153 research outputs found
原発性免疫不全症における原因遺伝子の復帰に関する研究
原発性免疫不全症において、遺伝子変異の復帰(gene reversion)を認めた症例を新たに2例見出した。白血球接着異常症(LAD-1)の乳児例は世界初の報告であり(Blood 2007)、X連鎖重症複合免疫不全症(XSCID)の乳児例は世界第2例目となる(投稿中)。前者では、患児の1つのCD8陽性T細胞において父親由来のスプライス変異が正常に戻るreversionが起きたと考えられた。本研究により、reversionはprogenitorレベルだけではなくある程度成熟した細胞でも起こり得ること、CD18陽性T細胞はCD18陰性T細胞に対して増殖優位性を有すること、reversion症例では必ずしも臨床症状の改善や修飾がみられないことなど、種々の重要な知見を得ることができた。一方、後者では、元の変異を代償する第二変異によるreversionがT細胞に検出された。Reversionを有するCD8陽性T細胞が主として皮膚にクローン性に増殖しており、通常XSCIDでは見られない皮疹と関連している可能性が示唆され、reversionは原発性免疫不全症の病態を修飾する重要な因子となる得ること等の重要な知見を得ることができた。in vitroの実験として計画しているWiskott-Aldrich症候群をモデルとした復帰変異の誘導実験に関しては、WASP遺伝子と薬剤耐性遺伝子の融合遺伝子を発現するレトロウイルスベクターの構築が終了し、感染性ウイルスを産生する段階にあり、基礎実験を継続している。今後の発展が期待される。We have identified two novel cases of genetic reversion in primary immunodeficiency including leukocyte adhesion deficiency type 1 (LAD-1) and X-linked severe combined immunodeficiency (XSCID).1) LAD-1 is an autosomal recessive disorder caused by mutations in the ITGB2 (CD18) gene, and characterized by recurrent severe infections, impaired pus formation, and defective wound healing. We describe an unusual case of severe phenotypic LAD-1 presenting somatic mosaicism. The patient is a compound heterozygote bearing two different frameshift mutations which abrogate protein expression. CD 18 expression was, however, detected in a small proportion of T cells, but was undetectable in granulocytes, monocytes, B cells, and NK cells. The T cells were not of maternal origin, lacked the paternal mutation, and showed a selective advantage in vivo. Molecular analysis using sorted CD18+ cells revealed them to be derived from a single CD84 T cell carrying T-cell receptor VB22. These findings suggest t hat spontaneous in vivo reversion was responsible for the somatic mosaicism in our patient. (Blood 2007)2) XSCID is caused by mutations of the common gamma chain (γc) of cytokine receptors and usually characterized by the absence of T and natural killer (NK) cells and the presence of B Cells. Here, we report an atypical case of XSCID presenting with autologous T and NK cells and Omenn syndrome-like manifestations including erythroderma, lymphadenopathy, hepatosplenomegaly, eosinophilia, low serum IgG, elevated serum IgE, and the presence of activated T cells. The patient carried a splice-site mutation (IVS 1+5G>A) that caused most of the mRNA to be incorrectly spliced but produced normally spliced transcript in lesser amount, leading to residual γc 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 that was located at position +1 of the cryptic donor site activated by the IVS1+5G>A, and to 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. (manuscript in submission)In addition to the clinical researches, we have constructed retroviral vectors expressing reversion mutations. These vectors will be used to evaluate conditions of induction of gene reversion in vitro in future experiments.研究課題/領域番号:18591186, 研究期間(年度):2006-2007出典:「原発性免疫不全症における原因遺伝子の復帰に関する研究」研究成果報告書 課題番号18591186 (KAKEN:科学研究費助成事業データベース(国立情報学研究所)) 本文データは著者版報告書より作
Elevation of fecal eosinophil-derived neurotoxin in infants with food protein-induced enterocolitis syndrome
Increased expression of epidermal thymic stromal lymphopoietin in inflammatory peeling skin syndrome
Experimental and Chcal Study of Dose-Reducing Effect of Normal Tissues in Interstitial Radiotherapy of the Tongue Carcinom
本論文の要旨は平成3年6月の第24回広島大学歯学会総会において発表した
Basophil activation by mosquito extracts in patients with hypersensitivity to mosquito bites
