A CD57+ CTL Degranulation Assay Effectively Identifies Familial Hemophagocytic Lymphohistiocytosis Type 3 Patients

Masayuki Hori, Takahiro Yasumi, Saeko Shimodera, Hirofumi Shibata, Eitaro Hiejima, Hirotsugu Oda, Kazushi Izawa, Tomoki Kawai, masataka ishimura, Naoko Nakano, Ryutaro Shirakawa, Ryuta Nishikomori, Hidetoshi Takada, Satoshi Morita, Hisanori Horiuchi, Osamu Ohara, Eiichi Ishii, Toshio Heike

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Abstract

Purpose: Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) is a genetic disorder that results in immune dysregulation. It requires prompt and accurate diagnosis. A natural killer (NK) cell degranulation assay is often used to screen for FHL3 patients. However, we recently encountered two cases of late-onset FHL3 carrying novel UNC13D missense mutations: in these cases, the degranulation assays using freshly isolated and interleukin (IL)-2-activated NK cells yielded contradictory results. Since the defective degranulation of CD57+ cytotoxic T lymphocytes (CTLs) in these cases was helpful for making the diagnosis, we assessed whether the CD57+ CTL degranulation assay more effectively identified FHL3 patients than the NK cell assays. Methods: Forty additional patients with hemophagocytic lymphohistiocytosis were prospectively screened for FHL3 by measuring the perforin expression in NK cells and the expression of Munc13-4, syntaxin-11, and Munc18-2 in platelets and by performing NK cell and CTL degranulation assays. The results were confirmed by genetic analysis. Results: The freshly isolated NK cell degranulation assay detected FHL3 patients with high sensitivity (100%) but low specificity (71%). The IL-2-stimulated NK cell assay had improved specificity, but 3 out of the 31 non-FHL3 patients still showed degranulation below the threshold level. The CD57+ CTL degranulation assay identified FHL3 patients with high sensitivity and specificity (both 100%). Conclusions: The CD57+ CTL degranulation assay more effectively identified FHL3 patients than the NK cell-based assays.

Original languageEnglish
Pages (from-to)92-99
Number of pages8
JournalJournal of Clinical Immunology
Volume37
Issue number1
DOIs
Publication statusPublished - Jan 1 2017

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Cytotoxic T-Lymphocytes
Natural Killer Cells
Hemophagocytic Lymphohistiocytosis
Cell Degranulation
Interleukin-2
Qa-SNARE Proteins
Perforin
Inborn Genetic Diseases
Hemophagocytic lymphohistiocytosis, familial, 3
Missense Mutation
Blood Platelets
Sensitivity and Specificity

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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A CD57+ CTL Degranulation Assay Effectively Identifies Familial Hemophagocytic Lymphohistiocytosis Type 3 Patients. / Hori, Masayuki; Yasumi, Takahiro; Shimodera, Saeko; Shibata, Hirofumi; Hiejima, Eitaro; Oda, Hirotsugu; Izawa, Kazushi; Kawai, Tomoki; ishimura, masataka; Nakano, Naoko; Shirakawa, Ryutaro; Nishikomori, Ryuta; Takada, Hidetoshi; Morita, Satoshi; Horiuchi, Hisanori; Ohara, Osamu; Ishii, Eiichi; Heike, Toshio.

In: Journal of Clinical Immunology, Vol. 37, No. 1, 01.01.2017, p. 92-99.

Research output: Contribution to journalArticle

Hori, M, Yasumi, T, Shimodera, S, Shibata, H, Hiejima, E, Oda, H, Izawa, K, Kawai, T, ishimura, M, Nakano, N, Shirakawa, R, Nishikomori, R, Takada, H, Morita, S, Horiuchi, H, Ohara, O, Ishii, E & Heike, T 2017, 'A CD57+ CTL Degranulation Assay Effectively Identifies Familial Hemophagocytic Lymphohistiocytosis Type 3 Patients', Journal of Clinical Immunology, vol. 37, no. 1, pp. 92-99. https://doi.org/10.1007/s10875-016-0357-3
Hori, Masayuki ; Yasumi, Takahiro ; Shimodera, Saeko ; Shibata, Hirofumi ; Hiejima, Eitaro ; Oda, Hirotsugu ; Izawa, Kazushi ; Kawai, Tomoki ; ishimura, masataka ; Nakano, Naoko ; Shirakawa, Ryutaro ; Nishikomori, Ryuta ; Takada, Hidetoshi ; Morita, Satoshi ; Horiuchi, Hisanori ; Ohara, Osamu ; Ishii, Eiichi ; Heike, Toshio. / A CD57+ CTL Degranulation Assay Effectively Identifies Familial Hemophagocytic Lymphohistiocytosis Type 3 Patients. In: Journal of Clinical Immunology. 2017 ; Vol. 37, No. 1. pp. 92-99.
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abstract = "Purpose: Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) is a genetic disorder that results in immune dysregulation. It requires prompt and accurate diagnosis. A natural killer (NK) cell degranulation assay is often used to screen for FHL3 patients. However, we recently encountered two cases of late-onset FHL3 carrying novel UNC13D missense mutations: in these cases, the degranulation assays using freshly isolated and interleukin (IL)-2-activated NK cells yielded contradictory results. Since the defective degranulation of CD57+ cytotoxic T lymphocytes (CTLs) in these cases was helpful for making the diagnosis, we assessed whether the CD57+ CTL degranulation assay more effectively identified FHL3 patients than the NK cell assays. Methods: Forty additional patients with hemophagocytic lymphohistiocytosis were prospectively screened for FHL3 by measuring the perforin expression in NK cells and the expression of Munc13-4, syntaxin-11, and Munc18-2 in platelets and by performing NK cell and CTL degranulation assays. The results were confirmed by genetic analysis. Results: The freshly isolated NK cell degranulation assay detected FHL3 patients with high sensitivity (100{\%}) but low specificity (71{\%}). The IL-2-stimulated NK cell assay had improved specificity, but 3 out of the 31 non-FHL3 patients still showed degranulation below the threshold level. The CD57+ CTL degranulation assay identified FHL3 patients with high sensitivity and specificity (both 100{\%}). Conclusions: The CD57+ CTL degranulation assay more effectively identified FHL3 patients than the NK cell-based assays.",
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T1 - A CD57+ CTL Degranulation Assay Effectively Identifies Familial Hemophagocytic Lymphohistiocytosis Type 3 Patients

