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Masakatsu D Yanagimachi,
Akira Niwa,
Takayuki Tanaka,
Fumiko Honda-Ozaki,
Seiko Nishimoto,
Yuuki Murata, Takahiro Yasumi,
Jun Ito,
Shota Tomida,
Koichi Oshima,
Isao Asaka,
Hiroaki Goto,
Toshio Heike,
Tatsutoshi Nakahata,
Megumu K Saito
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ABSTRACT: Monocytic lineage cells (monocytes, macrophages and dendritic cells) play important roles in immune responses and are involved in various pathological conditions. The development of monocytic cells from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) is of particular interest because it provides an unlimited cell source for clinical application and basic research on disease pathology. Although the methods for monocytic cell differentiation from ESCs/iPSCs using embryonic body or feeder co-culture systems have already been established, these methods depend on the use of xenogeneic materials and, therefore, have a relatively poor-reproducibility. Here, we established a robust and highly-efficient method to differentiate functional monocytic cells from ESCs/iPSCs under serum- and feeder cell-free conditions. This method produced 1.3×10(6)±0.3×10(6) floating monocytes from approximately 30 clusters of ESCs/iPSCs 5-6 times per course of differentiation. Such monocytes could be differentiated into functional macrophages and dendritic cells. This method should be useful for regenerative medicine, disease-specific iPSC studies and drug discovery.
PLoS ONE 01/2013; 8(4):e59243. · 4.09 Impact Factor
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ABSTRACT: BACKGROUND: Food allergy (FA) in childhood has been shown to be more prevalent in those born in autumn and winter. The mechanisms of this "season of birth" effect remain unclear, although shortage of vitamin D during infancy has been considered one possible mechanism. The purpose of this study was to investigate the effect of eczema on the "season of birth effect" on FA in infancy. METHODS: A questionnaire survey dealing with the prevalence of allergic diseases was administered to the parents of 14,669 Japanese schoolchildren, aged 7 to 15 years, in Kyoto City, Japan. Logistic regression models were constructed to compare the prevalence of FA in infancy according to season of birth. RESULTS: Those born in autumn and winter showed a significantly higher prevalence of FA in infancy compared to those born in spring and summer in a multivariate model (4.8% vs. 3.6%, p=0.001). However, the difference was no longer significant when eczema before 6 months was included as either an additional or only confounding factor. The difference among those with and without eczema before 6 months was further analyzed, and it was found that, in both groups, there was no difference between those born in spring and summer and those born in autumn and winter. CONCLUSIONS: The "season of birth effect" on FA in infancy was significantly affected by the existence of eczema before 6 months in Japanese children. Eczema before 6 months may be the factor directly related to the "season of birth effect" on FA in infancy.
Pediatrics International 09/2012; · 0.63 Impact Factor
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Rheumatology (Oxford, England) 07/2012; · 4.24 Impact Factor
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[Rinshō ketsueki] The Japanese journal of clinical hematology 07/2012; 53(7):664-71.
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Rheumatology (Oxford, England) 05/2012; 51(11):2107-9. · 4.24 Impact Factor
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Miyuki Tsumura,
Satoshi Okada,
Hidemasa Sakai,
Shin'ichiro Yasunaga,
Motoaki Ohtsubo,
Takuji Murata,
Hideto Obata, Takahiro Yasumi,
Xiao-Fei Kong,
Avinash Abhyankar, [......],
Tatsutoshi Nakahata,
Ryuta Nishikomori,
Saleh Al-Muhsen,
Stéphanie Boisson-Dupuis,
Jean-Laurent Casanova,
Mofareh Alzahrani,
Mohammed Al Shehri,
Geyhad Elghazali,
Yoshihiro Takihara,
Masao Kobayashi
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ABSTRACT: Patients carrying two loss-of-function (or hypomorphic) alleles of STAT1 are vulnerable to intracellular bacterial and viral diseases. Heterozygosity for loss-of-function dominant-negative mutations in STAT1 is responsible for autosomal dominant (AD) Mendelian susceptibility to mycobacterial disease (MSMD), whereas heterozygosity for gain-of-function loss-of-dephosphorylation mutations causes AD chronic mucocutaneous candidiasis (CMC). The two previously reported types of AD MSMD-causing STAT1 mutations are located in the tail segment domain (p.L706S) or in the DNA-binding domain (p.E320Q and p.Q463H), whereas the AD CMC-causing mutations are located in the coiled-coil domain. We identified two cases with AD-STAT1 deficiency in two unrelated patients from Japan and Saudi Arabia carrying heterozygous missense mutations affecting the SH2 domain (p.K637E and p.K673R). p.K673R is a hypomorphic mutation that impairs STAT1 tyrosine phosphorylation, whereas the p.K637E mutation is null and affects both STAT1 phosphorylation and DNA-binding activity. Both alleles are dominant negative and result in impaired STAT1-mediated cellular responses to interferon (IFN)-γ and IL-27. In contrast, STAT1-mediated cellular responses against IFN-α and IFN-λ1 were preserved at normal levels in patients' cells. We describe here the first dominant mutations in the SH2 domain of STAT1, revealing the importance of this domain for tyrosine phosphorylation and DNA binding, as well as for antimycobacterial immunity.
