遗传因素、环境因素和过敏原在犬特应性皮炎中的作用研究进展 ...

王帆

Update on the role of genetic factors, environmental factors and allergens in canine atopic dermatitis

遗传因素、环境因素和过敏原在犬特应性皮炎中的作用研究进展

 

Patrick Hensel | Manolis Saridomichelakis | Melissa Eisenschenk | Chie Tamamoto-Mochizuki | Cherie Pucheu-Haston | Domenico Santoro | for the International Committee on Allergic Diseases of Animals (ICADA)

 

翻译：徐晋

 

Abstract

摘要

Background: Canine atopic dermatitis (cAD) is a common, complex and multifactorial disease involving, among others, genetic predisposition, environmental factors and allergic sensitisation.

Objective: This review summarises the current evidence on the role of genetic and environmental factors and allergic sensitisation in the pathogenesis of cAD since the last review by ICADA in 2015.

Materials and Methods: Online citation databases and proceedings from international meetings on genetic factors, environmental factors and allergens relevant to cAD that had been published between 2015 and 2022 were reviewed.

Results: Despite intensive research efforts, the detailed genetic background predisposing to cAD and the effect of a wide range of environmental factors still need more clarification. Genome-wide association studies and investigations on genetic biomarkers, such as microRNAs, have provided some new information. Environmental factors appear to play a major role. Lifestyle, especially during puppyhood, appears to have an important impact on the developing immune system. Factors such as growing up in a rural environment, large size of family, contact with other animals, and a nonprocessed meat-based diet may reduce the risk for subsequent development of cAD. It appears that Toxocara canis infection may have a protective effect against Dermatophagoides farinae-induced cAD. House dust mites (D.farinae and D.pteronyssinus) remain the most common allergen group to which atopic dogs react. Currently, the major allergens related to D.farinae in dogs include Der f 2, Der f 15, Der f 18 and Zen 1.

Conclusions and Clinical Relevance: Canine atopic dermatitis remains a complex, genetically heterogeneous disease that is influenced by multiple environmental factors. Further, well-designed studies are necessary to shed more light on the role of genetics, environmental factors and major allergens in the pathogenesis of cAD.

背景：犬特应性皮炎(cAD)是一种常见的、复杂的多因素疾病，涉及遗传易感性、环境因素和过敏原致敏作用。

目的：本文总结了2015年ICADA关于遗传、环境因素和过敏原致敏作用在犬特应性皮炎发病机制中的作用。

材料与方法：检索2015-2022年公开发表的有关cAD遗传因素、环境因素和过敏原的国际会议论文集。

结果：尽管进行了深入的研究，但cAD的遗传背景和广泛的环境因素的影响仍有待进一步阐明。全基因组关联研究和对遗传生物标志物(如微小RNA)的研究提供了一些新的信息。环境因素似乎起着重要作用。生活方式，尤其是幼年阶段的生活方式，似乎对免疫系统的发育有重要影响。在农村环境中长大、家庭规模大、与其他动物接触以及未加工的肉类饮食等因素可能会降低随后患cAD的风险。犬弓首线虫感染可能对粉尘螨引起的cAD具有保护作用。屋尘螨(粉尘螨和屋尘螨)仍然是特应性犬最常见的过敏原。目前，与犬粉尘螨相关的主要过敏原包括Der f 2、Der f 15、Der f 18和Zen 1。

结论及临床意义：犬特应性皮炎是一种复杂的遗传异质性疾病，受多种环境因素影响。此外，还需要精心设计的研究来进一步阐明遗传、环境因素和主要过敏原在cAD发病中的作用。

 

KEYWORDS

allergy, dog, house dust mites, hygiene hypothesis, major allergens

关键词：

过敏症，犬，屋尘螨，卫生假说，主要过敏原

 

INTRODUCTION

简介

Canine atopic dermatitis (cAD) is a hereditary, generally pruritic and predominantly T-cell-driven inflammatory skin disease, involving an interplay between skin barrier abnormalities, allergen sensitisation and microbial dysbiosis. A 2015 review by the International Committee on Allergic Diseases of Animals (ICADA) concluded that a complex interaction between host and environment is involved in the development of the  disease. Scientific evidence was limited at that time, yet with new techniques, such as genome-wide linkage, genome-wide association and candidate gene association studies, it would be expected that relevant genetic abnormalities could be identified. Furthermore, it was suggested that these studies should focus on specific breeds and geographical regions to increase the chances of finding meaningful associations.

犬特应性皮炎(cAD)是一种遗传性、全身性瘙痒和主要由T细胞驱动的炎性皮肤病，涉及皮肤屏障异常、过敏原致敏和微生物生态失调之间的相互作用。国际动物过敏性疾病委员会(ICADA) 2015年的一项综述得出结论，宿主和环境之间的复杂相互作用参与了疾病的发展。当时的科学证据有限，但随着全基因组连锁、全基因组关联和候选基因关联研究等新技术的出现，相关的遗传异常有望得到识别。此外，有人建议这些研究应集中在特定的品种和地理区域，以增加发现有意义的关联的机会。

 

The aim of this update is to review the current evidence for the role of genetic and environmental factors, as well as the role of allergens in the pathogenesis of cAD based on studies that have been published since the last review by ICADA (2015). The role of cytokines, chemokines, skin barrier and microbiome will be reviewed in separate publications in this issue by the ICADA.

本次更新的目的是根据ICADA(2015年)上次审查以来发表的研究，回顾遗传和环境因素作用的现有证据，以及过敏原在cAD发病机制中的作用。细胞因子、趋化因子、皮肤屏障和微生物组的作用将由ICADA在本期的单独出版物中进行综述。

 

STUDY SEARCH METHODS

研究检索方法

Relevant articles, published between 2015 and 2022, were searched in Medline (via PubMed) and Thomson Reuter's Web of Science, using the terms “(dog or dogs or canine) and (atopic and dermatitis)”. The titles, abstracts and, when necessary, the full texts of these articles were scrutinised to identify those relevant to the topics of this review. Studies solely presented in abstract form during the same period, in the three leading international veterinary dermatology congresses, namely the World Congresses of Veterinary Dermatology, the annual congresses of the European Society of Veterinary Dermatology/European College of Veterinary Dermatology, and the North American Veterinary Dermatology Forum were hand-searched.

