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Update on the role of cytokines and chemokines in canine atopic dermatitis
细胞因子和趋化因子在犬特应性皮炎中的作用研究进展
翻译：王帆
Abstract
Background: Cytokines and chemokines play central roles in the pathogenesis of canine atopic dermatitis (cAD). Numerous studies have been published and provide new insights into their roles in cAD.
Objectives: To summarise the research updates on the role of cytokines and chemokines in the pathogenesis of cAD since the last review by the International Committee on Allergic Diseases of Animals in 2015.
Material and Methods: Online citation databases, abstracts and proceedings from international meetings on cytokines and chemokines relevant to cAD that had been published between 2015 and 2022 were reviewed.
Results: Advances in technologies have allowed the simultaneous analysis of a broader range of cytokines and chemokines, which revealed an upregulation of a multipolar immunological axis (Th1, Th2, Th17 and Th22) in cAD. Most studies focused on specific cytokines, which were proposed as potential novel biomarkers and/or therapeutic targets for cAD, such as interleukin31. Most other cytokines and chemokines had inconsistent results, perhaps as a consequence of their varied involvement in the pathogenesis of different endotypes of cAD.
Conclusions and Clinical Relevance: Inconsistent results for many cytokines and chemokines illustrate the difficulty of studying the complex cytokine and chemokine networks in cAD, and highlight the need for more comprehensive and structured studies in the future.
KEYWORDS allergy, cytokines, dog, hypersensitivity, skin
摘要
背景: 细胞因子和趋化因子在犬特应性皮炎(AD)的发病机制中起核心作用。许多研究已经发表，并为它们在犬AD中的作用提供了新的见解。
目的: 总结国际动物过敏性疾病委员会自2015年以来的最新综述，在犬AD发病机制中，细胞因子和趋化因子作用的研究进展。
材料和方法:回顾了2015年至2022年间发表的与犬AD相关的细胞因子和趋化因子国际会议的在线引文数据库、摘要和会议记录。
结果: 技术的进步使人们能够同时分析更广泛的细胞因子和趋化因子，这揭示了犬AD中多极免疫轴 (Th1、Th2、Th17和 Th22)的上调。大多数研究都集中在特异性细胞因子上，这些细胞因子被认为是犬AD的潜在新生物标志物和/或治疗靶 点，如白细胞介素-31。大多数其他细胞因子和趋化因子的结果不一致，可能是因为它们在犬AD不同内型的发病机制中的不同参与。
结论和临床相关性: 许多细胞因子和趋化因子的不一致结果说明了研究犬AD中复杂的细胞因子和化学因子网络的困难，并强调了未来需要更全面和结构化的研究。
关键词：过敏症、细胞因子、犬、超敏反应、皮肤
INTRODUCTION
介绍
Since the first recognition of atopic dermatitis (AD) in dogs in 1941,numerous studies have revealed new insights into this disease, notably during the last decade. However, the definition of canine AD (cAD) has not been updated since 2006. The International Committee on Allergic Diseases of Animals (ICADA) has proposed a new definition: ‘Canine AD 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’.
自1941年首次在犬身上发现特应性皮炎(AD)以来，特别是在过去的十年里，许多研究揭示了对这种疾病的新见解。然而，犬AD (cAD)的定义自2006年以来一直没有更新。国际动物过敏性疾病委员会(ICADA)提出了一个新的定义:“犬AD是一种遗传性、通常瘙痒，且主要由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失调之间的相互作用。”
In the past, AD was considered to be characterised by a T-helper type (Th)1/Th2 imbalance with a Th2-skewed cytokine milieu. This concept was further supported by the clinical improvement of atopic dogs treated with recombinant canine interferon (IFN)-γ (a Th1 cytokine). Also, a Th1 cytokine shift, characterised by a significant elevation of IFN-γ:IL-4 messenger (m)RNA ratio in peripheral blood monocular cells (PBMCs) was seen after effective allergen immunotherapy (AIT). These results suggested that a Th2 cytokine bias was dominant in cAD. However, subsequent studies showed more dynamic cytokine patterns, suggesting a lack of ‘Th2-polarisation’ in AD in both humans and dogs. In the previous review on the pathogenesis of cAD by ICADA published in 2015, the accepted model was a predominant Th2 cytokine milieu in acute skin lesions and Th1 cytokine responses contributing to the development of chronic lesions. The purpose of this paper is to summarise the updates on the role of cytokines and chemokines in cAD since the last review by ICADA in 2015 (Table 1).
过去，人们认为AD的特征是辅助性T细胞(Th)1/Th2失衡以及倾向Th2型细胞因子为主。特应性皮炎犬通过重组犬干扰素(IFN)-γ(一种Th1细胞因子)治疗，得到临床改善的表现，进一步支持了这一观点。此外，在过敏原免疫治疗(AIT)有效后，出现Th1细胞因子的变化，表现为外周血单个核细胞(PBMCs)中IFN-γ:IL-4信使(m)RNA的比例显著升高。这些结果表明，Th2细胞因子在cAD中占主导地位。然而，随后的研究显示了更动态的细胞因子模式，表明在人类和犬的AD中都缺乏“Th2极化”。在2015年ICADA发表的关于cAD发病机制的综述中，公认的模型是急性皮肤病变中以Th2细胞因子为主，而Th1细胞因子反应促进慢性病变的发展。本文的目的是总结自2015年ICADA上一篇综述以来关于细胞因子和趋化因子在cAD中作用的最新进展(表1)。
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), (atopic dermatitis) and (cytokine or chemokine)’. 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. Other articles that did not come up with these search criteria yet were relevant to the topic also were added as needed.
以“(犬dog或犬dogs或犬类canine)、(特应性皮炎)和(细胞因子或趋化因子)”为关键词，在Medline(通过PubMed)和汤森路透的科学网站中检索2015年至2022年发表的相关文献。对这些文章的标题、摘要和必要时的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。其他不符合这些搜索标准但与该主题相关的文章也会根据需要添加。
UPDATES ON CYTOKINES AND CHEMOKINES IN CANINE ATOPIC DERMATITIS
犬特应性皮炎的细胞因子和趋化因子研究进展
Advances in technologies [i.e. multiplex immunoassays, microarrays and next-generation sequencing (NGS)] have allowed the simultaneous analysis of a broader range of cytokines and chemokines. In particular, NGS allows full sequencing of the whole transcriptome, even at the single-cell level, resulting in more comprehensive cytokine expression profiles.
技术的进步[即多重免疫分析，微阵列和下一代测序(NGS)]已经允许同时分析更广泛的细胞因子和趋化因子。特别是，NGS允许整个转录组的完整测序，甚至在单个细胞水平，导致更全面的细胞因子表达谱。
In the last decade, these advanced technologies have become more accessible and affordable in veterinary medicine. They have provided many valuable insights into complex biological systems, including cAD. There are six studies (two peer-reviewed publications, four conference abstracts) utilising RNA sequencing (RNA-Seq) technology to more comprehensively characterise the cytokine transcriptome profiles in cAD. Interestingly, the results of these studies revealed multipolar immunological axis upregulation (Th1, Th2, Th17 and Th22) in cAD as is found in humans with AD. This indicates that cytokine network activation in AD is, in fact, no longer considered to simply involve a specific group of cytokines (i.e. upregulation of only Th2 cytokines) and is instead the interplay between a large number of cytokines. Furthermore, one study identified differential expression of microRNAs (small single-stranded noncoding RNAs that regulate other gene expression) in dogs with AD, which indicates that the immunological mechanisms may be even more complicated. However, the number of these comprehensive analyses is still limited, and most studies target only selected cytokines. Therefore, in the following sections, we reviewed the recent findings on the role of each cytokine and chemokine in cAD.
