犬异位性皮炎病理生理机制的研究进展

刘欣

王帆翻译，刘欣校对

犬异位性皮炎病理生理机制的研究进展

Current understanding of the pathophysiologic mechanisms of canine atopic dermatis

Rosanna Marsella, dvm, dacvd; Candace A. Sousa, dvm, dabvp, dacvd;

Andrea J. Gonzales, phd; Valerie A. Fadok, dvm, phd, dacvd

在过去的75年里，我们对犬皮肤病的认识已经发生了巨大的改变。最初在1933年Schnelle称为犬湿疹，后命名犬吸入性过敏性皮炎，再后为犬异位性皮炎。犬异位性皮炎简称为犬AD。

Our thinking about the skin disease in dogs currently called AD has undergone immense changes in the past 75 years. First called eczema in dogs by Schnelle in 1933, it was later termed canine allergic inhalant dermatitis and then canine atopy. The skin disease associated with atopy in dogs is now referred to as canine AD.

自从首次报道该病，人类医学，特别是生物医学科学，对免疫机制的研究取得了巨大进步。基础科学知识已经进入临床医学领域，大大提高了医疗水平。关于人过敏症的大部分知识都能应用到兽医的临床病例上，但应提醒的是——犬不是人。不过，尽管在物种之间，免疫功能在某些方面存在种属差异，但是哺乳动物的免疫功能是非常一致的，人医的有些规律可以应用于兽医病例，应该通过调查和临床研究，小心求证人医的病理生理机制是否适用于兽医面对的物种。为了了解有关犬AD的病理生理机制的当前的知识，必须放弃先入之见，审慎更新循证信息。

Since the first description of this condition, huge strides have been made in human medicine, particularly in the biomedical sciences, with regard to how the immune system works. Basic scientific knowledge has crossed over into the field of clinical medicine, resulting in improved patient care. Much of what is understood about allergies in humans can be applied to veterinary patients, with the caveat that dogs are not humans. Nevertheless, although there are species differences in some of the aspects of immune function among species, mammalian immune function is fairly consistent and some of the principles understood in human medicine can be applied to veterinary patients, always being careful to verify via research and clinical studies that the pathophysiologic mechanisms in humans hold true for species of interest in veterinary medicine. To understand the current knowledge on the pathophysiologic mechanisms of canine AD, preconceived notions must be put aside and the newer evidence-based information examined.

最初研究结果

Where We Started

1933年，Schnelle首次命名了犬湿疹。用12种商用食物过敏原进行过敏划痕试验。当这些犬被喂食了有阳性反应的食物时，它们好像会更痒。

Eczema in dogs was first described in 1933 by Schnelle. Dogs were tested by a scratch test with 12 commercially prepared food allergens. When the dogs were challenged by being fed foods to which they had reacted, they seemed to be more pruritic.

同年晚些时候，Burns发表了一份报告，描述了对25只犬进行21种食物提取物的更广泛测试。对65只犬进行食物提取物的皮内试验，结果为阴性。5只犬被喂食了它们测试呈阳性的食物。只有3只犬出现胃肠道紊乱，只有1只犬出现皮肤症状。

Later that same year, Burns published a report describing more extensive testing with 21 food extracts on 25 dogs. After a negative scratch test result, an intradermal test with food extracts was performed on 65 dogs. Five dogs were fed the food to which they had tested positive. Only 3 reacted with gastrointestinal disturbances, and only 1 dog developed a cutaneous reaction.

1934年，Pomeroy对76只有或没有皮肤病变的犬进行皮内试验。58只没有皮肤病变的犬中有19只（33%）出现阳性反应，18只有皮肤病变的犬中有9只（50%）出现了阳性反应。早期所有这些出现过敏性湿疹的犬的病例都被认为是单纯的食物原因导致的。

In 1934, Pomeroy intradermally tested 76 dogs with and without skin lesions. Positive reactions were seen in 19 of 58 (33%) dogs without skin lesions and 9 of 18 (50%) dogs with skin lesions. All of these early cases of dogs with allergic eczema were believed to be caused by foods alone.

1941年，内科医生Wittich发表了一篇病例报告，报告称一只犬有6年的季节性结膜炎、鼻炎、面部荨麻疹和瘙痒病史，但并不是现在常称的经典的犬AD临床症状。当这只犬换到一个没有花粉的环境时，临床症状就消失了，但当它回到家庭环境时症状复发。这只犬可能吸入了环境过敏原（杂草花粉），导致出现季节性过敏性鼻炎（花粉热），因为动物的眼内和鼻腔内对豚草花粉有刺激反应。Wittich称其为条件性特异性反应。经皮内试验确认过敏原后，进行过敏原特异性免疫治疗（脱敏治疗），第二年临床症状未复发。

In 1941, Wittich, a physician, published a case report of a dog that had a 6-year history of signs of seasonal conjunctivitis, rhinitis, facial urticaria, and pruritus, but not what is typically referred to now as the classic clinical signs of AD in dogs. The clinical signs resolved when the dog was moved to a different pollen-free environment but recurred when returning to its home environment. This dog had possibly inhaled environmental allergens (weed pollens), which may have been the the cause of the seasonal allergic rhinitis (hay fever) because the animal reacted to ophthalmic and intranasal challenges with ragweed pollens. Wittich termed the condition atopy. After intradermal testing to identify the offending allergens, allergen-specific immunotherapy was performed and the clinical signs did not recur the following year.

18年后的1959年，还是一名内科医生Patterson，他在兽医文献中首次发表了关于犬对豚草过敏的文章。同样，主要涉及到上呼吸道的临床症状，主要包括泪溢和结膜炎。患犬瘙痒、前腿和背部屈曲面有红斑和鳞屑性皮炎。将通过皮内试验确定的过敏原进行吸入刺激，发现呼吸道症状加重并出现哮喘。这只犬还出现了呕吐和腹泻，与静脉注射花粉提取物后的全身性过敏反应一致。豚草花粉眼结膜测试呈阳性。这些报告没有提到犬在受到豚草或花粉过敏原刺激后出现任何AD或瘙痒的症状。

Eighteen years later, in 1959, Patterson, also a physician, published the first articles in the veterinary literature on ragweed allergy in a dog. Again, the primary clinical signs involved the upper respiratory tract, consisting primarily of lacrimation and conjunctivitis. The dog was pruritic and had an erythematous and scaly dermatitis on the flexural surface of the forelegs and on the back. Following inhalant challenge with the offending allergens that had been identified with an intradermal test, the respiratory signs worsened and included those of asthma. The dog also developed vomiting and diarrhea consistent with anaphylaxis after IV challenge with the pollen extract. Conjunctival testing with ragweed pollen was positive. These reports do not mention any signs of AD or pruritus in the dog at the time of challenge with the ragweed or pollen allergens.

Patterson和Sparks接着Patterson等人之后，继续发表了这只豚草过敏的犬的血清抗体与花粉过敏的病人的皮肤致敏抗体的特性相同。同样，在这些报告中关注的临床症状是哮喘和全身性过敏反应，而不是AD。并且皮内试验结果为阳性。

Patterson and Sparks followed by Patterson et al went on to show that this same dog with ragweed hypersensitivity had a serum antibody with the same characteristics as human skin-sensitizing antibody from patients with pollen allergy. Again, the clinical signs noted in these reports were signs of asthma and anaphylaxis, not AD, and were confirmed with a positive intradermal test result.

所有这些观察结果都支持了这样一个事实，即当犬接触空气中的花粉过敏原时，能产生一种特异性过敏原抗体，当再次暴露时可能发生的临床症状与过敏性结膜炎、鼻炎、哮喘和全身性过敏反应一致。皮肤过敏反应可以通过皮内试验阳性结果得以证实，但是在早期报告中描述的犬都没有典型的AD临床症状。所描述的临床症状都与已知的I型超敏反应一致：哮喘、结膜炎、荨麻疹、瘙痒、全身性过敏反应，以及可能发生血管神经性水肿。

All of these observations supported the fact that dogs could produce an allergen-specific antibody after aerosolized allergen exposure to pollens and that with reexposure, clinical signs consistent with atopic conjunctivitis, rhinitis, asthma, and anaphylaxis could occur. Skin sensitivity could be confirmed with a positive intradermal test, but none of the dogs described in these early reports had classical clinical signs of AD. The clinical signs described were all consistent with what is known to be a type I hypersensitivity reaction: asthma, conjunctivitis, urticaria, pruritus, anaphylaxis, and possibly angioedema.

根据这些过敏性疾病患犬的早期描述，在1965年，Schwartzman开始将有过敏性上呼吸道疾病和瘙痒症状的犬归为一类，诊断为异位性皮炎。瘙痒性皮肤病的一个简单的病理生理机制被接受。犬会通过呼吸道途径或经皮肤吸收对环境过敏原产生过敏反应。这将触发产生过敏原特异性IgE抗体。这种抗体会与真皮中的肥大细胞和嗜碱性细胞结合。再次接触过敏原会导致肥大细胞和嗜碱性细胞脱颗粒，并释放出含有像组胺、血清素和嗜酸性细胞趋化因子的物质。这些炎性细胞因子导致患犬出现临床可见的红斑和瘙痒。犬异位性皮炎随后成为皮肤科医生诊断和治疗的一种疾病，如果存在呼吸道症状，则被认为是偶发性病例。这种对犬异位性皮炎反应机理的简要说明，多年来一直是公认的理论。（图1）

From these early descriptions of atopic disease in dogs, in 1965, Schwartzman began to group together dogs with signs of allergic upper respiratory disease and pruritus under the diagnosis of atopy. A simple pathophysiologic mechanism of the pruritic skin disease was accepted. Dogs would become sensitized to environmental allergens either by the respiratory route or by percutaneous absorption. This would trigger the production of allergen-specific IgE antibodies. These antibodies would bind to mast cells and basophils in the dermis. Reexposure to the offending allergen would result in the degranulation of the mast cell or basophil and the release of their contents, such as histamine, serotonin, and eosinophil chemotactic factor. These inflammatory cytokines caused the erythema and pruritus seen clinically in affected dogs. Atopic disease in dogs then became a disease that dermatologists diagnosed and treated, and if a respiratory component existed, it was considered an incidental finding. This simplified explanation of the mechanism of canine atopy remained the accepted dogma for many years (Figure 1).

图1——历史上公认的犬AD病理生理机制的描述。当皮肤发生I型超敏反应表现时，过敏原特异性IgE抗体与皮肤里的肥大细胞表面相结合。当再次接触过敏原时，通常是通过吸入途径，过敏原交联2个IgE分子，导致肥大细胞脱颗粒并释放出预先形成的介质，像是能引起炎性反应和瘙痒的组胺。

Figure 1—Depiction of the historically accepted pathophysiologic mechanism of canine AD. As a cutaneous manifestation of a type I hypersensitivity reaction, allergenspecific IgE antibodies bind to the surface of the mast cell in the skin. At the time of reexposure to the allergen, usually via the inhaled route, the allergen cross-links 2 IgE molecules, causing the mast cell to degranulate and release preformed mediators such as histamine that cause inflammation and pruritus.

刘欣

目前研究成果

Where We Are Now

IgE和组胺在犬和人AD中的作用——在20世纪70年代，首次描述了犬IgE，并表明具有与人IgE相似的特性。在1973年，Halliwell首次报道了临床症状正常的犬皮肤IgE。证明免疫球蛋白E位于犬皮肤的肥大细胞表面，提示其参与了犬AD的发病机制。几年后，进一步阐明了犬IgE的理化性质。

Role of IgE and histamine in AD in dogs and humans—Canine IgE was first described in the 1970s and was shown to have properties similar to human IgE. In 1973, Halliwell was the first to report on IgE in the skin of clinically normal dogs. Immunoglobulin E was shown to be localized to the surface of cutaneous mast cells in canine skin, suggesting its involvement in the pathogenesis of canine AD. Several years later, the physiochemical properties of canine IgE were further elucidated.