以“(dog or dogs or canine)”和“(atopic and dermatitis)”为关键词，在Medline(通过PubMed)和Thomson Reuter's Web of Science中检索2015年至2022年发表的相关文献。对这些文章的标题、摘要，必要时对全文进行了仔细审查，以确定那些与本综述主题相关的内容。手工检索同一时期在世界兽医皮肤病大会、欧洲兽医皮肤病学会/欧洲兽医皮肤病学院年度大会和北美兽医皮肤病论坛这三个主要的国际兽医皮肤病大会上以摘要形式发表的研究。

 

BREED-RELATED PREVALENCE OF CANINE AD

犬AD的品种相关性患病率

The prevalence of cAD differs between breeds, which may be caused by genetic factors. However, breed predisposition varies among different geographical regions and continents as well. Since 2015, five studies have been published evaluating the prevalence of cAD in different breeds. The aim of a study from Australia was to identify breeds at risk in the local canine population and to compare them with those reported worldwide. Eleven breeds [beagle, bichon frise, boxer, bulldog, bull mastiff, great Dane, Labrador retriever, pug, shar-pei, Staffordshire terrier and West Highland white terrier (WHWT)] showed an increased prevalence of AD. Of those, five breeds (boxer, bulldog, Labrador retriever, pug and WHWT) are considered as predisposed worldwide. In Finland, the WHWT, boxer, English bulldog, Dalmatian and French bulldog were more likely to show clinical signs compatible with AD according to their owners. In a cohort of 100 Swiss WHWT puppies, the prevalence of cAD by the age of threeyears was 52%. A fourth study compared breed distribution among dogs with AD sensu stricto [i.e. with positive intradermal test and/or serological confirmation of allergen-specific immunoglobulin (Ig)E] to dogs with atopic-like dermatitis (defined as clinical diagnosis of AD, negative intradermal test and negative serological results) and to the general hospital population at the Veterinary Teaching Hospital of the University of Minnesota, USA. Statistical analysis showed that American Staffordshire terrier, English bulldog, Labrador retriever and soft-coated wheaten terrier were over-represented compared to the general hospital population when all atopic dogs were considered together and when only dogs with AD sensu stricto were considered, whereas no breed predisposition for atopic-like dermatitis was found. Finally, a study from South Korea, available only as an abstract, showed an increased prevalence of cAD in cocker spaniels, pugs and fox terriers.

不同品种间cAD患病率存在差异，可能是遗传因素所致。然而，不同的地理区域和大陆也有不同的品种易感性。自2015年以来，已有5项研究对不同品种的cAD患病率进行了评估。来自澳大利亚的一项研究的目的是确定当地犬种群中有风险的品种，并与世界范围内的报告进行比较。11个品种[比格犬、比熊犬、拳师犬、斗牛犬、斗牛獒犬、大丹犬、拉布拉多寻回犬、巴哥犬、沙皮犬、斯塔福德郡㹴和西高地白㹴(WHWT)]的AD患病率增加。其中，5个品种(拳师犬、斗牛犬、拉布拉多寻回犬、巴哥犬和WHWT)被认为是世界范围内的易感犬。在芬兰，WHWT、拳师犬、英国斗牛犬、大麦町犬和法国斗牛犬的主人认为它们更有可能表现出与AD相符的临床症状。在100只瑞士WHWT幼犬中，到3岁时cAD的患病率为52%。第四项研究比较了狭义AD(即皮内试验和/或血清学证实过敏原特异性免疫球蛋白E阳性)和特应样皮炎(定义为临床诊断为特应性皮炎，皮内试验和血清学结果均为阴性)以及美国明尼苏达大学兽医教学医院的总体类群在犬的品种分布。统计分析显示，当将所有特应性皮炎的犬放在一起考虑时，以及仅考虑狭义AD犬时，美国斯塔福德郡犬、英国斗牛犬、拉布拉多寻回犬和软毛麦色㹴的比例高于医院总体类群，而没有发现有特应样皮炎易感性的品种。最后，来自韩国的一项研究(目前只有摘要)表明，可卡犬、巴哥犬和猎狐㹴的cAD患病率增加。

 

GENETIC FACTORS

遗传因素

Canine AD is a hereditary disease. The genetic background of the dog, in combination with environmental factors, determines the risk of disease development and the clinical phenotype.

犬AD是一种遗传性疾病。犬的遗传背景，结合环境因素，决定了疾病发展的风险和临床表型。

 

Genome-wide association studies

全基因组关联研究

Seven genome-wide linkage and association (GWAS) studies and one candidate gene study had been published before the previous review. In contrast to human AD, an association with filaggrin mutations was not detected in three studies with WHWTs. However, filaggrin was implicated in a group of Labrador retrievers with cAD in the UK. Because no association was found in Labrador retrievers from other geographical regions, the authors concluded that these differences are the result of breed-associated polymorphisms in cAD. A GWAS investigating single-nucleotide polymorphisms (SNPs) associated with AD in golden retrievers, identified two intronic SNPs [Prominin 1 (PROM1) and Ras related protein Rab-3c (RAB3C)] significantly associated with AD. In two further GWAS, associations with high IgE levels were found on chromosomes 5 and 35 in Labrador retrievers and WHWT dogs, respectively. In both studies, the SNPs were associated with elevated dust mite-specific IgE. Another GWAS in a Swedish population of German shepherd dogs found gene sequences, located in the plakophilin 2 (PKP2) gene region on chromosome 27, to be strongly associated with AD. The study concluded that PKP2 may be a relevant candidate gene for AD owing to its role in skin barrier function. However, a follow-up study published after the previous review disputed the relevance of these findings because no differences in the expression of PKP2 were observed between dogs with AD (with the risk alleles) and clinically healthy control dogs (without the risk alleles).

