Taizo Wada

Human heme oxygenase-1 deficiency presenting with hemolysis, nephritis, and asplenia.

Heme oxygenase-1 (HO-1) is a stress-induced enzyme that catalyses the oxidation of heme to biliverdin. The primary deficiency of this enzyme has been shown in HO-1 knockout mice, and is characterized by intrauterine death and chronic inflammation. The first case of human HO-1 deficiency was reported in 1999. Human HO-1 deficiency has been observed to involve the endothelial cells more severely, resulting in hemolysis and disseminated intravascular coagulation. We report another case of human HO-1 deficiency in a young girl with congenital asplenia, who presented with severe hemolysis, inflammation, nephritis, which was refractory to therapy with corticosteroids, cyclophosphamide, and rituximab.

Somatic mosaicism in primary immune deficiencies.

Purpose of reviewSpontaneous genetic reversions and second-site mutations resulting in revertant somatic mosaicism are poorly understood phenomena with a seemingly frequent occurrence in primary immunodeficiency diseases. Here we summarize the several cases that have been reported thus far with particular focus on the most recent observations. Recent findingsRevertant cells have been associated with attenuated clinical phenotypes in some, although not all, immunodeficient patients who presented with somatic mosaicism. Interestingly, the latest studies suggest that revertant cells may also be responsible for immune dysregulation. In addition, extensive molecular analysis of revertant cells has revealed that an unexpectedly large variety of genetic changes can be responsible for their emergence. SummaryThe occurrence of revertant somatic mosaicism in patients affected with primary immunodeficiency diseases is likely much more common than originally anticipated. The study of this fascinating phenomenon continues to provide clues as to the possible underlying mechanisms and to inform, albeit indirectly, the process of development of cell and gene therapy for these diseases.

Detection of T lymphocytes with a second-site mutation in skin lesions of atypical X-linked severe combined immunodeficiency mimicking Omenn syndrome

X-linked severe combined immunodeficiency (XSCID) is caused by mutations of the common gamma chain (gammac) and usually characterized by the absence of T and natural killer (NK) cells. Here, we report an atypical case of XSCID presenting with autologous T and NK cells and Omenn syndrome-like manifestations. The patient carried a splice-site mutation (IVS1+5G>A) that caused most of the mRNA to be incorrectly spliced but produced normally spliced transcript in lesser amount, leading to residual gammac expression and development of T and NK cells. The skin biopsy specimen showed massive infiltration of revertant T cells. Those T cells were found to have a second-site mutation and result in complete restoration of correct splicing. These findings suggest that the clinical spectrum of XSCID is quite broad and includes atypical cases mimicking Omenn syndrome, and highlight the importance of revertant mosaicism as a possible cause for variable phenotypic expression.

Colchicine-responsive chronic recurrent multifocal osteomyelitis with MEFV mutations: a variant of familial Mediterranean fever?

*KURAに登録されているコンテンツの利用については,著作権法に規定されている私的使用や引用などの範囲内で行ってください。 *著作権法に規定されている私的使用や引用などの範囲を超える利用を行う場合には,著作権者の許諾を得てください。ただし,著作権者 から著作権等管理事業者(学術著作権協会,日本著作出版権管理システムなど)に権利委託されているコンテンツの利用手続については ,各著作権等管理事業者に確認してください。 Title Colchicine-responsive chronic recurrent multifocal osteomyelitis with MEFV mutations: A variant of familial Mediterranean fever? Author(s) Shimizu, Masaki; Tone, Yumi; Toga, Akiko; Yokoyama, Tadafumi; Wada, Taizo; Toma, Tomoko; Yachie, Akihiro Citation Rheumatology, 49(11): 2221-2223

Analysis of mutations and recombination activity in RAG-deficient patients.

Mutations in the recombination activating genes (RAG1 or RAG2) can lead to a variety of immunodeficiencies. Herein, we report 5 cases of RAG deficiency from 5 families: 3 of Omenn syndrome, 1 of severe combined immunodeficiency, and 1 of combined immunodeficiency with oligoclonal TCRγδ(+) T cells, autoimmunity and cytomegalovirus infection. The genetic defects were heterogeneous and included 6 novel RAG mutations. All missense mutations except for Met443Ile in RAG2 were located in active core regions of RAG1 or RAG2. V(D)J recombination activity of each mutant was variable, ranging from half of the wild type activity to none, however, a significant decrease in average recombination activity was demonstrated in each patient. The reduced recombination activity of Met443Ile in RAG2 may suggest a crucial role of the non-core region of RAG2 in V(D)J recombination. These findings suggest that functional evaluation together with molecular analysis contributes to our broader understanding of RAG deficiency.