在过去十年中，这些先进技术在兽医学中变得更容易获得和负担得起。他们对包括cAD在内的复杂生物系统提供了许多有价值的见解。有6项研究(2项同行评议的出版物，4项会议摘要)使用RNA测序(RNA- seq)技术来更全面地描述cAD的细胞因子转录组谱。有趣的是，这些研究的结果表明，与AD患者一样，cAD患犬存在多极免疫轴上调(Th1、Th2、Th17和Th22)。这表明，事实上，AD患者的细胞因子网络激活不再被认为仅仅涉及一组特定的细胞因子(即仅Th2细胞因子的上调)，而是大量细胞因子之间的相互作用。此外，一项研究发现，在AD犬中，微小RNA(调节其他基因表达的单链非编码小RNA)存在差异表达，这表明免疫机制可能更为复杂。然而，这些综合分析的数量仍然有限，而且大多数研究仅针对特定的细胞因子。因此，在接下来的章节中，我们回顾了每种细胞因子和趋化因子在cAD中作用的最新发现。
Keratinocyte-derived cytokines
角质形成细胞驱动的细胞因子
Interleukin-33
白介素-33
Interleukin (IL)-33 was first described in humans and mice in 2005 as a new member of the IL-1 cytokine family that binds to IL-1 receptor family member suppression of tumorigenicity 2 (ST2). Unlike most cytokines, IL-33 is constitutively expressed as a nuclear protein in epithelial tissues of various organs, such as the lung, stomach and skin. It is released extracellularly upon tissue damage and cell death or cell stress, and functions as an endogenous danger signal (alarmin). Although the released full-length IL-33 is already active, it can be processed by inflammatory proteases into a shorter ‘hyperactive’ mature form to further enhance allergic inflammation.
白细胞介素(IL)-33作为IL-1细胞因子家族的新成员于2005年首次在人类和小鼠中被描述，它与IL-1受体家族成员ST2结合。与大多数细胞因子不同，IL-33作为一种核蛋白在肺、胃和皮肤等多种器官的上皮组织中组成性表达。在组织损伤、细胞死亡或细胞应激时被释放到细胞外，并作为内源性危险信号(警报素)发挥作用。虽然释放的全长IL-33已经具有活性，但它可以被炎症蛋白酶加工成一种更短的“过度活跃”的成熟形式，从而进一步增强过敏性炎症反应。
A recent study in dogs revealed significantly higher transcription levels of IL-33 in chronic lesional skin collected from dogs with spontaneous AD compared to the skin of healthy controls. The protein expression of IL-33 in keratinocytes, endothelial cells and dermal infiltrating cells of the AD skin also was confirmed by immunohistochemical analysis, while no IL-33 staining was detected in the skin of healthy dogs. Interestingly, the transcription levels of IL-33 were higher in skin lesions with excoriation, suggesting that self-trauma may be associated with the upregulation of IL-33 not only in pruritic AD, but also possibly in other pruritic skin diseases. The upregulation of IL-33 mRNA expression also was seen in the acute skin lesions or PBMCs collected from the experimental atopic model in dogs.
最近一项对犬的研究显示，与健康对照的皮肤相比，在自发性AD的犬的慢性有病变皮肤中，IL-33的转录水平显著较高。免疫组化结果显示，IL-33在AD犬皮肤角质形成细胞、内皮细胞和真皮浸润细胞中均有表达，而在健康犬皮肤中未检测到IL-33表达。有趣的是，IL-33的转录水平在有刮抓痕的皮肤病变中升高，这表明自我损伤不仅与瘙痒性AD的IL-33上调有关，也可能与其他瘙痒性皮肤病有关。在犬的急性皮肤病变或实验性特应性皮炎模型的PBMCs中也观察到IL-33 mRNA表达的上调。
Thymic stromal lymphopoietin
胸腺基质淋巴细胞生成素
Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that plays a critical role in linking events at interfaces between the body and environment to Th2 responses and the development of allergic inflammation.
胸腺基质淋巴生成素(TSLP)是一种上皮细胞驱动的细胞因子，在机体和环境导致Th2反应之间，以及过敏性炎症反应的发展中起关键作用。
The canine progenitor epidermal keratinocyte cell line (CPEK) stimulated by either trypsin [a protease activated receptor-2 (PAR-2) ligand] or synthetic triacylated lipopeptide [a toll-like receptor (TLR)1/2 ligand] shows significant upregulation of the mRNA expression of TSLP. PAR-2 and TLR1/2 are receptors for house dust mite (HDM)-derived proteases and for membrane proteins of Staphylococcus spp., respectively, and activation may follow exposure. These results suggest that TSLP might be involved in the induction of flares in cAD, although CPEK might not be an adequate model for cAD skin. Furthermore, the skin of a HDM-induced cAD model showed a distinctive distribution pattern of TSLP (i.e. a condensed staining pattern at the stratum basale) compared to normal control skin. However, another study in a cAD model showed downregulation of TSLP mRNA expression in the skin after HDM exposure. These in - consistent results indicate insufficient evidence for TSLP being a relevant therapeutic target in cAD at this point.
经胰蛋白酶[蛋白酶激活受体-2 (PAR-2)配体]或合成三酰化脂肽[toll样受体(TLR)1/2配体]刺激后，犬表皮角质形成原组细胞系(CPEK)的TSLP mRNA表达显著上调。PAR-2和TLR1/2分别是屋尘螨衍生的蛋白酶和葡萄球菌膜蛋白的受体，暴露后可能被激活。这些结果表明，TSLP可能参与诱导了cAD的突然发病，但CPEK可能不是一个适当的模型用于cAD皮肤。此外，与正常对照皮肤相比，HDM诱导的cAD模型的皮肤显示出独特的TSLP分布模式(即在基底层的浓缩染色模式)。然而，另一项在cAD模型中的研究显示，HDM暴露后皮肤中TSLP mRNA表达下调。这些不一致的结果表明，目前没有足够的证据表明TSLP是cAD的相关治疗靶点。
C motif chemokine ligand 17/Thymus and activation regulated chemokine
C-C基序趋化因子配体17/胸腺和活化调节趋化因子
C-C motif chemokine ligand (CCL)17, also known as thymus and activation regulated chemokine (TARC), is a potent Th2 chemoattractant via its receptor CCR4 that is selectively expressed on Th2 cells. In vitro studies in dogs demonstrated that CCL17/TARC was produced by CPEK, especially when they were co-cultured with a PAR-2 agonist. It has therefore been proposed that CCL17/TARC is an essential cytokine for the recruitment of Th2 cells to the skin in, for example, HDM-induced allergic inflammation. In fact, upregulation of CCL17 mRNA expression has been reported in the skin of dogs with both experimentally induced and spontaneous AD. One study with dogs with spontaneous AD further revealed that a significant difference in CCL17 mRNA expression was seen between the skin of healthy dogs and the lesional skin of atopic dogs, and not with nonlesional skin.
C-C基序趋化因子配体(CCL)17，也称为胸腺和活化调节趋化因子(TARC)，是一种有效的Th2趋化因子，通过其受体CCR4选择性表达于Th2细胞。体外实验表明CCL17/TARC是由CPEK产生的，尤其是当它们与PAR-2激动剂共培养时。因此，有人提出CCL17/TARC是Th2细胞募集到皮肤的必要细胞因子，例如，在HDM诱导的过敏性炎症中。事实上，在实验诱导和自发性AD的犬的皮肤中，CCL17 mRNA表达上调。一项对自发性AD犬的研究进一步表明，在健康犬的皮肤和特应性疾病犬的病变皮肤之间，CCL17 mRNA的表达有显著差异，而在非病变皮肤中无显著差异。
In human AD, numerous clinical studies have demonstrated that plasma or serum CCL17/TARC levels correlate with disease severity; thus, CCL17/TARC has been used as a biomarker in AD. In 2020, a study in dogs with AD investigated the relationship between serum CCL17/ TARC concentrations and disease severity; clientowned dogs with AD showed significantly higher serum CCL17/TARC concentrations than 42 healthy control dogs. The serum CCL17/TARC concentrations showed a moderate correlation with Canine Atopic Dermatitis Extent and Severity Index, 4th iteration (CADESI-04) scores. Also, the significant reduction of CCL17/TARC levels seen after treatment with prednisolone or oclacitinib further supports an essential role for CCL17/TARC in cAD. It could therefore be a valuable biomarker to evaluate objectively disease severity and therapeutic responses, although the response may be specific to inflammation rather than AD.However, it is interesting to note that one of the two outliers in the ‘healthy’ control group (with >10-fold higher CCL17/TARC concentrations than the median) subsequently developed typical clinical signs of cAD (the other outlier was lost to follow-up). This may suggest that CCL17/TARC concentrations can become elevated before the onset of AD.