Human Mutation 05/2012; 33(9):1377-87. · 5.69 Impact Factor
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Tomoki Kawai,
Ryuta Nishikomori,
Kazushi Izawa,
Yuuki Murata,
Naoko Tanaka,
Hidemasa Sakai,
Megumu Saito, Takahiro Yasumi,
Yuki Takaoka,
Tatsutoshi Nakahata, [......],
Atsushi Yoden,
Takuji Murata,
Shinya Sasaki,
Etsuro Ito,
Hiroshi Akutagawa,
Toshinao Kawai,
Chihaya Imai,
Satoshi Okada,
Masao Kobayashi,
Toshio Heike
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ABSTRACT: 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.
Blood 04/2012; 119(23):5458-66. · 9.90 Impact Factor
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Tomoki Kawai,
Megumu Saito,
Ryuta Nishikomori, Takahiro Yasumi,
Kazushi Izawa,
Tomohiko Murakami,
Shigefumi Okamoto,
Yasuko Mori,
Noriko Nakagawa,
Kohsuke Imai,
Shigeaki Nonoyama,
Taizo Wada,
Akihiro Yachie,
Katsuyuki Ohmori,
Tatsutoshi Nakahata,
Toshio Heike
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ABSTRACT: Reversion mosaicism is increasingly being reported in primary immunodeficiency diseases, but there have been few cases with clinically improved immune function. Here, a case is reported of X-linked severe combined immunodeficiency (SCID-X1) with multiple somatic reversions in T cells, which restored sufficient cell-mediated immunity to overcome viral infection. Lineage-specific analysis revealed multiple reversions in T cell receptor (TCR) αβ+ and TCRγδ+ T cells. Diversity of the TCRVβ repertoire was comparable to normal and, furthermore, mitogen-induced proliferation of the patient's T cells was minimally impaired compared to healthy controls. In vivo and in vitro varicella antigen-specific T cell responses were comparable to those of healthy controls, although a reduced level of T cell receptor excision circles suggested that recent thymic output was low. During long-term evaluation of the patient's immunologic status, both the number of CD4+ and CD8+ T cells and T cell proliferation responses were stable and the patient remained healthy. This case demonstrates that multiple but restricted somatic reversions in T cell progenitors can improve the clinical phenotype of SCID-X1.
Journal of Clinical Immunology 03/2012; 32(4):690-7. · 3.08 Impact Factor
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ABSTRACT: Higher birth order is associated with a smaller risk of allergy (birth order effect). The purpose of this study was to compare the significance of the birth order effect on the prevalence of specific allergic diseases [bronchial asthma (BA), atopic dermatitis (AD), allergic rhinitis (AR), allergic conjunctivitis (AC), and food allergy (FA)] among schoolchildren. A questionnaire survey dealing with the prevalence of allergic diseases was administered to the parents of 14,669 schoolchildren aged 7-15 yr. Based on the data, the prevalence of each allergic disease was compared according to birth order (1st, 2nd, and 3rd or later). Multiple regression analysis was performed to test the significance of the differences. There was no significant difference in the prevalence of BA or AD according to birth order. The prevalence of AR, AC, and FA decreased significantly as birth order increased. The prevalence of FA among those with 1st, 2nd, and 3rd or later birth order was 4.0%, 3.4%, and 2.6%, respectively (p = 0.01). With respect to symptoms in infancy, the prevalence of wheeze increased significantly and that of FA and eczema in infancy decreased significantly as birth order increased. The present data show a significant birth order effect on FA. The effect was also observed for the prevalence of FA and eczema in infancy. These data support the concept of early, non-allergen-specific programming of IgE-mediated immunity.