此前已发表7个全基因组连锁与关联(GWAS)研究和1个候选基因研究。与人类不同，在三项关于WHWT的研究中，未检测到AD与丝聚合蛋白突变相关。然而，丝聚合蛋白与英国一群患cAD的拉布拉多寻回犬有关。由于未在来自其他地理区域的拉布拉多寻回犬中发现关联，因此作者得出结论，这些差异是cAD的品种相关多态性的结果。通过对金毛猎犬AD相关单核苷酸多态性(SNPs)的GWAS研究，发现了两个与AD显著相关的内含子SNPs [prominent in 1 (PROM1)和Ras相关蛋白RAB3C (RAB3C)]。在另外两个GWAS中，分别在拉布拉多寻回犬和WHWT犬的第5和35号染色体上发现了与高IgE水平的关联。在这两项研究中，SNP均与尘螨特异性IgE升高相关。另一项GWAS在瑞典的德国牧羊犬种群中发现，位于27号染色体上的斑菲素蛋白2 (PKP2)基因区域的基因序列与AD强相关。PKP2在皮肤屏障功能中发挥重要作用，可能是AD的相关候选基因。然而，在之前的综述之后发表的一项后续研究对这些发现的相关性提出了质疑，因为在AD患犬(携带风险等位基因)和临床健康对照犬(不携带风险等位基因)之间，未观察到PKP2的表达有差异。

 

Since the last ICADA canine pathogenesis review in 2015, only two GWAS have been identified. In a cohort of WHWTs (97 atopic and 89 control dogs) born in the USA, a new 2.7-Mb genomic region on canine chromosome (CFA) 3, which includes 37 genes, was identified. A missense variant of one of the candidate genes located in this chromosomal region, the F2R (thrombin receptor) gene, a member of the protease-activated receptor (PAR) family, was identified in atopic and not in nonatopic WHWTs.17 Proteins in this family are thought to be involved in normal desquamation and epidermal barrier function, and it is tempting to speculate that these mutations might contribute to enhanced allergen exposure, xerosis and infection susceptibility.

自2015年ICADA最后一次犬类发病机制综述以来，只有两个GWAS被确定。在一个出生在美国的WHWT队列(97只特应性皮炎犬和89只对照组犬)中，我们在犬染色体(CFA) 3上发现了一个新的2.7 Mb的基因组区域，包含37个基因。位于该染色体区域的候选基因之一F2R(凝血酶受体)基因(蛋白酶激活受体(PAR)家族成员)的错义变异体在特应性皮炎WHWT中被发现，而在非特应性皮炎WHWT中未被发现。该家系蛋白参与正常脱屑和表皮屏障功能，推测这些突变可能导致过敏原暴露、干燥和感染易感性增强。

 

These findings are different than those in a similar study looking at a cohort of WHWTs in Australia, where a 1.3-Mb genomic region on CFA17 with a candidate gene protein tyrosine phosphatase nonreceptor type 22 (PTPN22) was identified. The corresponding protein is thought to be involved in the negative regulation of both the innate and adaptive (via downregulation of both Band T-cell receptor signalling) immune response. The markedly different findings of these studies underscore the difficulty and complexity of identifying genetic associations in cohorts from different geographical areas, even within the same breed.

这些发现与在澳大利亚对WHWT队列进行的一项类似研究的结果不同，在这项研究中，CFA17上有一个1.3 Mb的基因组区域，该区域含有一个候选基因蛋白酪氨酸磷酸酶非受体型22 (PTPN22)。相应的蛋白被认为参与了固有和适应性免疫应答的负性调节(通过下调两种Band T细胞受体信号传导)。这些研究的明显不同的结果强调了在不同地理区域的队列中识别遗传关联的难度和复杂性，即使是在同一个品种中。

 

Another GWAS attempted to find potential associations between four previously identified nonsynonymous SNPs [three in interleukin (IL)4R and one in IL13] and cAD in atopic and nonatopic shiba inus and miniature dachshunds. One finding in this study was that the IL4R Cys 688 variant reduces the risk of AD in miniature dachshunds, possibly by decreasing the signalling of IL-4 and/or IL-13 through this receptor.

另一项GWAS试图在特应性皮炎和非特应性皮炎柴犬和迷你腊肠犬中发现四个先前发现的非同义SNP[三个在白细胞介素(IL)4R中，一个在IL13中]与cAD之间的潜在关联。这项研究的一个发现是，IL4R Cys 688变体降低了迷你腊肠犬患AD的风险，可能是通过减少IL-4和/或IL-13通过该受体的信号传导。

 

Biomarkers

生物标记物

In recent years, the identification of microRNAs (miRNAs) has significantly advanced our knowledge on the pathogenesis of a variety of inflammatory and neoplastic diseases in humans. MicroRNAs are short, single-stranded RNA molecules, of about 22 nucleotides in length, that play a role in the regulation of gene expression at the post-transcriptional level. In allergies, miRNAs influence the cells of the innate and adaptive immune system including the keratinocytes, thereby potentially affecting the course of the disease. For this reason, miRNAs have become of great interest as biomarkers, as altered miRNA expression has been identified in atopic humans.

