TLDR：*湿疹的发病机制是多因素的，但大体上遵循的是一个与屏障完整性蛋白（如丝状蛋白（filaggrin）有关的遗传（或表观遗传，在早期肠道微生物组的情况下）失调的过程，皮肤微环境中的神经酰胺含量也发生了相应的变化。随着这些蛋白质结构和功能以及脂质数量的变化，受损的屏障容易受到刺激和感染，这就导致了异常的免疫反应，因为Th2细胞在皮肤的炎症过程中发挥作用（目前尚不清楚B细胞如何参与湿疹的发病机制）。
轻度-中度湿疹的治疗方案一般限于外用皮质类固醇和保湿软膏，以及外用免疫调节剂。对于更严重的疾病，患者可以选择光疗、口服（和其他全身性的）免疫抑制剂，或者最近推出的mAb dupilumab，它针对Th2-调节的细胞因子IL-4和IL-13。考虑到这种mAb的疗效，你可能会认为湿疹是一种自身免疫性疾病，具有非免疫性的致病因素。
一般来说，你描述的所有机制都参与了湿疹的发病机制。如前所述，特应性皮炎（湿疹）的发病机制并不完全清楚，但一些因素已被确定为临床干预的潜在目标。目前还不清楚湿疹是由皮肤屏障（"外在的"）还是由免疫系统（"内在的"）启动的，因为高质量的证据支持这两种假说，但湿疹的实际病因可能是外在的和内在的生理因素之间的复杂相互作用。这些因素综合起来，最终产生了慢性瘙痒性皮肤炎症，尤其是在屈肌表面（关节间的 “褶皱"）。
1.如果原因是神经酰胺的缺乏，那么是什么原因造成的呢？
神经酰胺是湿疹的一个有趣的话题。神经酰胺有12种亚种，其数量对表皮屏障的组织有重要作用。我们知道，湿疹患者的表皮屏障受到损害，我们知道湿疹患者皮肤上的神经酰胺相对浓度与健康对照组不同，所以我们说，神经酰胺分泌的改变与湿疹之间存在着_关系，尽管我们不能确定这种神经酰胺的 "缺乏 "就是湿疹的真正原因[[1]。 )。
神经酰胺是蜡质脂质分子家族中的一种，那么到底是哪种化学物质产生的呢？
来自[1]: The lipid bilayers of the stratum corneum consist predominantly of three different lipids: ceramides, cholesterol, and free fatty acids. The ceramides are further divided into 12 subspecies (ceramides 1–12), and are thought to be critical in the organization of the lipid bilayer. The synthesis of the lipids takes place in the stratum granulosum, from where the lipids are delivered to the stratum corneum. The lipids surround the corneocytes, which are flat nucleus‐free cells built of keratin filaments and surrounded by cross‐linked proteins called the cornified envelope.
是皮肤产生的另一种神经酰胺质量较低，还是因为皮肤产生的神经酰胺不够，所以才会产生？
来自 [1]: Comparisons of SC ceramides in healthy skin and atopic dermatitis skin were made by different groups in the 1990s, and showed lower levels of ceramides 1 and 3, as well as a lower ceramide/cholesterol ratio, for non‐lesional atopic skin.
1.如果原因是蛋白质的异常或缺失，那么是什么原因造成的呢？
皮肤屏障完整性的 "关键角色 "是脂质（如神经酰胺）和蛋白质（受基因表达的调节）。由于这种已知的关系，人们长期以来一直推测，湿疹的屏障完整性受损有一定的遗传失调，而双胞胎研究表明湿疹具有高度的遗传性，这一点也得到了支持。2006年，编码丝状蛋白（FLG）的基因突变被确定为湿疹的主要致病因素[[2 3]
是什么蛋白？
来自[2]：Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier.
至于它与神经酰胺的关系，来自[1]：...one research group studied atopic dermatitis skin, excluding patients with filaggrin mutations to ensure that the discoveries made were independent of the mutations, and correlated the ceramide composition with the lamellar lipid organization. They found significantly lower levels of ceramide 3 in atopic dermatitis individuals than in healthy controls, as well as a correlation between a low ceramide 3 level and lamellar lipid disorganization, despite the presence of wild‐type filaggrin in both groups.
