Publications by authors named "Hirokazu Kanegane"

271 Publications

Myelodysplastic Syndrome in a Patient with IPEX Syndrome.

J Clin Immunol 2021 Jul 12. Epub 2021 Jul 12.

Department of Pediatrics, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan.

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http://dx.doi.org/10.1007/s10875-021-01092-6DOI 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

Hematologically important mutations: X-linked chronic granulomatous disease (fourth update).

Blood Cells Mol Dis 2021 Jun 2;90:102587. Epub 2021 Jun 2.

Dept of Pediatrics and Laboratory for Leukocyte Function, Meir Medical Centre, Kfar Saba, Israel.

Chronic granulomatous disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. CGD patients suffer from severe bacterial and fungal infections. The disease is caused by a lack of superoxide production by the leukocyte enzyme NADPH oxidase. Superoxide and subsequently formed other reactive oxygen species (ROS) are instrumental in killing phagocytosed micro-organisms in neutrophils, eosinophils, monocytes and macrophages. The leukocyte NADPH oxidase is composed of five subunits, of which the enzymatic component is gp91, also called Nox2. This protein is encoded by the CYBB gene on the X chromosome. Mutations in this gene are found in about 70% of all CGD patients in Europe and in about 20% in countries with a high ratio of parental consanguinity. This article lists all mutations identified in CYBB and should therefore help in genetic counseling of X-CGD patients' families. Moreover, apparently benign polymorphisms in CYBB are also given, which should facilitate the recognition of disease-causing mutations. In addition, we also include some mutations in G6PD, the gene on the X chromosome that encodes glucose-6-phosphate dehydrogenase, because inactivity of this enzyme may lead to shortage of NADPH and thus to insufficient activity of NADPH oxidase. Severe G6PD deficiency can induce CGD-like symptoms.
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http://dx.doi.org/10.1016/j.bcmd.2021.102587DOI Listing
June 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

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

UNC13D mutation in a patient with juvenile polymyositis with recurrent macrophage activation syndrome.

Rheumatology (Oxford) 2021 Apr 30. Epub 2021 Apr 30.

Division of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, China.

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http://dx.doi.org/10.1093/rheumatology/keab391DOI Listing
April 2021

Case Report: Infantile-Onset Fulminant Type 1 Diabetes Mellitus Caused by Novel Compound Heterozygous Variants.

Front Immunol 2021 12;12:677572. Epub 2021 Apr 12.

Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan.

Lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency is a subtype of common variable immune deficiency (CVID). Numerous case reports and cohort studies have described a broad spectrum of clinical manifestations and variable disease phenotypes, including immune dysregulation, enteropathy, and recurrent infections. Although LRBA deficiency is an autosomal recessive primary immunodeficiency resulting in a phenotype similar to CVID, it is a monogenic disease and separate from CVID. Recently, in a report of monogenic primary immunodeficiency disorder associated with CVID and autoimmunity, the most common mutated gene was . We report the case of a girl who presented with fulminant type 1 diabetes at age 7 months. She later experienced recurrent bacterial infections with neutropenia and idiopathic thrombocytopenic purpura. Clinical genome sequencing revealed compound heterozygosity of the gene, which bore two novel mutations. A genetic basis should be considered in the differential diagnosis for very young patients with fulminant autoimmunity, and the diagnostic work-up should include evaluation of markers of immunodeficiency.
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http://dx.doi.org/10.3389/fimmu.2021.677572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072023PMC
April 2021

Epstein-Barr Virus-Negative Granulomatous Disease Due to SAP Deficiency.

J Clin Immunol 2021 Apr 7. Epub 2021 Apr 7.

Department of Pediatrics, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan.

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http://dx.doi.org/10.1007/s10875-021-01032-4DOI Listing
April 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

A Novel Homozygous Mutation Destabilizes IKKβ and Leads to Human Combined Immunodeficiency.

Front Immunol 2020 15;11:517544. Epub 2021 Feb 15.

National Clinical Research Center for Child Health and Disorders, Chongqing, China.