近年来，微小RNA(miRNA)的发现显著提高了我们对人类多种炎症和肿瘤性疾病发病机制的认识。微小RNA是一种长度约为22个核苷酸的短单链RNA分子，在转录后水平发挥基因表达调控作用。在过敏症中，微小RNA影响先天性和适应性免疫系统的细胞，包括角质形成细胞，从而可能影响疾病的病程。因此，由于在特应性体质人群中发现了miRNA表达的改变，miRNA作为生物标志物受到了极大的关注。

 

One of the first studies investigating miRNA expression in dogs showed a statistically significant increase in the expression of miR-203 in the plasma of dogs with AD compared to healthy controls. This study also demonstrated an increase in gene expression of phosphodiesterase 4D (PDE4D) in peripheral blood mononuclear cells (PBMCs) of atopic dogs. The enzyme PDE4 degrades cyclic adenosine monophosphate (cAMP), regulates pro- and anti-inflammatory activities of many immune cells, and is involved in epithelial functions, including the skin barrier. In addition, a significant decrease in the expression of three gene markers (Protein inhibitor of activated STAT 1 [PIAS1], RAR-related orphan receptor A [RORA] and SH2B adaptor protein 1 [SH2B1]) was identified. The downregulation of RORA may decrease the serum IL-10. However, the significance and role of the downregulation of these three genes needs further investigation.

最早的一项关于犬miRNA表达的研究表明，与健康对照组相比，AD病患的血浆中miR-203的表达有统计学显著性增加。特应性体质犬外周血单个核细胞(PBMC)中磷酸二酯酶4D (PDE4D)基因表达增加。酶PDE4降解环磷酸腺苷(cAMP)，调节许多免疫细胞的促炎和抗炎活性，并参与上皮功能，包括皮肤屏障。此外，我们鉴定了三个基因标记(激活的STAT蛋白抑制因子1 [PIAS1]， RAR相关孤儿受体a [RORA]和SH2B衔接蛋白1 [SH2B1])的表达显著降低。RORA表达下调可降低血清IL-10水平。然而，这三个基因下调的意义和作用有待进一步研究。

 

A study evaluated miRNA expression in the lesional, nonlesional and healthy skin of experimentally sensitised atopic beagles, before and after exposure to Dermatophagoides farinae.  The study showed a dysregulation of miRNAs in lesional and nonlesional skin, with an increased expression of miR-215 in healthy and nonlesional skin compared to the lesional skin of atopic dogs. This finding suggests that miR-215 may exert an antiinflammatory effect, possibly through suppression of IL17 receptor activation. The expression of another miRNA, miR-187, was decreased in lesional skin and may be associated with decreased TGF-β expression. Furthermore, a significant decrease in miR-141, miR-200a and miR-429 was noticed in both lesional and nonlesional skin compared to healthy skin, and it was suggested that these molecules may be involved in skin barrier defects. In a more recent study in golden and Labrador retrievers, 18 selected miRNAs were compared between atopic dogs, dogs with nonallergic inflammatory skin diseases and a group of healthy dogs. Four miRNAs (miR-142, miR-146a, miR-155 and miR-21) were overexpressed in the atopic compared to the healthy dogs. However, the same miRNAs were overexpressed in a similar way in other nonallergic inflammatory skin samples, suggesting that those miRNAs have a rather general role in the inflammatory skin response rather than being associated with atopic disease or an allergic reaction.

一项研究评估了实验致敏的特应性比格犬暴露于粉尘螨之前和之后的病变、非病变和健康皮肤中的miRNA表达。研究表明，miRNA在特应性体质犬的病变和非病变中表达失调，与病变相比，miR-215在健康和非病变中表达增加。这一发现表明miR-215可能通过抑制IL17受体的激活发挥抗炎作用。另一种miRNA miR-187在病变中表达降低，可能与TGF-β表达降低有关。此外，miR-141、miR-200a和miR-429在病变和非病变中均显著低于健康皮肤，提示这些分子可能参与了皮肤屏障缺陷。在最近一项对金毛和拉布拉多犬进行的研究中，研究者在特应性皮炎犬、患非过敏性炎性皮肤病的犬和一组健康犬之间比较了18种选定的miRNA。4种miRNA (miR-142、miR-146a、miR-155和miR-21)在特应性皮炎犬中高表达。然而，同样的miRNA在其他非过敏性炎症皮肤样本中以相似的方式过度表达，这表明这些miRNA在炎症皮肤反应中具有相当普遍的作用，而不是与特应性疾病或过敏反应相关。

 

ENVIRONMENTAL FACTORS

环境因素

There is a hypothesis that environmental factors may play a greater role in the pathogenesis of AD than previously thought and that they may have the potential to trigger an inflammatory reaction through activation of the innate immune system. There are harmful as well as protective environmental and lifestyle factors that act mainly in early life, sometimes even in utero. In humans, protective factors include growing up in a rural environment with contact with farm animals (“farming effect”), a diet rich in dietary fibre, high food diversity, and early contact with siblings or peers. It has been suggested that these protective factors are important for the development of a highly diverse microbiome in barrier organs, such as skin, gastrointestinal tract and lungs. A diverse microbiome during the period of immune system maturation in early life is crucial for the normal development of the innate immune system and its adaptation to nonharmful micro-organisms.

有一种假说认为，环境因素在AD发病机制中的作用可能比以前认为的更大，它们可能通过激活固有免疫系统引发炎症反应。有害的和保护性的环境和生活方式因素主要在生命早期起作用，有时甚至在子宫内起作用。对人类而言，保护因素包括在与农场动物接触的农村环境中长大(“养殖效应”)、富含膳食纤维的饮食、高度的食物多样性以及早期与兄弟姐妹或同龄人接触。研究表明，这些保护性因素对于屏障器官(如皮肤、胃肠道和肺)高度多样化的微生物组的发展至关重要。生命早期免疫系统成熟阶段的多样性微生物群对固有免疫系统的正常发育及其对无害微生物的适应至关重要。

 

The presumed protective effect of early-life exposure to infectious diseases, microbial agents and their products (e.g. endotoxin, fungal components), and to helminths has been supported by the so-called “hygiene hypothesis”. Although the protective effect of these exposures has not been proven directly, a few studies provide indirect evidence showing that rural environment, multi-animal household and walking in forests may reduce the risk for developing cAD.