在这些报道之后，用很多种过敏原对瘙痒犬进行皮内试验，结果显示犬对许多过敏原提取物的皮内试验都有反应，包括室内灰尘、来自树木、杂草和牧草的花粉、表皮抗原和来自各种食物和木棉的抗原杂项。这些报道中的有些犬只有AD的临床症状，但其他犬检查出有季节性过敏性鼻炎或哮喘的临床症状。不幸的是，直到1982年8月，使用25种过敏原提取物的6倍稀释液，包括室内灰尘、7种食物、2中霉菌混合物、多种树木和杂草花粉和各种各样的过敏原，对90只没有AD临床症状的犬进行皮内试验。该研究表明，使用标准皮内测试浓度（1500个蛋白质氮单位/ml）时，90%的犬的皮内试验对尘螨过敏原反应呈阳性，使用最低浓度（250个蛋白质氮单位/ml）时，60%的犬的皮内试验对尘螨过敏原反应呈阳性。用其他几种过敏原进行测试，在最低测试浓度时也会出现阳性反应。本研究证实临床正常的犬可能出现亚临床反应。1995年，Codner 和Tinker根据制造商推荐的说明进行测试发现，临床正常的犬中有50%至58%的犬对尘螨(1:5,000 wt/vol)和室内灰尘（100蛋白质氮单位/ml）的皮内试验结果呈阳性。异位性皮炎一词在兽医文献中出现了大约40年后，而皮内试验作为诊断犬AD的常规手段也已经使用了大约20年后，这些结果才被报道。

Subsequent to these reports, intradermal testing of pruritic dogs with a wide variety of antigens revealed that dogs reacted to intradermal tests involving numerous allergenic extracts, including house dust; pollens from trees, weeds, and grasses; epidermal antigens; and miscellaneous antigens from various foods and kapok. Some of the dogs included in these reports had clinical signs consistent with AD, whereas others were examined for clinical signs of seasonal allergic rhinitis or asthma. Unfortunately, it was not until 1982 when August intradermally tested 90 dogs with no clinical signs of AD with 6 dilutions of 25 allergenic extracts, including house dust, 7 foods, 2 mold mixtures, a variety of tree and weed pollens, and miscellaneous allergens. That study demonstrated positive intradermal test reactivity to house dust mite allergens in 90% of the dogs at a standard intradermal testing concentration (1,500 protein nitrogen units/mL) and in 60% of the dogs at the lowest concentration (250 protein nitrogen units/mL). Testing with several of the other allergens also resulted in positive reactions at the lowest test concentration. This study confirmed that subclinical reactions could occur in clinically normal dogs. In 1995, Codner and Tinker showed that 50% to 58% of clinically normal dogs had positive intradermal test results to house dust mites (1:5,000 wt/vol) and house dust (100 protein nitrogen units/mL) when tested as per the manufacturer’s recommendation. These results were reported about 40 years after the term atopy was used in the veterinary literature and about 20 years after intradermal testing was used routinely as a means to diagnose AD in dogs.

更有意思的是，现在人们已经认识到，有些患有AD的犬（和人），针对常见过敏原，不论皮内试验还是血清学试验，都不能测出过敏原特异性IgE。一项研究结果表明，在82只犬中21只(26%) AD患犬发生了这种情况。这些发现提示这些犬可能没有过敏反应或对常见过敏原不过敏。在人医中，异位样皮炎、本质性AD或无过敏反应性AD等术语，都用来描述这类病例（约10%），在这类病例中，存在典型的AD临床症状，但没有复发规律，也没有能证明过敏反应的皮肤过敏原特异性IgE。在这类人医病例中，有人推测，检测不到过敏原特异性IgE可能代表了AD的早期阶段，这一阶段过敏原的致敏作用还尚未发生。但是在其他个例中，似乎可以通过不依赖IgE的别的途径发生AD。还有的推测，这些病例可能对一组尚未明确的小众过敏原有反应。目前尚不明确上述情况是否同样适用于犬。

Even more interestingly, it is now recognized that there are dogs (and people) with AD for which no allergen-specific IgE can be identified with either intradermal testing or allergen-specific IgE serologic testing directed against common allergens. One study documented this fact in 21 of 82 (26%) consecutive dogs with AD. These findings raise the possibilities that these dogs were not allergic or they were not allergic to routinely tested allergens. In human medicine, the terms atopic-like dermatitis, intrinsic AD, or nonallergic AD have been used to describe a subset of patients (approx 10%) in which classic clinical signs of AD are present but no circulating nor cutaneous allergen-specific IgE can be demonstrated against major allergens. In some of these human patients, it is speculated that the absence of detectable allergenspecific IgE may represent the early stages of AD in which allergic sensitization has not yet occurred. In other individuals, however, it appears that AD can occur through alternative pathways that are not IgE dependent. It can also be speculated that these people could be reactive to a group of minor allergens that remain unidentified. Whether the same applies to dogs is unknown at this time.

同样，重点要说明在没有AD临床症状的犬身上能检测到过敏原特异性IgE，并且IgE检测不能用于鉴别犬未来会不会发病。

It is also important to point out that allergen-specific IgE may be detected in dogs that do not have clinical manifestations of AD and that measurement of IgE does not help to discriminate between dogs that will later develop disease and dogs that will not.

同样，IgE检测不能用与鉴别异位性皮炎犬、临床正常犬和患寄生虫病的犬。就此可推测出并非所有IgE都具有致病性。总而言之，这些考虑因素突出了这样一个事实：最初认为AD仅仅是IgE介导的过敏性疾病，并不能完全解释这一复杂疾病的发病机制，需要新的定义及方法。

Similarly, measurement of IgE is not helpful in discriminating between atopic dogs, clinically normal dogs, and dogs with parasitic diseases. It may be speculated that not all IgE is pathogenic. Altogether, these considerations highlight the fact that the initial view of AD as solely an IgE-mediated allergic disease does not completely explain the pathogenesis of this complex disease and that new definitions and approaches are needed.

犬和人的异位性皮炎和异位样皮炎的定义——在2001年，美国兽医学院犬异位性皮炎研究小组认可的异位性皮炎的定义是“一种具有遗传倾向的，能对环境过敏原产生IgE介导的过敏反应”。环境中使机体发生过度反应或异常反应的蛋白质称为过敏原，包括花粉、霉菌、粉尘、皮屑、螨虫，某些情况下还包括昆虫、化学物质和食物。

Definitions of atopy, AD, and atopic-like dermatitis in dogs and humans—In 2001, the American College of Veterinary Medicine Task Force on Canine Atopic Dermatitis accepted the definition of atopy as “a genetically predisposed tendency to develop IgE-mediated allergy to environmental allergens.” The environmental proteins to which the body overreacts or reacts in an abnormal manner are called allergens and include pollens, molds, dusts, danders, mites, and, in some cases, insects, chemicals, and foods.

异位性皮炎的发病机制是由许多遗传因素和环境因素共同作用的结果。倾向于IgE介导的过敏反应的病例称为特异性过敏症，这种情况定义为是典型的I型超敏反应。在人医中，临床上把季节性过敏性鼻炎、哮喘和AD三者通常特异性过敏反应，但是在犬上，特异性季节性过敏性鼻炎或哮喘很少被确诊。

The pathogenesis of atopy is mediated by numerous genetic as well as environmental factors. Patients prone to IgE-mediated allergic reactions are said to be atopic, and the condition is classically defined as a type I hypersensitivity. In humans, atopy comprises the clinical triad of seasonal allergic rhinitis, asthma, and AD, whereas in dogs, atopic seasonal allergic rhinitis or asthma is rarely diagnosed.

根据国际犬异位性皮炎研究小组在2006年的报道，目前公认的犬AD定义（以前称为吸入性过敏性皮炎、季节性过敏症、环境过敏症和特应性皮炎），即一种具有遗传倾向的炎性和瘙痒性过敏性皮肤病，产生与典型临床特征相关的IgE抗体直接对抗环境过敏原。这被称作AD的外因形式。

As per the International Task Force on Canine Atopic Dermatitis in 2006, the currently accepted definition for canine AD (previously known as allergic inhalant dermatitis, seasonal allergy, environmental allergy, and atopy) is a genetically predisposed inflammatory and pruritic allergic skin disease with characteristic clinical features associated with IgE antibodies most commonly directed against environmental allergens. This is referred to as the extrinsic form of AD.

犬异位样皮炎也被确认和定义为，一种炎性和瘙痒性皮肤疾病，其临床特征与犬AD相同，且无法证实IgE对环境或其他过敏原有反应。在过敏原特异性IgE的文献中，仅仅通过皮内或血清学试验未检测到过敏原特异性IgE，并不能证明环境或其他过敏原不参与其发病机制。有些人把这称为该病的内因形式。

Canine atopic-like dermatitis has also been recognized and defined as an inflammatory and pruritic skin disease with clinical features identical to those seen in canine AD, in which an IgE response to environmental or other allergens cannot be documented. Lack of documentation of allergen-specific IgE does not imply that environmental or other allergens are not involved in the pathogenesis, but simply that allergen-specific IgE has not been identified against the common allergens by intradermal or serologic testing. Some equate this with what is now called the intrinsic form of the disease.

人的异位性皮炎定义并不明确，被描述为一种免疫介导的皮肤炎症反应，有遗传和环境因素相互作用引起。一项研究结果表明，遗传性表皮屏障功能缺陷是导致人AD的主要原因；认为丝聚蛋白基因缺陷是最重要的发病因素之一。人的主要临床症状是红斑和瘙痒；皮肤病变范围从轻度红斑到严重苔藓样变。外因型AD（70%到80%病例）是当接触环境过敏原时，触发免疫学反应，有遗传倾向的人通常发生过敏反应（例如，IgE介导）。内因型AD没有IgE介导。内因型AD是非遗传性和特发性的，且其病理生理特征通常尚不明确。在人医中，目前认为AD的内因形式可能是AD发生的最初阶段，在所有过敏反应发生前。

Atopic dermatitis in humans is poorly defined and is described as an immune-mediated inflammation of the skin arising from an interaction between genetic and environmental factors. Findings of 1 study indicate that a heritable epidermal barrier defect is a primary cause of AD in humans; a defect in the filaggrin gene is specifically implicated as one of the most important risk factors. Erythema and pruritus are the primary clinical signs in humans; skin lesions range from mild erythema to severe lichenification. Extrinsic AD (70% to 80% of cases) occurs when environmental exposures trigger immunologic, usually allergic (ie, IgE-mediated) reactions in genetically susceptible people. Intrinsic AD is not mediated by IgE. Intrinsic AD is nonfamilial and idiopathic, and its pathophysiologic features are generally not well understood. In human medicine, it is currently suggested that the intrinsic form of AD may represent the initial step of AD, before any allergic sensitization has occurred yet.

对犬AD的认识——目前人们普遍认为，犬AD与人AD相似，是一种由遗传和环境因素共同决定的多方面疾病，这些因素通过原发和继发的形式，既影响免疫反应，也影响皮肤屏障功能。

Understanding AD in dogs—It is now accepted that canine AD, similar to the human counterpart, is a multifaceted disease determined by a combination of genetic and environmental factors affecting both the immunologic response as well the skin barrier function to be either a primary or secondary aspect.

