Demodex and Rosacea Revisited
Abstract
摘要
英文原文
Demodex mites are part of the vast microbiome living on and within human skin. The interaction of the various microorganisms with the skin plays a key role in the maintenance of homeostasis. The precise role and function of Demodex mites within normal and diseased human skin remains elusive. The emergence of ivermectin as a key therapy for rosacea has refocused interest in the role of Demodex mites in the pathogenesis of this skin disease and the ablity of Demodex to modulate the host immune system.
对应中文
蠕形螨是生活在人类皮肤上和皮肤内的巨大微生物群落的一部分。各种微生物与皮肤的相互作用在维持体内平衡方面起着关键作用。蠕形螨在正常和患病人体皮肤中的确切作用和功能仍不清楚。伊维菌素作为玫瑰痤疮的一种关键疗法的出现使人们重新关注蠕形螨在该皮肤病发病机制中的作用以及蠕形螨调节宿主免疫系统的能力。
英文原文
The skin is home to a vast array of biological life forms. These reside both on the skin surface and within the various skin appendages such hair follicles, sebaceous and sweat glands. The physical barrier of the stratum corneum, the various epidermal and specialized appendageal cells as well as the immune cells dynamically interact with the various microorganisms to maintain the homeostasis of the skin. Recent research relating to the Innate Immune system has focused on the cutaneous bacterial community. The presence and potential role of Demodex mites in normal and disordered human skin has been largely overlooked.
对应中文
皮肤是各种生物生命形式的家园：它们既存在于皮肤表面，也存在于毛囊、皮脂腺和汗腺等各种皮肤附属器中。角质层的物理屏障、各种表皮和特殊的附属物细胞以及免疫细胞与各种微生物动态相互作用，以维持皮肤的稳态。最近有关先天免疫系统的研究主要集中在皮肤细菌群落上。蠕形螨在正常和紊乱人体皮肤中的存在和潜在作用在很大程度上被忽视。
英文原文
The widely varied biogeography of the cutaneous surface suggests that organisms may play specific roles in particular biological niches. Demodex mites are complex organisms that are ubiquitously present on adult human skin, particularly in the pilosebaceous units of the face. We review the possible role of these mites in the orchestration of the immune response within the facial pilosebaceous unit. Topical ivermectin, an anti-parasitic agent, has recently been approved for the treatment of papulopustular rosacea. Similar to other rosacea treatments the exact mechanism by which it improves the clinical signs of rosacea is unclear. However the compound has been shown to display a broad range of activities; antimicrobial; anti-parasitic, anti-bacterial and anti-inflammatory. The advent of ivermectin as a major treatment for rosacea has stimulated renewed interest in the possible role of Demodex mites in the pathogenesis of this disorder and the capacity of Demodex mites to interact with the host immune system.
对应中文
皮肤表面多种多样的生物地理学表明，生物体可能在特定的生物生态位中扮演特定的角色。蠕形螨是一种复杂的有机体，广泛存在于成人皮肤上，尤其是面部的毛皮脂腺部位。我们回顾了这些螨虫在面部毛皮脂腺单位的免疫反应协调中的可能作用。伊维菌素是一种外用抗寄生虫药，最近已被批准用于治疗丘疹性玫瑰痤疮。与其他玫瑰痤疮治疗方法相似，其改善玫瑰痤疮临床症状的确切机制尚不清楚。然而，该化合物已显示出广泛的活性；抗微生物；抗寄生虫、抗细菌和抗炎。伊维菌素作为治疗玫瑰痤疮的主要药物的出现，重新激发了人们对蠕形螨在这种疾病的发病机制中的可能作用以及蠕形螨与宿主免疫系统相互作用的能力的新的兴趣。
Demodex and Healthy Skin
蠕形螨与健康皮肤
英文原文
Mites are microscopic arthropods closely related to ticks that belong to the class Arachnida subclass Acari. They are considered to be one of the most diverse and successful of all the invertebrate groups with over 48,000 species described. They inhabit a vast range of ecological niches. Two species of Demodex mite are known to inhabit the human pilosebaceous unit; Demodex folliculorum and Demodex brevis. Demodex folliculorum resides within the hair follicle whereas Demodex brevis is found predominantly in the sebaceous and meibomian glands. Both species are ubiquitous amongst adult humans with normal skin. It has been suggested that Demodex mites are acquired after birth as a result of skin contact between adults and children with numbers increasing with the age of the host and presumably maturity of the pilosebaceous unit after puberty.