从这些结果我们可以看出，蛋白质（丝状蛋白）和脂质（神经酰胺）都参与了湿疹的发病机制，但它们之间似乎没有明显的关系。*湿疹/异位性皮炎，正如我们目前所理解的那样，有可能被分解成许多亚型，它们的表现形式相似（皮肤发痒、红斑），但病因不同，就像癌症和败血症一样。 *
那是和T细胞（识别抗原）还是B细胞（产生抗体）有关吗？
如上文所述，皮肤细胞（不是T细胞）负责脂质的产生，而丝分裂素 "促进表皮的终末分化"（不是淋巴细胞发育）。然而，T淋巴细胞_参与湿疹的发生，因为湿疹是一个炎症过程（由这些免疫细胞调节）[4]。为了避免走入太多的兔子洞，你可以先熟悉一下辅助性T细胞和细胞因子，然后再继续往下说。来自[4]：...a subgroup of patients with atopic dermatitis has a filaggrin loss-of-function mutation. Recently, it was shown that filaggrin expression is reduced in atopic dermatitis even in the absence of any mutation. Keratinocytes differentiated in the presence of IL- 4 and IL-13 exhibited significantly reduced filaggrin gene expression and neutralization of IL-4 and IL-13 improves skin barrier integrity. This indicates that Th-2 lymphocytes directly contribute to the skin barrier defect in atopic dermatitis...Microscopic studies revealed a sparse perivascular T cell infiltrate in unaffected atopic dermatitis skin that is not seen in normal healthy skin.
在B细胞方面，关于B细胞参与湿疹的发病机制，存在着相互矛盾的证据。一些患者在使用利妥昔单抗（一种抗B细胞mAb）[[[5]]治疗时，症状明显改善，而另一些患者对该药没有反应[[6]]，这标志着需要进行正式的RCT研究，以检查利妥昔单抗在治疗湿疹和 进一步的研究阐明了B细胞在发病机制中的作用。
湿疹是皮肤问题还是免疫系统问题？
这其实是在问 "湿疹是外在的问题还是内在的问题？” 想必大家已经意识到了，答案是：其实比这更复杂。湿疹的 “问题 "来自于皮肤的通透性被破坏，各种内在因素和外在因素都可以引起和加重湿疹[[7]：
1。另外，听很多人说，这是免疫系统的问题。而这个问题的根源是肠道。他们引用希波克拉底的话说。"所有的疾病都是从肠道开始的"。这是真的吗
确实有研究表明，早期生活中肠道微生物多样性的减少与湿疹有一定的关联，但最好的证据并不支持肠道微生物群在本病的发病机制中起着明确的致病作用[[8]。
来自[8]：Culture-based studies have shown strong associations between cutaneous Staphylococcus aureus colonisation and established atopic eczema during and outside of the context of disease flares. Using the same approach, there is also evidence for an inverse relationship between gut bacterial diversity in early life and the later development of atopic eczema, in keeping with the ‘biodiversity hypothesis’...both Staphylococcus aureus and epidermidis proliferate whilst bacterial diversity drops at lesional sites when atopic eczema flares, but S. aureus elimination is not the main reason why atopic eczema gets better...studies have not found evidence that S. aureus colonisation triggers atopic eczema development...
因为湿疹是一种炎症性疾病，免疫系统是其发病和解决的内在参与者。最新研究发现Th2细胞是湿疹发病机制中的重要参与者[9]。来自[9]：Early models of aetiology attributed symptoms of [eczema] to cutaneous inflammation at lesion sites, but recent studies have established that activated immune mediators in the circulation drive disease severity. Activation of T helper 2 (Th2) and Th22 cells in the circulation appears to be the principal initiator of acute [eczema] pathology, with the emergence of Th1 and Th17/interleukin (IL)‐23 pathway activation marking the transition to a chronic state.