IgE和其他反应性抗体的参与

Involvement of IgE and other reaginic antibodies

最初的研究重点大多集中在过敏原的体液反应上（主要是IgE）。这一观点影响了这种疾病的定义（是一种导致肥大细胞脱颗粒的I型超敏反应）和最常用的治疗方法之一（例：抗组胺药）。

Most of the initial research emphasis had been placed on the humoral response (mostly IgE) to allergens. This view affected both the definition of this disease (as a type I hypersensitivity with consequent mast cell degranulation) and one of the most commonly used treatment options (eg, antihistamines).

在犬IgE最初被发现后，大量的后续研究证实了AD患犬体内有过敏原特异性IgE，包括皮内试验和过敏原特异性IgE体外试验。虽然IgE可能参与了大多数犬AD的发病机制，但该病的发展可能取决于一系列其他因素，包括T细胞亚群极化、肥大细胞脱颗粒作用改变和屏障功能缺陷。在犬AD的发病机制中，也曾提过过敏原特异性IgG的作用，但现在其他作者认为这种作用有争议。随着研究的深入，已经明确IgE只是其中的一部分，尽管IgE在AD的传入阶段和诱导阶段都起着重要的作用，但IgE本身并不能解释这种复杂疾病的所有方面。虽然目前公认的IgE不仅能扩大和提高过敏原的捕获效率，而且能参与导致炎性反应，但是AD可能检测不到过敏原特异性IgE。

After the initial discovery of canine IgE, extensive subsequent research demonstrated the presence of allergen-specific IgE in dogs with AD and involved the use of both intradermal tests and in vitro allergen-specific IgE assays. But although IgE may be involved in the pathogenesis of most cases of canine AD, the development of the disease is likely to be dependent on a range of other factors that may include T-cell subpopulation polarization, altered mast cell releasability, and defective barrier function. A role for allergen-specific IgG in the pathogenesis of canine AD had also been proposed, but this is now regarded as controversial by other authors. As research progressed, it was clear that IgE was only a piece of the puzzle and that although IgE plays an important role in AD in both the afferent phase and the elicitation phase, IgE per se cannot explain all aspects of this complex disease. Although it is currently accepted that IgE amplifies and increases the efficiency in capturing the allergen as well as participates in the inflammatory response that results, AD can manifest in the absence of detectable allergen-specific IgE.

I型超敏反应

type I hypersensItIvIty

I型过敏反应的临床表现为全身性过敏反应、过敏性哮喘、荨麻疹、血管神经性水肿、过敏性鼻炎、某些类型的药物反应和AD。这些反应通常由IgE介导，与不依赖IgE的肥大细胞和嗜碱性细胞脱颗粒作用的类过敏反应不同。有趣的是，最经典的I型超敏反应（全身性过敏反应、哮喘）并不痒，但其他情况比如过敏性荨麻疹和鼻炎会痒。组胺是由肥大细胞和嗜碱性细胞产生的预制分子之一，高浓度存在于周围结缔组织中。其主要功能是导致血管扩张，引起炎性反应。组胺被释放出来，作为对外来病原体的免疫反应的一部分。它增加了毛细血管对白细胞和其他蛋白质的通透性，允许它们在感染组织中与入侵的外源物质对抗。

Type I allergic reactions manifest clinically as anaphylaxis, allergic asthma, urticaria, angioedema, allergic rhinitis, some types of drug reactions, and AD. These reactions tend to be mediated by IgE, which differentiates them from anaphylactoid reactions that involve IgE-independent mast cell and basophil degranulation. Interestingly, the most classic type I hypersensitivity reactions (anaphylaxis, asthma) are not pruritic, although other conditions such as allergic urticaria and rhinitis can be. Histamine is one of the preformed molecules produced in high concentrations by mast cells and basophils found in nearby connective tissues. Its major function is to cause vasodilatation, and it also triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is released. It increases the permeability of the capillaries to WBCs and other proteins to allow them to engage foreign invaders in the affected tissues.

H1组胺受体存在于平滑肌、内皮细胞和中枢神经系统组织中。组胺的结合导致血管扩张、支气管收缩、支气管平滑肌收缩、内皮细胞分离（导致荨麻疹）和昆虫叮咬后的疼痛和瘙痒反应。H1组胺受体是引起过敏性鼻炎和晕动症临床症状的主要受体。

H1 histamine receptors are found on smooth muscle, endothelium, and CNS tissue. Binding of histamine causes vasodilatation, bronchoconstriction, bronchial smooth muscle contraction, separation of endothelial cells (responsible for hives), and pain and itching in response to an insect sting. H1 histamine receptors are the primary receptors involved in the clinical signs of allergic rhinitis and motion sickness.

组胺作为犬AD瘙痒的主要介质，其重要性存在争议。虽然AD的传统观念认为，组胺是一个关键的调节因子，但是在一项研究中，通过检测血浆组胺浓度发现健康犬和AD患犬的组胺浓度相似。与正常犬相比，AD患犬的皮肤组胺浓度更高，但与血浆组胺浓度无关。在另一项研究中，未证实犬注射组胺后瘙痒行为增加。这两项研究结果进一步支持了AD不该被简单地认为是I型超敏反应。

The importance of histamine as a major mediator of pruritus in dogs with AD is controversial. Although the traditional view of AD would have suggested that histamine was a key mediator, a study in which plasma histamine concentrations were measured found that the concentrations in healthy dogs and dogs with AD are similar. Cutaneous histamine concentrations were shown to be greater in dogs with AD than in clinically normal dogs, but they did not correlate with the plasma histamine concentrations. In another study, dogs injected ID with histamine did not demonstrate an increase in pruritic behavior. The results of both of these studies further support the concept that AD should not be simplified as a type I hypersensitivity.

细胞因子、淋巴细胞和免疫异常

cytokInes, lymphocytes, and ImmunologIc abnormalities

很明显，T淋巴细胞在犬AD中起着关键作用，T细胞数量的不均衡是疾病不同阶段的特征（例如，急性期以Th2为主，慢性期以Th1为主）。与临床表现正常犬相比，完整的粉尘螨抗原或从螨虫中提纯的主要过敏原，能刺激外周血中的单核细胞，导致异位性皮炎的犬发生过敏原特异性反应。因此，加强关于细胞因子失衡的研究更重要，虽然人医的发现与犬并不完全相同，但是通过测量细胞因子转录子确定，证实异位性皮炎的犬也存在T细胞因子极化反应。这些研究表明，异位性皮炎犬在无病变表现的异位性皮炎的皮肤中存在以IL-4过表达，这是一种Th2为主的细胞因子反应。已知白介素-4是IgE产生的主要调节因子。与临床表现正常犬相比，异位性皮炎犬也有低mRNA表达的免疫抑制型细胞因子转化生长因子β。后一项发现如果得到证实，则可能解释AD患犬对环境过敏原不耐受的原因。在异位性皮炎的皮肤病变部位，可简单描述为Th1细胞因子的一种混合型细胞因子转录作用，比如IL-2、干扰素-γ和肿瘤坏死因子-α，以及IL-4过表达。这表明在慢性皮肤病变中，可见Th1-Th2的混合反应，可能与自我损伤或继发感染有关。一旦建立了犬AD的实验模型，就可以通过特异性斑片实验模型，评估过敏原诱导皮肤病变的细胞因子转录动力学。这些研究结果表明，细胞因子转录模式随着双相反应的改变而改变。具体而言，Th2细胞因子可能在急性期（接触过敏原后12至24小时）发挥更重要的作用，而Th1细胞因子可能与慢性期（接触过敏原后48至96小时）更相关。这种过程的动态性质，可以解释临床病例研究结果的差异性，在这些研究中，具体病变在动态过程中何时出现尚不明确。然而，在明确细胞因子在犬AD中作用之前，还需要进一步研究来证明存在生物活性细胞因子。

It became evident that T lymphocytes play a critical role in canine AD and that an imbalance in the T-cell populations characterizes different stages of the disease (eg, Th2 predominance in the acute phase vs Th1 in the chronic phase). Stimulation of peripheral blood mononuclear cells by whole Dermatophagoides farinae antigens, or purified major allergens from the mite, resulted in an antigen-specific response in atopic dogs, compared with clinically normal dogs. Great importance was therefore placed on studies focusing on cytokine imbalances, and although dogs did not completely mirror the findings in human medicine, it was demonstrated that a polarization of the T-cell cytokine response may also exist in atopic dogs, as determined  by measurement of cytokine transcripts. These studies showed that atopic dogs have a Th2dominated cytokine response in nonlesional atopic skin in which IL-4 is overexpressed. Interleukin-4 is known to be a major regulatory factor in the production of IgE. Atopic dogs also have low mRNA expression of the immunosuppressive cytokine transforming growth factor-β, compared with clinically normal dogs. This latter finding, if substantiated, provides a possible explanation for the lack of tolerance to environmental allergens in dogs with AD. In lesional atopic skin, a mixed cytokine transcription profile is seen in which Th1 cytokines such as IL-2, interferon-γ, and tumor necrosis factor-α as well as IL-4 are overexpressed. This suggests that in chronic skin lesions, a mixed Th1-Th2 response is seen, possibly associated with self-trauma or secondary infection. Once an experimental model for canine AD was established, it was possible to evaluate the kinetics of cytokine transcription involved in the allergen-induced lesions via the atopy patch test model. Results of those studies show that the cytokine transcription pattern changes over time with a biphasic response. More specifically, Th2 cytokines may play a more important role in the acute phase (12 to 24 hours after allergen exposure), whereas Th1 cytokines may be more relevant in the chronic phase (48 to 96 hours after allergen exposure). The dynamic nature of the process may help explain the variability in the results reported in studies involving clinical patients in which it is unknown when specific lesions actually started within the dynamic process. Further research to demonstrate the presence of biologically active cytokines is required, however, before the role of cytokines in canine AD can be actively determined.

白三烯

Lts

兽医病例很少有测量皮肤LT浓度的研究报道。在一项研究中，测量了犬多种炎性皮肤病中（脓皮病、皮脂溢、AD和跳蚤过敏）的皮肤LTB4浓度，发现在这些情况下的含量都很高。研究发现，LTB4浓度与瘙痒程度呈正相关性。在犬AD的诊断中，缺乏特异性LT的测量并不能降低这些发现的病理学意义，因为不同疾病可能引发相似的炎症反应。

Few studies have been performed to measure cutaneous LT concentrations in veterinary patients. In 1 study, cutaneous LTB4 content was measured in dogs with a variety of inflammatory skin diseases (pyoderma, seborrhea, AD, and flea allergy) and was found to be high in all of these conditions. A positive correlation between LTB4 concentrations and the degree of pruritus was found in that study. The lack of specificity of LT measurement in the diagnosis of canine AD does not lessen the pathogenic implications of these findings because different diseases may trigger similar inflammatory responses.

在一项初步研究中，使用生理盐水溶液（0.9%NaCl）、脂多糖和一种参照过敏原进行刺激，对AD犬和健康对照犬的皮肤产生的硫化LT进行评估。两组间对所有刺激物发应产生的硫化LT无明显差异。临床表现正常的犬与无皮肤病变的AD患犬之间皮肤产生的硫化LT无差异；同样，在AD患犬中，发现在有皮肤病变和无皮肤病变的犬之间产生的硫化LT无差异。虽然是预备研究，但这些结果并不支持硫化LT在犬AD中起作用。

In a pilot study, sulphido-LT production in the skin of dogs with AD and healthy control dogs was evaluated after stimulation with saline (0.9% NaCl) solution, lipopolysaccharide, and a reference allergen. No significant difference in sulphido-LT production was found between groups in response to any of the stimuli. No difference in sulphido-LT production was detected in the skin between clinically normal dogs and dogs with AD with no skin lesions; similarly, no difference in sulphido-LT production was found between dogs with AD that did and did not have skin lesions. Although preliminary, these results do not support a role for sulphido-LT in canine AD.