对应中文
螨类是微小的节肢动物，与蜱类关系密切，属于蛛形纲螨亚纲。它们被认为是所有无脊椎动物中最多样化和最成功的类群之一，有超过48000个物种被描述。它们栖息在广泛的生态环境中。已知有两种蠕形螨栖息于人类毛囊皮脂腺单位：毛囊蠕形螨和皮脂蠕形螨。毛囊蠕形螨位于毛囊内，而皮脂蠕形螨主要存在于皮脂腺和睑板腺中。这两个物种在皮肤正常的成年人中随处可见。有人认为，蠕形螨是在出生后由于成人和儿童之间的皮肤接触而获得的，随着宿主年龄的增长，蠕形螨的数量可能会随着青春期后毛皮脂腺单位的成熟而增加。
英文原文
Research into the lifecycle of Demodex mites has been limited to date due to the difficulties in culturing Demodex in vitro. On the basis of studies by Spickett in the early 1960s the lifecycle of Demodex is estimated at between 14-18 days. Spickett detailed how the male mites move about the surface of the skin mainly at night-time and copulate with females at the opening of hair follicles. After 12 hours the female lays eggs within the hair follicles or sebaceous glands. Larvae hatch after 3-4 days and proceed through developmental stages to become an adult in about 7 days.
对应中文
由于体外培养蠕形螨困难，迄今为止对蠕形螨生命周期的研究受到限制。根据Spickett在20世纪60年代早期的研究，蠕形螨的生命周期估计在14-18天之间。Spickett详细描述了雄性螨主要在夜间在皮肤表面移动，并在毛囊开口处与雌性螨交配。12小时后，雌性在毛囊或皮脂腺内产卵。幼虫在3-4天后孵化，并在大约7天内进入发育阶段成为成虫。
英文原文
The morphological and anatomical features of both Demodex species are well characterised These mites possess a gnathosoma, podosoma and striated opisthosoma with a transparent chitinous exoskeleton. Scanning electron microscopy has confirmed the presence of piercing mouthparts in Demodex folliculorum and bifid claws capable of penetrating cellular membranes and possibly keratin. Demodex mites are believed to perforate the skin cells (primarily keratinocytes) lining the pilosebaceous follicle and ingest their contents. They may also ingest sebum for nutrition. Both mite species are hypothesized to secrete salivary enzymes containing proteases that break down food sources. This is supported by the observation of specific binding of IgD and serum protease inhibitors to Demodex mites as a possible protective host response.
对应中文
这两种蠕形螨的形态和解剖特征都很明显，它们具有颚状体，足状体〈蜱螨体躯具有第一、二、三、四对足的部分。〉和条纹末体，外骨骼透明。扫描电镜已证实毛囊蠕形螨和双歧爪中存在能穿透细胞膜和可能存在角蛋白的穿孔口器。蠕形螨被认为是将毛囊内衬的皮肤细胞(主要是角质形成细胞)穿孔并摄取其内容物。它们还可能摄取皮脂进行营养。据推测，这两种螨虫都会分泌含有分解食物来源的蛋白酶的唾液酶。IgD和血清蛋白酶抑制剂与蠕形螨特异性结合，可能是宿主的保护性反应，这支持了这一点。
英文原文
The presence of lipase enzymes within Demodex are probably related to the digestion of lipid material but may also have a role in digesting bacteria or other microorganisms. Demodex mites lack an anus and are thought to store their faeces internally in crystallized fashion. Large numbers of dying mites both by releasing their internal contents as well as exposure of the host to the chitinous exoskeleton of the decomposing mites, may initiate an immune response by the host with subsequent inflammatory changes.
对应中文
蠕形螨中脂肪酶的存在可能与脂肪物质的消化有关，但也可能在消化细菌或其他微生物方面起作用。蠕形螨没有肛门，被认为在内部以结晶的方式储存粪便。大量死亡的螨虫通过释放其内部内容物以及将宿主暴露于分解螨虫的几丁质外骨骼中，可能启动宿主的免疫反应，随后发生炎症变化。
Demodex Mites and Skin Disorders
蠕形螨与皮肤疾病
英文原文
Only a few mite species cause dermatological issues in humans. These include the scabies, food, house dust, poultry, murine and harvest mites. Demodex mites differ in that they have not been proven to cause disease in man.
