A fast procedure for the detection of defects in toll-like receptor signaling

被引:49
作者
von Bernuth, Horst
Ku, Cheng-Lung
Rodriguez-Gallego, Carlos
Zhang, Shenying
Garty, Ben-Zion
Marodi, Laszlo
Chapel, Helen
Chrabieh, Maya
Miller, Richard L.
Picard, Capucine
Puel, Anne
Casanova, Jean-Laurent
机构
[1] Univ Paris 05, INSERM, Lab Genet Humaine Malad Infect, U550,Fac Med Necker,Necker Med Sch, F-75015 Paris, France
[2] Gran Canaria Dr Negrin Hosp, Dept Immunol, Las Palmas Gran Canaria, Spain
[3] Shneider Med Ctr, Tel Aviv, Israel
[4] Tel Aviv Univ, Sch Med, IL-69978 Tel Aviv, Israel
[5] Univ Debrecen, Dept Infectol & Pediat Immunol, Med & Hlth Sci Ctr, Debrecen, Hungary
[6] John Radcliffe Hosp, Nuffield Dept Med, Dept Clin Immunol, Oxford OX3 9DU, England
[7] 3M Co, St Paul, MN USA
[8] Immunodefiency Study Ctr, Paris, France
[9] Hop Necker Enfants Malad, Pediat Hematol Immunol Unit, Paris, France
关键词
innate immunity; interleukin 1 receptor-associated kinase-4 deficiency; L-selectin; primary immunodeficiency; toll-like receptors; UNC-93B deficiency;
D O I
10.1542/peds.2006-1845
中图分类号
R72 [儿科学];
学科分类号
100202 ;
摘要
OBJECTIVES. Inborn defects in Toll-like receptor signaling are recently described primary immunodeficiencies that predispose affected children to life-threatening infections. Patients with interleukin-1 receptor-associated kinase-4 deficiency are prone to invasive pneumococcal disease, and patients with UNC-93B deficiency are prone to herpes simplex virus encephalitis. These genetic disorders are under-diagnosed, partly because diagnosis currently requires expensive and time-consuming techniques available at only a few specialized centers worldwide. We, therefore, aimed to develop a cheap and fast test for the detection of defects in Toll-like receptor signaling. PATIENTS AND METHODS. We used flow cytometry to evaluate the cleavage of membrane-bound L-selectin on granulocytes in 38 healthy controls and in 7 patients with genetically defined Toll-like receptor signaling defects (5 patients with interleukin-1 receptor-associated kinase-4 deficiency and 2 patients with UNC-93B deficiency), on activation with various Toll-like receptor agonists. RESULTS. Impaired L-selectin shedding was observed with granulocytes from all of the interleukin-1 receptor-associated kinase-4-deficient patients on activation with agonists of Toll-like receptors 1/2, 2/6, 4, 7, and 8 and with granulocytes from all of the UNC-93B-deficient patients on activation with agonists of Toll-like receptors 7 and 8. All of the healthy controls responded to these stimuli. CONCLUSIONS. The assessment of membrane-bound L-selectin cleavage on granulocytes by flow cytometry may prove useful for the detection of primary immunodeficiencies in the Toll-like receptor pathway, such as interleukin-1 receptor-associated kinase-4 deficiency and UNC-93B deficiency. This procedure is cheap and rapid. It may, therefore, be suitable for routine testing worldwide in children with invasive pneumococcal disease and in patients with herpes simplex encephalitis.
引用
收藏
页码:2498 / 2503
页数:6
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