仅仅是吃健康的食物、多补充益生菌、涂抹保湿霜就能有效帮助皮肤吗？
"健康的食物 "不一定有帮助，但避免吃含有诱发你湿疹发作的过敏原的食物会。此外，吃得更健康会让你感觉更好。"多吃些益生菌 "几乎可以肯定不会_有帮助，正如[8]所澄清的那样：...there is further evidence that a reduced diversity of the faecal microbiota precedes the development of atopic eczema, an association that appears lost in established disease. 如果 "既定疾病 "的特点是粪便微生物群的多样性没有像湿疹发生前那样减少，那么既定疾病中的微生物群就不是真正的治疗目标。来自[7]：Application of creams and ointments containing lipids and lipid-like substances, hydrocarbons, fatty acids, cholesterol esters and triglycerides stimulates barrier repair and increases stratum corneum hydration...As AD is often accompanied by reduced lipid composition, topical application of lipids and hydrocarbons may partially correct permeability barrier defects. It has been shown that topical treatment with hydrocortisone ointments may lead to rapid improvement in barrier function in atopic skin...several research groups and companies report that creams containing ceramides and a mixture of the three key lipids are not superior to ‘‘classical’’ cream or ointment preparations, such preparations have not yet been widely used. More research is necessary to determine the significance of ceramides and the treatment composition with the most therapeutic benefit.
湿疹的发病机理是多因素的，但大致上遵循着一个与屏障完整性蛋白（如丝状蛋白）有关的遗传（或表观遗传，在早期肠道微生物组的情况下）失调的过程，而皮肤微环境中的神经酰胺含量也发生了相应的变化。随着这些蛋白质结构和功能以及脂质数量的变化，受损的屏障容易受到刺激和感染，这就导致了异常的免疫反应，因为Th2细胞在皮肤的炎症过程中发挥作用（目前尚不清楚B细胞如何参与湿疹的发病机制）。
轻度-中度湿疹的治疗方案一般限于外用皮质类固醇和保湿软膏，以及外用免疫调节剂。对于较严重的湿疹，患者可以采用光疗、口服（和其他全身性）免疫抑制剂，或者最近使用的mAb dupilumab，其靶向Th2-调节的细胞因子IL-4和IL-13[[10]。考虑到这种mAb的疗效，你可能会将湿疹视为一种自身免疫性疾病，具有非免疫性的诱发因素。
[1]Jungersted, J. M. and Agner, T. (2013), Eczema and ceramides: an update. Contact Dermatitis,69:65-71. doi:10.1111/cod.12073
[2] Palmer, C. N. A. et al. (2006), Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nature Genetics,38:441-446. doi:10.1038/ng1767
[3] Weidinger, S. et al.(2006), Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations. J Allergy Clin Immunol,118(1):214-219. doi:10.1016/j.jaci.2006.05.004
[4] Werfel, T. and Wittmann, M. (2008), Regulatory Role of T Lymphocytes in Atopic Dermatitis. Chem Immunol Allergy,94:101-111. doi:10.1159/000154935
[5] Simon, D. et al.(2008), 抗CD20(利妥昔单抗)治疗提高了特应性湿疹. J Allergy Clin Immunol,121(1):122-128. doi:10.1016/j.jaci.2007.11.016
[6] McDonald, B. S. et al.(2015), Rituximab as a treatment for severe atopic eczema: failure to improve in three consecutive patients. Clin Exp Dermatol,41:45-47. doi:10.1111/ced.12691
[7] Proksch, E. et al. (2006), Skin barrier function, epidermal proliferation and differentiation in eczema. J Derm Sci,43(3):159-169. doi:10.1016/j.jdermsci.2006.06.003
[8] Marrs, T. and Flohr, C. (2016), The role of skin and gut microbiota in the development of atopic eczema. Br J Dermatol,175:13-18. doi:10.1111/bjd.14907
[9] Guttman-Yassky, E. et al. (2017), Systemic immune mechanisms in atopic dermatitis and psoriasis with implications for treatment. Exp Dermatol,27:409-417. doi:10.1111/exd.13336
[10] Simpson, E. L. et al. (2016), Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis. N Engl J Med,。375(24):2335-2348. doi: 10.1056/NEJMoa1610020.