Mutations in the gene cause severe immunodeficiency, characterized clinically by persistent respiratory or gastrointestinal infections. Targeted gene panel sequencing revealed a novel homozygous missense mutation in the gene of a patient with immune dysregulation and combined T and B cell functional defects. PBMCs from the patient, Y397H mice, and transfected cells were used to elucidate how the Y395H mutation triggers IKKβ deficiency and impairs immune function. Here, we found that cells from both the patient and Y397H mice lacked or showed decreased levels of IKKβ protein, along with impaired lymphocyte function. IKKα and IKKγ protein expression by human PBMCs harboring the Y395H mutation was normal, but degradation of IKKβ protein was accelerated. Binding of human NF-κB to DNA in patient PBMCs fell upon stimulation with TNF-α or LPS. Additionally, a structural model of Y395H revealed loss of the hydrogen bond with D389. These data suggest that deficiency induces abnormal IKKβ protein degradation, leading to impaired NF-κB signaling and immune function. We postulate that the Y395H variant in the IKKβ protein lost the hydrogen bond with D389, thereby affecting interaction between Y395 and D389 and increasing protein instability.
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http://dx.doi.org/10.3389/fimmu.2020.517544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917045PMC
April 2021

Functional analysis of novel A20 variants in patients with atypical inflammatory diseases.

Arthritis Res Ther 2021 02 6;23(1):52. Epub 2021 Feb 6.

Department of Pediatrics, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, Gifu, 501-1194, Japan.

Background: A20 haploinsufficiency (HA20) is an early-onset autoinflammatory disease caused by mutations in the TNFAIP3 gene, which encodes the protein A20. Numerous truncating mutations in the TNFAIP3 gene have been reported in HA20 patients, whereas fewer missense variants have had their pathogenicity confirmed. Here, we evaluated the pathogenic significance of three previously unreported missense variants of the TNFAIP3 gene in suspected cases of HA20.

Methods: We obtained the clinical features and immunological data of three patients with missense variants (Glu192Lys, Ile310Thr, and Gln709Arg) of unknown significance of TNFAIP3. We then performed in vitro functional assays including analysis of nuclear factor (NF)-κB reporter gene activity, detection of A20 expression and phosphorylation of A20 by IκB kinase β (IKKβ), and K63-deubiquitination assay using TNFAIP3-deficient HEK293 cells. Three known pathogenic missense mutations reported previously were also investigated.

Results: The inhibitory effect on NF-κB reporter gene activity was significantly disrupted by A20 Glu192Lys and the three known mutations. The variants Ile310Thr and Gln709Arg did not show a difference from the wild type in any of the assays performed in this study.

Conclusions: Among the three variants in the TNFAIP3 gene, Glu192Lys was interpreted as being likely pathogenic, but Ile310Thr and Gln709Arg as being not pathogenic (uncertain significance and likely benign, respectively), based on the American College of Medical Genetics and Genomics standards and guidelines. Our study highlights the necessity of performing in vitro functional assays, notably, NF-κB reporter gene assay, to evaluate the pathogenicity of TNFAIP3 missense variants for the accurate diagnosis of HA20.
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http://dx.doi.org/10.1186/s13075-021-02434-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866758PMC
February 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

A case of autoimmune enteropathy with CTLA4 haploinsufficiency.

Intest Res 2021 Jan 22. Epub 2021 Jan 22.

Division of Gastroenterology, Department of Internal Medicine, Kobe University Hospital, Kobe, Japan.

Autoimmune enteropathy (AIE) is a rare disease, characterized by intractable diarrhea, villous atrophy of the small intestine, and the presence of circulating anti-enterocyte autoantibodies. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, and mutations in FOXP3, which is a master gene of regulatory T cells (Tregs), are major causes of AIE. Recent studies have demonstrated that mutations in other Treg-associated genes, such as CD25 and CTLA4, show an IPEX-like phenotype. We present the case of a 13-year-old girl with CTLA4 haploinsufficiency, suffering from recurrent immune thrombocytopenic purpura and intractable diarrhea. We detected an autoantibody to the AIE-related 75 kDa antigen (AIE-75), a hallmark of the IPEX syndrome, in her serum. She responded well to a medium dose of prednisolone and a controlled dose of 6-mercaptopurine (6-MP), even after the cessation of prednisolone administration. Serum levels of the soluble interleukin-2 receptor and immunoglobulin G (IgG) were useful in monitoring disease activity during 6-MP therapy. In conclusion, autoimmune-mediated mechanisms, similar to the IPEX syndrome, may be involved in the development of enteropathy in CTLA4 haploinsufficiency. Treatment with 6-MP and monitoring of disease activity using serum levels of soluble interleukin-2 receptor and IgG is suggested for such cases.
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http://dx.doi.org/10.5217/ir.2020.00041DOI Listing
January 2021