在人类AD中，大量临床研究表明，血浆或血清CCL17/TARC水平与疾病严重程度相关;因此，CCL17/TARC已被用作AD的生物标志物。2020年，一项针对AD犬的研究调查了血清CCL17/ TARC浓度与疾病严重程度之间的关系;AD患犬的血清CCL17/TARC浓度显著高于42只健康对照犬。血清CCL17/TARC浓度与犬特应性皮炎严重程度指数第4版(CADESI-04)评分呈中度相关。此外，泼尼松龙或奥拉替尼治疗后观察到的CCL17/TARC水平的显著降低进一步支持CCL17/TARC在cAD中的重要作用。因此，它可能是一个有价值的生物标志物，以客观评估疾病严重程度和治疗反应，但反应可能是针对炎症而不是AD。然而，值得注意的是，“健康”对照组的两个异常值之一(CCL17/TARC浓度比中位数高10倍)随后发展为典型的cAD临床症状(另一个异常值失访)。这可能表明CCL17/TARC浓度在AD发病前升高。
A CCR4 inhibitor (AZ445) has been tested in a randomised cross-over study of 14 dogs with experimentally induced AD to evaluate the therapeutic potential of inhibiting the CCL17/TARC-CCR4 signalling pathway. Although there was no significant overall reduction of CADESI-03 scores in treated dogs compared to vehicle-treated controls, five treated dogs (35%) showed a moderate clinical improvement (40% reduction of CADESI-03 scores) with a reduction of acanthosis and dermal inflammation. As in humans, variation of clinical phenotypes has been reported in cAD, and variation in immunological profiles is strongly suspected. Such immunological diversity could explain the heterogeneous efficacy of CCL17/TARC-inhibitor; thus,further studies to identify particular AD phenotypes are needed. This would aid the selection of appropriate patients for targeted cytokine pathway inhibition.
一种CCR4抑制剂(AZ445)在14只实验诱导AD的犬的随机交叉研究中进行了测试，以评估抑制CCL17/TARC-CCR4信号通路的治疗潜力。虽然与佐剂治疗对照组相比，治疗组犬的CADESI-03评分总体上没有显著降低，但5只治疗组犬(35%)显示出中度临床改善(CADESI-03评分降低40%)，棘皮症和真皮炎症减轻。与人类一样，cAD的临床表型也有变化，我们强烈怀疑其免疫学特征也有变化。这种免疫多样性可以解释CCL17/TARC抑制剂疗效的异质性;因此，需要进一步的研究来确定特定的AD表型。这将有助于选择合适的患犬进行靶向细胞因子途径抑制。
C-C motif chemokine ligand 22/Macrophage-derived chemokine
C-C基序趋化因子配体22/巨噬细胞来源的趋化因子
C-C motif chemokine ligand 22, also known as macrophage-derived chemokine (MDC), is another ligand for CCR4; therefore, CCL22/MDC also can recruit Th2 cells to the inflammatory loci of AD skin.
C-C基元趋化因子配体22，也称为巨噬细胞衍生趋化因子(MDC)，是CCR4的另一个配体;因此，CCL22/MDC也可以将Th2细胞募集到AD皮肤的炎症位点。
Similar to human AD, upregulation of CCL22/MDC mRNA expression in both lesional and nonlesional skin was detected in 12 client-owned dogs with AD compared to healthy controls. Furthermore, there was a positive correlation with the pruritus Visual Analog Scale (pVAS) and CADESI-04 scores, suggesting that CCL22/ MDC might play an essential role in the pathogenesis of Th2-dominated cAD skin lesions. Another study with a HDM-induced cAD model also showed upregulation of mRNA expression of CCL22/MDC in AD skin compared to untreated controls. Still, as a consequence of minimal data, further studies are needed to determine the more precise role of CCL22/MDC in cAD.
与人类AD病相似，12只AD家养患犬的皮肤病变和非皮肤病变中CCL22/MDC mRNA的表达均高于健康对照。此外，CCL22/ MDC与瘙痒视觉模拟评分(pVAS)和CADESI-04评分呈正相关，提示CCL22/ MDC可能在Th2为主型cAD皮肤病变的发病机制中发挥重要作用。另一项使用HDM诱导的cAD模型的研究也表明，与未治疗的对照相比，AD皮肤中CCL22/MDC的mRNA表达上调。然而，由于数据较少，需要进一步的研究来确定CCL22/MDC在cAD中更精确的作用。
T-helper type 2 cytokines
Th2型细胞因子
Interleukin-4
白介素-4
Interleukin-4 is a potent regulator of immunity that is primarily secreted by Th2 cells, mast cells, eosinophils and basophils. IL-4 plays an important role in leucocyte survival in Th2 cell-mediated immune responses and in IgE class switching of B cells; thus, it is commonly considered as one of the most important Th2 cytokines.
白细胞介素-4是一种有效的免疫调节剂，主要由Th2细胞、肥大细胞、嗜酸性粒细胞和嗜碱性粒细胞分泌。IL-4在Th2细胞介导的免疫应答和B细胞的IgE类转换中对白细胞存活起重要作用;因此，它通常被认为是最重要的Th2细胞因子之一。
Although IL-4 is commonly considered to be a cornerstone cytokine in the pathogenesis of AD, gene and protein expression of IL-4 has been variable in atopic dogs. More recent studies, published after 2015, continue to show this inconsistent IL-4 expression in cAD. Two studies in a HDM-induced cAD model and one study in dogs with spontaneous AD demonstrated elevated mRNA or protein expression in the skin or PBMCs, respectively. By contrast, four other studies on sera from client-owned dogs did not find a difference in the concentration of IL-4 between dogs with AD and healthy controls. Since the HDM-induced experimental AD model represents the earliest stages of acute flares of AD and most client-owned dogs have more chronic lesions, it is possible that IL-4 only plays an important role during the induction or acute phase of cAD. Furthermore, it is interesting to note that the percentage of IL-4-producing T cells in dogs with AD did not change after one year of treatment with oclacitinib, despite the clinical improvement, which indicates that IL-4 might be a less important inflammatory cytokine in chronic cAD. Still, the significance of IL-4 might have been underestimated in client-owned dogs owing to the variety of the AD phenotypes (e.g. breeds, stages of AD or immunological phenotypes). Finally, two studies in experimental models of acute cAD showed increased expression of the IL-4 receptor α subunit (IL-4RA) in the skin, while the IL-4 levels remained unchanged; therefore, it also is possible that the effect of IL-4 may be substantially enhanced in AD skin as a result of the increased susceptibility of its effector cells.
尽管IL-4通常被认为是AD发病机制中的基础细胞因子，但IL-4的基因和蛋白表达在特应性皮炎犬中是多变的。2015年后发表的更多最新研究继续表明，IL-4在cAD中的表达不一致。在HDM诱导的cAD模型中的两项研究和在自发性AD的犬中的一项研究表明，皮肤或PBMCs中mRNA或蛋白的表达分别升高。相比之下，其他四项关于家养犬血清的研究没有发现AD患犬和健康对照之间的IL-4浓度有差异。由于HDM诱导的实验性AD模型代表了AD急性发作的早期阶段，而且大多数家养犬有更多的慢性病变，IL-4可能只在cAD的诱导或急性期起重要作用。此外，有趣的是，尽管奥拉替尼治疗一年后临床改善，但AD犬的生成IL-4的T细胞的比例没有变化，这表明IL-4在慢性cAD中可能是一种不那么重要的炎症细胞因子。尽管如此，因为AD表型的多样性(例如品种，AD阶段或免疫表型)，所以IL-4在家养犬中的意义可能被低估了。最后，两项在急性cAD实验模型中的研究表明，皮肤中IL-4受体α亚基(IL-4RA)的表达增加，而IL-4水平保持不变;因此，IL-4在AD皮肤中的作用也可能由于其效应细胞的易感性增加而显著增强。
Interleukin-5
白介素-5
Interleukin-5 is produced primarily by Th2 cells and mast cells, and induces survival, activation and migration of eosinophils; therefore, IL-5 is considered as a critical cytokine in allergic diseases, including AD. Since the review of cAD by ICADA in 2015, several studies have consistently reported upregulation of IL-5 mRNA expression in the skin of different cAD models (HDM-, anti-IgE- or compound 48/80-induced AD). Nevertheless anti-IL-5 monoclonal antibody (mepolizumab) therapy showed limited success in human AD. Considering the similarities of cytokine transcriptome profiles between human and cAD, it might not be such an important therapeutic target as it is in humans. Still, studies to investigate IL-5-targeting therapy in cAD are needed.