相比之下，LT在AD发病机制中的重要意义在于通过使用必需脂肪酸治疗可能有良好效果。这种治疗的其中一种作用机制是，必需脂肪酸与花生四烯酸对环氧化酶和脂氧化酶的竞争，导致LT合成的改变和减少高促炎产物（例：LTB4）。

By contrast, the importance of LT in the pathogenesis of AD is suggested by the possible beneficial effects of treatment with essential fatty acids. One of the proposed mechanisms of action of such treatment is the competition of the essential fatty acids with arachidonic acid for cyclooxygenase and lipoxygenase enzymes, resulting in a modification of LT synthesis and reduction of highly proinflammatory products (eg, LTB4).

有关LT在犬AD中的重要意义仍存在争议。最终，AD似乎无法通过单一介质、抗体或细胞因子得到解释，但它是多种介质共同作用的结果，这些介质都参与最后的炎性反应过程。

Controversies still exist on the importance of LT in canine AD. Ultimately, it appears that AD cannot be explained with a single mediator, antibody, or cytokine, but it is the result of a multitude of mediators that all contribute to the final inflammatory process.

皮肤屏障功能异常

abnormalities in the barrier function of the skin

最近的研究重新发现了皮肤屏障受损在人AD中的重要性。虽然早就认识到过敏原在人AD发病机制中的作用，但皮肤屏障受损与环境过敏原结合有助于解释IgE对过敏原的反应。众所周知，如果受损皮肤反复接触一种物质，随后IgE对这种物质会做出反应。因此，IgE、过敏原和皮肤屏障损伤都是能导致相同临床症状的不同重要方面。

Recent research has rediscovered the importance of an impaired skin barrier in humans with AD. Although the role of allergens in the pathogenesis of AD in humans has been known for a long time, the combination of impaired skin barrier with allergen exposure has helped explain the development of an IgE response to the offending allergens. It is indeed known that if a substance is repetitively applied on a disrupted skin, an IgE response to such substance will ensue. Therefore, the IgE, allergens, and skin barrier impairment are all different and important aspects of the same clinical syndrome.

能证明AD患犬的皮肤屏障功能障碍的证据迅速增加。在最初的预备研究中，记录了患有自然发病的异位性皮炎犬的表皮上层的超显微结构不规则（例如：皮脂层薄且不连续），最近的几项研究描述了皮肤屏障功能的超显微结构和功能的变化。这些研究是针对自然发病的AD犬和实验室诱导的AD犬进行的。这些损害是通过经表皮水分丢失的增加，进行超显微结构和功能测量的。具体而言，据报道，角质层超显微结构的改变，在无病变表现的异位性皮炎的皮肤上原本就存在，并在接触过敏原和产生皮肤病变之后加重。包括细胞间隙扩大以及片层小体在角质细胞内的残留，以及皮脂腺的不规则和破裂。这些改变与人AD的报道惊人的相似，报道认为片层小体被扰动挤出是导致这些细胞器残留在角质细胞内的原因。

Evidence of skin barrier dysfunction in dogs with AD has also been rapidly building. After an initial pilot study documented irregularities (eg, lipid lamellae thinning and discontinuity) in the ultrastructure of the upper layers of the epidermis of atopic dogs with naturally occurring disease, several more recent studies have described both ultrastructural as well as functional changes of the skin barrier function. These studies were performed on dogs with naturally occurring AD as well as dogs with experimentally induced AD. These impairments are both ultrastructural and functional as measured by increased transepidermal water loss. More specifically, ultrastructural changes in the stratum corneum were reported to be already present in nonlesional atopic skin and were aggravated after allergen exposure and development of skin lesions. These included widening of the intercellular spaces as well as retention of lamellar bodies in the corneocytes and irregularities and fragmentation of lipid lamellae. These changes are strikingly similar to the ones reported in humans with AD, in which a disturbed extrusion of lamellar bodies is thought to be responsible for the retention of these organelles inside the corneocytes.

在人AD中，超显微结构改变伴随着表皮神经酰胺的减少。多种酶的改变而导致降解增加，可以解释这种减少的原因。先前的研究结果表明，犬异位性皮炎也有神经酰胺减少，但目前还不清楚这是因为酶的改变、细胞器扰动挤出，还是两者都有。此外，目前还不清楚无病变表现犬的皮肤超显微结构改变，是因为原发性缺失还是继发性亚临床炎症反应。我们清楚的是，皮肤已经经表皮水分丢失已经增加，因此通透性增加，特别是在幼犬中。在人医中，异位性皮炎的通透性增加，以及对Th2反应的遗传倾向，在增加过敏原通透和过敏性致敏风险方面起着重要作用。由于经皮途径在犬AD接触过敏原中很重要，因此在人AD发病机制中提出的类似情况也适用于犬。

In humans with AD, the ultrastructural changes are accompanied by a decrease in epidermal ceramides. This decrease has been explained by increased degradation due to multiple enzymatic alterations. Results from previous studies indicate that atopic dogs also have decreased ceramides, but it is presently unknown whether this is due to an enzymatic alteration, a disturbance in organelle extrusion, or both. Also, it is presently unknown whether the ultrastructural changes noted in canine nonlesional skin are due to a primary defect or are secondary to subclinical inflammation. What is known is that the skin has increased transepidermal water loss and is therefore more permeable, particularly in young dogs. In humans, it is proposed that the increased permeability of atopic skin combined with genetic predilection toward a Th2 response plays an important role in increasing the allergen penetration and the risk for allergic sensitization. Because the percutaneous route of allergen exposure appears to be important in dogs, it is possible that a similar scenario as that proposed for the pathogenesis of AD in humans may also apply to dogs.

过敏原递呈和加工过程

routes of allergen presentation and processing

在早期犬AD的报道中，这种疾病被称为过敏性吸入性皮炎。虽然一些瘙痒（过敏）皮肤病患犬身上可以见到呼吸道症状，但这种报道很不常见。通过吸入接触过敏原在犬AD已被证实，但是这似乎不是主要的接触过敏原途径。最近的研究已经提供证据，证明在AD患犬身上最重要的过敏原递呈途径是通过皮肤发生的。这也许可以解释在患犬身上临床病变分布情况。一般情况下，四肢的病变和瘙痒情况更严重，尤其是腕部和跗关节尾侧、腹侧、嘴周和眼周皮肤，以及耳廓。这些研究证实了异位性皮炎患犬的皮肤表皮中有朗格罕氏细胞群增生。朗格罕氏细胞是表皮中主要的抗原递呈细胞，存在于患病皮肤中，强烈提示他们会接触到穿透皮肤屏障的过敏原。这些细胞很可能将经过加工的抗原递呈给T淋巴细胞，从而引起免疫反应。患犬表皮存在γδ T细胞也证明外部有抗原刺激。研究发现异位性皮炎患犬表皮屏障缺陷，这一发现进一步支持了抗原的进入途径。研究实验室小鼠和犬的诱导型AD后发现，当皮肤屏障受损时，皮肤反复接触过敏原会引发Th2反应并导致皮炎发生。对犬AD早期病变的免疫组化研究发现，接触过敏原部位的树突状细胞有明显积累。这些CD1c+细胞对IgE呈阳性。因此，IgE可以提高捕获皮肤中过敏原的效率。

In early reports of dogs with AD, the disease was termed allergic inhalant dermatitis. Although respiratory signs can be seen in some dogs with pruritic (allergic) skin disease, this is uncommonly reported. The inhalant route of allergen exposure has been shown to contribute to AD in dogs but does not appear to be the main route of allergen exposure. Recent studies have provided evidence that the most important route of allergen presentation in dogs with AD occurs percutaneously. This might explain the distribution of the clinical lesions seen in affected dogs. In general, lesions and pruritus are worse on the limbs, particularly the caudal aspect of the carpus and tarsus, ventral aspect of the abdomen, perioral and periocular skin, and pinnae. These studies have demonstrated hyperplasia of the epidermal Langerhans cell population in lesional skin of atopic dogs. Langerhans cells represent the chief antigen-presenting cell in the epidermis, and their presence in diseased skin strongly suggests that they are exposed to allergens that have penetrated the skin barrier. These cells are likely to present processed antigen to T lymphocytes, thus initiating the immune response. The presence of γδ T cells in the epidermis of affected dogs also provides evidence that there is localized antigenic stimulation. The finding that atopic dogs have a defective epidermal barrier adds further support to this proposed route of antigen challenge. Studies in mice and dogs with experimentally induced AD have demonstrated that repeated epicutaneous exposure to allergen when the skin barrier is impaired triggers a Th2 response and leads to the development of dermatitis. Immunohistochemical studies of early lesions of canine AD highlight the accumulation of dendritic cells at the site of allergen exposure. These CD1c+ cells are also positive for IgE. Thus, IgE is used as a way to increase the efficiency in the capture of the allergen after epicutaneous exposure.

继发感染的皮肤屏障的作用

role of secondary infections and skin barrier

反复发生的继发感染也增加了犬AD的管理难度，加重了临床症状，异位性皮肤更容易让葡萄球菌增殖，这可能是由于多种因素造成的，从抗微生物肽的减少，到由于Th2细胞因子的过表达而导致粘附性增加。增殖可导致从T细胞释放的IL-4和IL-13增加。IL-4增加能诱导产生纤维连接蛋白，从而有助于葡萄球菌粘附在角质细胞上。葡萄球菌的增殖进一步破坏异位性皮肤，因为细菌会产生神经酰胺酶和蛋白酶，进而使角质层的神经酰胺减少，造成皮肤屏障损伤和炎症的恶性循环。

The challenge of managing AD in dogs also lies in the frequent secondary infections that aggravate the clinical signs. Atopic skin is more prone to be colonized by Staphylococcus spp, and this may occur because of a variety of factors, ranging from decreased anti- microbial peptides to increased adherence due to the overexpression of Th2 cytokines. Colonization can result in an increase in IL-4 and IL-13 from cutaneous T cells. This increase in IL-4 can induce the production of fibronectin, which can contribute to the adherence of Staphylococcus spp to keratinocytes. Colonization by Staphylococcus spp further damages atopic skin as bacteria produce ceramidases and proteases, which additionally decrease ceramides in the stratum corneum and create a self-perpetuating cycle of disruption of skin barrier and inflammation.

肥大细胞和其他效应细胞的作用

role of mast cells and other effector cells

许多炎性细胞都被认为在犬AD的发病机制中起作用，虽然在过去，认为肥大细胞是最重要的。但这种假设缺乏证据，而且很可能存在多种细胞间复杂的相互作用。在犬AD发病机制中起关键作用的细胞有朗格罕氏细胞和真皮层的树突状细胞，它们负责抗原的处理和表达；B淋巴细胞负责产生反应性抗体；过敏原特异性辅助T淋巴细胞，负责产生细胞因子，导致B细胞和其他炎性细胞活化；肥大细胞产生炎性介质，导致炎症反应。根据有异位性皮炎的皮肤病变切片的组织学检查来看，单核细胞似乎起着主导作用，但这种高细胞密度是否与致病性有关尚不明确。

Numerous inflammatory cells are thought to play a role in the pathogenesis of canine AD, although in the past, mast cells were considered the most important. But evidence for this assumption is lacking, and it is likely that a complex interplay exists between wide varieties of cell types. The cells that play a pivotal role in the pathogenesis of canine AD are Langerhans cells and dermal dendritic cells, which are responsible for antigen processing and presentation; B lymphocytes that are responsible for reaginic antibody production; allergen-specific helper T lymphocytes that are responsible for cytokine production, leading to activation of B cells and other inflammatory cells; and mast cells that produce inflammatory mediators, leading to inflammation. In terms of cell numbers seen by histologic examination of sections of lesional atopic skin, mononuclear cells would appear to have the predominant role, but it is not clear whether this high cell density is correlated to pathogenicity.