所谓的"卫生假说"支持生命早期接触传染性疾病、微生物制剂及其产物(如内毒素、真菌成分)和肠道寄生虫的假定保护作用。虽然这些暴露的保护作用尚未得到直接证明，但一些研究提供了间接证据，表明农村环境、多动物家庭和在森林中行走可能降低患cAD的风险。

 

The aim of one cross-sectional, observational study was to investigate possible associations between environmental factors and owner-reported allergy-like skin signs or veterinarian-diagnosed cAD. Using an online questionnaire, a total of 8643 dogs were included in this study. The results indicated that living with another dog, having been born in the current owner's household and living in a detached house (compared to an apartment) were associated with a decreased risk of allergic/atopic skin disease. It was speculated that less exposure to diesel exhaust particles, better indoor air quality, greater microbial contact and more time spent outdoors may explain these findings. However, an increased risk for the development of AD was observed in dogs living in extremely clean households. Likewise, another large-scale survey from Finland identified factors such as rural environment, large family size and animal contacts (pets and farm animals) as being rather protective, while living in an urban environment was associated with an increased prevalence of cAD. The most recent study assessed environmental risk factors for AD in Labrador and golden retrievers. Dogs raised in an urban environment, receiving flea control and being allowed on upholstered furniture were risk factors, whereas living with another dog, and walking in woodlands, fields and beaches were protective factors for AD. In another study using a web-based questionnaire for pet owners with atopic dogs in Finland, the pre- and postnatal dietary exposure was assessed. The findings suggest that feeding a nonprocessed meat-based diet early in life seemed to be protective against cAD.

一项横向观察性研究的目的是调查环境因素与主人报告的过敏样皮肤症状或兽医诊断的cAD之间的可能关联。通过网络问卷调查，共8643只犬纳入本研究。结果表明，与另一只犬一起生活，在当前主人的家里出生和住在独立的房子(与公寓相比)与降低过敏性/特应性皮肤病的风险相关。据推测，减少暴露于柴油废气颗粒、更好的室内空气质量、更多的微生物接触以及更多的户外时间可能可以解释这些发现。然而，我们观察到生活在极度清洁家庭中的犬患AD的风险增加。同样，来自芬兰的另一项大规模调查发现，农村环境、大家庭和动物接触(宠物和农场动物)等因素具有相当的保护性，而生活在城市环境与cAD患病率增加相关。最近的一项研究评估了拉布拉多犬和金毛犬患AD的环境危险因素。在城市环境中饲养、接受跳蚤控制和允许在有软垫的家具上活动是AD的危险因素，而与另一只犬生活以及在林地、田野和海滩散步是AD的保护因素。在另一项研究中，芬兰对养有特应性皮炎犬的宠物主人进行了基于网络的问卷调查，评估了出生前后的饮食暴露情况。研究结果表明，在生命早期以非加工肉类为基础的饮食似乎可以预防cAD。

 

All of these studies show that environmental factors are associated with cAD, yet they do not prove causality.

所有这些研究都表明环境因素与cAD有关，但它们并不能证明为因果关系。

 

ENDOTOXINS AND OTHER BACTERIAL AND FUNGAL COMPONENTS

内毒素和其他细菌与真菌成分

In humans, it has been speculated that exposure to endotoxins and microbial proteases may have a protective effect against the development of allergies. However, their significance in cAD is not clear, and since the last review, only one study has investigated the role of endotoxins in cAD. This study did not find a significant difference in dust endotoxin concentration between households with atopic and healthy WHWTs. This result was attributed to the small sample size and the similar indoor living environment of both groups of dogs.

在人类中，据推测，暴露于内毒素和微生物蛋白酶可能对过敏的发展有保护作用。然而，它们在cAD中的意义尚不清楚，自上次综述以来，只有一项研究调查了内毒素在cAD中的作用。本研究未发现特应性皮炎与健康WHWT家庭间粉尘内毒素浓度有显著差异。这一结果归因于两组犬的小样本量和相似的室内生活环境。

 

Coagulase-positive (CoPS) and coagulase-negative (CoNS) staphylococci are normal commensals of the skin and mucosa, yet also are opportunist pathogens. In dogs with AD they contribute to the severity of clinical signs; however, the complete role of these bacteria in the pathogenesis of cAD remains unknown.40 A study showed that a synthetic triacylated lipopeptide (TLR1/2 ligand) cell-wall component of Staphylococcus spp. induced transcription of thymic stromal lymphopoietin (TSLP) via Toll-like receptor 2 (TLR2) activation in a canine keratinocyte cell line. However, additional studies are required to investigate whether Staphylococcus spp. contributes to helper T-cell (Th)2 responses in cAD through TLR2-mediated TSLP production.

凝固酶阳性(CoPS)和凝固酶阴性(CoNS)葡萄球菌是皮肤和黏膜的正常共生菌，但也是条件致病性病原体。在AD患犬中，它们加重了临床症状的严重程度；然而，这些细菌在cAD发病机制中的完全作用仍然未知。一项研究表明，在犬角质形成细胞系中，葡萄球菌属的一种合成的三酰化脂肽(TLR1/2配体)通过激活toll样受体2 (TLR2)诱导胸腺基质淋巴细胞生成素(TSLP)的转录。然而，我们需要进一步研究葡萄球菌属是否通过TLR2介导的TSLP产生参与cAD中辅助性 T细胞(Th)2应答。

 

Similar to Staphylococcus spp., Malassezia pachydermatis is a commensal micro-organism, commonly found on mammalian skin, and is associated with secondary infections in cAD. In a group of 15 dogs with nonfood-induced AD (NFIAD) the IgE-reactivity to a 50-kDa protein of M.pachydermatis and the skin reactivity through intradermal testing (IDT) was investigated. Specific IgE for M. pachydermatis was found in nine of 15 dogs, and 11 of 15 dogs showed a positive IDT. This study concluded that dogs with NFIAD have an increased risk to be sensitised to M.pachydermatis.  