AU - Hori, Masayuki

AU - Yasumi, Takahiro

AU - Shimodera, Saeko

AU - Shibata, Hirofumi

AU - Hiejima, Eitaro

AU - Oda, Hirotsugu

AU - Izawa, Kazushi

AU - Kawai, Tomoki

AU - ishimura, masataka

AU - Nakano, Naoko

AU - Shirakawa, Ryutaro

AU - Nishikomori, Ryuta

AU - Takada, Hidetoshi

AU - Morita, Satoshi

AU - Horiuchi, Hisanori

AU - Ohara, Osamu

AU - Ishii, Eiichi

AU - Heike, Toshio

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Purpose: Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) is a genetic disorder that results in immune dysregulation. It requires prompt and accurate diagnosis. A natural killer (NK) cell degranulation assay is often used to screen for FHL3 patients. However, we recently encountered two cases of late-onset FHL3 carrying novel UNC13D missense mutations: in these cases, the degranulation assays using freshly isolated and interleukin (IL)-2-activated NK cells yielded contradictory results. Since the defective degranulation of CD57+ cytotoxic T lymphocytes (CTLs) in these cases was helpful for making the diagnosis, we assessed whether the CD57+ CTL degranulation assay more effectively identified FHL3 patients than the NK cell assays. Methods: Forty additional patients with hemophagocytic lymphohistiocytosis were prospectively screened for FHL3 by measuring the perforin expression in NK cells and the expression of Munc13-4, syntaxin-11, and Munc18-2 in platelets and by performing NK cell and CTL degranulation assays. The results were confirmed by genetic analysis. Results: The freshly isolated NK cell degranulation assay detected FHL3 patients with high sensitivity (100%) but low specificity (71%). The IL-2-stimulated NK cell assay had improved specificity, but 3 out of the 31 non-FHL3 patients still showed degranulation below the threshold level. The CD57+ CTL degranulation assay identified FHL3 patients with high sensitivity and specificity (both 100%). Conclusions: The CD57+ CTL degranulation assay more effectively identified FHL3 patients than the NK cell-based assays.

AB - Purpose: Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) is a genetic disorder that results in immune dysregulation. It requires prompt and accurate diagnosis. A natural killer (NK) cell degranulation assay is often used to screen for FHL3 patients. However, we recently encountered two cases of late-onset FHL3 carrying novel UNC13D missense mutations: in these cases, the degranulation assays using freshly isolated and interleukin (IL)-2-activated NK cells yielded contradictory results. Since the defective degranulation of CD57+ cytotoxic T lymphocytes (CTLs) in these cases was helpful for making the diagnosis, we assessed whether the CD57+ CTL degranulation assay more effectively identified FHL3 patients than the NK cell assays. Methods: Forty additional patients with hemophagocytic lymphohistiocytosis were prospectively screened for FHL3 by measuring the perforin expression in NK cells and the expression of Munc13-4, syntaxin-11, and Munc18-2 in platelets and by performing NK cell and CTL degranulation assays. The results were confirmed by genetic analysis. Results: The freshly isolated NK cell degranulation assay detected FHL3 patients with high sensitivity (100%) but low specificity (71%). The IL-2-stimulated NK cell assay had improved specificity, but 3 out of the 31 non-FHL3 patients still showed degranulation below the threshold level. The CD57+ CTL degranulation assay identified FHL3 patients with high sensitivity and specificity (both 100%). Conclusions: The CD57+ CTL degranulation assay more effectively identified FHL3 patients than the NK cell-based assays.

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U2 - 10.1007/s10875-016-0357-3

DO - 10.1007/s10875-016-0357-3

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JO - Journal of Clinical Immunology

JF - Journal of Clinical Immunology

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