Conclusions: RIC-HCT with FluBU is a safe and effective strategy for obtaining high-level donor chimerism, immune reconstitution including B cell function, and long-term survival in patients with SCID. In patients with non-SCID PID, the results varied according to the subtype of the disease. Further prospective studies are required to optimize the conditioning regimen for non-SCID PID.
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http://dx.doi.org/10.1007/s10875-021-00966-zDOI Listing
July 2021

Clinical and Immunological Heterogeneity in Japanese Patients with Gain-of-Function Variants in STAT3.

J Clin Immunol 2021 May 26;41(4):780-790. Epub 2021 Jan 26.

Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.

Purpose: Germline loss-of-function variants in the signal transducer and activator of transcription 3 (STAT3) gene result in autosomal dominant hyper IgE syndrome, whereas somatic gain-of-function (GOF) variants in STAT3 are associated with some malignancies. In addition, germline GOF variants in STAT3 are linked to disorders involving autoimmunity and lymphoproliferation. In this study, we describe five Japanese families with germline GOF variants in STAT3, including three novel variants. We also present the clinical and immunological characteristics of these patients.

Methods: Eight patients from five families were enrolled in this study. We performed genetic and immunological analyses, and collected the associated clinical information.

Results: We identified five heterozygous variants in STAT3 using whole-exome sequencing and target gene sequencing. Two of these (E286G and T716M) were previously reported and three (K348E, E415G, and G618A) were novel. A STAT3 reporter assay revealed that all of the variants were GOF. However, the immunological and clinical characteristics among the patients were highly variable.

Conclusion: Patients with STAT3 GOF variants exhibited clinical and immunological heterogeneity with incomplete penetrance.
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http://dx.doi.org/10.1007/s10875-021-00975-yDOI Listing
May 2021

Copy Number Alteration Analysis for Neuroblastoma using Droplet Digital PCR.

Pediatr Int 2021 Jan 19. Epub 2021 Jan 19.

Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Yushima 1-5-45, Bunkyo-Ku, Tokyo, 113-8519, Japan.

Background: Neuroblastoma (NB) is a malignant tumor derived from the neural crest. MYCN amplification is a well-known adverse molecular prognostic factor for NB. Genome copy number alterations (CNAs) such as chromosome (Chr) 11q deletion, 1p deletion, and 17q gain are associated with a poor prognosis. Fluorescence in situ hybridization (FISH) and Southern blotting analysis are frequently used to detect MYCN amplification. Although comparative genomic hybridization (CGH) and single-nucleotide polymorphism (SNP) chip arrays can easily detect CNAs, these methods are impractical for clinical use due to their cost and run time. Consequently, genome copy number analysis using digital droplet PCR (ddPCR) has become widely used to monitor CNAs.

Methods: In this study, we used ddPCR to detect MYCN amplification and Chr 11q CNA, which was used for risk stratification according to the International Neuroblastoma Risk Group (INRG) classification system. We compared the results with data from SNP chip arrays in seven NB cell lines and eight primary NB samples.

Results: ddPCR assays successfully detected MYCN amplification and 11q CNA. The results of ddPCR were highly consistent with those obtained by SNP chip assay.

Conclusion: ddPCR can be conducted more rapidly than FISH or Southern blotting. Accordingly, it should be useful for on-site clinical applications aimed at detecting CNAs in NB and performing risk stratification promptly after diagnosis.
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http://dx.doi.org/10.1111/ped.14606DOI Listing
January 2021

Duodenal nodular lymphoid hyperplasia in a patient with IgA deficiency.

Clin Case Rep 2020 Dec 8;8(12):3594-3595. Epub 2020 Sep 8.

Department of Hematology National Cancer Center Hospital Tokyo Japan.

Most patients with IgA deficiency are asymptomatic, but duodenal nodular lymphoid hyperplasia is one symptom known to be associated with common variable immunodeficiency (CVID), including selective IgA deficiency and agammaglobulinemia.
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http://dx.doi.org/10.1002/ccr3.3298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752382PMC
December 2020

Hospitalisations due to respiratory syncytial virus infection in children with Down syndrome before and after palivizumab recommendation in Japan.

Acta Paediatr 2021 04 12;110(4):1299-1306. Epub 2020 Nov 12.

Department of Lifetime Clinical Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

Aim: Down syndrome has been considered an independent risk factor for respiratory syncytial virus (RSV) infection. Palivizumab, an anti-RSV humanised monoclonal antibody, was currently approved for all children with Down syndrome in Japan. To investigate the change in RSV-associated hospitalisation (RSVH) rates before and after the universal approval of palivizumab in Japan in 2013, we conducted a nationwide retrospective survey.

Methods: We conducted a nationwide, retrospective, questionnaire survey across paediatric institutions in Japan. The recruited children with Down syndrome were divided into two groups: those born April 2010 to March 2013 (2010-2012 cohort) and those born April 2013 to March 2016 (2013-2015 cohort).

Results: Of the 664 institutions, 321 (48.3%) replied, and a total of 3929 children with Down syndrome were registered. The percentage of children who received palivizumab increased from 49.2% to 82.2%. The cumulative RSVH rate showed a decreased trend in the 2013-2015 cohort (OR, 0.83; 95%CI, 0.63-1.10), while the rate of these children (without CHD and born at a gestational age ≥ 36 weeks) was significantly decreased in the 2013-2015 cohort (OR, 0.56; 95%CI, 0.34-0.92).