对应中文
只有少数螨类会引起人类的皮肤病问题。这些包括疥疮、食物、室内灰尘、家禽、鼠类和螨类。蠕形螨的不同之处在于，它们尚未被证明能引起人类疾病。
英文原文
The causal role of Demodex mites in the generation of diseases such as mange in dogs is well established. In man an increased mite density of greater than 5 mites on 1cm2 of skin has been associated with rosacea and associated blepharitis. Patients with perioral dermatitis caused by steroid use or other immunomodulatory drugs show increased facial mite density.
对应中文
蠕形螨在狗的螨病等疾病发生中的因果作用已得到充分证实。在人类中，皮肤螨密度增加（1㎝²皮肤上的螨密度增加超过5个）可能与玫瑰痤疮和相关眼睑炎有关。使用类固醇或其他免疫调节药物引起的口周皮炎患者面部螨密度增加。
英文原文
Higher numbers of Demodex mites have also been documented in patients with alopecia, various malignancies, polycystic ovary syndrome, underweight and overweight patients, those undergoing immunosuppressive therapy and patients infected with HIV/AIDS. Several reports have indicated an increased population of Demodex in patients with diabetes and the mites present were found to be larger than normal.
对应中文
在脱发、各种恶性肿瘤、多囊卵巢综合征、体重不足和超重患者、接受免疫抑制治疗的患者和感染艾滋病毒/获得性免疫缺陷综合征患者中，蠕形螨数量也有所增加。几份报告表明，糖尿病患者体内蠕形螨的数量增加，并且发现存在的蠕形螨比正常人多。
Evasion of the Innate Immune Response by Demodex: Clues from the Scabies mite
蠕形螨逃避固有免疫应答：来自疥螨的线索
英文原文
Arthropods such as mites and ticks have evolved various mechanisms that modulate or circumvent host immune responses in order to survive within the host.
对应中文
节肢动物，如螨类和蜱类，已经进化出各种机制来调节或绕过宿主的免疫反应，以便在宿主内生存。
英文原文
Scabies mites secrete molecules that down regulate the human complement system and macrophage function. Scabies mite secreted complement inhibitors are also hypothesized to support the promotion of a microenvironment in which non-commensal pathogenic bacteria could flourish. These molecules also show homology to allergens of house dust mites. In the case of Norwegian or crusted scabies there is a hyperproliferation of the scabies mites in and on the skin and hyperkeratotic skin crusts form. Norwegian scabies occurs in patients with an underlying immunodeficiency and the disease is thought to occur as a result of an inadequate host immune response to the mites.
对应中文
疥螨分泌的分子可降低人类补体系统和巨噬细胞功能；疥螨分泌的补体抑制剂也被假设为促进利于非共生病原菌繁衍的微环境形成。这些分子与室内尘螨的过敏原也有同源性。在挪威型或结痂型的疥疮中，皮肤内和皮肤上的疥螨过度增殖，形成过度角化的皮肤结痂。挪威型疥疮发生在有潜在免疫缺陷的患者身上，这种疾病被认为是由于宿主对螨类的免疫反应不足所致。
英文原文
A number of studies suggest Demodex mites may suppress the innate immune response of the host in order to evade expulsion. Demodex mites have been shown to express Tn antigen, a carbohydrate coating known to protect cancer cells and parasites from immune surveillance. Demodex mites also appear to interact with cells of the pilosebaceous unit modulating the secretion of inflammatory mediators such as IL-8 and TNF-α, TLR expression and the recruitment of inflammatory cells. This suggests a mechanism through which mites may actively promote an immunosuppressed status, as well as opportunistically expanding their population when immunosuppression is caused by other factors.
对应中文
许多研究表明，蠕形螨可能会抑制宿主的先天免疫反应，以逃避驱逐。目前已被证明，蠕形螨表达TN抗原；这是一种已知的碳水化合物涂层，可保护癌细胞和寄生虫免受免疫监视。蠕形螨似乎还与毛囊皮脂腺单位的细胞相互作用，调节炎症介质的分泌，如IL-8和TNF-α，TLR的表达和炎性细胞35-41的募集。这表明了一种机制，通过这种机制、螨类可以积极促进免疫抑制状态，并在其他因素导致免疫抑制时，机会性地扩大其种群。
英文原文
Suppression of the adaptive immune system may occur as evidenced by both animal and human studies. Down modulation of T cell expression and function occurs during canine demodicosis and a mouse model of inflammatory skin disease suggests defects in the TH2 response may facilitate hyper proliferation of Demodex. A decrease in lymphocytes, T effector cells and NK cells has been observed in rosacea patients. In animals depression of the immune system allows for a hyperproliferation of mites and disease development.