与葡萄球菌相似，厚皮马拉色菌是一种哺乳动物皮肤常见的共生微生物，与cAD继发感染相关。本文观察了15只非食物诱导的AD(NFIAD)患犬对50 kDa厚皮马拉色菌蛋白的 IgE反应性及皮内试验(IDT)的皮肤反应性。15只犬中9只检测出厚皮马拉色菌特异性IgE, 11只检测出IDT阳性。这项研究的结论是，NFIAD患犬对厚皮马拉色菌敏感的风险增加。

 

PARASITES

寄生虫

The results of studies about the effect of helminths on the development of atopic diseases in humans and of AD in dogs have been inconsistent, showing that they can be risk factors, protective factors or have no effect. IgE levels in dogs are in general much higher than in humans and this has been linked to the more common presence of intestinal helminths (and perhaps other parasites) in dogs.

关于蠕虫（肠道寄生虫）对人类特应性疾病和犬AD发展影响的研究结果并不一致，表明它们可能是危险因素，也可能是保护因素，也可能没有影响。犬体内的IgE水平通常比人类高得多，这与犬体内更常见的肠道蠕虫(可能还有其他寄生虫)有关。

 

Two recent studies investigated the relationship between Toxocara canis and cAD. In the first study, nonatopic dogs showed higher total IgE and T.canis specific IgE compared to dogs with AD. This finding may indicate that infection by T.canis may protect against the development of cAD.

最近的两项研究调查了犬弓首蛔虫与cAD之间的关系。在第一项研究中，与AD患犬相比，非特应性皮炎犬显示出更高的总IgE和犬弓首蛔虫特异性IgE。这一发现可能表明，感染犬弓首蛔虫可以防止cAD的发展。

 

In another study, 12 young laboratory beagles, six of which were initially infected by T.canis and six of which served as uninfected controls, were experimentally sensitised to D.farinae. The infected dogs showed higher levels of T. canis-specific IgG and IgE, D.farinae specific IgE, and total IgE, and lower lesional scores and shorter duration of pruritus after challenge with D.farinae compared to dogs not infested by T. canis. Thus, it appears that T.canis infections may have a protective effect against D.farinae-induced cAD flares.

在另一项研究中，12只年轻的实验室比格犬，其中6只最初感染了犬弓首蛔虫，6只作为未感染的对照组，在实验中被粉尘螨致敏。与未感染犬相比，感染犬表现出较高的犬弓首蛔虫特异性IgG和IgE、粉尘螨特异性IgE和总IgE水平；感染犬的病变评分较低，瘙痒持续时间较短。因此，似乎犬弓首蛔虫感染对粉尘螨诱导的cAD发作有保护作用。

 

HOUSE DUST AND STORAGE MITES

屋尘螨和储存螨

Previous studies indicated that house dust mite (HDM) components, such as cysteine (group 1 mite allergens) and serine (group 3, 6 and 9 allergens) proteases may induce a wide variety of inflammatory reactions, which could promote allergic sensitisation. The findings of a recent study suggest that D.farinae-derived serine can upregulate IL-33 mRNA expression in canine progenitor epidermal keratinocytes (CPEK) via protease-activated receptor-2 (PAR-2) activation and may be involved in cAD. Interleukin (IL)-33 produced by keratinocytes is suspected to be involved in the pathogenesis of cAD. Whether these in vitro findings translate into an in vivo situation needs to be proven.

既往研究表明，屋尘螨(HDM)成分，如半胱氨酸(第1组螨过敏原)和丝氨酸(第3、6和9组过敏原)蛋白酶可诱导多种炎症反应，从而促进过敏原致敏。最近的一项研究表明，粉尘螨来源的丝氨酸可通过激活蛋白酶激活受体-2 (PAR-2)上调犬祖表皮角质形成细胞(CPEK)中IL-33 mRNA的表达，并可能参与cAD的发生。角质形成细胞产生的白细胞介素(IL)-33可能参与cAD的发病过程。这些体外研究结果是否能转化为体内情况还需要证实。

 

Group 2 and 7 mite allergens are speculated to play a role in Toll-like receptor interactions. No studies to further investigate this theory have been performed.

2组和7组螨过敏原被推测在toll样受体相互作用中起作用。目前还没有进一步调查这一理论的研究。

 

ALLERGENS

过敏原

In an early review by the International Task Force on Canine Atopic Dermatitis in 2001 numerous environmental allergens, such as grasses, weeds, trees, mould spores, insects and dust mites were collated. Those allergens were identified in various studies by IDT, allergen-specific IgE serological (ASIS) testing, electrophoresis, immunoblotting and response to immunotherapy. These test methods lack standardisation and only crude allergen extracts were used. The review concluded that the findings only provided indirect evidence for the importance of the identified allergens and that more studies would be necessary to identify major allergens.

在2001年国际犬特应性皮炎工作组的早期审查中，许多环境过敏原，如草、杂草、树木、霉菌孢子、昆虫和尘螨已经验证。这些过敏原是通过IDT，过敏原特异性IgE血清学(ASIS)检测，电泳，免疫印迹和免疫治疗反应来鉴定的。这些检测方法缺乏标准化，仅使用粗提物。该综述的结论是，这些发现仅为已确定的过敏原的重要性提供了间接证据，还需要更多的研究来确定主要的过敏原。

 

House dust and storage mite allergens

屋尘螨和储存螨过敏原

The most common allergens in humans and dogs are house dust mite (HDM) species belonging to the genus Dermatophagoides. The positivity rate to HDM in humans was observed in 40%–80% of patients, while in dogs its frequency, determined by IDT or ASIS, ranges between 60% and 90%.51–56 However, ≤63% of clinically healthy dogs can show positive IDT reactions to HDM, while ASIS can be positive in ≤97% of cases. These findings indicate that a correct interpretation of allergen test results for HDM may be complex. Dermatophagoides farinae appears to be the most prevalent HDM allergen involved in cAD worldwide, yet sensitisation to storage mites [e.g. Tyrophagus putrescentiae (36%–80%) and Acarussiro (18%–80%)] is common too. Dogs with AD are frequently (≥45%) co-sensitised to house dust and storage mites, which could be the result of parallel exposure and sensitisation to different mite species and/or of in vitro crossreactivity.A high rate of cross-reactivity among dust mites, storage mites or ectoparasites such as sarcoptic mites may explain false-positive results in allergen testing.

