Comeau Jeannette L, Lin Tong-Jun, Macken Marian B, Li Bo, Ku Cheng-Lung, von Bernuth Horst, Casanova Jean-Laurent, Issekutz Andrew C
Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada.
Pediatr Infect Dis J. 2008 Feb;27(2):170-4. doi: 10.1097/INF.0b013e318157ad01.
A deficiency in the interleukin-1 receptor activated kinase 4 (IRAK-4) has recently been associated with severe recurrent, predominantly Gram-positive bacterial infections.
Two unrelated Canadian children with unique presentations of IRAK-4 deficiency are described. Both children had multiple Gram-positive bacterial infections, specifically Staphylococcus aureus and Streptococcus pneumoniae. Although these microorganisms in patients with IRAK-4 deficiency commonly cause invasive infections, such as meningitis, arthritis, and sepsis, the sites of infection in our patients were unique. In the first patient, staphylococcal pericarditis and, on a separate occasion, staphylococcal liver abscesses with generalized peritonitis were presentations. In the second child, S. aureus infection caused submandibular and periauricular lymphadenitis with unsuspected paratracheal abscess as well. These severe infections were not accompanied by the expected constitutional symptoms or hematologic and acute phase responses despite findings of advanced infection on diagnostic imaging.
Cytokine production [interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-alpha] by whole blood leukocytes and adherent monocytes after stimulation with IL-1beta or various Toll-like receptor agonists [lipopolysaccharide, Poly I:C, S. aureus peptidoglycan (PGN)] was analyzed. IRAK-4 genes were sequenced by standard techniques.
Failure by whole blood leukocytes to produce IL-6 or TNF-alpha in response to any of these stimuli was the most consistent finding. In striking contrast, IL-8 production in response to PGN was normal in both cases. Both patients had novel and heterozygous mutations and deletions in the IRAK-4 gene.
Our results indicate that PGN-induced IL-6 production is via IRAK-4 dependent mechanisms, whereas IL-8 response to PGN is via IRAK-4 independent mechanisms. Patients with relatively silent but invasive bacterial infection should raise suspicion of IRAK-4 immunodeficiency.
白细胞介素-1受体相关激酶4（IRAK-4）缺陷最近被发现与严重的复发性感染相关，主要为革兰氏阳性菌感染。
本文描述了两名患有IRAK-4缺陷的加拿大儿童，他们的临床表现独特。两名儿童均有多次革兰氏阳性菌感染，特别是金黄色葡萄球菌和肺炎链球菌感染。虽然IRAK-4缺陷患者体内的这些微生物通常会引发侵袭性感染，如脑膜炎、关节炎和败血症，但我们这两名患者的感染部位却很独特。第一名患者出现了葡萄球菌性心包炎，另一次出现了伴有弥漫性腹膜炎的葡萄球菌肝脓肿。第二名儿童，金黄色葡萄球菌感染导致下颌下和耳周淋巴结炎，同时还伴有未被怀疑的气管旁脓肿。尽管诊断性影像学检查发现感染已进展，但这些严重感染并未伴有预期的全身症状或血液学及急性期反应。
分析全血白细胞和贴壁单核细胞在受到白细胞介素-1β或各种Toll样受体激动剂[脂多糖、聚肌胞苷酸、金黄色葡萄球菌肽聚糖（PGN）]刺激后细胞因子的产生情况[白细胞介素（IL）-6、IL-8和肿瘤坏死因子（TNF）-α]。采用标准技术对IRAK-4基因进行测序。
全血白细胞对上述任何一种刺激均无法产生IL-6或TNF-α，这是最一致的发现。与之形成鲜明对比的是，两名患者对PGN刺激产生IL-8的能力均正常。两名患者的IRAK-4基因均存在新的杂合突变和缺失。
我们的结果表明，PGN诱导的IL-6产生是通过依赖IRAK-4的机制，而IL-8对PGN的反应是通过不依赖IRAK-4的机制。对于患有相对隐匿但具有侵袭性细菌感染的患者，应怀疑其存在IRAK-4免疫缺陷。