对应中文
动物和人类的研究都证明，适应性免疫系统可能会受到抑制。T细胞表达和功能的下调发生在犬蠕形螨病期间，一个炎症性皮肤病的小鼠模型表明，TH2反应的缺陷可能促进蠕形螨的过度增殖。而在玫瑰痤疮患者中观察到淋巴细胞、T效应细胞和NK细胞的减少。在动物中，免疫系统的抑制允许螨虫过度增殖和疾病发展。
Identification of Demodex by the immune system and implications for disease pathogenesis
通过免疫系统识别蠕形螨及其在疾病发病机制中的意义
英文原文
In veterinary medicine the pathogenic role of Demodex in causing mange is well established although the exact mechanisms involved are unclear. In human skin Demodex are generally considered symbiotic inhabitants and their role in mediating dermatological conditions is still under debate.
对应中文
在兽医学中，蠕形螨在引起疥癣中的致病作用已得到充分证实，尽管其确切机制尚不清楚。在人类皮肤中，蠕形螨通常被认为是共生生物，它们在介导皮肤病方面的作用仍在争论中。
英文原文
In rosacea increased numbers of mites could contribute to its pathogenesis in a number of ways. An overabundance of mites may lead to a blockage of the hair follicles and sebaceous glands resulting in cutaneous barrier disruption and tissue damage. The resulting increase in TLR expression and recognition of the mite’s chitin exoskeleton could trigger an inflammatory reaction.
对应中文
在玫瑰痤疮中螨虫数量增加可能以多种方式促进其发病。过多的螨虫可能导致毛囊和皮脂腺堵塞，导致皮肤屏障破坏和组织损伤。由此导致的TLR表达的增加和对螨几丁质外骨骼的识别可能引发炎症反应。
英文原文
As already pointed out the large numbers of dying mites in the follicles of patients with rosacea may increase the released internal contents including endogenous bacterial antigen load to critical levels. At such levels, the effect of mites could potentially switch from being immunosuppressive to being proinflammatory. The presence of multiple mites (both dead and alive) and their skeletal disruption could release their gut contents including various bacteria, enzymes and mite faeces into the follicular canal in contact with the keratinocytes lining with the potential to trigger a type IV hypersensitivity reaction or innate immune response. Disruption of the epithelium and recognition of exoskeletal chitin may also result in a Th2 and/or Th17 response leading to tissue damage as a result of neutrophil and macrophage activation. This can be observed histologically in rosacea skin whereby the enlarged hair follicle containing Demodex mites is surrounded by a significant immune cell infiltrate.
对应中文
正如已经指出的，玫瑰痤疮患者滤泡中大量垂死的螨虫可能会使内源性细菌抗原负荷等内部内容物的释放增加到临界水平。在这样的水平下，螨虫的作用可能会从免疫抑制转变为促进炎症反应。多个螨虫的存在（死了或活着的），它们的骨骼破坏可以释放肠内容物，包括各种细菌、酶和螨虫粪便进入与角质形成细胞衬里接触的卵泡管，有可能引发IV型超敏反应或先天免疫反应。上皮细胞的破坏和外骨骼几丁质的识别也可能导致Th2和/或Th17反应，导致中性粒细胞和巨噬细胞的激活导致组织损伤。组织学上可以在玫瑰痤疮皮肤中观察到，大毛囊中含有蠕形螨，周围有明显的免疫细胞浸润。
英文原文
Increased mite density may not be the only and/or principal factor driving skin inflammation as evidenced by the example of pityriasis folliculorum. In this condition despite a very high Demodex density (higher than that reported in rosacea patients) little or no skin inflammation is observed. A recent study found that Demodex density is higher in patients with oily versus dry skin regardless of the presence of rosacea. Furthermore, while there is a trend towards a higher Demodex density in erythematotelangiectatic (ETR) versus papulopustular rosacea (PPR) patients, skin sample analysis demonstrated a higher expression of inflammatory genes in PPR compared to ETR.