Hyper IgE Syndrome Associated With Warts: A First Case of Dedicator of Cytokinesis 8 Deficiency in the Philippines.

Front Pediatr 2020 30;8:604725. Epub 2020 Oct 30.

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

Hyper IgE syndrome (HIES) encompasses a group of primary immunodeficiency diseases (PIDs) that is characterized by severe atopy, and recurrent infections and markedly elevated serum IgE levels. The majority of HIES cases suffer from autosomal dominant mutations in the gene. A minority of cases display autosomal recessive inheritance, and one form is caused by mutations in the () gene. Here we describe the first recognized and diagnosed case of DOCK8 deficiency in the Philippines. A 14 year-old-girl was referred due to recalcitrant atopic dermatitis, recurrent sinopulmonary infections, with widespread warts on the face, trunk and extremities. She had no coarse facial features or retained primary teeth, whereas she presented with widespread viral skin infections and multiple allergic diseases. Laboratory examinations revealed elevations in eosinophil count and serum IgE. The level of T-cell receptor excision circles was undetectable. The patient was suspected to have HIES with a probable DOCK8 deficiency. Genetic analysis disclosed a large genomic deletion involving exons 2-4 in the gene. A combination of recalcitrant atopic dermatitis, asthma, food allergies, with viral skin infections should increase the physician's consideration of a PID. Patients with HIES accompanied by warts and T-cell deficiency can be strongly suspected to have DOCK8 deficiency.
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http://dx.doi.org/10.3389/fped.2020.604725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673426PMC
October 2020

Impaired B-Cell Differentiation in a Patient With Gain-of-Function Mutation.

Front Immunol 2020 29;11:557521. Epub 2020 Sep 29.

Department of Pediatrics, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan.

Hypogammaglobulinemia is a rare complication of gain-of-function (GOF) mutations. We report an adult patient diagnosed with hypogammaglobulinemia caused by B-cell depletion during the treatment of disseminated cryptococcosis. The patient carried the GOF mutation (c.820C>T, p.R274W). The flow cytometric analysis of his bone marrow revealed that B-cell differentiation was blocked in the stages between pre-B1b and pre-B2 cells. On the other hand, his brother who carried the same mutation displayed normal B-cell counts, thereby indicating that the unrecognized variants in same or other gene might be associated with abnormal B-cell differentiation in the patients. In conclusion, impaired B-cell differentiation in the bone marrow can cause hypogammaglobulinemia in patients with GOF mutations.
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http://dx.doi.org/10.3389/fimmu.2020.557521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550620PMC
May 2021

Fatal Progressive Meningoencephalitis Diagnosed in Two Members of a Family With X-Linked Agammaglobulinemia.

Front Pediatr 2020 18;8:579. Epub 2020 Sep 18.

Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Chronic enteroviral meningoencephalitis is a well-known complication in patients with X-linked agammaglobulinemia (XLA). However, progressive neurodegenerative disorders or chronic neuroinflammatory diseases with no causative microorganisms have been recognized as rare central nervous system (CNS) complications in XLA. We herein report a family in which two of three members with XLA had developed progressive meningoencephalitis with an unknown etiology. A 15-month-old male infant presented with left-sided ptosis. Initially, the family denied any family history of inherited diseases, but later disclosed a family history of agammaglobulinemia previously diagnosed in two family members. In the early 1980s, one of the elder brothers of the index patient's mother who had been treated with intramuscular immunoglobulin [or later intravenous immunoglobulin (IVIG)] for agammaglobulinemia deceased at 10 years of age after showing progressive neurological deterioration during the last several years of his life. The index patient was diagnosed with XLA caused by Bruton tyrosine kinase deficiency (654delG; Val219Leufs9), and chronic meningoencephalitis with an unknown infectious etiology. Magnetic resonance imaging of the brain demonstrated inflammatory changes in the basal ganglia, hypothalamus, midbrain, and pons, with multiple nodular lesions with ring enhancement, which showed impressive amelioration after the initiation of IVIG replacement therapy. Pleocytosis, which was characterized by an increase in CD4-positive and CD8-positive T cells expressing an activation marker and an elevation in inflammatory cytokines in the cerebrospinal fluid, was identified. No microorganism was identified as a cause of CNS complications. He thereafter developed brain infarction at 19 months of age and fatal status epilepticus at 5 years of age, despite regular IVIG with high trough levels and regular intraventricular immunoglobulin administration. The etiology of this rare CNS complication in XLA is currently unknown. Previous studies have suggested a possible association of IVIG, which was clearly denied in our index case because of the demonstration of his neurological disorder at presentation. In the future, extensive and unbiased molecular methods to detect causative microorganisms, as well as to investigate the possible role of autoimmunity are needed to clarify the etiology of CNS complications.
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http://dx.doi.org/10.3389/fped.2020.00579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530192PMC
September 2020

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

Infection Presenting as an Endobronchial Polyp and Upper Lobe Atelectasis.

Am J Respir Crit Care Med 2020 12;202(11):e144-e145

Department of Respiratory Medicine and.

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http://dx.doi.org/10.1164/rccm.202005-1652IMDOI Listing
December 2020

Predictive Prenatal Diagnosis for Infantile-onset Inflammatory Bowel Disease Because of Interleukin-10 Signalling Defects.

J Pediatr Gastroenterol Nutr 2021 02;72(2):276-281

Translational Gastroenterology Unit, University of Oxford, Oxford, UK.

Objectives: Advances in genetic technologies provide opportunities for patient care and ethical challenges. Clinical care of patients with rare Mendelian disorders is often at the forefront of those developments. Whereas in classical polygenic inflammatory bowel disease (IBD), the predictive value of genetic variants is very low, predictive prenatal genetic diagnosis can inform families at high risk of severe genetic disorders. Patients with IL-10 signalling defects because of pathogenic variants in IL10RA, Il10RB, and IL10 develop severe infantile onset inflammatory bowel disease that is completely penetrant and has a high morbidity and substantial mortality despite treatment.

Methods: We performed a survey among tertiary specialist paediatric centers of 10 countries on the utilization of predictive prenatal genetic diagnosis in IL-10 signalling defects. We retrospectively report prenatal genetics in a series of 8 families.

Results: International variation in legislation, guidelines, expert opinion, as well as cultural and religious background of families and clinicians results in variable utilization of preimplantation and prenatal genetic testing for IL-10 signalling defects. Eleven referrals for prenatal diagnosis for IL-10 signalling defects were identified across 4 countries. We report on 8 families who underwent prenatal preimplantation monogenic testing after in vitro fertilization (n = 2) and/or by amniocentesis/chorion villus sampling (n = 6). A genetic diagnosis was established in 1 foetus and excluded in 7 foetuses (all IL10RA variants).

Conclusions: Prenatal genetic testing for IL10R-defects is feasible, yet the legal and ethical considerations are complex and controversial. In some countries, predictive genetics for IL-10-related signalling defects is entering clinical practice.
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http://dx.doi.org/10.1097/MPG.0000000000002937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191811PMC
February 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

A Cry for the Development of Newborn Screening for Familial Hemophagocytic Lymphohistiocytosis.

J Clin Immunol 2020 11 10;40(8):1196-1198. Epub 2020 Sep 10.

Department of Pediatrics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.

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http://dx.doi.org/10.1007/s10875-020-00863-xDOI Listing
November 2020

Current Perspectives and Unmet Needs of Primary Immunodeficiency Care in Asia Pacific.

Front Immunol 2020 13;11:1605. Epub 2020 Aug 13.

