Tomoyuki Mizukami

Apoptosis under hypercytokinemia is a possible pathogenesis in influenza-associated encephalopathy.

Abstract  Background : Influenza‐associated encephalopathy is reported to be frequent in Japan and East Asia. No evaluating markers except interleukin (IL)‐6 and tumor necrosis factor (TNF)‐α and no likely pathological mechanism for the disease have yet been elucidated.

Successful Treatment with Infliximab for Inflammatory Colitis in a Patient with X-linked Anhidrotic Ectodermal Dysplasia with Immunodeficiency

X-linked anhidrotic ectodermal dysplasia with immunodeficiency (X-EDA-ID) is caused by hypomorphic mutations in the gene encoding nuclear factor-κB essential modulator protein (NEMO). Patients are susceptibile to diverse pathogens due to insufficient cytokine and frequently show severe chronic colitis. An 11-year-old boy with X-EDA-ID was hospitalized with autoimmune symptoms and severe chronic colitis which had been refractory to immunosuppressive drugs. Since tumor necrosis factor (TNF) α is responsible for the pathogenesis of NEMO colitis according to intestinal NEMO and additional TNFR1 knockout mice studies, and high levels of TNFα-producing mononuclear cells were detected in the patient due to the unexpected gene reversion mosaicism of NEMO, an anti-TNFα monoclonal antibody was administered to ameliorate his abdominal symptoms. Repeated administrations improved his colonoscopic findings as well as his dry skin along with a reduction of TNFα-expressing T cells. These findings suggest TNF blockade therapy is of value for refractory NEMO colitis with gene reversion.

Frequent somatic mosaicism of NEMO in T cells of patients with X-linked anhidrotic ectodermal dysplasia with immunodeficiency

Somatic mosaicism has been described in several primary immunodeficiency diseases and causes modified phenotypes in affected patients. X-linked anhidrotic ectodermal dysplasia with immunodeficiency (XL-EDA-ID) is caused by hypomorphic mutations in the NF-κB essential modulator (NEMO) gene and manifests clinically in various ways. We have previously reported a case of XL-EDA-ID with somatic mosaicism caused by a duplication mutation of the NEMO gene, but the frequency of somatic mosaicism of NEMO and its clinical impact on XL-EDA-ID is not fully understood. In this study, somatic mosaicism of NEMO was evaluated in XL-EDA-ID patients in Japan. Cells expressing wild-type NEMO, most of which were derived from the T-cell lineage, were detected in 9 of 10 XL-EDA-ID patients. These data indicate that the frequency of somatic mosaicism of NEMO is high in XL-ED-ID patients and that the presence of somatic mosaicism of NEMO could have an impact on the diagnosis and treatment of XL-ED-ID patients.

PEGylated D-amino acid oxidase restores bactericidal activity of neutrophils in chronic granulomatous disease via hypochlorite.

Chronic granulomatous disease (CGD) causes impaired hydrogen peroxide (H2O2) generation. Consequently, neutrophils in patients with CGD fail to kill infecting pathogens. We expected that supplementation with H2O2 would effectively restore the bactericidal function of neutrophils in CGD. Here, we used polyethylene glycol-conjugated d-amino acid oxidase (PEG-DAO) as an H2O2 source. The enzyme DAO generates H2O2 by using d-amino acid and oxygen as substrates. PEG-DAO plus d-amino acid indeed exerted bacteriostatic activity against Staphylococcus aureus via H2O2 in vitro. Furthermore, use of PEG-DAO plus d-amino acids, which increased the amount of intracellular H2O2, restored bactericidal activity of neutrophils treated with diphenylene iodonium, in which nicotinamide adenine dinucleotide phosphate (NADPH) oxidase was defective. This restoration of bactericidal activity was mediated by myeloperoxidase, with concomitant production of H2O2 by PEG-DAO plus d-Ala. We also confirmed that PEG-DAO treatment restored bactericidal activity of congenitally defective neutrophils from patients with CGD. These results indicate that PEG-DAO can supply additional H2O2 for defective NADPH oxidase of neutrophils from patients with CGD, and thus neutrophils regain bactericidal activity.

