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Clinical and Genetic Characteristics of XIAP Deficiency in Japan

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Abstract

Deficiency of X-linked inhibitor of apoptosis (XIAP) caused by XIAP/BIRC4 gene mutations is an inherited immune defect recognized as X-linked lymphoproliferative syndrome type 2. This disease is mainly observed in patients with hemophagocytic lymphohistiocytosis (HLH) often associated with Epstein–Barr virus infection. We described nine Japanese patients from six unrelated families with XIAP deficiency and studied XIAP protein expression, XIAP gene analysis, invariant natural killer T (iNKT) cell counts, and the cytotoxic activity of CD8+ alloantigen-specific cytotoxic T lymphocytes. Of the nine patients, eight patients presented with symptoms in infancy or early childhood. Five patients presented with recurrent HLH, one of whom had severe HLH and died after cord blood transplantation. One patient presented with colitis, as did another patient’s maternal uncle, who died of colitis at 4 years of age prior to diagnosis with XIAP deficiency. Interestingly, a 17-year-old patient was asymptomatic, while his younger brother suffered from recurrent HLH and EBV infection. Seven out of eight patients showed decreased XIAP protein expression. iNKT cells from patients with XIAP deficiency were significantly decreased as compared with age-matched healthy controls. These results in our Japanese cohort are compatible with previous studies, confirming the clinical characteristics of XIAP deficiency.

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Abbreviations

BIR:

Baculovirus IAP repeat

CTL:

Cytotoxic T lymphocyte

HSCT:

Hematopoietic stem cell transplantation

HLH:

Hemophagocytic lymphohistiocytosis

IAP:

Inhibitor of apoptosis

LCL:

Lymphoblastoid cell line

MMC:

Mitomycin C

mAb:

Monoclonal antibody

MFI:

Mean fluorescence intensity

iNKT:

Invariant natural killer T

PCR:

Polymerase chain reaction

PBMC:

Peripheral blood mononuclear cells

TCR:

T cell receptor

XIAP:

X-linked inhibitor of apoptosis

XLP:

X-linked lymphoproliferative syndrome

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Acknowledgments

This study was supported by Grant-in-Aids for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (H. Kanegane and T. Miyawaki) and grants from the Ministry of Health, Labour, Welfare of Japan (T. Miyawaki), the XLP Reserch Trust (S. Latour) and Agence Nationale pour la Recherche (ANR-08-MIEN-012-01) and an Erasmus MC Fellowship (M.C. van Zelm). We thank Ms. Chikako Sakai and Mr. Hitoshi Moriuchi for their excellent technical assistance. We are also grateful for the support, cooperation, and trust of the patients and their families.

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Authors and Affiliations

  1. Department of Pediatrics, Graduate School of Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan

    Xi Yang, Hirokazu Kanegane, Naonori Nishida & Toshio Miyawaki

  2. Division of Immunology, Children’s Hospital of Chongqing Medical University, Chongqing, China

    Xi Yang & Xiao-Dong Zhao

  3. Department of Pediatrics, Graduate School of Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Toshihiko Imamura

  4. Department of Pediatrics, Hiroshima Red Cross Hospital, Hiroshima, Japan

    Kazuko Hamamoto

  5. Department of Pediatrics, Izumiotsu Municipal Hospital, Izumiotsu, Japan

    Ritsuko Miyashita

  6. Department of Pediatrics, National Defense Medical College, Tokorozawa, Japan

    Kohsuke Imai & Shigeaki Nonoyama

  7. Department of Pediatrics, Japanese Red Cross Narita Hospital, Narita, Japan

    Kazunori Sanayama

  8. Department of Allergy and Rheumatology, Chiba Children’s Hospital, Chiba, Japan

    Akiko Yamaide

  9. Department of Pediatrics, Tokyo Women’s Medical University Medical Center East, Tokyo, Japan

    Fumiyo Kato

  10. Department of Pediatrics, Ehime University Graduate School of Medicine, Toon, Japan

    Kozo Nagai & Eiichi Ishii

  11. Department of Immunology, Erasmus MC, Rotterdam, The Netherlands

    Menno C. van Zelm

  12. INSERM U768, Hôpital Necker-Enfants Malades, Paris, France

    Sylvain Latour

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  1. Xi Yang
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  2. Hirokazu Kanegane
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  4. Toshihiko Imamura
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  7. Kohsuke Imai
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  13. Eiichi Ishii
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  14. Menno C. van Zelm
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  15. Sylvain Latour
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  16. Xiao-Dong Zhao
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  17. Toshio Miyawaki
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Correspondence to Hirokazu Kanegane.

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Yang, X., Kanegane, H., Nishida, N. et al. Clinical and Genetic Characteristics of XIAP Deficiency in Japan. J Clin Immunol 32, 411–420 (2012). https://doi.org/10.1007/s10875-011-9638-z

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  • DOI: https://doi.org/10.1007/s10875-011-9638-z

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