IL -5主要由Th2细胞和肥大细胞产生，诱导嗜酸性粒细胞存活、活化和迁移;因此，IL-5被认为是过敏性疾病包括AD的关键细胞因子。自2015年ICADA对cAD进行综述以来，多项研究一致报道了不同cAD模型(HDM、抗IgE或化合物48/80诱导的AD)皮肤中IL-5 mRNA的表达上调。然而，抗IL -5单克隆抗体(美泊利单抗)治疗人类AD的疗效有限。考虑到细胞因子转录组谱在人类和cAD之间的相似性，它可能不像在人类中那样是一个重要的治疗靶点。尽管如此，仍需要开展IL -5靶向治疗cAD的研究。
Interleukin-13
白介素-13
Interleukin-13 is regarded as a primary disease-inducing effector cytokine in allergic diseases, as it contributes to IgE production and to the differentiation of T cells towards the Th2 subtype. Therefore, IL-13 is considered an important and relevant therapeutic target in human AD. Indeed, remarkable success in the treatment of human AD with dupilumab (the monoclonal antibody targeting the common receptor of IL-4 and IL-13; IL-4RA) and favourable outcomes after targeting IL-13 itself (lebrikizumab and tralokinumab) further confirm the critical role of this cytokine in the pathogenesis of human AD.
在过敏性疾病中，白细胞介素-13被认为是一种主要的诱发疾病的效应细胞因子，因为它有助于IgE的产生和T细胞向Th2亚型的分化。因此，IL-13被认为是AD重要的相关治疗靶点。事实上，度普利尤单抗(靶向IL-4和IL-13共同受体的单克隆抗体;IL-4RA)和靶向IL-13 (lebrikizumab和tralokinumab)后的良好结果进一步证实了这种细胞因子在人类AD发病机制中的关键作用。
By contrast, IL-13 has not been investigated as a therapeutic target in cAD, despite many studies demonstrating significant upregulation. Since 2015, eight studies have reported the expression of IL-13 in either experimental cAD models or client-owned dogs. All except one showed increased mRNA or protein levels of IL-13 in either skin or blood (sera or PBMCs) samples of dogs with AD compared to the controls.10,12–14,21,38,40,50 The consistency of these results suggests that IL-13 may play an important role in cAD, especially compared to IL-4, and could be a valid therapeutic target as in human AD.
相比之下，尽管许多研究表明IL-13显著上调，但还没有研究将其作为cAD的治疗靶点。自2015年以来，已有8项研究报道了IL-13在实验性cAD模型或家养犬中的表达。除1只外，所有AD犬的皮肤或血液(血清或PBMCs)样本中IL-13的mRNA或蛋白水平均高于对照组。这些结果的一致性表明，IL-13可能在cAD中发挥重要作用，尤其是与IL-4相比，并可能成为人类AD的有效治疗靶点。
One study from Japan showed nonsynonymous polymorphisms of IL-13 receptor (IL-4RA) in miniature dachshunds, one of the less common breeds for cAD. When 19 atopic and 39 healthy miniature dachshunds were compared, one single nucleotide polymorphism (Arg688Cys) was significantly less common in the former. This result suggests that impaired IL-4 and/or IL-13 signalling may protect this breed from AD. By contrast, polymorphisms of IL-4RA or of IL-13 itself were not detected in shiba inu dogs, one of the most predisposed breeds in Japan.
来自日本的一项研究显示，IL-13受体(IL-4RA)在小型腊肠(cAD不常见的品种之一)中存在非同义多态性。将19只特应性皮炎迷你腊肠犬与39只健康迷你腊肠犬进行比较，发现前者的单核苷酸多态性(Arg688Cys)显著低于后者。这一结果表明，受损的IL-4和/或IL-13信号可能保护该品种免受AD。相比之下，IL-4RA或IL-13本身的多态性未在日本最易感品种之一的柴犬中检测到。
Interleukin-31
白介素-31
Interleukin-31 is a cytokine known to cause severe itch in humans, dogs and other animal species. It has been investigated as a key cytokine in several pruritic skin diseases, including AD. As had been suggested already by in vitro studies with canine PBMCs, T cells and most likely Th2 cells, were the primary source of IL-31 in the skin of an acute cAD model. IL-31 expression also was detected by mRNA in situ hybridisation in keratinocytes of client-owned dogs with AD, yet at a very low level.
白细胞介素-31是一种已知会导致人类、犬和其他动物严重瘙痒的细胞因子。已有研究，IL-31是包括AD在内的几种瘙痒性皮肤病的关键细胞因子。正如对犬PBMC的体外研究已经表明的那样，T细胞和最有可能的Th2细胞是急性cAD模型皮肤中IL-31的主要来源。通过mRNA原位杂交也检测到了IL-31在家养AD犬的角质形成细胞中的表达，但水平很低。
There are currently five mRNA splice variants of IL31 receptor α subunit (IL-31RA) in dogs encoding two protein isoforms: the full-length isoform X1 and the truncated isoform X2. The latter lacks the N-terminal signal peptide and parts of the cytokine-binding domain; therefore, it may not bind to IL-31. Although the transcription of IL-31RA X2 was significantly higher than that of IL-31RA X1 in both HDM-induced atopic and healthy dogs, the difference in the function between these isoforms remains to be confirmed.
犬IL-31受体α亚基(IL-31RA)目前有5种mRNA剪接亚型，编码两种蛋白亚型:全长亚型X1和截断亚型X2。后者缺乏N端信号肽和部分细胞因子结合域;因此，它可能不与IL-31结合。尽管IL-31RA X2在HDM诱导的特应性皮炎犬和健康犬中的转录均显著高于IL-31RA X1，但这些亚型之间的功能差异仍有待证实。
As in humans and mice, several studies in dogs have described the expression of IL-31RA on dorsal root ganglia, where the cell bodies of cutaneous sensory neurons are located. Expression of IL-31RA protein also has been demonstrated in nerve fibres in the skin of dogs with AD. These findings suggest direct stimulation of itch sensory neurons by IL-31, which also explains the acute onset of pruritus after administration of this cytokine. In addition, protein expression of IL-31RA in epidermal keratinocytes in a cAD model indicates an indirect effect of IL-31 via keratinocyte stimulation. One clinical study of 10 client-owned dogs with AD showed decreased trans epidermal water loss (TEWL) during 12weeks of treatment with an anti-canine IL-31 monoclonal antibody (lokivetmab; Cytopoint, Zoetis), suggesting a direct or indirect contribution of excessive IL-31 to skin barrier dysfunction, as reported in humans.
与人类和小鼠一样，对犬的几项研究也描述了IL-31RA在背根神经节(皮肤感觉神经元的胞体所在)上的表达。IL-31RA蛋白在AD犬皮肤的神经纤维中也有表达。这些发现表明，IL-31直接刺激了瘙痒感觉神经元，这也解释了给予这种细胞因子后瘙痒的急性发作。此外，在cAD模型中，表皮角质形成细胞中IL-31RA的蛋白表达表明IL-31通过角质形成细胞刺激产生间接作用。一项临床研究表明，使用抗犬IL-31单克隆抗体(洛基维特单抗;赛妥敏)治疗12周后，10只患有AD的家养犬的经表皮失水量(TEWL)减少，表明过量的IL-31皮肤屏障功能异常有直接或间接的作用，正如人类报道的一样。
Serum IL-31 concentrations in 243 dogs with spontaneous AD were much higher than in 55 healthy controls (average concentrations of 13,541 and 531fgmL−1, respectively). Likewise, significantly higher expression of IL-31 mRNA was seen in PBMCs from HDMsensitised or spontaneous AD dogs compared to those from healthy controls. One study using a HDMinduced cAD model, demonstrated a significant positive correlation between serum IL-31 concentrations and CADESI-03 scores; by contrast, in client-owned dogs there was no correlation between serum concentrations and lesional scores, and only between serum concentrations and pVAS scores. In another study, there was no correlation between the Canine Atopic Dermatitis Lesion Index (CADLI) or pVAS and IL-31 gene expression in PBMCs of 11 client-owned dogs with AD. These inconsistent results suggest a need for further studies focusing on the local (i.e. skin) rather than the systemic (i.e. blood) immune responses. This idea is supported by human studies showing no correlation of mRNA or protein expressions of many cytokines, including IL-31, between blood and skin.