Conclusion: The cumulative RSVH rate tended to be decreased after approval for all children with Down syndrome although the result was not significant.
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http://dx.doi.org/10.1111/apa.15641DOI Listing
April 2021

Cytomegalovirus Laryngitis in Primary Combined Immunodeficiency Diseases.

J Clin Immunol 2021 Jan 8;41(1):243-247. Epub 2020 Oct 8.

Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.

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http://dx.doi.org/10.1007/s10875-020-00873-9DOI Listing
January 2021

The progression of salt-wasting and the body weight change during the first 2 weeks of life in classical 21-hydroxylase deficiency patients.

Clin Endocrinol (Oxf) 2021 02 20;94(2):229-236. Epub 2020 Oct 20.

Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

Background: One of the major purposes of newborn screening for 21-hydroxylase deficiency (21OHD) is preventing life-threatening adrenal crisis. However, the details of adrenal crisis in newborns are not precisely documented.

Aim: We aimed to clarify the clinical details of salt-wasting in newborn 21OHD patients.

Methods: Based on the follow-up survey of the screening in Tokyo from 1989 to 2017, we retrospectively analysed the conditions of classical 21OHD neonates before the initiation of therapy.

Results: One hundred classical 21OHD patients (55 male, 45 female) were analysed. The age at the first hospital visit was 0-20 days with sex difference (male: 9.0 ± 3.5 days; female: 6.2 ± 3.9 days). Thirty-seven (37.4%) patients exhibited severe salt-wasting (SSW), that is, Na < 130 mEq/L, K > 7 mEq/L or Na/K ratio < 20; except for one case, SSW developed in or after the second week of life. The serum concentrations of Na, K and Na/K were linearly correlated with age in days (R  = .38, .25, and .34 respectively), suggesting that the risk of SSW increases linearly without a threshold. The age at which the regression lines reached Na < 130 mEq/L, K > 7 mEq/L and Na/K < 20 was approximately coincided, 11.1, 12.3 and 11.2 days, respectively. All SSW patients exhibited decreased body weight from birth in their second week of life.

Conclusion: Our data revealed that the risk of developing SSW increases during the second week of life without a threshold, and for preventing SSW, early intervention, ideally during first week of life, is desirable. An increased body weight in the second week of life indicates the absence of SSW.
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http://dx.doi.org/10.1111/cen.14347DOI Listing
February 2021

Long-term outcome in patients with Fanconi anemia who received hematopoietic stem cell transplantation: a retrospective nationwide analysis.

Int J Hematol 2021 Jan 19;113(1):134-144. Epub 2020 Sep 19.

Department of Innovative Medical Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.

We retrospectively analyzed nationwide records of 163 Fanconi anemia (FA) patients [aplastic anemia (AA), n = 118; myelodysplastic syndrome (MDS), n = 30; acute leukemia, n = 15] who underwent first allogeneic hematopoietic stem cell transplantation (HSCT) between 1987 and 2015 in Japan. An alternative donor was used in 119 (73%) patients, and 160 (98%) patients received a non-T-cell-depleted graft. With an 8.7-year median follow-up, 5-year overall survival (OS) was 81%. The 5-year OS was significantly higher in AA patients than in MDS and acute leukemia patients (89%, 71%, and 44%, respectively). In the MDS/leukemia group, factors associated with poor outcome in univariate analysis were older age at HSCT (≥ 18 years), conditioning regimen without anti-thymocyte or lymphocyte globulin, and grade II-IV acute graft-versus-host disease. After 1 year, of 137 survivors, 15 developed subsequent malignancies, of whom 12 were diagnosed with head and neck (HN)/esophageal cancer. An irradiation regimen and older age were associated with the risk of HN/esophageal cancer. Five of seven deaths were attributed to subsequent malignancies more than 5 years after HSCT. On the basis of the risk factors for HSCT in MDS/leukemia patients and subsequent malignancies, a more effective HSCT approach is required.
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http://dx.doi.org/10.1007/s12185-020-02991-xDOI Listing
January 2021

Helicobacter cinaedi-Associated Refractory Cellulitis in Patients with X-Linked Agammaglobulinemia.

J Clin Immunol 2020 11 10;40(8):1132-1137. Epub 2020 Sep 10.

Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.

X-linked agammaglobulinemia (XLA) is characterized by severe or recurrent infections, hypogammaglobulinemia, and circulating B cell deficiency. The frequent pathogens seen in patients with XLA include Streptococcus pneumoniae, Haemophilus influenzae, Pseudomonas aeruginosa, and enterovirus as well as Campylobacter and Helicobacter species. Here, we describe two patients with XLA who developed cellulitis and bacteremia caused by Helicobacter cinaedi even when administered an appropriate immunoglobulin replacement therapy. H. cinaedi may be difficult to isolate using a conventional blood culture system and could be identified by sequence analysis and mass spectrometry. H. cinaedi infection causes recurrent symptoms frequently, and patients require a long course of antibiotic treatment. Recently, the case of non-H. pylori Helicobacter (NHPH) infection such as H. cinaedi and H. bilis infection is increasing in number in patients with XLA. Systemic NHPH infection should be suspected, and extensive microbiological analysis should be performed to appropriately treat patients with XLA who present with fever and skin lesions.
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http://dx.doi.org/10.1007/s10875-020-00830-6DOI Listing
November 2020

DNA Ligase IV Deficiency Identified by Chance Following Vaccine-Derived Rubella Virus Infection.

J Clin Immunol 2020 11 10;40(8):1187-1190. Epub 2020 Sep 10.

Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

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http://dx.doi.org/10.1007/s10875-020-00831-5DOI Listing
November 2020
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