Department of Pediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

The Asia Pacific Society for Immunodeficiencies (APSID) conducted nine primary immunodeficiency (PID) Schools in 5 years since inauguration to provide PID care training for early career physicians in Asia Pacific, a region with divergent needs in PID resources and training. To identify differences in PID patient care resource and training needs across Asia Pacific and propose a corresponding action plan. The Human Development Index (HDI) indicates the degree of socio-economic development in each country/region. Information related to investigations and learning issues were extracted from the abstracts and personal statements from all Schools and mapped onto resource and training needs. Correlations between HDI and country/region-specific parameters were tested by two-tailed Pearson correlation. A total of 427 abstracts were received in nine Schools between 2015 and 2020, predominantly on immunodeficiencies affecting cellular and humoral immunity. Genetic confirmation was described in 61.8% of abstracts, and its absence negatively correlated with HDI ( = -0.696, = 0.004). Essential immunologic and genetic tests were not available in 25.4 and 29.5% of abstracts, respectively, and their absence negatively correlated with HDI ( = -0.788, < 0.001; = -0.739, = 0.002). HDI positively correlated with average testing level ( = 0.742, = 0.002). Cases from medium-HDI countries/regions focused on learning how to investigate a patient for PIDs in cases of severe or atypical infections, whereas those from very-high-HDI countries/regions, from which most faculty members originated, listed hematopoietic stem cell transplantation and gene therapy, newborn screening, and research as learning issues more frequently. There are unique HDI-related PID resource and training needs in each country/region. APSID proposes HDI group-specific strategies to improve PID care and education in her member countries/regions. Further quantitative analysis of needs in PID care in Asia Pacific is needed for lobbying governments to increase their support for PID care and research.
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http://dx.doi.org/10.3389/fimmu.2020.01605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438539PMC
April 2021

Influenza-induced hemolytic crisis in glucose-6-phosphate dehydrogenase deficiency.

Pediatr Int 2020 Aug 10;62(8):1003-1004. Epub 2020 Aug 10.

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/10.1111/ped.14226DOI Listing
August 2020

Prospective Study of Allogeneic Hematopoietic Stem Cell Transplantation with Post-Transplantation Cyclophosphamide and Antithymocyte Globulin from HLA-Mismatched Related Donors for Nonmalignant Diseases.

Biol Blood Marrow Transplant 2020 11 14;26(11):e286-e291. Epub 2020 Aug 14.

Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan; Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan. Electronic address:

Allogeneic hematopoietic stem cell transplantation (HSCT) is performed as a curative treatment for children with nonmalignant diseases, such as bone marrow failure syndromes and primary immunodeficiencies. Because graft-versus-host-disease (GVHD) is a major factor affecting survival probability and quality of life after HSCT, the availability of HLA-matched donors restricts the application of HSCT. Recently, HSCT with post-transplantation cyclophosphamide (PTCy) has emerged as a potent method to prevent GVHD after HSCT from HLA-haploidentical donors, and some studies have suggested the safety of PTCy-HSCT for nonmalignant diseases. We conducted a prospective clinical trial aiming to help confirm the safety of HSCT and further reduction of GVHD using a combination of PTCy and low-dose antithymocyte globulin (ATG) from HLA-mismatched related donors for children with nonmalignant diseases. Six patients underwent HSCT and achieved engraftment at a median of 14.5 days, and no patient developed severe acute GVHD. All patients had sustained donor chimerism without developing chronic GVHD at the last follow-up. In conclusion, HSCT with PTCy and low-dose ATG from an HLA-mismatched related donor were feasible to control GVHD for nonmalignant diseases in the children involved in our study. © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
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http://dx.doi.org/10.1016/j.bbmt.2020.08.008DOI Listing
November 2020

Successful Artery Embolization in a Patient with Autoimmune Lymphoproliferative Syndrome Associated with Splenic Rupture.

J Clin Immunol 2020 07 25;40(5):780-782. Epub 2020 Jun 25.

Department of Pediatrics, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.

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http://dx.doi.org/10.1007/s10875-020-00809-3DOI Listing
July 2020