推测犬AD的发病机制——参考最近一项关于犬AD发病机制的研究，我们可以推测一种可能发生在犬异位性皮炎皮肤上的途径。异位性皮炎患犬在遗传上可能具有表皮屏障功能缺陷和淋巴细胞容易向Th2亚群分化。皮肤缺乏转换生长因子-β这可能导致对环境过敏原（特别是高分子量D粉尘螨过敏原Der f 15）缺乏抵抗力，这种环境过敏原会穿透表皮被朗格罕氏细胞拦截。朗格罕氏细胞会对抗原进行处理，并将其递呈给引流淋巴结中的T淋巴细胞，从而引起Th2极化。淋巴细胞分泌过多的IL-4会导致B细胞分化，产生能与皮肤肥大细胞结合的过敏原特异性IgE。肥大细胞在接触过敏原后发生脱颗粒，以及淋巴细胞返回皮肤会导致皮肤炎性反应。此外T细胞释放的细胞因子会导致瘙痒和自我损伤，再加上继发感染，可能导致慢性阶段中Th1诱导的炎性反应。因此，犬AD的成功管理可能需要逆转和控制上述所有途径（图2）。

Hypothesized pathogenesis of canine AD—Taking into account a recent study on the pathogenesis of canine AD, it is possible to postulate a pathway that is likely to occur in the atopic skin of dogs. Atopic dogs may be genetically predisposed to have defective epidermal barrier function and polarization of lymphocytes toward the Th2 subset. A deficiency of transforming growth factor-β in the skin could lead to a lack of tolerance toward environmental allergens (especially the high–molecular weight D farinae allergen Der f 15), which would penetrate the epidermis and be intercepted by Langerhans cells. The Langerhans cells would process the antigen and present it to T lymphocytes in the draining lymph node and drive Th2 polarization. Overproduction of IL-4 by the lymphocytes would lead to class switching by B cells and production of allergen specific IgE, which would bind to cutaneous mast cells. Degranulation of mast cells following exposure to allergen as well as homing of lymphocytes to the skin would lead to cutaneous inflammation. Additional cytokines released by the T cells would lead to pruritus and self-trauma, which, in conjunction with the secondary infections, could lead to development of Th1-driven inflammation in the chronic phase. Hence, successful management of AD in dogs is likely to require reversal or control of the above pathways (Figure 2).

图2——根据犬和人AD的研究，目前提出的关于犬AD的病理生理机制的描述。疾病过程皮肤先接触并吸收过敏原，过敏原穿过有屏障功能缺陷的表皮。左图——犬AD致敏过程。幼稚的朗格罕氏细胞捕捉过敏原，并使其进入细胞内部。然后对过敏原进行加工，将其包在朗格罕氏细胞表面大的组织相容性复合体分子上，并递呈给引流淋巴结内的幼稚T辅助细胞（Th0）。来自微环境中的特定线索能使树突状细胞激活T辅助细胞，并将它们极化成为能产生细胞因子，比如IL-4和IL-13的Th2表现型。这些细胞因子可以刺激B细胞变成能开始产生过敏原特异性IgE的浆细胞。激活的Th2细胞借助皮肤中各种细胞产生的趋化因子（如胸腺和活化调节的趋化因子）移行至皮肤。过敏原特异性IgE也进入循环和其他组织内，并与细胞表面能表达高和低亲和力的Fcε受体相结合。右图——从疾病的神经和免疫系统研究犬AD的进展。当再次接触相同过敏原时，表皮的朗格罕氏细胞的细胞表面结合的过敏原特异性IgE，与过敏原发生有效结合，并移至真皮内。这些朗格罕氏细胞将过敏原递呈给T辅助淋巴细胞，并继续将其极化成Th2表现型。此外Th2细胞因子，如IL-31，能被释放并激活感觉神经元，诱发瘙痒。过敏原还可以将过敏原特异性IgE交叉结合在真皮内的肥大细胞的细胞表面，刺激炎性介质释放，比如组胺、血清素和与细胞因子例如嗜酸性细胞趋化因子在一起的P物质。抓挠使皮肤受损，葡萄球菌和马拉色菌等微生物毒素，或环境过敏原激活角质细胞和其他先天免疫细胞，释放促炎细胞因子（例如IL-12），以及能极化T辅助细胞成为Th1，后者能产生细胞因子比如干扰素（IFN）-γ。反过来，IFN-γ促进单核细胞-巨噬细胞的激活。被激活的角质细胞、单核细胞和肥大细胞产生另一种促炎细胞因子，如肿瘤坏死因子(TNF)-α，正调节内皮细胞上P-选择素和E-选择素的表达，从而从血液中募集更多的白细胞。角质层增厚同样使表皮增厚；使屏障功能更加恶化，能渗透进来的过敏原增多；此循环持续存在。TSLP=胸腺基质淋巴生成素

Figure 2—Depiction of the currently proposed pathophysiologic mechanism of canine AD based on research findings in dogs and humans with AD. The disease process starts with percutaneous exposure and absorption of allergens through an epidermis that may have a defective barrier function. Left panel—The process of sensitization in canine AD. The naïve Langerhans cell captures and internalizes allergens. Allergens are then processed, packaged in major histocompatibility complex molecules on the Langerhans cell surface, and presented to naïve T-helper cells (Th0) cells in the draining lymph node. Specific cues from the microenvironment enable dendritic cells to activate T-helper cells and polarize them toward a Th2 phenotype, where they produce cytokines such as IL-4 and IL-13. These cytokines can stimulate B cells to become plasma cells that begin producing allergen-specific IgE. Activated Th2 cells migrate to the skin with the help of chemokines produced by various cells in the skin, such as thymus and activation-regulated chemokine. Allergenspecific IgEs also enter into the circulation and other tissues and bind to cells expressing high- and low-affinity Fcε receptors on their cell surface.

Right panel—Progression of canine AD in terms of neurologic and immune components of disease. Upon reexposure to the same allergen, the epidermal Langerhans cell with cell surface–bound allergen-specific IgE efficiently binds the allergen and migrates to the dermis. These Langerhans cells then present the allergen to T-helper lymphocytes and continue to polarize them toward a Th2 phenotype. Additional Th2 cytokines such as IL-31 can be released and activate the sensory neuron to induce pruritus. Allergens can also cross-link allergen-specific IgE bound on the cell surface of dermal mast cells and stimulate the release of preformed inflammatory mediators such as histamine, serotonin, and substance P along with cytokines such as eosinophil chemotactic factor. Skin injury by scratching, microbial toxins from Staphylococcus sp and Malassezia sp, or environmental allergens activate keratinocytes and other innate immune cells to release proinflammatory cytokines (eg, IL-12) and chemokines that can polarize T-helper cells toward a Th1 phenotype, where they produce cytokines such as interferon (IFN)-γ. In turn, IFN-γ promotes monocyte-macrophage cell activation. Activated keratinocytes, monocytes, and mast cells produce additional proinflammatory cytokines such as tumor necrosis factor (TNF)-α, upregulating the expression of P-selectin and E-selectin, on endothelial cells, thus recruiting more leukocytes from the blood. The epidermis thickens as does the stratum corneum; the barrier function worsens, allowing increased allergen penetration; and the cycle is perpetuated. TSLP = Thymic stromal lymphopoietin.

刘欣

未来研究方向

Where We Are Going

只有在更好地了解疾病过程的情况下，才能提高对犬AD的治疗和管理。这包括更多有关改变导致这种复杂疾病发生的屏障功能障碍、细胞类型和组织的研究，以及更多关于介导瘙痒和炎症反应信号通路的研究。

Improvements in the treatment and management of dogs with AD can be made only when there is a better understanding of the disease process. This includes more research into the alterations involved in barrier dysfunction, the cell types and tissues contributing to this complex disease, and the signaling pathways mediating pruritus and inflammation.

皮肤屏障功能——目前关于AD发病机制的争论是，它是由原发性免疫缺陷，导致的皮肤炎性反应(由内而外的假说)，还是由原发性皮肤屏障缺陷，导致AD炎性反应(由外而内的假说)。了解这种复杂疾病的关键，可能在于不同的方面在不同的发展阶段起重要作用，并且交叉存在。例如，某些个体可能先出现原发性皮肤屏障缺陷，而另一些可能不是。但最终，一旦过敏原致敏和炎性反应发生，皮肤屏障功能就会下降，导致过敏反应、炎性反应和皮肤损伤的持续循环。

Skin barrier—The ongoing debate regarding the pathogenesis of AD is whether it is caused by a primary immune defect, leading to skin inflammation (inside-outside hypothesis), or whether the inflammation of AD is a result of a primary defect in the skin barrier (outside-inside hypothesis). The key to understanding this complex disease may lie in the fact that different aspects may be important at different stages of development and that overlap exists. For example, some individuals may start with a primary defect of skin barrier, whereas others may not. But ultimately, once allergic sensitization has occurred and inflammation has developed, decreased skin barrier function occurs, leading to a self-perpetuating cycle of sensitization, inflammation, and skin damage.

未来在屏障功能障碍领域的研究应该包括，鉴定AD患犬体内能导致形成皮肤屏障缺陷的缺陷基因。最近一项犬异位性皮炎的研究,使用了免疫荧光显微镜检查，发现18只犬中有15只犬的丝聚蛋白表达异常,这是一种由皮肤细胞产生的蛋白质，在皮肤细胞成熟过程中降解成氨基酸, 对维持皮肤表层的水分至关重要。18只犬中有4只的丝聚蛋白染色模式与丝聚蛋白基因功能突变的缺失相一致。在人医病例中，同一丝聚蛋白基因的几种功能丧失的突变基因已被确认，并被认为是AD的主要诱发因素。例如，丝聚蛋白功能丧失突变的后果是皮肤干燥、有皮屑，这导致对过敏原、病原体和化学刺激物更具渗透性。皮肤对外来物质的渗透性可能会使免疫系统参与进来，并促使身体对这种异常路径进入的抗原作出反应。

Future study in the area of barrier dysfunction should include identifying genetic defects in dogs with AD that might lead to the formation of a defective skin barrier. A recent study in atopic dogs that involved use of immunofluorescent microscopy revealed that 15 of 18 dogs had abnormal expression of the filaggrin protein, a protein produced by skin cells that degrades into amino acids during skin cell maturation and that is essential for maintaining moisture in the outer layers of intact skin. Four of 18 dogs had a filaggrin-staining pattern consistent with a loss of function mutation in the filaggrin gene. In affected humans, several loss of-function mutations in the same filaggrin gene have been identified and are considered a major predisposing factor for AD. The consequence of a loss of function mutation in filaggrin, for example, is the formation of dry, flaky skin that is more permeable to allergens, pathogens, and chemical irritants. Skin permeability to foreign substances likely engages the immune system and primes the body to react to antigens that it would not normally encounter by this route.

如果像人医一样，能证明犬皮肤屏障功能障碍是原发因素，可能会极大地改变兽医治疗这种疾病的方式。首先，需要考虑更多的预防性治疗，旨在恢复皮肤屏障，以尽量减少过敏原的渗透和致敏。众所周知，外部应用富含神经酰胺的制剂，可以改善异位性皮炎患犬的皮肤超微结构。目前尚不清楚，皮肤超微结构的改善是否与临床改善相一致，正如人医所证明的那样，在外部应用神经酰胺的临床疗效令人印象深刻。未来的兽医临床研究，应侧重于外部治疗对改善屏障功能的临床疗效，以及改善皮肤屏障与AD临床症状严重程度的相关性研究。

If the importance of skin barrier dysfunction proves to be primary in dogs as it is in humans, it may greatly change the way veterinarians approach this disease. For one, more preventative treatments aimed at restoration of the skin barrier to minimize allergen penetration and sensitization would need to be considered. It is already known that topical application of ceramide-rich preparations can help improve the skin ultrastructure in atopic dogs. What is not known is whether any improvement in the ultrastructure of the skin is paralleled by clinical improvement, as demonstrated in human medicine, where the clinical efficacy of ceramides applied topically is impressive. Future clinical studies in veterinary medicine should focus on evaluation of the clinical efficacy of topical treatments aimed at improving barrier function and the correlation of the improvement of skin barrier with severity of clinical signs in AD.

