A new functional assay for the diagnosis of X-linked inhibitor of apoptosis (XIAP) deficiency
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A new functional assay for the diagnosis of X-linked inhibitor of apoptosis (XIAP) deficiency. / Ammann, S; Elling, R; Gyrd-Hansen, M; Dückers, G; Bredius, R; Burns, S O; Edgar, J D M; Worth, A; Brandau, H; Warnatz, K; Zur Stadt, U; Hasselblatt, P; Schwarz, K; Ehl, S; Speckmann, C.
In: CLIN EXP IMMUNOL, Vol. 176, No. 3, 01.06.2014, p. 394-400.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - A new functional assay for the diagnosis of X-linked inhibitor of apoptosis (XIAP) deficiency
AU - Ammann, S
AU - Elling, R
AU - Gyrd-Hansen, M
AU - Dückers, G
AU - Bredius, R
AU - Burns, S O
AU - Edgar, J D M
AU - Worth, A
AU - Brandau, H
AU - Warnatz, K
AU - Zur Stadt, U
AU - Hasselblatt, P
AU - Schwarz, K
AU - Ehl, S
AU - Speckmann, C
N1 - © 2014 British Society for Immunology.
PY - 2014/6/1
Y1 - 2014/6/1
N2 - X-linked inhibitor of apoptosis (XIAP) deficiency, caused by mutations in BIRC4, is an immunodeficiency associated with immune dysregulation and a highly variable clinical presentation. Current diagnostic screening tests such as flow cytometry for XIAP expression or lymphocyte apoptosis assays have significant limitations. Based on recent evidence that XIAP is essential for nucleotide-binding and oligomerization domains (NOD)1/2 signalling, we evaluated the use of a simple flow cytometric assay assessing tumour necrosis factor (TNF) production of monocytes in response to NOD2 stimulation by muramyl dipeptides (L18-MDP) for the functional diagnosis of XIAP deficiency. We investigated 12 patients with XIAP deficiency, six female carriers and relevant disease controls. Irrespective of the diverse clinical phenotype, the extent of residual protein expression or the nature of the mutation, the TNF response was severely reduced in all patients. On average, L18-MDP induced TNF production in 25% of monocytes from healthy donors or female carriers, while fewer than 6% of monocytes responded in affected patients. Notably, the assay clearly discriminated affected patients from disease controls with other immunodeficiencies accompanied by lymphoproliferation, hypogammaglobulinaemia or inflammatory bowel disease. Functional testing of the NOD2 signalling pathway is an easy, fast and reliable assay in the diagnostic evaluation of patients with suspected XIAP deficiency.
AB - X-linked inhibitor of apoptosis (XIAP) deficiency, caused by mutations in BIRC4, is an immunodeficiency associated with immune dysregulation and a highly variable clinical presentation. Current diagnostic screening tests such as flow cytometry for XIAP expression or lymphocyte apoptosis assays have significant limitations. Based on recent evidence that XIAP is essential for nucleotide-binding and oligomerization domains (NOD)1/2 signalling, we evaluated the use of a simple flow cytometric assay assessing tumour necrosis factor (TNF) production of monocytes in response to NOD2 stimulation by muramyl dipeptides (L18-MDP) for the functional diagnosis of XIAP deficiency. We investigated 12 patients with XIAP deficiency, six female carriers and relevant disease controls. Irrespective of the diverse clinical phenotype, the extent of residual protein expression or the nature of the mutation, the TNF response was severely reduced in all patients. On average, L18-MDP induced TNF production in 25% of monocytes from healthy donors or female carriers, while fewer than 6% of monocytes responded in affected patients. Notably, the assay clearly discriminated affected patients from disease controls with other immunodeficiencies accompanied by lymphoproliferation, hypogammaglobulinaemia or inflammatory bowel disease. Functional testing of the NOD2 signalling pathway is an easy, fast and reliable assay in the diagnostic evaluation of patients with suspected XIAP deficiency.
KW - Acetylmuramyl-Alanyl-Isoglutamine
KW - Adolescent
KW - Adult
KW - Aged
KW - Case-Control Studies
KW - Child
KW - Child, Preschool
KW - Female
KW - Flow Cytometry
KW - Humans
KW - Immunologic Deficiency Syndromes
KW - Immunophenotyping
KW - Infant
KW - Leukocytes, Mononuclear
KW - Male
KW - Middle Aged
KW - Mutation
KW - Nod2 Signaling Adaptor Protein
KW - Phenotype
KW - T-Lymphocytes
KW - Tumor Necrosis Factors
KW - X-Linked Inhibitor of Apoptosis Protein
KW - Young Adult
U2 - 10.1111/cei.12306
DO - 10.1111/cei.12306
M3 - SCORING: Journal article
C2 - 24611904
VL - 176
SP - 394
EP - 400
JO - CLIN EXP IMMUNOL
JF - CLIN EXP IMMUNOL
SN - 0009-9104
IS - 3
ER -