243只自发性AD犬的血清IL-31浓度远高于55只健康对照犬(平均浓度分别为13,541和531fgmL - 1)。同样，在HDM致敏或自发性AD犬的PBMCs中，IL-31 mRNA的表达显著高于健康对照组。一项使用HDM诱导的cAD模型的研究表明，血清IL-31浓度与CADESI-03评分显著正相关;相比之下，在家养犬中，血清浓度和病变评分之间没有相关性，只有血清浓度和pVAS评分之间有相关性。在另一项研究中，11只患特应性皮炎的犬的PBMCs中，犬特应性皮炎病变指数(CADLI)或pVAS与IL-31基因表达没有相关性。这些不一致的结果表明，需要进一步研究局部(即皮肤)而不是系统性(即血液)免疫反应。这一观点得到了人类研究的支持，研究表明血液和皮肤之间许多细胞因子(包括IL-31)的mRNA或蛋白表达没有相关性。
One early study showed upregulation of mRNA encoding IL-31 in the skin of HDM-sensitised experimental atopic dogs as early as sixhours after the allergen challenge. Later on, IL-31 mRNA expression continued to increase and became the most upregulated gene at 24h. Consistent with this, a later study in the same model showed that peak IL-31 protein expression in the skin occurred at 24–48h postchallenge, thereby indicating that IL-31 is one of the earliest and major cytokines involved in acute cAD. It also is important to note that the latter study could not find a correlation between IL-31 protein expression scores in the skin and serum IL-31 concentrations. Furthermore, a more recent study with a chronic cAD model demonstrated the upregulation of IL-31 mRNA in the skin lesions for up to 28days (the end-point of the experiment).
一项早期研究表明，早在过敏原激发后6小时，在HDM致敏的实验性特应性皮炎犬的皮肤中，编码IL-31的mRNA表达上调。随后IL-31 mRNA表达持续升高，至24h时上调最为明显。与此一致的是，在同一模型中，随后的一项研究表明，皮肤中IL-31蛋白的表达高峰出现在激发后24 - 48小时，从而表明IL-31是参与急性cAD的最早和主要的细胞因子之一。值得注意的是，后一项研究没有发现皮肤IL-31蛋白表达评分和血清IL-31浓度之间的相关性。此外，最近的一项慢性cAD模型研究表明，皮肤病变中IL-31 mRNA的表达上调长达28天(实验终点)。
Interleukin-31 took centre stage in the pathogenesis of cAD, after oclacitinib (Apoquel; Zoetis), a selective Janus kinase inhibitor targeting the IL-31 signalling pathway, and (even more) when lokivetmab were launched in 2014 and 2017, respectively. A significant reduction of atopic pruritus has been seen in 57%–100% of clientowned dogs following injections of lokivetmab. Three randomised clinical studies also have reported that about half of atopic dogs treated with lokivetmab exhibited a 50% or greater reduction, or even a ‘remission’, of their skin lesions compared to baseline or to placebo controls. However, a study with a canine atopic model showed that a single injection of lokivetmab only prevented the HDM-induced itch and not the generation of skin lesions, which indicated the limited effect of blocking IL-31 in the prevention of atopic skin inflammation. Lokivetmab also prevented atopic flares for more than oneyear in 28% of client-owned dogs, when it was used as proactive monotherapy.
在奥拉替尼(爱波克)，一种靶向IL-31信号通路的选择性Janus激酶抑制剂，以及洛基维特单抗分别于2014年和2017年上市后，IL-31成为CAD发病机制中的焦点。注射洛基维特单抗后，57%-100%的家养犬的特应性皮炎的瘙痒显著减轻。三项随机临床研究也显示，与基线或安慰剂对照相比，约有一半接受洛基维特单抗治疗的特应性皮炎犬的皮肤病变减轻50%或更多，甚至“缓解”。然而，一项关于犬特应性皮炎模型的研究表明，单次注射洛基维特单抗只能预防HDM诱导的瘙痒，而不能防止产生皮肤病变，这表明阻断IL-31在预防特应性皮肤炎症方面的作用有限。洛基维特单抗为单药主动治疗时，在家养犬中，有28%的犬可预防特应性皮炎发作超过一年。
Although not commercially available, an anti-IL-31 vaccine, containing IL-31 coupled to virus-like particles, induced the production of anti-IL-31 antibodies and resulted in an apparent reduction of itching induced by HDM allergens. However, there are no follow-up studies on client-owned dogs with spontaneous AD.
一种含有IL-31与病毒样颗粒偶联的抗IL-31疫苗，虽然没有市售，但可诱导产生抗IL-31抗体，并使HDM过敏原引起的瘙痒明显减少。然而，没有对家养自发性AD的犬进行后续研究。
T-helper type 1 cytokines
ThI型细胞因子
Interferon-γ
干扰素-γ
Interferon-γ is considered the ‘canonical’ or representative Th1 cytokine and is produced preferentially, and not exclusively, by Th1 cells, Tc cells and natural killer cells. Besides promoting Th1 responses by enhancing antigen presentation and inhibiting viral replication, IFN-γ also inhibits Th2 immune responses.
干扰素-γ被认为是“典型的”或代表性的Th1细胞因子，并优先产生，而不是完全由Th1细胞、Tc细胞和自然杀伤细胞产生。除了通过增强抗原呈递呈和抑制病毒复制来促进Th1应答外，IFN-γ还抑制Th2免疫应答。
It has been proposed that increased expression of Th1 cytokines takes place in dogs with chronic skin lesions of AD, and in fact, overexpression of IFN-γ mRNA transcription in the skin of these dogs had been demonstrated.However, the results of studies published after the last ICADA review are contradictory. Among six studies with client-owned dogs, only one showed an increased IFN-γ mRNA expression in PBMCs compared to healthy controls. Of the remaining studies, four showed no difference, and one showed reduced, although not significantly, protein and mRNA levels of IFN-γ in the blood (sera, plasma and PBMCs). The mRNA expression of IFN-γ also was unchanged after HDM challenge in the acute skin lesions or primary keratinocytes collected from the cAD model, whereas its mRNA expression was significantly increased in PBMCs collected from dogs of a similar AD model. A study of dogs treated with oclacitinib showed that IFN-γ production by peripheral blood CD4+ and CD8+ T cells was significantly reduced on Day (D)240 and D300 after the initiation of treatment yet returned to baseline levels on D360 without an associated clinical relapse. These results suggest that the relevance and the precise role of Th1 cytokines, such as IFN-γ, in cAD remain to be determined.
有研究认为，在慢性特应性皮炎的犬中，Th1细胞因子的表达增加，事实上，在这些犬的皮肤中，IFN-γ mRNA转录的过度表达已被证实。然而，ICADA评审后发表的研究结果相互矛盾。在6项研究中，与健康对照相比，只有1项研究显示PBMCs中IFN-γ mRNA表达增加。在其余研究中，4项无差异，1项血液(血清、血浆和PBMCs)中IFN-γ蛋白和mRNA水平降低，但不显著。在cAD模型的急性皮肤病变或原代角质形成细胞中，HDM刺激后IFN-γ的mRNA表达也没有变化，而在类似AD模型犬的PBMC中，IFN-γ的mRNA表达显著增加。对接受奥拉替尼治疗的犬进行的一项研究表明，外周血CD4+和CD8+ T细胞产生的IFN-γ在治疗开始后的第240天和第300天显著降低，但在第360天恢复到基线水平，且无相关临床复发。这些结果表明，Th1细胞因子，如IFN-γ，在cAD中的相关性和确切作用仍有待确定。
Interleukin-12, interleukin-15 and interleukin-18
白介素-12、白介素-15和白介素-18
Interleukin-12, IL-15 and IL-18 are capable of inducing IFN-γ secretion; therefore, they are referred to as ‘IFNγ-inducing factors’ and considered part of the Th1 cytokine group.
IL-12、IL-15和IL-18能够诱导IFN-γ分泌;因此，它们被称为“IFN - γ诱导因子”，并被认为是Th1细胞因子组的一部分。
There is still a lack of data regarding the role of these cytokines in cAD. A few studies have reported the expression of mRNA and protein in the skin or plasma, yet the results are variable. This may be partially due to different subunits or the dual roles of these cytokines. IL-12 consists of two subunits, IL-12p35 and IL-12p40, and the latter is considered a more ‘specific’ inducer of Th1 inflammation. Interleukin-18 enhances Th1-mediated immune responses in the presence of IL-12, and in its absence, it also stimulates Th2 responses. The complicated interaction of cytokines makes it challenging to interpret exact role of each cytokine the entire cytokine milieu, and their relevance in cAD is still unknown.