人类和犬最常见的过敏原是屋尘螨(HDM)，属于表皮螨属。人HDM阳性率为40% ~ 80%，犬HDM阳性率为60% ~ 90%。然而，≤63%的临床健康犬对HDM的IDT反应呈阳性，而≤97%的情况下ASIS呈阳性。这些发现表明，对屋尘螨过敏原检测结果的正确解读可能是复杂的。粉尘螨似乎是全球范围内与cAD相关的最普遍的尘螨过敏原，但对储存螨[例如腐食酪螨(36%-80%)和粗脚粉螨(18%-80%)]的敏感性也很常见。特应性皮炎患犬通常(≥45%)对屋尘螨和储存螨共同敏感，这可能是对不同种类螨虫平行暴露和敏感的结果和/或体外交叉反应。尘螨、储存螨或体表寄生虫(如疥螨)之间的高交叉反应率可能解释过敏原检测的假阳性结果。

 

Plant-based allergens

植物性过敏原

The prevalence of some plant-based allergens depends on the geographical location (e.g. trees such as acacia, almond, olive, Japanese cedar). In a Japanese study, the Japanese cedar was reported to be the second most common allergen after HDM in atopic dogs. Other plants may be prevalent in many different vegetation zones (e.g. grasses such as Bermuda, rye and fescue). The most common plant-based allergens in one study from South Korea were ash, sage, Johnson grass and plantain,while in another study, also from South Korea, oak, white ash, sheep's sorrel, mugwort and Bermuda grass were the most commonly found positive reaction in ASIS. The different outcomes between these two studies may be related to the use of different serological test methods, the season and maybe drug use when the serum was collected. It has been hypothesised that allergen test positivity may depend on specific seasons. Indeed, in one study, more pollen reactivity was seen during summer and autumn.

一些植物性过敏原的流行程度取决于地理位置(如刺槐、杏仁、橄榄、日本柳杉等树木)。在日本的一项研究中，据报道，在特应性皮炎犬中，日本柳杉是仅次于HDM的第二常见过敏原。其他植物可能在许多不同的植被区流行(如百慕大草，黑麦和羊茅等草)。在一项来自韩国的研究中，最常见的植物性过敏原是白蜡、鼠尾草、约翰逊草和车前草，而在另一项同样来自韩国的研究中，橡树、白蜡、羊草、艾草和百慕大草是ASIS中最常见的阳性反应。两项研究结果的差异可能与使用不同的血清学检测方法、采集血清时的季节以及可能使用的药物有关。有人假设过敏原试验的阳性可能取决于特定的季节。事实上，在一项研究中，夏秋两季的花粉反应性更强。

 

Mould allergens and Malassezia

霉菌过敏原和马拉色菌

Several studies indicated that mould species may play a role in the sensitisation of atopic dogs. In one study moulds (Rhizopus and a mould mix) were reported to be the second most common allergens after HDM. In another study based on IDT in atopic dogs the most common positive reaction in 67.3% of dogs was observed with a Rhizopus mix. The positivity rate, based on ASIS in another study of 101 dogs with AD, was 44.8% for Pullularia and 39.6% for Alternaria,  while in another study Aspergillus fumigatus was the most commonly detected mould in 39.6% of cases.66 Although these studies show a frequent positivity rate for moulds, the prevalence seems to be much more variable, likely related to geographical and climatic factors.

一些研究表明，霉菌种类可能在特应性皮炎犬的致敏过程中发挥作用。在一项研究中，据报道，霉菌(根霉菌和一种霉菌混合物)是仅次于屋尘螨的第二常见过敏原。在另一项基于IDT的特应性皮炎犬的研究中，67.3%的犬对根霉菌混合物有最常见的阳性反应。在另一项对101只AD犬的研究中，根据ASIS，肺曲霉的阳性率为44.8%，链格孢霉的阳性率为39.6%，而在另一项研究中，烟曲霉是最常检出的霉菌，占39.6%。虽然这些研究显示了霉菌的高阳性率，但流行率似乎变化更大，可能与地理和气候因素有关。

 

Malassezia pachydermatis is part of the normal cutaneous microbiota of dogs, yet Malassezia allergen can trigger a hypersensitivity reaction in atopic dogs. The positivity rate to Malassezia varies between studies and ranges from 21.9% to 60% with ASIS and from 24% to 73% with IDT.

厚皮马拉色菌是犬正常皮肤微生物群的一部分，但马拉色菌过敏原可引发特应性皮炎犬的超敏反应。马拉色菌的阳性率在不同的研究中有所不同，在ASIS中为21.9%至60%，在IDT中为24%至73%。

 

Major allergens

主要过敏原

The current knowledge about relevant allergens in cAD is mainly based on the positivity rate of IDT or ASIS of crude allergen extracts and the response to immunotherapy. It is hypothesised that the identification and use of specific antigens in those allergens will allow standardisation of canine allergen testing and immunotherapy, and thus improve the overall efficacy of these interventions. An allergen is considered to be a major allergen if ≥50% of patients allergic to the “parent” allergen source have detectable positive IgE serological results or immediate skin test reactivity. Although a wide range of major allergens have been identified in human medicine, such information remains limited in cAD. The following major allergens are known in dogs (Table 1): D.farinae, Japanese cedar,short ragweed (Ambrosia artemisiifolia), M.pachydermatis and Ctenocephalides felis.  