角质细胞在皮肤屏障功能中的作用

keratinocyte function In skin barrier

角质细胞是皮肤屏障的主要细胞，是通过表皮分化和移行过程形成的。随着角质细胞的成熟，它们会积累角质和脂质，如胆固醇、游离脂肪酸和神经酰胺。当它们从颗粒层迁移到角质层时，细胞会破裂，从而形成高密度的蛋白质和脂质屏障，阻止环境中有害物质进入。

Keratinocytes are the primary cells that lead to skin barrier formation through the process of epidermal differentiation and migration. As keratinocytes mature, they accumulate keratin and lipids such as cholesterol, free fatty acids, and ceramides. As they migrate from the stratum granulosum to the stratum corneum, the cells rupture and thus form a dense protein and lipidrich barrier capable of preventing the entry of harmful substances from the environment.

角质细胞功能的缺陷在人AD中已得到确认，并可能导致皮肤屏障功能障碍。例如，发现在异位性皮炎患者的无病变和有病变皮肤中，存在角质细胞的异常增殖和分化，可能与某些角质的表达减少和角化包膜蛋白的表达改变有关，比如内皮蛋白和兜甲蛋白。这些发现促使一些研究小组寻找能诱导人皮肤细胞产生更多形成皮肤屏障的蛋白质的方法，发现外部治疗可使病变皮肤恢复产生和分泌正常脂质，或者减少人角质细胞增殖的方法。如果屏障功能是犬AD的原发因素，这种治疗方法也可能对患犬的治疗有用。

Defects in keratinocyte function have been identified in humans with AD and could contribute to skin barrier dysfunction. For example, abnormal keratinocyte proliferation and differentiation have been found in nonlesional and lesional skin of atopic humans and can be associated with reduced expression of certain keratins and changes in expression of cornified envelope proteins such as involucrin and loricrin. These findings have led some groups to search for ways to induce human skin cells to produce more proteins involved in skin barrier formation, discover topical treatments that may allow for normal lipid production and secretion, or find ways to reduce proliferation of human keratinocytes in lesional skin. Such approaches to treatment may also be useful for the treatment of affected dogs if barrier dysfunction becomes a primary driver in canine AD.

角质细胞在先天免疫中的作用

keratinocyte function in innate immunity

角质细胞还能通过产生细胞因子、趋化因子和抗菌肽，来应对恶劣环境或入侵的微生物，例如细菌、病毒和真菌。这些应对可以预防感染、控制炎症反应、促进伤口愈合以及促进与神经系统的交流。然而，当这些过程调解异常时，它们会促进AD的病理生理特征。

Keratinocytes also have a great capacity to respond to environmental insult or invading organisms such as bacteria, viruses, and fungi by producing cytokines, chemokines, and antimicrobial peptides. Many of these responses lead to the protection against infection, control of inflammation, promotion of wound healing, and communication with the nervous system. When these processes are dysregulated, however, they can contribute to the pathophysiologic features of AD.

已证明犬的角质细胞能产生促炎因子，如能对过敏原和细菌的成份，分别为Der f1和脂多糖，作出反应的粒细胞巨噬细胞集落刺激因子、IL-8和肿瘤坏死因子-α。另一种备受关注的，与人AD有关的角质细胞细胞因子是胸腺基质淋巴细胞生成素。胸腺基质淋巴生成素是一种类IL -7的细胞因子，能刺激树突状细胞诱导初级T细胞分化为类Th2细胞。

已证实胸腺基质淋巴生成素在人AD的病变皮肤中含量较高，它能刺激幼稚型T细胞产生促过敏反应细胞因子，例如IL-4、IL-5和IL-13。已发现人有胸腺基质淋巴生成素的基因变异，并与AD相关。

Canine keratinocytes have already been shown to produce pro-inflammatory agents such as granulocyte macrophage colony-stimulating factor, IL-8, and tumor necrosis factor-α in response to allergen and bacterial components such as Der f1 and lipopolysaccharide, respectively. An additional keratinocyte cytokine of great interest that has been implicated in AD in humans includes thymic stromal lymphopoietin. Thymic stromal lymphopoietin is an IL-7-like cytokine that stimulates dendritic cells to induce naïve T cells to differentiate into Th2-like cells. Thymic stromal lymphopoietin has been shown to be high in lesional skin of humans with AD, and it can stimulate naïve T cells to produce pro-allergic cytokines such as IL-4, IL-5, and IL-13. Genetic variants in thymic stromal lymphopoietin have also been found in humans and are associated with AD.

在AD中角质细胞产生的许多抗菌肽也会发生改变，可能导致皮肤屏障抗感染功能异常。但是，在人AD中的研究结果尚不明确。两个研究表明,在人AD的皮肤病变处，抗菌肽的诱导生成(抗菌肽和β-防御素（hBD-2和-3）)大大减少,且增加微生物感染的易感性，如金黄色葡萄球菌和单纯疱疹病毒。但另一项研究显示，抗微生物肽(核糖核酸酶7、银屑素，以及hBD-2和hBD-3)在人AD病变皮肤中的表达增强，与金黄色葡萄球菌定植无关。有一份评估犬AD皮肤抗菌肽含量的研究。在这项研究中发现，在皮肤病变中β-防御素cBD1 含量显著增加,而cBD103表达下降。显然，抗菌肽在AD继发性皮肤感染中的作用需要进一步评估。

Keratinocyte production of many antimicrobial peptides can also be altered in AD and may contribute to the abnormal skin barrier against infection. However, results of studies on humans with AD are not clear cut. Two studies have shown that antimicrobial peptide induction (cathelicidin and β-defensins hBD-2 and -3) is greatly decreased in lesional skin of humans with AD and is associated with an increased susceptibility to microbial infections such as Staphylococcus aureus and herpes simplex virus. But another study revealed enhanced expression of antimicrobial peptides (RNase 7, psoriasin, and hBD-2 and hBD-3) in lesional skin of humans with AD and no correlation with S aureus colonization. There has been 1 study in dogs with AD in which the cutaneous content of antimicrobial peptides was evaluated. In that study, it was found that the β-defensin cBD1 was significantly increased in lesional skin, whereas cBD103 was downregulated. Clearly, the role of antimicrobial peptides regarding secondary skin infections in AD needs further evaluation.

犬异位性皮炎的皮肤常被细菌定植，如假中间葡萄球菌和厚皮马拉色菌，因此，能够调节皮肤抗菌肽浓度和减少皮肤感染的治疗是有价值的。抗菌肽作为抗菌药物的一些好处包括:它们可以光谱杀菌，且基本不存在微生物耐药问题，因为其作用机制是通过阳离子电荷和疏水氨基酸与微生物膜发生物理作用。人AD的临床试验评估维生素D3调节组织蛋白酶抑制素（抗菌肽）在角质形成细胞中的表达，在犬也备受关注，值得未来进行这方面的研究。

The skin of atopic dogs is often colonized with bacteria such as Staphylococcus pseudintermedius and Malassezia pachydermatis, so treatments that could regulate the cutaneous concentration of antimicrobial peptides and reduce cutaneous infections would be valuable. Some benefits of antimicrobial peptides acting as antimicrobial agents include the following: they kill a broad spectrum of microbes, and microbe resistance is essentially absent because their mechanism of action is via physical interaction with microbial membranes through their cationic charge and hydrophobic amino acids. Future research in this area is clearly needed, and results of clinical trials in humans with AD to evaluate the efficacy of vitamin D3, which regulates cathelicidin expression in keratinocytes, will also be of great interest.

炎症反应和免疫功能障碍——皮肤屏障功能障碍以外的其他因素，在AD的病理生理机制中也起着关键作用，如免疫细胞功能失调和炎症。大量的研究集中在免疫系统对环境过敏原的超敏反应、过敏原特异性IgE的产生、肥大细胞脱颗粒和皮肤内T细胞的双向反应(图2)。关于AD中促炎介质的作用和识别这些来自于新细胞的介质的信息更新，已经在人类疾病中进行，并且这些信息可以提供额外的研究领域,以更好地了解犬AD的病理生理学特点。树突状细胞，如存在于皮肤的表皮和真皮中的朗格罕氏细胞，被认为在犬AD发病机制中是关键。

Inflammation and immune dysfunction—Factors other than barrier dysfunction play a critical role in the pathophysiologic mechanisms of AD, such as dysregulation of immune cell function and inflammation. A large amount of research has focused on the immune system’s hypersensitization to environmental allergens, allergen-specific IgE production, mast cell degranulation, and a biphasic T-cell response within the skin (Figure 2). Updated information on the role of proinflammatory mediators in AD and the identification of novel cellular sources of these agents has been generated for the human disease condition and may provide additional areas of research to better understand the pathophysiologic features of canine AD. Dendritic cells such as the Langerhans cells are present in the epidermis and dermis of the skin and are thought to be critical players in the pathogenesis of canine AD.

树突状细胞作为抗原呈递细胞，将抗原递呈给T淋巴细胞，首次为先天性免疫应答，第二次为获得性免疫应答。在首次过敏原致敏后，已证明表皮和真皮中的朗格罕氏细胞能与过敏原特异性IgE结合，并能继续有效地对过敏原作出反应，调动类Th2细胞因子反应。最近，已证实人的真皮树突状细胞能产生IL-25，这是IL-17细胞因子家族的一种。这种细胞因子诱导产生与Th2相关的细胞因子，使角质细胞产生丝聚蛋白减少。此外，在人AD皮肤中检测到浓度升高。这些研究表明，在AD中树突状细胞可能除了抗原呈递外，还有其他的作用，如皮肤中Th2反应的诱导因子以及导致屏障功能障碍。

Dendritic cells function as antigen-presenting cells and present antigen to T lymphocytes, initiating the primary and secondary adaptive immune responses. After initial allergen sensitization, Langerhans cells in the epidermis and dermis have been shown to bind allergen-specific IgE and can continue to respond efficiently to allergens, driving the Th2-like cytokine response. Recently, human dermal dendritic cells have been shown to produce IL-25, a member of the IL-17 cytokine family. This cytokine induces the production of Th2-associated cytokines and reduces the production of filaggrin by keratinocytes. Furthermore, high concentrations have been detected in the skin from humans with AD. These studies suggested that dendritic cells may have additional roles in AD beyond antigen presentation such as inducers of the Th2 response in the skin and contributors to barrier dysfunction.

在人AD慢性病变中，巨噬细胞是细胞浸润的主要细胞类型。巨噬细胞在犬AD皮肤活检标本中也很常见。这些细胞在起始、传播、炎症反应消退中都发挥关键作用,并且产生炎性介质的能力强，例如IL - 1、IL-18、IL-6和与细胞因子一样有助于炎症反应消退的肿瘤坏死因子-α(如转换增长因子-β)。这种细胞类型与人的各种慢性炎症疾病有关，并且很可能是犬AD发展的关键因素。

Macrophages are a major cell type detected in the cellular infiltrate in chronic lesions of AD in humans. They are also commonly observed in skin biopsy specimens from dogs with AD. These cells play a key role in the initiation, propagation, and resolution of inflammation and have great capacity to produce proinflammatory mediators such as IL-1, IL-18, IL-6, and tumor necrosis factor-α as well as cytokines that aid in the resolution of inflammation (eg, transforming growth factor-β). This cell type has been implicated in a variety of chronic inflammatory diseases in humans and is likely to be a key player in the development of canine AD.