关于这些细胞因子在cAD中的作用仍然缺乏数据。少数研究报道了皮肤或血浆中mRNA和蛋白的表达，但结果不一。这可能部分由于不同的亚单位或这些细胞因子的双重作用。IL-12包括两个亚单位，IL-12p35和IL-12p40，后者被认为是Th1炎症的更特异的诱导因子。IL -18在IL-12存在的情况下增强th1介导的免疫应答，在IL-12不存在的情况下也刺激Th2应答。细胞因子之间复杂的相互作用使我们难以解释每种细胞因子在整个细胞因子环境中的确切作用，而且它们与cAD的相关性仍不清楚。
T-regulatory cytokines
调节T细胞细胞因子
Interleukin-10 and Transforming growth factor β
白细胞介素-10和转化生长因子β
There is a consensus that CD4+ CD25+ Foxp3+ Tregulatory (Treg) cells play an essential role in controlling or suppressing T cells, especially the Th2 cell response to allergens. Therefore, impaired Treg-mediated suppression is considered to be involved in the pathogenesis of AD. Interleukin-10 and transforming growth factor (TGF)-β, are representative of Treg cytokines, and often referred to as immunosuppressive cytokines.
CD4+ CD25+ Foxp3+ Treg细胞在控制或抑制T细胞，特别是Th2细胞对过敏原的反应中起着至关重要的作用。因此，Treg介导的抑制受损被认为参与了AD的发病机制。白细胞介素-10和转化生长因子(TGF)-β是Treg细胞因子的代表，通常被称为免疫抑制细胞因子。
Recent studies investigating the expression of IL-10 and TGF-β in cAD have shown controversial results. For example, one study of 20 client-owned atopic dogs showed significantly lower plasma IL-10 and TGF-β concentrations compared to those in healthy controls.Interestingly, the number of CD4+ CD25+ Foxp3+ Tregs in peripheral blood collected from these AD dogs was significantly increased compared to that from healthy dogs. This may indicate a functional insufficiency of Treg cells in cAD. By contrast, a more recent study could not detect any difference in plasma IL-10 and TFG-β concentration between atopic and healthy dogs. Some studies in canine experimental AD or client-owned dogs even showed an upregulation of IL10 or TGF-β mRNA in the PBMCs or lesional skin samples. One could infer that this upregulation of immunosuppressive cytokines is merely a normal compensatory response to control skin inflammation and is not specific to AD. Either way, these results highlight the difficulty of evaluating isolated cytokines in AD that are characterised by remarkably complicated and dynamic cytokine networks.
最近关于IL-10和TGF-β在cAD中表达的研究显示出有争议的结果。例如，一项对20只客户养的特应性皮炎犬的研究表明，与健康对照组相比，血浆IL-10和TGF-β浓度显著较低。有趣的是，与健康犬相比，AD犬外周血中CD4+ CD25+ Foxp3+调节性T细胞的数量显著增加。这可能提示在cAD中Treg细胞的功能不足。相比之下，最近的一项研究未发现特应性皮炎犬和健康犬的血浆IL-10和TFG-β浓度有任何差异。一些对实验性AD犬或家养犬的研究甚至显示，PBMCs或皮肤病变样本中IL-10或TGF-β mRNA的表达上调。我们可以推断这种免疫抑制性细胞因子的上调仅仅是控制皮肤炎症的正常代偿反应，而不是特应性皮炎所特有的。无论如何，这些结果凸显了评估AD中孤立的细胞因子的难度，这些细胞因子的特征是非常复杂和动态的细胞因子网络。
One of the proposed mechanisms of action of AIT in human and cAD is by increasing IL-10 and TGF-β secretion by Treg cells. However, the latest study, published in 2021 could not find any significant change in plasma IL-10 and TGF-β concentration after oneyear of immunotherapy. Also, the individual treatment success and the concentration of these cytokines were not correlated. These results leave open the question about the importance of regulatory cytokines in cAD.
AIT在人类和cAD中的作用机制之一是通过增加Treg细胞分泌IL-10和TGF-β。而2021年发表的最新研究未发现免疫治疗1年后血浆IL-10和TGF-β浓度有明显变化。此外，个体治疗的成功率与这些细胞因子的浓度不相关。这些结果留下了关于调节性细胞因子在cAD中的重要性的问题。
T-helper type 17 cytokines
Th17型细胞因子
Interleukin-17
白介素-17
IL-17-producing CD4+ Th cells (Th17 cells) have a crucial role in host defence and exhibit effector functions distinct from those of Th1 and Th2 cells.96,97 IL-17 cytokines (IL-17A–IL-17F) are potent inducers of local tissue inflammation through the upregulation of proinflammatory and neutrophil-mobilising cytokines. Those include IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), tumour necrosis factor (TNF)-α, IL-1β, keratinocyte-derived chemokine/C-X-C motif chemokine ligand (CXCL)1, monocyte chemoattractant protein (MCP)-1/C-C motif chemokine ligand (CCL)2, MCP-3/ CCL7, macrophage inflammatory protein-3α/CCL20 and matrix metalloproteases. Previous findings in humans have suggested that Th17 cells and IL-17 cytokines are important in the pathogenesis of certain skin disorders, in particular psoriasis, and also AD.
产生IL -17的CD4+ Th细胞(Th17细胞)在宿主防御中起着至关重要的作用，具有不同于Th1和Th2细胞的效应功能。IL-17细胞因子(IL-17A-IL-17F)通过上调促炎和动员中性粒细胞的细胞因子，是局部组织炎症的强效诱导因子。其中包括IL-6、粒细胞-巨噬细胞集落刺激因子(GM-CSF)、肿瘤坏死因子(TNF)-α、IL-1β、角质形成细胞源性趋化因子/C-X-C基序趋化因子配体(CXCL)1、单核细胞趋化蛋白(MCP)-1/C-C基序趋化因子配体(CCL)2、MCP-3/ CCL7、巨噬细胞炎症蛋白-3α/CCL20和基质金属蛋白酶。先前的人类研究表明，Th17细胞和IL-17细胞因子在某些皮肤病的发病机制中起重要作用，特别是银屑病和特应性皮炎。
In dogs, CPEK stimulated by recombinant canine IL-17A showed upregulation of IL-19 mRNA expression (an inducer of Th2-cytokine production), GMCSF (an activator of Langerhans cells) and S100 calcium-binding protein (S100) A8 and IL-8 (both neutrophil-attracting chemokines), and showed no upregulation of CCL17, CCL22 (Th2-cytokine inducers) or IFN-γ (a Th1 cytokine). Therefore, it was suggested that IL-17A plays a role in the development of Th2-associated inflammation, activation of antigenpresenting cells, and recruitment of neutrophils in skin diseases, such as cAD. The mRNA expression of IL-17A was upregulated in PMBCs collected from dogs of the HDM-sensitised AD model, and serum IL-17 concentrations in client-owned dogs with AD were significantly higher than in healthy controls. By contrast, cutaneous IL-17 mRNA and protein expression of both experimental allergen-induced and spontaneous cAD did not differ from controls. Therefore, the role and importance of Th17 responses in cAD are still unclear.
在犬中，重组犬IL-17A刺激CPEK后，IL-19 (Th2细胞因子的诱导因子)、GMCSF(朗格汉斯细胞的激活因子)、S100钙结合蛋白(S100) A8和IL-8(中性粒细胞趋化因子)的mRNA表达上调，而CCL17、CCL22 (Th2细胞因子的诱导因子)和IFN-γ (Th1细胞因子)的mRNA表达无上调。因此，IL-17A在皮肤疾病如cAD的Th2相关炎症、抗原递呈细胞活化、中性粒细胞募集中发挥作用。尘螨致敏的AD模型犬外周血单个核细胞中IL-17A mRNA表达上调，AD模型犬血清中IL-17浓度显著高于健康对照组。相反，实验过敏原诱导和自发性cAD的皮肤IL-17 mRNA和蛋白表达与对照组无差异。因此，Th17反应在cAD中的作用和重要性尚不清楚。
T-helper type 22 cytokines
Th22型细胞因子
Interleukin-22
白介素-22
Interleukin-22 is considered an activator of keratinocyte proliferation. High levels of IL-22 can induce the expression of epidermal host defence peptides (HDPs), such as S100A7, S100A8, S100A9, β-defensins and cathelicidin, and neutrophil chemoattractants, such as CXCL1, CXCL5 and CXCL8.
