Comprehensive flow cytometry-based diagnosis of XIAP deficiency

Deficiency of X-linked inhibitor of apoptosis protein (XIAP) is an X-linked recessive inborn error of immunity characterized by abnormal immune responses leading to inflammatory bowel disease and hemophagocytic lymphohistiocytosis. Although XIAP protein expression analysis by flow cytometry (XIAP flow) is commonly used to diagnose XIAP deficiency, certain variants may not affect the protein expression, thereby complicating the diagnostic process. XIAP is crucial for the nucleotide-binding and oligomerization domain 2 (NOD2) signaling pathway. In this study, we aimed to perform a comprehensive analysis of nine patients diagnosed with XIAP deficiency through genetic testing. In addition to XIAP flow, we employed a previously reported method utilizing muramyl dipeptide (MDP) stimulation, a specific agonist of NOD2, to quantitatively evaluate the downstream tumor necrosis factor-alpha (TNFα) production by flow cytometry in patient monocytes (MDP flow). The median mean fluorescence intensity in healthy controls with XIAP flow was 711 (95% confidence interval [CI], 653-815) compared to 195 (95% CI, 161-386) in patients with XIAP deficiency (P < 0.0001). The median percentage of TNFα-producing monocytes in controls with MDP flow was 29.1% (95% CI, 19.6-53.7), while in patients it was 0.34% (95% CI, 0.18-0.82) (P = 0.0008). The receiver operating characteristic curves demonstrated that both XIAP flow and MDP flow exhibited 100% sensitivity and specificity. Taken together, combining XIAP flow and MDP flow analyses allows for a highly accurate diagnosis.

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Journal
Clinical & Experimental Immunology
Published
2025-01-01
DOI
https://doi.org/10.1093/cei/uxaf020
Citations
1
Primary Topic
Viral gastroenteritis research and epidemiology
Type
article
Field-Weighted Citation Impact
1.40
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Comprehensive flow cytometry-based diagnosis of XIAP deficiency

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Comprehensive flow cytometry-based diagnosis of XIAP deficiency

Takeshi Isoda, Eri Okura, Masatoshi Takagi, Akihiro Hoshino, Yukako Maeda, Masaki Shimizu, Dan Tomomasa, T TAKAYAMA, Rebecca Marsh, Hirokazu Kanegane, Satoshi Okada, Masataka Ishimura, Kosuke Fujimoto, Tomohiro Morio, Shuya Kaneko, Atsushi Hijikata, Ryosuke Wakatsuki, Rei Watanabe, Satoshi Miyamoto, Madoka Nishimura, Takahiro Kamiya, Takaaki Meguro, Kazushi Izawa, Tomoko Uehara, Kay Tanita, K. Eguchi, Kyogo Suzuki, Ayami Ohya, Etsuko Ishikita-Murayama
article en
1 citations

Abstract

Deficiency of X-linked inhibitor of apoptosis protein (XIAP) is an X-linked recessive inborn error of immunity characterized by abnormal immune responses leading to inflammatory bowel disease and hemophagocytic lymphohistiocytosis. Although XIAP protein expression analysis by flow cytometry (XIAP flow) is commonly used to diagnose XIAP deficiency, certain variants may not affect the protein expression, thereby complicating the diagnostic process. XIAP is crucial for the nucleotide-binding and oligomerization domain 2 (NOD2) signaling pathway. In this study, we aimed to perform a comprehensive analysis of nine patients diagnosed with XIAP deficiency through genetic testing. In addition to XIAP flow, we employed a previously reported method utilizing muramyl dipeptide (MDP) stimulation, a specific agonist of NOD2, to quantitatively evaluate the downstream tumor necrosis factor-alpha (TNFα) production by flow cytometry in patient monocytes (MDP flow). The median mean fluorescence intensity in healthy controls with XIAP flow was 711 (95% confidence interval [CI], 653-815) compared to 195 (95% CI, 161-386) in patients with XIAP deficiency (P < 0.0001). The median percentage of TNFα-producing monocytes in controls with MDP flow was 29.1% (95% CI, 19.6-53.7), while in patients it was 0.34% (95% CI, 0.18-0.82) (P = 0.0008). The receiver operating characteristic curves demonstrated that both XIAP flow and MDP flow exhibited 100% sensitivity and specificity. Taken together, combining XIAP flow and MDP flow analyses allows for a highly accurate diagnosis.

Clinical & Experimental ImmunologyVol. 219(1)
Hiroshima University (JP), Tokyo Medical and Dental University (JP), Cincinnati Children's Hospital Medical Center (US), Children's Medical Center (US), Kyushu University (JP), Shinshu University (JP), Royal College of Surgeons in Ireland (IE), Tokyo University of Pharmacy and Life Sciences (JP), Inserm (FR), Gunma University (JP), Kyoto University (JP), Cardiovascular Institute Hospital (JP), Shanghai Institute for Science of Science (CN), Tokyo Institute of Psychiatry (JP), University of Tokyo Hospital (JP), Nara Medical University Hospital (JP), Institute of Medicinal Molecular Design (JP), Children's Medical Center (US), Okinawa Prefectural Agricultural Research Center (JP), Naha City Hospital (JP), Tokyo Metropolitan Children's Medical Center (JP), Gunma Children's Medical Center (JP), Shizuoka Children's Hospital (JP), Institut des Maladies Génétiques Imagine (FR), Nara Medical University (JP), Kumamoto University (JP)
Good health and well-being
Openalex Percentile: Top 23%
Viral gastroenteritis research and epidemiology
1.40
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