T辅助细胞在AD发病机制中起着关键作用。人AD可见双向T辅助细胞调节，产生大量Th2细胞因子mRNA(例：IL - 4、IL-5和IL-13)，然后随着Th2细胞因子产生信号，在疾病长期慢性阶段产生Th1(例：干扰素-γ)。这些T细胞的细胞因子可导致皮肤发生有害变化，如屏障蛋白、抗菌产品和粘附因子的表达减少，角质细胞活力降低，皮肤感染的易感性增加。

T-helper cells play a key role in the pathogenesis of AD. Biphasic T-helper cell responses are seen in humans with AD in which Th2 cytokine mRNA production occurs acutely (eg, IL-4, IL-5, and IL-13) and then Th1 (eg, interferon-γ) along with Th2 cytokine message production occurs in the more chronic form of the disease. These T-cell cytokines can cause deleterious changes in the skin, such as decreased expression of barrier proteins, antimicrobial products, and adherence factors as well as decreased viability of keratinocytes and increased susceptibility to cutaneous infections.

新的Th1-和Th2 -细胞因子已经被发现，并成为最近几项研究的焦点。例如，IL-21是人的Th1细胞产生的细胞因子，似乎参与了皮肤的各种炎症过程，如使自然杀伤细胞、淋巴细胞和角质细胞的增殖和功能增强;B细胞向浆细胞分化;使初级T细胞分化成T辅助型17细胞；以及抑制调控T细胞的功能。最近，研究表明IL-21及其受体在人AD皮肤病变中上调，提示这种细胞因子可能参与了皮肤病的病理生理特征。

Newer Th1- and Th2-cytokines have been identified and have been the focus of several recent studies. For example, IL-21 is a cytokine produced by Th1 cells in humans and appears to be involved in a variety of inflammatory processes in the skin, such as enhanced proliferation and function of natural killer cells, lymphocytes, and keratinocytes; differentiation of B-cells into plasma cells; differentiation of naïve T cells into T-helper type 17 cells; and suppression of regulatory T-cell function. Recently, studies have shown that IL-21 and its receptor are upregulated in skin lesions of patients with AD, suggesting this cytokine may contribute to the pathophysiologic features of skin disease.

最近发现的另一种感兴趣的细胞因子是IL-31。发现这种细胞因子由活化的Th2淋巴细胞产生，并在人AD淋巴细胞抗原阳性的皮肤的回流T细胞中表达。白介素-31与异二聚体受体结合，组成IL-31受体A和抑瘤素-M受体β。这些受体存在于各种细胞上，如角质细胞、巨噬细胞和嗜酸性粒细胞，并参与调节这些细胞类型的免疫反应。通过研究转基因小鼠IL-31的表现型，发现了IL-31和AD之间的联系。当IL-31在小鼠中过表达时，小鼠会出现严重的瘙痒、脱毛和皮肤病变，并且抗IL-31抗体可以改善IL-31的瘙痒作用。其他研究小组评估了IL-31在人AD中的作用。例如，Sonkoly等人在人AD皮肤中发现了高浓度的IL-31 mRNA。IL-31是否会像小鼠一样引起犬的抓挠行为和皮炎，还有待确定。在一项研究中，研究人员测定了犬IL-31的核苷酸序列，但在犬异位性皮炎的皮肤中没有发现高浓度的mRNA。

Another recently identified cytokine of interest is IL-31. This cytokine was found to be produced by activated Th2 lymphocytes and expressed in cutaneous lymphocyte antigen–positive skin homing T cells in human patients with AD. Interleukin-31 binds to a heterodimeric receptor consisting of the IL-31 receptor A and the oncostatin-M receptor β. These receptors are found on a variety of cells such as keratinocytes, macrophages, and eosinophils and participate in regulating immune responses in these cell types. A link between IL-31 and AD has been shown by studying the phenotype of IL-31 transgenic mice. When IL-31 is overexpressed in mice, they have severe pruritus, alopecia, and skin lesions, and the pruritic effects of IL-31 can be ameliorated by an anti–IL-31 antibody. Other groups have evaluated the role of IL-31 in humans with AD. For example, Sonkoly et al found high concentrations of IL-31 mRNA in the skin of humans with AD. Whether IL-31 causes scratching behavior and dermatitis in dogs, as seen in mice, still needs to be determined. One study, in which the nucleotide sequence of canine IL-31 was determined, did not find high mRNA concentrations in the skin of atopic dogs.

最近，强调了AD中其他类型的T辅助细胞，如T辅助型17细胞在的作用。T辅助型17细胞似乎不仅在对细胞外病原体起保护性免疫作用，而且也能有效诱导组织炎症反应。这些CD4+T细胞已被证明能够产生细胞因子，如IL-17、IL-22和IL-25。白介素-17似乎在AD的急性病变中有表达，但在慢性AD病变中基本不表达，这产生一些假说，即白介素-17的减少导致人AD皮肤出现持续感染。然而，在慢性AD皮肤病变中一种细胞因子白介素-22升高，并已被证明能使皮肤后期分化的基因下降，这可能导致表皮增生。白介素-25在Th2极化中起重要作用，已证明可以诱导产生IL-4、IL-5和IL-13。调节性T细胞反应异常也可能在AD中发挥作用。调节性T细胞是一种维持免疫稳态或外周耐受性的特殊T细胞群，并已证明能抑制过敏原特异性T细胞的激活。有研究评估了人AD皮肤病变中存在的调节性T细胞，结果喜忧参半。

Recently, the role of other types of T-helper cells in AD such as T-helper type 17 cells has been highlighted. T-helper type 17 cells not only appear to play a role in protective immunity against extracellular pathogens but can also be potent inducers of tissue inflammation. These CD4+ T cells have been shown to produce cytokines such as IL-17, IL-22, and IL-25. Interleukin-17 appears to be expressed in acute lesions in AD but is largely absent in chronic AD lesions, allowing some to hypothesize its reduction may contribute to persistent infections in the skin of AD patients. Interleukin-22, however, is a cytokine that is upregulated in chronic AD skin lesions and has been shown to downregulate genes involved in terminal differentiation of the skin, which could lead to epidermal hyperplasia. Interleukin-25 plays an important role in driving Th2 polarization and has been shown to induce the production of IL-4, IL-5, and IL-13. Abnormal regulatory T-cell responses may also play a role in AD. Regulatory T-cells are a specialized population of T cells that maintain immune homeostasis or peripheral tolerance and have been shown to suppress allergen-specific T-cell activation. There have been studies evaluating the presence of regulatory T-cells in lesional skin of humans with AD, and results are mixed.

皮肤中神经免疫的相互作用——越来越多的证据表明，皮肤内的神经系统和免疫系统之间存在协同作用。常驻免疫细胞，如肥大细胞、朗格罕氏细胞和炎症发应时短暂存在的免疫细胞(如粒细胞和T淋巴细胞)与神经纤维密切相关。当这些免疫细胞被激活时，它们可以释放神经肽(如：组胺和P物质)、细胞因子(如：IL-31)和神经营养因子(如：神经生长因子)等物质，这些物质可以直接与感觉神经上的受体结合，从而引起神经细胞的激活、增敏和抽芽。同样，被激活的神经可以释放神经肽(如：P物质和降钙素生成蛋白)和神经营养因子(如：神经生长因子)，它们能调节免疫细胞及其炎症反应。由于感觉神经纤维对皮肤复杂的神经支配，所以免疫细胞和感觉神经纤维之间交流明确，并相互调节对方的活动。它们还可能协同参与皮肤病的发病机制。

Neuroimmune interactions in the skin—There is increasing evidence suggesting a synergistic interaction between the nervous system and the immune system within the skin.Resident immune cells such as mast cells, Langerhans cells, and transient immune cells present during inflammation (eg, granulocytes and T lymphocytes) are intimately associated with nerve fibers. When such immune cells are activated, they can release substances such as neuropeptides (eg, histamine and substance P), cytokines (eg, IL-31), and neurotrophins (eg, nerve growth factor) that can bind directly to receptors on sensory nerves to cause activation, sensitization, and sprouting of nerve cells. Similarly, activated nerves can release neuropeptides (eg, substance P and calcitonin generelated protein) and neurotrophins (eg, nerve growth factor) that can modulate immune cells and their responses during inflammation. As a result of the complex innervation of the skin with sensory nerve fibers, immune cells and sensory nerve fibers clearly communicate with one another and regulate each other’s activity. They also likely participate synergistically in the pathogenesis of skin diseases.

在人AD中，已发现这种物质被调节升高。例如，IL-31，即在皮肤淋巴细胞抗原阳性的引流T细胞中表达的Th2细胞因子，最先发现在瘙痒皮肤内比非瘙痒皮肤含量高。有趣的是,这个细胞因子受体,IL-31受体A和抑瘤素-M受体β,最近在C感觉纤维和啮齿动物的背根神经节也有发现，这些部位可能促进瘙痒信号的转导。

In the human with AD, such mediators have been found to be upregulated. For example, IL-31, the Th2 cytokine expressed in cutaneous lymphocyte antigen– positive skin homing T cells, is preferentially found in higher amounts in pruritic versus nonpruritic skin conditions. Interestingly, the receptors to this cytokine, the IL-31 receptor A and the oncostatin-M receptor β, have most recently been found on sensory C-fibers and in the dorsal root ganglia in rodents where they likely contribute to the transduction of pruritus signals.

神经生长因子是皮肤中一个重要的神经营养因子，它在AD中的调节下降。这种分子是由皮肤中的各种细胞产生的，包括角质细胞、肥大细胞、嗜酸性粒细胞和淋巴细胞。它通过低亲和力的泛神经营养因子受体p75NTR和高亲和力的酪氨酸激酶家族的神经营养因子受体结合并发挥作用，这些受体存在于角质细胞、免疫细胞和神经元上。神经生长因子具有多种功能，包括组织重塑、免疫细胞激活和神经生长。已发现人AD皮肤细胞中神经生长因子的表达和释放增强，以及神经生长因子血清浓度与疾病严重程度相关，提示神经生长因子等神经营养因子当在皮肤病中调节降低时可能具有致病作用。

An important neurotrophin in the skin that can be dysregulated in AD is nerve growth factor. This molecule is produced by a variety of cells in the skin including keratinocytes, mast cells, eosinophils, and lymphocytes. It binds and exerts its effects through the low-affinity pan-neurotrophin receptor p75NTRand the high-affinity neurotrophin receptor of the tyrosine kinase family, and these receptors are present on keratinocytes, immune cells, and neurons. Nerve growth factor has a variety of functions that include tissue remodeling, immune cell activation, and neuronal growth. Enhanced expression and release of nerve growth factor from skin cells have been found in humans with AD, and nerve growth factor serum concentrations correlate with disease severity, suggesting neurotropic factors such as nerve growth factor can have a pathogenic role in skin diseases when dysregulated.