对应中文
螨虫密度增加可能不是导致皮肤炎症的唯一和/或主要因素，毛囊糠疹的例子就证明了这一点：尽管蠕形螨密度很高(高于玫瑰痤疮患者的报告)，但几乎没有观察到皮肤炎症。最近的一项研究发现，无论是否存在玫瑰痤疮，油性皮肤患者的蠕形螨密度高于干性皮肤患者。此外，尽管在红斑狼疮（ETR）和丘疹脓疱性玫瑰痤疮（PPR）患者中有较高蠕形螨密度的趋势，但皮肤样本分析显示PPR中的炎症基因表达高于ETR。
Demodex mites as vectors of disease
蠕形螨是疾病的媒介
英文原文
Recent studies suggest mites from rosacea patients harbour pathogenic bacteria and other microorganisms on their surface which drive inflammatory skin responses and typically non-pathogenic bacteria display an altered functional profile in rosacea patients in comparison to normal controls. Interestingly the microbiome profile may be specific to rosacea disease subtype. Furthermore, serum immunoreactivity against the bacterium Bacillus oleronius has been significantly correlated with rosacea. It remains to be determined whether this altered microbiota in rosacea is a direct cause of disease or a consequence of the altered skin environment in rosacea patients. A role for bacteria in the pathogenesis of disease is supported by the response shown by patients to antibiotic therapy however it is still unclear if the antibiotics are having an anti-inflammatory or antimicrobial effect in the context of rosacea.
对应中文
慢性最近的研究表明，玫瑰痤疮患者的螨类在其表面含有致病菌和其他微生物，它们驱动皮肤炎症反应，与正常对照相比，典型的非致病性细菌在玫瑰痤疮患者中表现出不同的功能特征。有趣的是，微生物群谱可能是玫瑰痤疮疾病亚型所特有的。此外，血清对芽孢杆菌的免疫反应性与玫瑰痤疮显著相关。玫瑰痤疮患者这种改变的微生物区系是疾病的直接原因还是皮肤环境改变的结果还有待确定。细菌在疾病发病机制中的作用得到了患者对抗生素治疗反应的支持，但目前尚不清楚抗生素是否对玫瑰痤疮有抗炎或抗菌作用。
Genetically susceptible individuals
遗传易感个体
英文原文
A number of studies indicate a genetic component to rosacea. The condition is more common in fair skinned individuals of European descent. A number of MHC class II HLA alleles have been associated with rosacea all of which have been associated with autoimmune diseases such as multiple sclerosis, type 1 diabetes and retinopathy. Gene polymorphisms in HLA-DRA and Butyrophilin-like 2 (BTNL2) have also been associated with rosacea. Such variations in these molecules have been previously linked to T-cell responses to mite allergens. Associations with MHC class I molecules and Demodicosis patients have also been observed patients with a Cw2 or Cw4 phenotype were found to be more susceptible to Demodicosis and had an altered immune function phenotype whereas the HLA A2 phenotype were less susceptible.
对应中文
许多研究表明玫瑰痤疮的发病有遗传因素，这种情况在欧洲血统的白皮肤个体中更为常见。一些MHCII类HLA等位基因与玫瑰痤疮相关，所有这些都与自身免疫性疾病相关，如多发性硬化症、1型糖尿病和视网膜病变。HLA-DRA和BTNL2的基因多态性也与玫瑰痤疮相关。这些分子的这种变异以前被认为与T细胞对螨过敏原的反应有关。还观察到与MHC I类分子和蠕形螨患者的相关性，发现Cw2或Cw4表型的患者更易患蠕形螨病，并具有改变的免疫功能表型，而HLA A2表型的患者不易患蠕形螨病。
英文原文
Thus there are many new studies indicating that the ubiquitous Demodex mite, previously considered a harmless commensal, may well play a significant role in orchestrating the host immune reactive status in the complex environment of the cutaneous microbiome of facial skin and possibly plays a significant role in the genesis of disorders such as rosacea.
对应中文
因此，许多新的研究表明，先前被认为是无害共生的无处不在的蠕形螨，在面部皮肤皮肤微生物群的复杂环境中，很可能在宿主免疫反应状态中发挥重要作用，并可能在玫瑰痤疮等疾病的发生中发挥重要作用。
REFERENCES
1.Moran EM, Foley R, Powell FC. Demodex and rosacea revisited. Clin Dermatol. 2017;35(2):195-200.