目前对cAD相关过敏原的认识主要基于粗提物的IDT或ASIS阳性率以及对免疫治疗的反应。我们假设在这些过敏原中识别和使用特定抗原将使犬过敏原测试和免疫治疗标准化，从而提高这些干预措施的整体疗效。如果≥50%的病患对“父源”过敏原过敏，其IgE血清学结果或即刻皮肤试验反应阳性，则认为该过敏原是主要过敏原。虽然在人类医学中已经确定了广泛的主要过敏原，但这些信息在cAD中仍然有限。以下是犬已知的主要过敏原(表1)：粉尘螨、日本柳杉、短豚草(豚草Ambrosia artemisiifolia)、厚皮马拉色菌和猫栉首蚤。

 

The HDM D. pteronyssinus (Der p 1 and Der p 2) and D. farinae (Der f 1 and Der f 2) are considered the major allergens in humans, while in dogs Der f 2, Der f 15, Der f 18 as well as Zen 1 seem to be more relevant, as indicated by several studies.

几项研究表明，HDM屋尘螨(Der p1和Der p2)和粉尘螨(Der f1和Der f2)被认为是人类的主要过敏原，而在犬中，Der f2、Der f15、Der f18和Zen 1似乎更相关。

 

Other major allergens identified are Cry j 1 and Cry j 3 for Japanese cedar (Cryptomeria japonica), Amb a 1 (including five isoallergens) for A. artemisiifolia,  and four epitopes (molecular weights f 45, 52, 56 and 63kDa) for M.pachydermatis.

鉴定出的其他主要过敏原有日本柳杉的Cry j 1和Cry j 3，豚草的Amb a 1(包括5个单独过敏原)，厚皮马拉色菌的4个表位(分子量分别为45、52、56和63kDa)。

 

CONCLUSIONS

结论

Canine atopic dermatitis has a complex genotype that varies among breeds and geographically defined gene pools within each breed. Although five breeds (boxer, bulldog, Labrador retriever, pug and WHWT) are considered as predisposed worldwide, the prevalence continues to vary between geographical regions and continents. With the help of GWAS and detection of genetic biomarkers, such as miRNAs, some progress has been made to better understand the genetic background of this complex disease. Only two GWAS have been performed since 2015 identifying new genomic regions, which may play a role in epidermal barrier function or immune response regulation. Several miRNAs have been identified in recent years that have been shown to play a role in the regulation of gene expression in immune cells and keratinocytes at the post-transcriptional level. Potential genetic biomarkers of cAD are miR-141, miR-187, miR-200a, miR-203, miR-215 and miR-429, and the genes PDE4D, PIAS1, RORA and SH2B1.  However, further studies are needed to confirm that these genetic biomarkers are specific to cAD and not an upregulation caused by other nonallergic inflammatory skin responses. The protective or detrimental role of environmental factors such as living environment during early life, and exposure to bacterial, fungal and parasitic components have undergone continued investigation. It appears that a rural environment, multi-animal household, walking in forests, fields and beaches, having been born in the current owner's household, living in a detached house and being fed a nonprocessed meat-based diet, may be associated with a decreased risk of cAD. These environmental factors appear to be associated with cAD yet they do not prove causality. House dust mites remain the most common cause of cAD worldwide. Currently, Der f 2, Der f 15, Der f 18 and Zen 1 are considered the major HDM allergens for cAD.

犬特应性皮炎有一个复杂的基因型，因不同的品种而变；在每个品种中，又因地理上定义的基因库而变。虽然有五个品种(拳师犬、斗牛犬、拉布拉多寻回犬、巴哥犬和WHWT)被认为在世界范围内具有易感性，但患病率在不同地理区域和不同大陆之间仍然存在差异。借助GWAS和miRNA等遗传生物标志物的检测，人们对该病的遗传背景有了更深入的了解。自2015年以来，仅有2项GWAS发现了可能在表皮屏障功能或免疫应答调节中发挥作用的新基因组区域。近年来发现的一些miRNA在转录后水平调控免疫细胞和角质形成细胞的基因表达。cAD的潜在遗传标志物有miR-141、miR-187、miR-200a、miR-203、miR-215和miR-429，以及基因PDE4D、PIAS1、RORA和SH2B1。然而，需要进一步研究来证实这些遗传生物标志物是cAD特异性，而不是由其他非过敏性炎性皮肤反应引起的上调。环境因素的保护或有害作用，如生命早期的生活环境，暴露于细菌、真菌和寄生虫成分，已被不断地研究。农村环境、多动物家庭、在森林、田野和海滩散步、在当前主人家中出生、住在独立的房子里以及以未加工的肉类为基础的饮食喂养可能与cAD风险降低相关。这些环境因素似乎与cAD相关，但不能证明因果关系。在全球范围内，屋尘螨仍然是cAD最常见的病因。目前，Der f 2、Der f 15、Der f 18和Zen 1被认为是cAD的主要HDM过敏原。

 

Although progress has been made, further welldesigned studies are necessary to shed more light on the precise pathogenetic mechanisms triggered by genetics, environmental factors, and major allergens in dogs with AD.

虽然已经取得了进展，但需要进一步精心设计的研究来阐明由遗传、环境因素和主要过敏原引发的AD犬的确切发病机制。

 

 

 

主要过敏原	分子量（kDa）	阳性率（％）	参考文献
粉尘螨
Der f 2	14	51-89	84,86-88
Der f 15	98, 109	95	73
Der f 18	60	57-77	74
Zen 1	150-250	83-100	71, 84.86-88
日本柳杉
Cry j 1	NR	100	75
Cry j 3	NR	>70	76
短豚草
Amb a 1	38	81	77
厚皮马拉色菌	45, 52, 56, 63	>50	78
猫栉首蚤
Cte f 1	18	80-100	79

TABLE 1  Overview of major allergens in dogs.

Abbreviation: NR, not reported.

表1犬主要过敏原概述。

缩略词：NR，未报道。

 

 

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杨先生