Pediatric Allergy and Immunology 02/2012; 23(3):250-4. · 2.46 Impact Factor
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Kazushi Izawa,
Atsushi Hijikata,
Naoko Tanaka,
Tomoki Kawai,
Megumu K Saito,
Raphaela Goldbach-Mansky,
Ivona Aksentijevich, Takahiro Yasumi,
Tatsutoshi Nakahata,
Toshio Heike,
Ryuta Nishikomori,
Osamu Ohara
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ABSTRACT: Chronic infantile neurological cutaneous and articular syndrome (CINCA), also known as neonatal-onset multisystem inflammatory disease (NOMID), is a dominantly inherited systemic autoinflammatory disease and is caused by a heterozygous germline gain-of-function mutation in the NLRP3 gene. We recently found a high incidence of NLRP3 somatic mosaicism in apparently mutation-negative CINCA/NOMID patients using subcloning and subsequent capillary DNA sequencing. It is important to rapidly diagnose somatic NLRP3 mosaicism to ensure proper treatment. However, this approach requires large investments of time, cost, and labour that prevent routine genetic diagnosis of low-level somatic NLRP3 mosaicism. We developed a routine pipeline to detect even a low-level allele of NLRP3 with statistical significance using massively parallel DNA sequencing. To address the critical concern of discriminating a low-level allele from sequencing errors, we first constructed error rate maps of 14 polymerase chain reaction products covering the entire coding NLRP3 exons on a Roche 454 GS-FLX sequencer from 50 control samples without mosaicism. Based on these results, we formulated a statistical confidence value for each sequence variation in each strand to discriminate sequencing errors from real genetic variation even in a low-level allele, and thereby detected base substitutions at an allele frequency as low as 1% with 99.9% or higher confidence.
DNA Research 01/2012; 19(2):143-52. · 5.16 Impact Factor
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ABSTRACT: Even though allergic diseases continue to increase among children, it is unclear as to how many of these children are receiving appropriate medical care.
To establish the number of schoolchildren being diagnosed and receiving consultation for their allergic diseases and to determine if their disease status is associated with their total and allergen-specific IgE levels. Additionally, the study examined whether providing information on the total and allergen-specific IgE levels to the parents resulted in improvement of the medical care their children received.
A total of 618 out of the 627 (94.5%) parents of 11-year-old schoolchildren living in Ohmi-Hachiman City, Shiga, Japan, answered a questionnaire designed to determine the presence of allergic diseases (bronchial asthma, atopic dermatitis, allergic rhinitis, and allergic conjunctivitis) and the status of medical care in their children. Levels of total IgE, mite-specific IgE, and three pollen-specific IgEs were measured at the same time that the questionnaires were filled out. Information from the questionnaires was used to analyze the relationships between the questionnaire data and IgE levels. After parents were given the IgE results, medical consultations were recommended for those children having allergic symptoms and positive allergen-specific IgEs. One year after providing the information, a follow-up survey was performed to determine whether parents took any actions in response to their children's test results.
The mean total IgE level was 138 IU/ml, with a total of 62.8% of the children sensitized to one or more allergens. Even among those without any allergic disease, 49.2% or the children sensitized to one or more allergens. In children with bronchial asthma, diagnosis and consultation rates were 100% and 81%, respectively. However, the diagnosis and consultation rates among those with other types of allergic diseases were significantly lower, ranging from 44 to 88% for diagnosis and 28 to 52% for consultation. A total of 63% of the parents with children having allergic diseases indicated they undertook further efforts designed to improve their child's allergy disease symptoms after they were informed of the total and allergen-specific IgE levels.
Results of the present survey demonstrated that significant numbers of children with atopic dermatitis, allergic rhinitis or allergic conjunctivitis were not given appropriate medical care. In order to conclusively determine whether total and allergen-specific IgE screening at schools is useful in ensuring that children receive appropriate medical care, further evaluations will need to be conducted.
Arerugī = [Allergy] 01/2012; 61(1):41-50.
