Renner Ellen D, Hartl Dominik, Rylaarsdam Stacey, Young Marguerite L, Monaco-Shawver Linda, Kleiner Gary, Markert M Louise, Stiehm E Richard, Belohradsky Bernd H, Upton Melissa P, Torgerson Troy R, Orange Jordan S, Ochs Hans D
Dr v Haunersches Kinderspital, Ludwig-Maximilians-Universität, Munich, Germany.
J Allergy Clin Immunol. 2009 Sep;124(3):536-43. doi: 10.1016/j.jaci.2009.06.009. Epub 2009 Aug 14.
Mutations in serine protease inhibitor Kazal-type 5 (SPINK5), encoding the serine protease inhibitor lympho-epithelial Kazal-type 5 related inhibitor (LEKTI), cause Comèl-Netherton syndrome, an autosomal-recessive disease characterized by congenital ichthyosis, bamboo hair, and atopic diathesis. Despite increased frequency of infections, the immunocompetence of patients with Comèl-Netherton syndrome has not been extensively investigated.
To define Comèl-Netherton syndrome as a primary immunodeficiency disorder and to explore the benefit of intravenous immunoglobulin replacement therapy.
We enrolled 9 patients with Comèl-Netherton syndrome, sequenced SPINK5, and analyzed LEKTI expression by immunohistochemistry. Immune function was assessed by measuring cognate immunity, serum cytokine levels, and natural killer cell cytotoxicity.
All patients presented with recurrent skin infections caused predominantly by Staphylococcus aureus. All but 1 reported recurrent respiratory tract infections; 78% had sepsis and/or pneumonia; 67% had recurrent gastrointestinal disease and failure to thrive. Mutations in SPINK5-including 6 novel mutations-were identified in 8 patients. LEKTI expression was decreased or absent in all patients. Immunologic evaluation revealed reduced memory B cells and defective responses to vaccination with Pneumovax and bacteriophage phiX174, characterized by impaired antibody amplification and class-switching. Immune dysregulation was suggested by a skewed T(h)1 phenotype and elevated proinflammatory cytokine levels, whereas serum concentrations of the chemokine (C-C motif) ligand 5 and natural killer cell cytotoxicity were decreased. Treatment with intravenous immunoglobulin resulted in remarkable clinical improvement and temporarily increased natural killer cell cytotoxicity.
These data provide new insights into the immunopathology of Comèl-Netherton syndrome and demonstrate that this multisystem disorder, characterized by lack of LEKTI expression in epithelial cells, is complicated by cognate and innate immunodeficiency that responds favorably to intravenous immunoglobulin therapy.
丝氨酸蛋白酶抑制剂Kazal型5（SPINK5）发生突变，该基因编码丝氨酸蛋白酶抑制剂淋巴细胞上皮Kazal型5相关抑制剂（LEKTI），可导致Comèl-Netherton综合征，这是一种常染色体隐性疾病，其特征为先天性鱼鳞病、竹节发和特应性素质。尽管Comèl-Netherton综合征患者感染频率增加，但其免疫功能尚未得到广泛研究。
将Comèl-Netherton综合征定义为一种原发性免疫缺陷疾病，并探索静脉注射免疫球蛋白替代疗法的益处。
我们招募了9名Comèl-Netherton综合征患者，对SPINK5进行测序，并通过免疫组织化学分析LEKTI表达。通过测量同源免疫、血清细胞因子水平和自然杀伤细胞细胞毒性来评估免疫功能。
所有患者均出现主要由金黄色葡萄球菌引起的复发性皮肤感染。除1例患者外，所有患者均报告有复发性呼吸道感染；78%的患者发生败血症和/或肺炎；67%的患者有复发性胃肠道疾病且生长发育不良。在8名患者中鉴定出SPINK5突变，包括6种新突变。所有患者的LEKTI表达均降低或缺失。免疫评估显示记忆B细胞减少，对肺炎球菌疫苗和噬菌体phiX174接种的反应存在缺陷，表现为抗体扩增和类别转换受损。T（h）1表型偏斜和促炎细胞因子水平升高提示免疫失调，而趋化因子（C-C基序）配体5的血清浓度和自然杀伤细胞细胞毒性降低。静脉注射免疫球蛋白治疗导致临床显著改善，并使自然杀伤细胞细胞毒性暂时增加。
这些数据为Comèl-Netherton综合征免疫病理学提供了新见解，并表明这种以上皮细胞中LEKTI表达缺失为特征的多系统疾病，因同源免疫和先天免疫缺陷而复杂化，对静脉注射免疫球蛋白治疗反应良好。