Hypersensitivity to mosquito bites (HMB) is a cutaneous disorder belonging to the group of Epstein-Barr virus (EBV)-associated T/natural killer (NK)-cell lymphoproliferative diseases, and is primarily mediated by EBV-infected NK cells. It is characterized by intense local skin reactions accompanied by general symptoms after mosquito bites, and infiltration of EBV-infected NK cells into the bite sites. However, the mechanisms underlying these reactions have not been fully examined. We recently described the activation of circulating basophils by mosquito extracts in vitro in a patient with HMB. To further investigate this finding, we studied four additional patients with HMB. All patients showed typical clinical features of HMB after mosquito bites and they had NK lymphocytosis and high peripheral blood EBV DNA loads. We found evidence of EBV infection in NK cells through in situ hybridization that detected EBV-encoded small RNA-1, and flow cytometry showed HLA-DR expression on almost all NK cells. Basophil activation tests with the extracts of epidemic mosquitoes Culex pipiens pallens and Aedes albopictus showed positive responses to one or both extracts in all samples from patients with HMB, suggesting the presence of mosquito antigen-specific IgE and its binding to basophils. In particular, the extract of Aedes albopictus was able to activate basophils in all available patient samples. These results indicate that basophils and/or mast cells activated by mosquito bites may be involved in initiation and development of severe skin reactions to mosquito bites in HMB. © 2015 The Authors
Cytokine profiles in children with primary Epstein-Barr virus infection
Primary Epstein-Barr virus (EBV) infection causes infectious mononucleosis and hemophagocytic lymphohistiocytosis (HLH) in children, where EBV infects B and CD8+ T cells, respectively. We measured pro-inflammatory and anti-inflammatory cytokines in both diseases. Significantly higher concentrations of various mediators, including interferon-γ, neopterin, interleukin (IL)-6, IL-10, IL-18, and heme oxygenase-1, were observed in EBV-HLH. Because of their similarity to the profile of familial HLH, this profile was likely a consequence of HLH, but not ectopic infection. TNF-α levels were elevated in both diseases. Elevation of those mediators may contribute to the disease pathogenesis of EBV-HLH by activating and inhibiting host immune responses. © 2013 Wiley Periodicals, Inc
Increased CD69 Expression on Peripheral Eosinophils from Patients with Food Protein-Induced Enterocolitis Syndrome
Background: Food protein-induced enterocolitis syndrome (FPIES) is an uncommon, non-IgE-mediated food allergy. We recently described a significant increase in fecal eosinophil-derived neurotoxin (EDN) after ingestion of the causative food. However, little is known about the activation status of circulating eosinophils in patients with an acute FPIES reaction. Methods: Surface CD69 expression was assessed by flow cytometry on peripheral eosinophils from 5 patients with FPIES before and after ingestion of the causative food. Fecal EDN was measured by enzyme-linked immunosorbent assay. Results: No eosinophil activation was observed before ingestion; however, a significant increase in CD69 expression on eosinophils after an acute FIPES reaction was demonstrated in all of the patients. There was no significant change in absolute eosinophil counts in the peripheral blood. The levels of fecal EDN increased on the day after ingestion of the causative food in all patients. Conclusion: These results suggest that circulating eosinophils as well as eosinophils in the intestinal mucosal tissue are activated in acute FPIES reactions and might be associated with systemic immune events in FPIES. © 2016 S. Karger AG, Basel.Embargo Period 12 month
Differential resistance to antiviral drugs in an immunocompromised patient with cytomegalovirus encephalitis
金沢大学附属病院小児
- …