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ABSTRACT: The presence of Langhans giant cells (LGCs) is one of the signatures of systemic granulomatous disorders such as tuberculosis and sarcoidosis. However, the pathophysiological mechanism leading to LGC formation, especially the contribution of the T cells abundantly found in granulomas, has not been fully elucidated. To examine the role of T cells in LGC formation, a new in vitro method for the induction of LGCs was developed by co-culturing human monocytes with autologous T cells in the presence of concanavalin A (ConA). This system required close contact between monocytes and T cells, and CD4+ T cells were more potent than CD8+ T cells in inducing LGC formation. Antibody inhibition revealed that a CD40-CD40 ligand (CD40L) interaction and IFN-γ were essential for LGC formation, and the combination of exogenous soluble CD40L (sCD40L) and IFN-γ efficiently replaced the role of T cells. Dendritic cell-specific transmembrane protein (DC-STAMP), a known fusion-related molecule in monocytes, was up-regulated during LGC formation. Moreover, knock-down of DC-STAMP by siRNA inhibited LGC formation, revealing that DC-STAMP was directly involved in LGC formation. Taken together, these results demonstrate that T cells played a pivotal role in a new in vitro LGC formation system, in which DC-STAMP was involved, and occurred via a molecular mechanism that involved CD40-CD40L interaction and IFN-γ secretion.
International Immunology 11/2011; 24(1):5-15. · 3.41 Impact Factor
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Hideaki Ohta,
Emiko Miyashita,
Ikuko Hirata,
Risa Matsumura,
Hisao Yoshida,
Yoshiko Hashii,
Takeshi Higashiura, Takahiro Yasumi,
Yuuki Murata,
Toshio Heike,
Xi Yang,
Hirokazu Kanegane,
Osamu Ohara,
Keiichi Ozono
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ABSTRACT: Allogeneic hematopoietic stem cell transplantation is the only curative method for patients with familial hemophagocytic lymphohistiocytosis (FHL). We present a case of a 3-month-old girl with Munc13-4 mutation (FHL3), who underwent bone marrow transplantation (BMT) from her human leukocyte antigen-haploidentical mother following reduced intensity conditioning (RIC) with fludarabine, melphalan, and busulfan. Engraftment after BMT was generally uneventful, with only mild acute graft versus host disease. Munc13-4 protein was restored following BMT, and she is well and free of disease 14 months after BMT. These results suggest that BMT with RIC from a family haploidentical donor may sufficiently restore immune regulation in infants, while lessening treatment-related mortality and long-term sequelae.
International journal of hematology 08/2011; 94(3):285-90. · 1.17 Impact Factor
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Naoko Tanaka,
Kazushi Izawa,
Megumu K Saito,
Mio Sakuma,
Koichi Oshima,
Osamu Ohara,
Ryuta Nishikomori,
Takeshi Morimoto,
Naotomo Kambe,
Raphaela Goldbach-Mansky, [......],
Jordi Yagüe,
Rosa Merino,
Mercedes Ibañez,
Alessandra Pontillo,
Hidetoshi Takada,
Tomoyuki Imagawa,
Tomoki Kawai, Takahiro Yasumi,
Tatsutoshi Nakahata,
Toshio Heike
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ABSTRACT: Chronic infantile neurologic, cutaneous, articular (CINCA) syndrome, also known as neonatal-onset multisystem inflammatory disease (NOMID), is a dominantly inherited systemic autoinflammatory disease. Although heterozygous germline gain-of-function NLRP3 mutations are a known cause of this disease, conventional genetic analyses fail to detect disease-causing mutations in ∼40% of patients. Since somatic NLRP3 mosaicism has been detected in several mutation-negative NOMID/CINCA syndrome patients, we undertook this study to determine the precise contribution of somatic NLRP3 mosaicism to the etiology of NOMID/CINCA syndrome.
An international case-control study was performed to detect somatic NLRP3 mosaicism in NOMID/CINCA syndrome patients who had shown no mutation during conventional sequencing. Subcloning and sequencing of NLRP3 was performed in these mutation-negative NOMID/CINCA syndrome patients and their healthy relatives. Clinical features were analyzed to identify potential genotype-phenotype associations.