Bicipital Synovial Cyst in Systemic-Onset Juvenile Idiopathic Arthritis

Figure. Contrast CT scan. Sagittal view (left) and transverse view (right) showing a large multiloculated collection of fluid along the margin of the biceps muscle extending from the synovium. A 4-year-old girl with systemic-onset juvenile idiopathic arthritis (s-JIA) relapsed while on prednisolone and ibuprofen therapy. She presented with swelling of upper left arm. The masses were firm and slightly tender, and the skin was slightly warm but not hyperemic. Ultrasonography revealed a large collection of hypoechogenic fluid (30 15 mm) along the margin of the biceps muscle. Contrast computed tomography (CT) scan showed moderate joint effusion with synovial hypertrophy. A large multiloculated collection of fluid was found along the margin of the biceps muscle extending from the synovitis (Figure). Magnetic resonance imaging (MRI) also demonstrated fluid collection with synovial hypertrophy. A large multiloculated cystic mass, hyperintense on T2-weighted MRI and hypointense on T1-weighted MRI, was seen along the margin of the biceps muscle extending from the synovitis. The collected fluid was hyperintense on fat-suppression T1-weighted MRI, suggesting that the cyst had inflammatory contents. A diagnosis of brachial synovial cyst was made. The swelling decreased and then disappeared with control of disease activity. How bicipital synovial cysts arise remains unclear. The findings in this patient demonstrate communication between the shoulder and the cyst. This might suggest that the fluid arises within the shoulder joint and then descends into the contiguous bicipital tendon sheath. The tendon eventually ruptures, leading to collection of fluid in the bicipital area. Another possibility is that the cyst arises as a collection of fluid secreted by the inflamed synovial sheath of the biceps tendon extending from the synovium of the shoulder joint. Even though bicipital synovial cyst is a rare manifestation of s-JIA, synovial cyst should be considered in the differential diagnosis in all children with s-JIA presenting with swelling of the upper arm. n

Flow cytometric analysis of skin blister fluid induced by mosquito bites in a patient with chronic active Epstein-Barr virus infection

In chronic active Epstein–Barr virus (EBV) infection (CAEBV), ectopic EBV infection has been described in T or natural killer (NK) cells. NK cell-type infection (NK-CAEBV) is characterized by large granular lymphocytosis, high IgE levels and unusual reactions to mosquito bites, including severe local skin reactions, fever and liver dysfunction. However, the mechanisms underlying these reactions remain undetermined. Herein, we describe a patient with NK-CAEBV whose blister fluid after mosquito bites was analyzed. The patient exhibited significant increases in the percentage of CD56+ NK cells in the fluid compared with a simple mosquito allergy, in which the majority of infiltrated cells were CD203c+ cells, indicating basophils and/or mast cells. His fluid also contained CD203c+ cells, and his circulating basophils were activated by mosquito extracts in vitro. These results suggest that CD203c+ cells as well as NK cells may play pathogenic roles in the severe skin reactions to mosquito bites in NK-CAEBV.

Complete arrest from pro‐ to pre‐B cells in a case of B cell‐negative severe combined immunodeficiency (SCID) without recombinase activating gene (RAG) mutations

The B‐cell lineage in a patient with B‐cell‐negative severe combined immunodeficiency (SCID) was analysed by using antisurrogate light chain (SL) MoAbs. Peripheral CD3+ T cells and CD19+ B cells were absent in the patient. The common gamma (γc) chain was expressed normally on the patients peripheral NK cells and his peripheral mononuclear cells did not possess any mutations in recombinase activating gene (RAG)‐1, 2. Normal levels of expression of Ku70 and Ku80 protein were found by Western blot analysis. The patient did, however, display an increase in fibroblast sensitivity to irradiation. Furthermore, flow cytometric analyses of bone marrow cells showed that surface IgM and cytoplasmic µ positive cells were absent and that CD19+ B cells were composed of only CD34+ terminal deoxynucleotidyl transferase (TdT)+ SL+ pro‐B cells. The complete arrest of pro‐ to pre‐B cell development in the SCID patients bone marrow suggests that some genes involved in V(D)J recombination, excepting the RAG gene, may play a causative role in the immunodeficiency.

Differential resistance to antiviral drugs in an immunocompromised patient with cytomegalovirus encephalitis.

*KURAに登録されているコンテンツの利用については,著作権法に規定されている私的使用や引用などの範囲内で行ってください。 *著作権法に規定されている私的使用や引用などの範囲を超える利用を行う場合には,著作権者の許諾を得てください。ただし,著作権者 から著作権等管理事業者(学術著作権協会,日本著作出版権管理システムなど)に権利委託されているコンテンツの利用手続については ,各著作権等管理事業者に確認してください。 Title Differential resistance to antiviral drugs in an immunocompromised patient with cytomegalovirus encephalitis Author(s) Wada, Taizo; Mase, Shintaro; Shibata, Fumie; Shimizu, Masaki; Toma, Tomoko; Yachie, Akihiro Citation Journal of Clinical Virology, 49(3): 223-224