Lack of cathelicidin processing in Papillon-Lefèvre syndrome patients reveals essential role of LL-37 in periodontal homeostasis.
Lack of cathelicidin processing in Papillon-Lefèvre syndrome patients reveals essential role of LL-37 in periodontal homeostasis.
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DOI：
10.1186/s13023-014-0148-y
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发表时间：
2014-09-27
影响因子：
3.7
通讯作者：
Potempa J
中科院分区：
文献类型：
--
作者：
Eick S;Puklo M;Adamowicz K;Kantyka T;Hiemstra P;Stennicke H;Guentsch A;Schacher B;Eickholz P;Potempa J
组织蛋白酶C基因的功能丧失点突变是Papillon-Lefèvre综合征（PLS）患者的潜在遗传事件。PLS嗜中性粒细胞缺乏从hCAP 18前体产生凯萨林菌素LL-37所必需的丝氨酸蛋白酶活性。我们推测，局部缺乏LL-37在受感染的牙周组织是主要负责PLS的临床标志之一：严重的牙周炎已经在幼儿期。为了证实这一效应，我们比较了PLS、侵袭性牙周炎和慢性牙周炎患者龈沟液（GCF）和唾液中嗜酸性粒细胞衍生酶和抗菌肽的水平。尽管在所有牙周炎组中GCF中的中性粒细胞数量处于相同水平，但PLS患者的GCF中完全不存在LL-37，尽管其前体hCAP 18的量很大。PLS患者LL-37的缺乏与组织蛋白酶C和蛋白酶3活性的缺乏相一致。PLS患者GCF中其他嗜酸性抗菌肽的存在，如α-防御素，与慢性牙周炎中发现的相当。PLS微生物分析显示伴放线菌聚集杆菌感染的患病率很高。大多数菌株对LL-37的杀伤敏感。总的来说，这些发现意味着PLS患者中功能失调的组织蛋白酶C缺乏蛋白酶3活化导致牙龈中LL-37的抗微生物和免疫调节功能的缺陷，从而允许A.放线菌共生菌与严重牙周病的发展。本文的在线版本（doi：10.1186/s13023-014-0148-y）包含补充材料，可供授权用户使用。
Loss-of-function point mutations in the cathepsin C gene are the underlying genetic event in patients with Papillon-Lefèvre syndrome (PLS). PLS neutrophils lack serine protease activity essential for cathelicidin LL-37 generation from hCAP18 precursor. We hypothesized that a local deficiency of LL-37 in the infected periodontium is mainly responsible for one of the clinical hallmark of PLS: severe periodontitis already in early childhood. To confirm this effect, we compared the level of neutrophil-derived enzymes and antimicrobial peptides in gingival crevicular fluid (GCF) and saliva from PLS, aggressive and chronic periodontitis patients. Although neutrophil numbers in GCF were present at the same level in all periodontitis groups, LL-37 was totally absent in GCF from PLS patients despite the large amounts of its precursor, hCAP18. The absence of LL-37 in PLS patients coincided with the deficiency of both cathepsin C and protease 3 activities. The presence of other neutrophilic anti-microbial peptides in GCF from PLS patients, such as alpha-defensins, were comparable to that found in chronic periodontitis. In PLS microbial analysis revealed a high prevalence of Aggregatibacter actinomycetemcomitans infection. Most strains were susceptible to killing by LL-37. Collectively, these findings imply that the lack of protease 3 activation by dysfunctional cathepsin C in PLS patients leads to the deficit of antimicrobial and immunomodulatory functions of LL-37 in the gingiva, allowing for infection with A. actinomycetemcomitans and the development of severe periodontal disease. The online version of this article (doi:10.1186/s13023-014-0148-y) contains supplementary material, which is available to authorized users.
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DOI：
10.1038/nrmicro2873
发表时间：
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期刊：
Nature reviews. Microbiology
影响因子：
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