Somatic NLRP3 mosaicism was identified in 18 of the 26 patients (69.2%). Estimates of the level of mosaicism ranged from 4.2% to 35.8% (mean ± SD 12.1 ± 7.9%). Mosaicism was not detected in any of the 19 healthy relatives (18 of 26 patients versus 0 of 19 relatives; P < 0.0001). In vitro functional assays indicated that the detected somatic NLRP3 mutations had disease-causing functional effects. No differences in NLRP3 mosaicism were detected between different cell lineages. Among nondescript clinical features, a lower incidence of mental retardation was noted in patients with somatic mosaicism. Genotype-matched comparison confirmed that patients with somatic NLRP3 mosaicism presented with milder neurologic symptoms.
Somatic NLRP3 mutations were identified in 69.2% of patients with mutation-negative NOMID/CINCA syndrome. This indicates that somatic NLRP3 mosaicism is a major cause of NOMID/CINCA syndrome.
Arthritis & Rheumatism 06/2011; 63(11):3625-32. · 7.87 Impact Factor
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Yuuki Murata, Takahiro Yasumi,
Ryutaro Shirakawa,
Kazushi Izawa,
Hidemasa Sakai,
Junya Abe,
Naoko Tanaka,
Tomoki Kawai,
Koichi Oshima,
Megumu Saito,
Ryuta Nishikomori,
Osamu Ohara,
Eiichi Ishii,
Tatsutoshi Nakahata,
Hisanori Horiuchi,
Toshio Heike
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ABSTRACT: Familial hemophagocytic lymphohistiocytosis (FHL) is a potentially lethal genetic disorder of immune dysregulation that requires prompt and accurate diagnosis to initiate life-saving immunosuppressive therapy and to prepare for hematopoietic stem cell transplantation. In the present study, 85 patients with hemophagocytic lymphohistiocytosis were screened for FHL3 by Western blotting using platelets and by natural killer cell lysosomal exocytosis assay. Six of these patients were diagnosed with FHL3. In the acute disease phase requiring platelet transfusion, it was difficult to diagnose FHL3 by Western blot analysis or by lysosomal exocytosis assay. In contrast, the newly established flow cytometric analysis of intraplatelet Munc13-4 protein expression revealed bimodal populations of normal and Munc13-4-deficient platelets. These findings indicate that flow cytometric detection of intraplatelet Munc13-4 protein is a sensitive and reliable method to rapidly screen for FHL3 with a very small amount of whole blood, even in the acute phase of the disease.
Blood 06/2011; 118(5):1225-30. · 9.90 Impact Factor
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Masahiro Tahara,
Hidemasa Sakai,
Ryuta Nishikomori, Takahiro Yasumi,
Toshio Heike,
Ikuo Nagata,
Ayano Inui,
Tomoo Fujisawa,
Yosuke Shigematsu,
Koji Nishijima,
Katsuji Kuwakado,
Shinichi Watabe,
Junji Kameyama
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ABSTRACT: A Japanese girl with neonatal-onset chronic hepatitis and systemic inflammation was diagnosed with hyper-immunoglobulinemia D and periodic fever syndrome (HIDS). However, she lacked the typical HIDS features until the age of 32 months. She had compound heterozygous MVK mutations, H380R and A262P, the latter of which was novel. These findings suggest that HIDS patients could lack typical episodes of recurrent fever at the onset and that HIDS should be considered as a possible cause of neonatal-onset chronic hepatitis.
Modern Rheumatology 03/2011; 21(6):641-5. · 1.58 Impact Factor
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ABSTRACT: Analysis of general childhood population data showed that there was a significant positive association between total and low-density lipoprotein cholesterol levels and atopy, independent of obesity or sex, which suggest a relationship between hyperlipidemia and greater allergic sensitization among schoolchildren.
The Journal of pediatrics 02/2011; 158(2):334-6. · 4.02 Impact Factor
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ABSTRACT: The influence of food avoidance due to allergic symptoms in infancy on the growth of children at school age has not been well evaluated.
To determine the growth of schoolchildren who avoided eggs, milk, or wheat due to immediate allergic symptoms in infancy (food avoiders in infancy) (FAI), a questionnaire on the presence of allergic diseases, as well as present height and weight, was administered to the parents of 14,669 schoolchildren. 11,473 subjects had available data. The height and weight standard deviation scores (HtSDS and WtSDS) and body mass index percentile (BMI percentile) of each subject were calculated.