白细胞介素-22被认为是角质形成细胞增殖的激活剂。高水平的IL-22可诱导表皮宿主防御肽(HDPs)如S100A7、S100A8、S100A9、β-防御素和抗菌肽的表达，以及中性粒细胞趋化因子如CXCL1、CXCL5和CXCL8的表达。
The up-to-date concept of the pathogenesis of human AD describes a profound increase in Th22- mediated responses in acute lesions, which is further intensified in chronic lesions. Considering cAD as a natural homologue of human disease, one can infer a similar role of IL-22, especially in atopic dogs with marked lichenification. However, current data are still insufficient to support this. On the one hand, a study of a HDM-induced cAD model reported significant upregulation of IL-22 mRNA expression in the skin after allergen exposure. On the other, in another experimental model of cAD induced by injection of anti-canine IgE, there was downregulation of IL-22 in the skin. One study with client-owned atopic dogs did not find any difference in the expression of IL-22 in the skin compared to healthy dogs.
人类AD发病机制的最新概念描述了Th22介导的反应在急性病变中显著增加，在慢性病变中进一步增强。考虑到cAD与人类疾病相同，我们可以推断出IL-22的类似作用，特别是在有明显苔藓化的特应性皮炎犬中。然而，目前的数据仍不足以支持这一观点。一方面，在屋尘螨诱导的cAD模型中，过敏原暴露后皮肤中IL-22 mRNA的表达显著上调。在另一种犬IgE诱导的cAD实验模型中，IL-22在皮肤中表达下调。一项针对家养特应性皮炎犬的研究发现，与健康犬相比，皮肤中IL-22的表达没有任何差异。
Other cytokines and chemokines
其他细胞因子和趋化因子
Interleukin-7
白介素-7
Interleukin-7 is a haematopoietic growth factor that is secreted by stromal cells in the bone marrow and thymus, although it is also produced by keratinocytes. IL-7 contributes to the development and homeostasis of immune cells, including CD4+ memory T cells, which play a central role in the pathogenesis of chronic inflammatory disorders such as asthma and AD.
白细胞介素-7是一种造血生长因子，由骨髓和胸腺的基质细胞分泌，但它也由角质形成细胞产生。IL-7有助于免疫细胞的发育和稳态，包括CD4+记忆T细胞，在哮喘和AD等慢性炎性疾病的发病机制中发挥核心作用。
Although an earlier study showed almost negligible IL-7 secretion from HDM-stimulated keratinocytes collected from a HDM-sensitised cAD model, a more recent investigation demonstrated significantly higher plasma IL-7 levels in client-owned atopic dogs than in healthy controls. The latter study was the first that implied the role of IL-7 in cAD. Further studies are warranted to determine the relevance of IL-7 in cAD.
尽管早期的研究显示，从HDM致敏cAD模型中收集的HDM刺激的角质形成细胞中分泌的IL-7几乎可以忽略不计，但最近的一项研究表明，家养特应性皮炎犬的血浆IL-7水平明显高于健康对照组。后一项研究是第一个暗示IL-7在cAD中的作用。需要进一步的研究来确定IL-7在cAD中的相关性。
Interleukin-34
白介素-34
Interleukin-34 is a novel cytokine first identified in humans in 2008. IL-34 is almost exclusively expressed by keratinocytes and by neurons in the brain; in steady-state conditions in humans and mice, it contributes to the development and maintenance of some myeloid cells in a tissue-specific manner (Langerhans cells in the skin and microglia in the brain).
白细胞介素-34是2008年首次在人体中发现的一种新型细胞因子。IL-34几乎只在角质形成细胞和大脑神经元中表达;在人类和小鼠的稳态条件下，它以组织特异性的方式促进一些髓样细胞的发育和维持(皮肤中的朗格汉斯细胞和大脑中的小胶质细胞)。
Expressions of IL-34 gene and protein have been reported to be significantly decreased in the epidermis of humans with AD; therefore, IL-34 is considered to inhibit propagation of the inflammatory cascades leading to the development of active skin lesions. By contrast, client-owned dogs with AD showed significantly higher serum IL-34 concentrations compared to healthy dogs with a significant positive correlation with CADESI-04 and pVAS scores. These results may indicate a different role of IL-34 in canine compared to human AD. However, concentrations of IL-34 remained increased in atopic dogs during glucocorticoid or oclacitinib treatment despite the clinical improvement, which may suggest that IL-34 is not of major importance in the pathogenesis of cAD.
据报道，在人AD患者的表皮中，IL-34基因和蛋白的表达显著降低;因此，IL-34被认为可以抑制导致活跃性皮肤病变的炎症级联的传播。与此相反，患AD的家养犬的血清IL-34浓度显著高于健康犬，并且与CADESI-04和pVAS评分呈显著正相关。这些结果可能表明IL-34在犬AD中的作用与人类AD不同。然而，在糖皮质激素或奥拉替尼治疗过程中，IL-34的浓度在临床改善的情况下仍然升高，这可能表明IL-34在cAD的发病机制中并不重要。
Interleukin-36
白介素-36
Interleukin-36 is another cytokine with a recently reported association with AD. IL-36 cytokines (IL-36α, IL-36β, IL-36γ and IL-36 receptor antagonist) are expressed mainly on the barrier sites of the body, such as bronchial, intestinal and dermal epithelium. They are secreted in an inactive form and activated by different proteases upon N-terminal cleavage. The normal function of IL-36 appears to be associated with host defence against pathogenic microbes, especially Staphylococcus aureus, and amplifying inflammatory responses in the skin.
白细胞介素-36是最近报道的另一种与AD相关的细胞因子。IL-36细胞因子(IL-36α、IL-36β、IL-36γ和IL-36受体拮抗剂)主要表达于机体屏障部位，如支气管、肠道和真皮上皮。它们以非活性形式分泌，并在N端切割时被不同的蛋白酶激活。IL-36的正常功能似乎与宿主对病原微生物(尤其是金黄色葡萄球菌)的防御以及皮肤炎症反应的增强有关。
Interestingly, recent RNA-Seq studies in both humans and dogs found a significant upregulation of IL-36 mRNA in AD skin lesions compared to healthy controls.More studies are needed to assess the importance of IL-36 in the pathogenesis of AD and its therapeutic relevance.
有趣的是，最近对人类和犬的RNA-Seq研究发现，与健康对照组相比，AD皮肤病变中IL-36 mRNA的显著上调。需要更多的研究来评估IL-36在AD发病机制中的重要性及其治疗相关性。
Macrophage migration inhibitor factor
巨噬细胞迁移抑制因子
Macrophage migration inhibitor factor (MIF) is an immunoregulatory cytokine ubiquitously expressed on both immune and nonimmune cells.It is involved in T-cell activation and delayed-type hypersensitivity by recruiting and activating macrophages at inflammatory loci; in humans, several studies demonstrated the potential role of MIF in dermatological conditions including AD.
巨噬细胞迁移抑制因子(MIF)是一种普遍表达于免疫和非免疫细胞的免疫调节因子。它通过在炎症位点招募和激活巨噬细胞参与T细胞激活和延迟型超敏反应;在人类中，几项研究证明了MIF在包括AD在内的皮肤病中的潜在作用。
There is one recent study showing that serum MIF concentrations in client-owned dogs with AD were significantly higher compared to healthy controls. However, there was no significant correlation between the MIF concentrations and CADESI-04 or pVAS scores. The role of MIF in the pathogenesis of cAD warrants further studies.
最近的一项研究表明，患有AD的家养犬的血清MIF浓度明显高于健康对照组。然而，MIF浓度与CADESI-04或pVAS评分之间没有显著相关性。MIF在cAD发病机制中的作用有待进一步研究。
Neuropeptides and neurotransmitters
神经肽和神经递质
Emerging studies in human AD have highlighted that the nervous system can reciprocally influence pruritus and skin inflammation. In addition to transmitting itch perception, excitation of itch-mediating skin sensory neurons leads to an axonal and antidromic release of neuropeptides and neurotransmitters, such as nerve growth factor (NGF), substance P (SP) and periostin in the skin.These have been implicated, to varying degrees, in promoting vasodilation and leucocyte-mediated inflammation. This type of inflammation is called ‘neurogenic inflammation,’ and it can potentiate chronic AD. Although this field is new and we have minimal information for dogs, it may have great potential to highlight novel treatment approaches for cAD.