Leopard Skin-Like Colonic Mucosa: A Novel Endoscopic Finding of Chronic Granulomatous Disease-Associated Colitis.

Background: Chronic granulomatous disease (CGD) is a rare inherited disorder in which phagocytes are unable to eradicate pathogens because of a deficit of nicotinamide adenine dinucleotide phosphate oxidase. Among CGD patients, ∼30% to 50% develop severe gastrointestinal tract symptoms. Although characteristic histologic findings of CGD-associated colitis have been reported, information on endoscopic features remained vague. Methods: A total of 8 male patients with CGD (ages 2–23 years) from 2 Japanese institutions underwent colonoscopy for the evaluation of their fever, diarrhea, bloody stool, and abdominal pain. The endoscopic and histologic findings were retrospectively reviewed. Results: The endoscopic findings of CGD-associated colitis appeared varied. Notably, brownish dots over a yellowish edematous mucosa were observed in 3 of the 8 patients. Prominent pigment-laden macrophages were noted histologically on the mucosa. Conclusions: Although nonspecific endoscopic findings of CGD-associated colitis have been reported before, our observation of brownish dots spread across a yellowish edematous mucosa, termed “leopard sign,” could be a unique feature of this condition.

A Dual Reporter Splicing Assay Using HaloTag-containing Proteins

To evaluate the effects of genetic variations on mRNA splicing, we developed a minigene-based splicing assay using reporter genes encoding luciferase and the multifunctional HaloTag protein. In addition to conventional RT-PCR analysis, splicing events can be monitored in this system using two parameters: luciferase activity and signals derived from HaloTag-containing proteins bound to a fluorescent ligand following SDS-PAGE. The luciferase activity reflects the accumulated amounts of successfully spliced HaloTag–luciferase fusion products, whereas the amounts and sizes of HaloTag-containing proteins provide quantitative insights into precursor, correctly spliced, and aberrantly spliced mRNA species. Preliminary experiments confirmed that the dual reporter minigene assay can provide estimates of overall splicing efficiency based on the levels of protein products. We then used the minigene assay to analyze a case of chronic granulomatous disease that was caused by a G>C mutation at position +5 in the 5’-splice donor site of intron 5 of the CYBB gene. We found that the G>C mutation affected CYBB mRNA splicing by changing a delicate balance of splicing efficiencies of introns 4, 5, and 6.

Successful bone marrow transplantation in chronic granulomatous disease

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Necrotizing Ulcer After BCG Vaccination in a Girl With Leukocyte-adhesion Deficiency Type 1

Leukocyte-adhesion deficiency-1 is a recessively inherited disorder associated with recurrent bacterial infections, severe periodontitis, peripheral leukocytosis, and impaired wound healing. We diagnosed moderate-type leukocyte-adhesion deficiency-1 in a 7-year-old girl who developed a necrotizing ulcer after Bacillus Calmette-Guerin vaccination. The patient showed moderate expression of CD18 in neutrophils with a homozygous splice mutation with c.41_c.58+2dup20 of ITGB2 and experienced recurrent severe infections complicated with systemic lupus erythematosus. She received hematopoietic stem cell transplantation from a matched elder brother with heterozygous mutation of ITGB2, and has since remained free of infection and systemic lupus erythematosus symptoms without immunosuppression therapy.

Idiopathic disseminated bacillus Calmette-Guerin infection in three infants.

We describe the cases of three infants between 4 and 9 months of age with disseminated bacillus Calmette–Guerin (BCG) infection who developed persistent fever, skin rash, and multiple chest nodules visible on computed tomography 22–34 days after BCG vaccination. These infants were healthy before inoculation, and their detailed immunological profiles, including T cell and neutrophil levels, were within normal range. Most reported BCG cases involve impaired immunity, such as children with chronic granulomatous disease, severe combined immunodeficiency, or human immunodeficiency virus infections. Because of their immature immune systems, BCG vaccination can be hazardous even in early infants without immune abnormalities. Hence, we advise caution when administering BCG vaccines to early infants.