神经肽也可能是皮肤的致病条件。例如，位于初级皮肤感觉神经元的神经肽P物质，激活后由周围神经末梢释放。然后，P物质可以与存在于多种免疫细胞上的神经激肽-1受体结合，如中性粒细胞、淋巴细胞、巨噬细胞、淋巴细胞和肥大细胞，导致它们被激活。在脊髓背角神经元上也发现了神经激肽-1受体，并且最近已证明这些神经元可以介调节小鼠的抓挠行为。在人异位性皮炎的血浆中发现高浓度的P物质，这表明神经肽可能也参与了过敏性皮肤病的发病机制。

Neuropeptides can also contribute to pathogenic conditions in the skin. For example, the neuropeptide substance P can be localized in primary cutaneous sensory neurons and released by nerve endings in the periphery after activation. Substance P can then bind neurokinin-1 receptors present on a variety of immune cells such as neutrophils, lymphocytes, macrophages, lymphocytes, and mast cells, leading to their activation. Neurokinin-1 receptors have also been found on neurons within the dorsal horn, and recently, these neurons have been shown to mediate scratching behavior in mice. Substance P concentration has been found to be high in the plasma of atopic humans, suggesting that neuropeptides may also contribute to the pathogenesis of allergic skin disease.

瘙痒——瘙痒是犬AD的标志。由于对瘙痒的潜在路径和机制了解不足，有关瘙痒的有效治疗方法的开发能力受到了限制。在小鼠、大鼠和非灵长类动物中，研究表明瘙痒和疼痛的感觉是由不同的神经元传递的。通过位于皮肤表皮和真皮上的瘙痒选择性感觉神经上的相关瘙痒受体检测到了瘙痒信号。然后，这些信号沿着无髓鞘的C神经纤维传播，并由脊髓背根神经节和脊髓背角内的椎板I区接收。瘙痒信号最终通过丘脑脊髓束神经元到达大脑。

Pruritus—Pruritus is the hallmark of canine AD. The ability to develop effective treatments for pruritus has been hampered by the poor knowledge of the underlying pathways and mechanisms. In mice, rats, and nonhuman primates, it has been shown that the itch and pain sensations are transmitted by distinct neurons. The itch signals are detected through relevant itch receptors present on cutaneous itch-selective sensory nerves residing in the epidermis and dermis. The signals then travel along unmyelinated C nerve fibers and are received by the dorsal root ganglia and the lamina I region within the dorsal horn of the spinal cord. The itch signal finally reaches the brain through spinothalamic tract neurons.

啮齿类动物的神经消融技术已经识别出脊髓中瘙痒选择性神经元的一些特征。例如,一项研究研究表明，由背角神经元表达的NK-1 受体在抓挠行为中起关键作用，第二项研究表明, 由背角神经元的第I椎板表达的胃泌素释放肽受体，选择性地调制各种瘙痒反应，但不影响啮齿动物的疼痛反应。如果啮齿动物瘙痒选择性神经元的这些特征与犬类似，那么就可以开发各种新的瘙痒治疗方法。

Nerve ablation techniques in rodents have identified some of the characteristics of itch-selective neurons in the spinal cord. For example, 1 study suggested that NK-1 receptor–expressing dorsal horn neurons play a key role in scratching behavior and a second study suggested that gastrin-releasing peptide receptor–expressing neurons in the lamina I of the dorsal horn selectively modulated a variety of itch responses but do not affect pain responses in rodents. If these characteristics of itch-selective neurons in rodents translate similarly into dogs, then a variety of new treatment approaches to pruritus could be explored.

抗组胺药物是治疗人过敏性皮肤病最常用的药物之一，它可以对抗组胺H1和H2受体，这些受体存在于各种组织中，包括外周神经、血管和平滑肌细胞内，抗组胺药物通过降低瘙痒、疼痛和血管通透性发挥作用。虽然兽医皮肤科医生通常推荐抗组胺剂用于治疗犬AD引起的瘙痒，但其疗效尚不清楚。

One of the most commonly used treatments for allergic skin disease in humans is antihistamines, which antagonize the histamine H1 and H2 receptors present in a variety of tissues including peripheral neurons, blood vessels, and smooth muscle cells and works by reducing pruritus, pain, and vascular permeability. Although antihistamines are commonly recommended by veterinary dermatologists for the treatment of pruritus associated with AD in dog, their efficacy is unclear.

已证明具有新作用机理的新药对实验性引起瘙痒的啮齿动物有效。这些药物包括针对组胺H4受体的组胺拮抗剂、μ-阿片受体拮抗剂、κ-阿片受体激动剂、蛋白酶激活受体-2拮抗剂、血清素拮抗剂、a2d配体、大麻素受体激动剂和神经激肽-1受体拮抗剂。其中某些方法目前正在人医临床研究进行对照研究，以检查其止痒效果。

Newer agents with novel mechanisms have been shown to be active in rodents with experimentally induced pruritus. These agents include histamine antagonists that target the histamine H4 receptor, μ opioid receptor antagonists, κ-opioid receptor agonists, protease-activated receptor 2 antagonists, serotonin antagonists, a2d ligands, cannabinoid receptor agonists, and neurokinin-1 receptor antagonists. Some of these approaches are currently being investigated in controlled human clinical studies to examine their antipruritic effects.

·      细胞内机制——通过细胞因子、趋化因子、神经肽和神经营养因子调节的细胞内信号机制非常复杂。许多神经肽和趋化因子通过G蛋白偶联受体发挥作用,许多细胞因子和神经营养因子通过多种途径激活受体信号，包括Janus激酶信号传感器、转录途径激活剂、丝裂原活化蛋白激酶通路、磷脂酰肌醇3-激酶通路、核因子kappa B通路或激活T细胞核因子通路。这些信号通路都有详细的描述，许多用于靶向调节这些通路的小分子抑制剂现在已被开发，或者目前正处于某些疾病的临床研究中，像是肿瘤学、移植病例和自体免疫性疾病。目前用环孢素治疗犬AD就是其中一种。这种药物与一种胞质蛋白，即亲环蛋白结合。环孢素亲环蛋白复合物随后抑制钙调磷酸酶，一种具有丝氨酸-苏氨酸磷酸酶活性的酶，阻止活化T细胞的去磷酸化和核因子的激活。激活的T细胞核因子如果被去磷酸化激活，通常会转位到细胞核，诱导T细胞中IL-2的表达。因此，环孢素是一种信号转导抑制剂，其部分功能是阻断T细胞激活。随着其他信号转导抑制剂在人类疾病中的安全性和有效性的评估变得更加明确，一些药物可能对治疗犬AD具有价值。

Intracellular mechanisms—A great complexity of intracellular signaling mechanisms is used by cytokines, chemokines, neuropeptides, and neurotrophins. Many neuropeptides and chemokines exert their effects via G protein–coupled receptors, and many cytokines and neurotrophins will activate receptors that signal through a variety of pathways including the Janus- activated kinase signal transducer and activator of transcription pathway, mitogen-activated protein kinase pathway, phosphatidylinositol 3-kinase pathway, nuclear factor kappa B pathway, or nuclear factor of activated T cells pathways. These signaling pathways have been well described, and a variety of small molecule inhibitors have been developed to target many of these pathways or are currently under clinical investigation in diseases such as oncology, transplantation, and autoimmune disorders. One example currently used for the treatment of dogs with AD is cyclosporine. This drug binds to a cytoplasmic protein, cyclophilin. The cyclosporine-cyclophilin complex then inhibits calcineurin, an enzyme with serine-threonine phosphatase activity, preventing the dephosphorylation and activation of nuclear factor of activated T cells. Nuclear factor of activated T cells, if activated by dephosphorylation, would normally translocate to the nucleus and induce the expression of IL-2 in T cells. Therefore, cyclo- sporine is a signal transduction inhibitor, functioning in part by blocking T-cell activation. As the safety and efficacy of other signal transduction inhibitors being evaluated in human diseases become better characterized, some may have value in the treatment of dogs with AD.

诊断CAD

Diagnosis of Canine AD

目前，没有明确的检测方式能确诊犬AD。因此，兽医在对这些动物进行皮内试验和血清学测试之前，会花大量时间排除寄生虫传染、微生物感染和食物过敏性。基于血清的诊断或基因检测可与临床评估联合使用，有助于兽医更快地为AD病例制定最合适的治疗方案。

Currently, there is no definitive test to confirm a diagnosis of AD in dogs. Veterinarians therefore spend a substantial amount of time ruling out infections, infestations, and food allergies before intradermal testing and serologic tests are performed in these animals. Serum-based diagnostic or genetic testing that could be used in collaboration with clinical assessments may help veterinarians prescribe the most appropriate treatments for AD patients more quickly.

某些品种的犬和AD之间似乎有很强的关联，这表明确实存在遗传关系，且诊断试验可能有用。Wood等人最近的一项研究，针对不同品种和地区的242只AD患犬和417只健康对照犬，在25个候选基因中评估各种单核苷酸多态性。该研究的初步发现表明，存在与该疾病相关的候选基因，并明确支持进一步的基因研究，这些研究对象是来自特定地理区域的个体犬种，以加强基因联系。明确与AD相关的基因功能，也能提供给兽医血清学诊断试验。

There appears to be a strong link between dog breed and the development of AD, suggesting a genetic link does exist and diagnostic testing could be useful. A recent study by Wood et al evaluated a variety of single nucleotide polymorphisms in 25 candidate genes in 242 dogs with AD and 417 healthy control dogs across several breeds and regions. Initial findings of that study suggest there are candidate genes associated with the disease and clearly support further genetic studies with larger numbers of dogs of individual breeds from defined geographic regions to strengthen genetic associations. Understanding the function of genes associated with AD may also lead to serum-based diagnostic testing that could be made available to veterinarians.

总结

Summary

70年来，兽医对犬瘙痒性过敏性皮肤病的诊断和治疗发生了很大变化。最初认为异位性皮炎是一种主要由吸入性过敏原引起的I型超敏反应，并且许多关于发病机制和治疗的研究都集中在肥大细胞和过敏原特异性IgE上。现在我们知道AD是一种多因素疾病，疾病发展的关键因素是皮肤的树突状细胞、T淋巴细胞、多种其他细胞以及屏障功能改变。对于那些可能具有遗传易感性或先天表皮通透性改变的犬，环境过敏原可以穿透皮肤屏障，引发复杂的免疫反应。这些细胞释放的许多不同的细胞因子是这一过程的驱动信号。皮肤炎性病变联同神经机制启动了无休止的瘙痒循环。在犬之间和随着时间推移的犬个体上，疾病的过程在不断变化。这增加了确诊难度，也表明没有一种普遍有效的单一治疗方案。

During the 70 years that veterinarians have been diagnosing and treating pruritic allergic skin disease in dogs, much has changed. Atopic dermatitis was originally thought to be a type I hypersensitivity with inhaled allergens as the main cause, and much of the research on the pathogenesis and treatment focused on mast cells and allergen-specific IgE. It is now known that AD is a multifactorial disease that instead has cutaneous dendritic cells, T lymphocytes, a multiplicity of other cells, and an altered barrier function at the center of the disease process. In dogs that may have a genetic predisposition or congenital alteration in epidermal permeability, environmental allergens can penetrate this cutaneous barrier and trigger a complex immunologic reaction. Many different cytokines released by these cells are the signals that drive this process. Cutaneous lesions of inflammation coupled with neuronal mechanisms start the never-ending cycle of pruritus. Among dogs and also over time within an individual dog, the disease process is continuously changing. This adds to the challenges in making an accurate diagnosis and suggests that no single treatment will ever be universally effective.

随着对人类、犬和其他动物的研究进展，AD的许多部分和复杂的相互作用正在慢慢被揭示。有了这些新信息，针对疾病循环中许多环节的更有效和更安全的治疗方案现已成为可能。

As research in humans and dogs as well as other animals progresses, the many parts and complex interplay to AD are slowly being uncovered. With this new information, more effective and safer modes of treatment targeting the disease at many points in the cycle are now possible.

鑫玺

谢谢老师

黄精庭

辛苦刘老师了。

附离

辛苦啦

王帆

siping宝康

辛苦了，刘老师！

叮叮

周瑞