FAI had significantly lower WtSDS than non-FAI (P = 0.01). Among those with avoidance at age 3 years, those who avoided two or more foods and those who avoided milk had significantly lower HtSDS than their counterparts (P = 0.02 and 0.04, respectively). FAI had a significantly lower prevalence of obesity (P = 0.01) and overweight (P = 0.002), while there was no difference in the prevalence of underweight (P = 0.58), resulting in a significantly higher prevalence of appropriate weight (P = 0.01) compared to non-FAI. Significantly lower prevalence of obesity and overweight was observed even among those who terminated the avoidance by age 3 years.
FAI were less likely to be obese or overweight, resulting in a higher prevalence of appropriate weight at school age. Further investigation should contribute to better management of food allergy and obesity.
Allergology International 12/2010; 59(4):369-74.
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ABSTRACT: Infants at higher risk of allergic diseases might be breastfed for longer periods compared with infants at lower risk in the hope that breastfeeding might reduce the risk of atopic disorders. Therefore, this intention could manifest as an apparent allergy-promoting effect of breastfeeding or reverse causation. To analyze the effect of breast feeding on the prevalence of allergic diseases at school age, a large questionnaire survey was administered to the parents of schoolchildren aged 7-15 yrs. 13,215 parents responded (response rate, 90.1%). Prevalence rates of allergic diseases were compared according to the type of feeding in infancy (either complete breastfeeding, mixed feeding or complete artificial feeding). In both univariate and multivariate analysis, compared with those with complete artificial feeding, those with mixed and complete breastfeeding showed a significantly lower prevalence of bronchial asthma (BA) (p = 0.01 and 0.003, respectively). On the other hand, in univariate analysis, the prevalence of atopic dermatitis (AD) and food allergy (FA) were significantly higher in those with complete breastfeeding (p = 0.04 and 0.01, respectively). There was a significantly higher proportion of complete breastfeeding among those with greater risk of allergic diseases (presence of family history, either eczema or wheeze within 6 months after birth, or FA in infancy). Therefore, our multivariate analysis included these risks as confounding factors, and we found that the promoting effects of breastfeeding on AD and FA disappeared. In conclusion, our data clearly showed the inhibitory effect of breastfeeding on the prevalence of BA at school age. The apparent promoting effect of breastfeeding on the prevalence of AD and FA is most likely because of reverse causation.
Pediatric Allergy and Immunology 02/2010; 21(1 Pt 1):60-6. · 2.46 Impact Factor
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Kozo Nagai,
Ken Yamamoto,
Hiroshi Fujiwara,
Jun An,
Toshiki Ochi,
Koichiro Suemori, Takahiro Yasumi,
Hisamichi Tauchi,
Katsuyoshi Koh,
Maho Sato,
Akira Morimoto,
Toshio Heike,
Eiichi Ishii,
Masaki Yasukawa
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ABSTRACT: Familial hemophagocytic lymphohistiocytosis (FHL) is a rare disease of infancy or early childhood. To clarify the incidence and subtypes of FHL in Japan, we performed genetic and functional analyses of cytotoxic T lymphocytes (CTLs) in Japanese patients with FHL.
Among the Japanese children with hemophagocytic lymphohistiocytosis (HLH) registered at our laboratory, those with more than one of the following findings were eligible for study entry under a diagnosis of FHL: positive for known genetic mutations, a family history of HLH, and impaired CTL-mediated cytotoxicity. Mutations of the newly identified causative gene for FHL5, STXBP2, and the cytotoxicity and degranulation activity of CTLs in FHL patients, were analyzed.
Among 31 FHL patients who satisfied the above criteria, PRF1 mutation was detected in 17 (FHL2) and UNC13D mutation was in 10 (FHL3). In 2 other patients, 3 novel mutations of STXBP2 gene were confirmed (FHL5). Finally, the remaining 2 were classified as having FHL with unknown genetic mutations. In all FHL patients, CTL-mediated cytotoxicity was low or deficient, and degranulation activity was also low or absent except FHL2 patients. In 2 patients with unknown genetic mutations, the cytotoxicity and degranulation activity of CTLs appeared to be deficient in one patient and moderately impaired in the other.
FHL can be diagnosed and classified on the basis of CTL-mediated cytotoxicity, degranulation activity, and genetic analysis. Based on the data obtained from functional analysis of CTLs, other unknown gene(s) responsible for FHL remain to be identified.
PLoS ONE 01/2010; 5(11):e14173. · 4.09 Impact Factor
