TY - JOUR
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
N1 - Funding Information:
This work was supported by JSPS KAKENHI (Grant Numbers 26461582 and 25670475) and by grants from the “Research on Measures for Intractable Diseases” Project: matching fund subsidy from the Japanese Ministry of Health, Labor, and Welfare.
Publisher Copyright:
© 2016, Springer Science+Business Media New York.
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.
KW - Familial hemophagocytic lymphohistiocytosis type 3
KW - UNC13D
KW - functional screening assay
KW - lysosomal degranulation defect
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U2 - 10.1007/s10875-016-0357-3
DO - 10.1007/s10875-016-0357-3
M3 - Article
C2 - 27896523
AN - SCOPUS:84997815906
VL - 37
SP - 92
EP - 99
JO - Journal of Clinical Immunology
JF - Journal of Clinical Immunology
SN - 0271-9142
IS - 1
ER -