对人类AD的研究表明，神经系统可以相互影响瘙痒和皮肤炎症。除传递瘙痒感觉外，刺激介导瘙痒的皮肤感觉神经元可导致神经肽和神经递质的轴突和逆向释放，如神经生长因子(NGF)、P物质(SP)和骨膜蛋白。这些药物在不同程度上与促进血管舒张和白细胞介导的炎症有关。这种类型的炎症被称为“神经源性炎症”，它会加剧慢性AD。虽然这是一个新领域，我们对犬的信息很少，但它可能有很大的潜力来突出cAD的新治疗方法。
Nerve growth factor
神经生长因子
Nerve growth factor is a neurotrophin that has been reported to have a role in atopic itch. It is mainly produced by keratinocytes and promotes the growth of nerve endings in the skin; thereby, NGF is considered partly responsible for neuronal sensitisation, also known as ‘sensitive skin,’ in human AD patients. In a study in a HDM-induced cAD model, significant upregulation of mRNA expression of NGF in the skin was demonstrated at six hours after allergen exposure yet was followed by a significant decrease at 48 h.In another study in the same model, the number of NGF-positive keratinocytes and the intensity of immunoreactivity were increased in the lesional skin 72 h after epicutaneous exposure to HDM compared to nonlesional or normal skin. The upregulation of NGF also was seen in different cAD models (e.g. antiIgE- and compound 48/80-induced AD models). Likewise, upregulation of NGF mRNA expression has been reported in lesional, yet not in the nonlesional, atopic skin of client-owned dogs. These results indicate that NGF may be involved in the induction of AD flares. Nevertheless, in a pilot cross-over study enrolling five client-owned dogs with AD a proactive injection of ranevetmab (this mAb is no longer under development), an anti-canine NGF monoclonal antibody, did not delay AD flares or pruritus compared to the placebo. This is consistent with the findings of a study with client-owned dogs with AD in which plasma NGF concentrations did not differ from healthy controls.
神经生长因子是一种神经营养因子，据报道在特应性疾病瘙痒中起作用。主要由角质形成细胞产生，促进皮肤内神经末梢的生长;因此，NGF被认为是导致人类AD患者神经元敏化的部分原因，也被称为“敏感皮肤”在一项由HDM诱导的cAD模型研究中，皮肤中NGF的mRNA表达在过敏原暴露后6小时显著上调，但随后在48小时显著降低。在同一模型的另一项研究中，与非皮肤病变或正常皮肤相比，经皮接触HDM后72小时，皮肤病变中NGF阳性角质形成细胞的数量和免疫反应强度增加。NGF的上调也见于不同的cAD模型(例如抗ige和化合物48/80诱导的AD模型)。同样，在家养犬的皮肤病变中，NGF mRNA表达上调，但在非皮肤病变的特应性皮肤中没有报道。这些结果提示NGF可能参与了AD发作的诱导。然而，在一项试验性交叉研究中，与安慰剂相比，主动注射ranevetmab(一种抗犬NGF单克隆抗体)(该mAb已不再研发中)并未延缓AD发作或瘙痒。这与一项对家养的AD犬的研究结果一致，在该研究中，血浆NGF浓度与健康对照组无差异。
Substance P
P物质
Substance P is a neuropeptide proposed as an important mediator of pruritus in AD. It is secreted from free nerve endings in the skin, keratinocytes and various inflammatory cells, and also may induce cutaneous inflammation.
P物质是一种神经肽，被认为是AD患者瘙痒的重要介质。它由皮肤的游离神经末梢、角质形成细胞和各种炎症细胞分泌，也可引起皮肤炎症。
In a recent study of client-owned dogs with AD, RNA-Seq analysis found an upregulation of SP in lesional and not in nonlesional skin compared to healthy dogs.However, mRNA expression did not change in the acute skin lesions of a HDM-induced cAD model. Although maropitant citrate (Cerenia; Zoetis), a SP receptor [neurokinin 1 receptor (NK-1R)] antagonist, decreased skin lesion and pruritus scores in cats with feline atopic skin syndrome, there are no such clinical studies published in dogs. In fact, anecdotal clinical evidence shows a disappointing antipruritic effect of maropitant citrate in this species. Interestingly, a recent mouse study has shown that only mas-related G protein-coupled receptor (Mrgpr), the second receptor of SP, is responsible for pruritus. Therefore, one can speculate that SP-induced itch in dogs also might be induced by the activation of Mrgpr rather than NK-1R. Unfortunately, no information is available on the SP/Mrgprs signalling pathway in cAD at this moment.
在最近一项对家养的AD犬的研究中，RNA-Seq分析发现，与健康犬相比，SP在皮肤病变中上调，而在非皮肤病变中没有上调。然而，在HDM诱导的cAD模型的急性皮肤病变中，mRNA表达没有改变。虽然枸橼酸马罗匹坦(赛瑞宁)是一种SP受体[神经激肽1受体(NK-1R)]拮抗剂，可降低猫特应性皮肤综合征患猫的皮肤病变和瘙痒评分，但目前尚未发表在犬上的此类临床研究。事实上，临床证据表明，枸橼酸马罗匹坦对犬的止痒效果令人失望。有趣的是，最近的一项小鼠研究表明，只有mas相关的G蛋白偶联受体(Mrgpr)是SP的第二受体，与瘙痒有关。因此，我们可以推测sp引起的犬瘙痒也可能是由Mrgpr而不是NK-1R激活引起的。不幸的是，目前还没有关于cAD中SP/Mrgprs信号通路的信息。
Periostin
骨膜蛋白
Periostin is an extracellular matrix protein secreted by fibroblasts, epithelial and endothelial cells. Periostin promotes differentiation and migration of fibroblasts and the proliferation of keratinocytes; thereby, it plays a critical role in the remodelling and repair of damaged tissues.
骨膜蛋白是一种由成纤维细胞、上皮细胞和内皮细胞分泌的细胞外基质蛋白。骨膜蛋白促进成纤维细胞的分化和迁移以及角化细胞的增殖;因此，它在受损组织的重塑和修复中起着至关重要的作用。
Besides these well-known functions, a recent study revealed that periostin can directly activate itch sensory neurons and induce robust itch behaviours in different species, including dogs. Periostin mRNA expression in CPEK and primary canine dermal fibroblasts was significantly upregulated when they were co-cultured with recombinant canine IL-13. Although CPEK might not be representative of atopic skin, these results indicate that periostin may play an essential role in inducing itch in Th2 cytokine milieu, such as AD. In fact, periostin mRNA and protein were highly expressed in the skin of dogs with experimental and spontaneous AD.
除了这些众所周知的功能外，最近的一项研究表明，骨膜蛋白可以直接激活瘙痒感觉神经元，并在不同物种(包括犬)中诱导强烈的瘙痒行为。与重组犬IL-13共培养时，CPEK和犬真皮成纤维原组细胞中Periostin mRNA表达显著上调。虽然CPEK可能不是特应性皮炎皮肤的代表，但这些结果表明，骨膜蛋白可能在Th2细胞因子环境(如AD)中诱导瘙痒的重要作用。事实上，骨膜蛋白mRNA和蛋白在实验性和自发性AD犬的皮肤中高表达。
CONCLUSIONS
结论
Recent studies have identified new therapeutic targets or potential biomarkers in cAD. Notably, IL-31-targeted therapy has become one of the main treatments. However, inconsistent findings in cAD for many cytokines further demonstrate the complexity of the cytokine and chemokine networks in different stages (acute or chronic) of atopic inflammation, and, perhaps, in the pathogenesis of different endotypes of cAD. More comprehensive and structured studies (e.g. at specific disease stages and/or specific defined AD endotypes) are warranted to better understand the precise cytokine and chemokine networks in cAD.
最近的研究发现了新的cAD治疗靶点或潜在的生物标志物。值得注意的是，以IL-31为靶点的治疗已成为主要的治疗手段之一。然而，许多细胞因子在cAD中的不一致结果进一步证明了细胞因子和趋化因子网络在特应性炎症的不同阶段(急性或慢性)，以及可能在不同内型cAD的发病机制中的复杂性。需要更全面和结构化的研究(例如在特异性疾病阶段和/或特定定义的AD内型)以更好地理解cAD中精确的细胞因子和趋化因子网络。
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|Archiver|手机版|小黑屋|宠医帮
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发表于 2023-8-9 13:58:53
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