J Clin Invest. 2000 Jul 1;
No eczema without keratinocyte death
Thomas Schwarz
Ludwig Boltzmann Institute for Cell Biology and Immunobiology of the Skin, Department of Dermatology, University Münster,
Eczematous dermatitis comprises a heterogenous group of inflammatory skin diseases characterized by a typical morphological reaction pattern. In the acute stage, the typical clinical features include itching, redness, papules, and vesicles associated with exudation. The two most frequent reasons for an eczematous reaction are atopic dermatitis (AD) and allergic contact dermatitis (ACD). Although AD and ACD are completely different in nature and pathogenetically unrelated, both disorders in the acute stage share common morphological features, especially vesicle formation, which ultimately causes a disruption of the epidermal barrier. The loss of this protective shield allows additional external noxious agents of microbial, chemical, or physical origin to enter the skin and to aggravate and to perpetuate the disease. Hence, vesicle formation and subsequent loss of the epidermal barrier is a key event in acute eczematous reactions.
Histopathologically, eczematous reactions are characterized by a mononuclear infiltrate with an intercellular epidermal edema, a condition called spongiosis. Severe spongiosis causes keratinocytes’ intercellular attachments to rupture and is regarded as the major culprit in generating vesicles in acute eczematous dermatitis (1). In this issue of the JCI, however, Trautmann et al. (2) provide evidence that another pathway, induction of apoptosis of keratinocytes via activation of the Fas receptor system, also disrupts the epidermal barrier, and they argue that infiltrating T lymphocytes are the direct cause of keratinocyte death through this novel pathway.
Cell death by apoptosis is a tightly regulated process that enables removal of unnecessary, aged, or damaged cells. During apoptosis a complex death program becomes initiated that ultimately leads to the fragmentation of the cell, finally breaking it up into membrane-enclosed bodies that are phagocytosed by macrophages. Because it does not involve the release of inflammatory mediators, apoptosis, in sharp contrast to necrosis, does not typically provoke an inflammatory reaction. Nevertheless, inflammation can induce local apoptosis, and apoptosis-associated inflammation is seen in such conditions as viral hepatitis and Hashimoto’s thyroiditis, as well as eczematous dermatitis.
One way to induce apoptosis is by triggering a family of transmembrane proteins called death receptors (3), of which the Fas protein (CD95) may be the most important (4), since Fas-induced apoptosis appears to be involved in a variety of diseases, including Hashimoto’s thyroiditis and Helicobacter pylori–induced gastritis (5, 6). Triggering of Fas either by agonistic antibodies or by its cognate ligand FasL induces apoptosis. Ligand binding causes trimerization of Fas, and the trimerized cytoplasmic region transduces the signal by recruiting the adapter molecule FADD (Fas-associating protein with death domain). FADD is responsible for downstream signal transduction by recruitment of the cysteine protease, caspase-8. Subsequently, a cascade of downstream caspases executes apoptotic cell death (4).
Perhaps the best studied of the cells subject to this apoptotic pathway are lymphocytes. Fas and its ligand are essential for normal homeostasis of the lymphoid system, as seen when defects in the Fas system result in lymphadenopathy, splenomegaly, or autoimmunity (7). This pathway is also implicated in the progression of tumors, since tumor cells that express high levels of FasL have been shown to escape an immune response by killing Fas-bearing lymphocytes (8). The paper by Trautmann et al. (2) now identifies the keratinocyte as an additional target of Fas-induced apoptosis and provides evidence that this form of cell death contributes to the pathogenesis of eczematous dermatitis. Keratinocytes normally express low levels of Fas, but IFN-γ upregulates Fas on these cells (9, 10). The authors show that cultured keratinocytes are driven into apoptosis upon coincubation with autologous activated T lymphocytes. Addition of a blocking Fas-Fc fragment inhibited apoptosis, indicating that keratinocyte death is due to triggering of the Fas system. Secretion of IFN-γ by T lymphocytes, which promotes Fas upregulation in keratinocytes, is a crucial early step in this pathway. Therefore, in this case keratinocyte apoptosis occurs only in association with an inflammatory reaction; but it is important to mention that the inflammatory infiltrate is not the consequence but the cause of apoptosis. A similar mechanism may apply to hepatitis B virus–related liver cirrhosis, where T lymphocytes kill hepatocytes using the Fas system (11). In Hashimoto’s thyroiditis, the inflammatory mediator IL-1β seems to be the initiator of thyrocyte death by upregulating Fas on these cells (5).
Fas-mediated keratinocyte death recently has been shown to be involved in another dermatosis, toxic epidermal necrolysis (TEN) (12). TEN is a life-threatening drug-induced cutaneous reaction with extensive epidermal destruction. Unlike in AD and ACD, in TEN keratinocytes kill themselves by expressing FasL and thus do not need the help of lymphocytes. Although the mechanism for upregulation of the killer ligand is unknown, inhibition of the Fas pathway by application of neutralizing Fas antibodies appears to be a promising therapeutic approach (12).
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Clinical implications of keratinocyte apoptosis
From the pathophysiologic point of view, it is interesting that the same mechanism is demonstrated in AD and ACD, since these dermatoses are usually regarded as mutually exclusive, AD being a classic example of a T-helper 2–mediated (Th2-mediated) and ACD of a Th1-mediated process (13). Th2 cells preferentially release IL-4, IL-5, and IL-10 but not IFN-γ. Since IFN-γ promotes a Th1 response, IFN-γ has even been applied therapeutically in AD, unfortunately not with great success (14). However, Grewe et al. recently suggested that Th2 cells are important only in the initial stage of AD and that a shift toward a Th1 response occurs later and leads to high expression of IFN-γ in lesions (15). These authors speculated that IFN-γ expression via upregulation of the adhesion molecule ICAM-1 contributes to the subsequent accumulation of inflammatory cells. Consistent with this suggestion, the present findings (2) imply that the high expression of IFN-γ also propagates the inflammatory process via disruption of the epidermal barrier. Interestingly, in histologic sections of AD and ACD lesions alike, the majority of apoptotic keratinocytes were found not in spongiotic regions, but in areas that retained normal cohesion of epidermal cells. Hence, one can speculate that apoptosis precedes spongiosis and, further, that apoptotic death of keratinocytes promotes spongiosis by enabling the influx of extracellular fluid into the epidermis.
ACD has always been regarded as a Th1-driven immune response, and the crucial role of the Th1 cytokine IFN-γ, especially during the induction (sensitization) phase, remains undisputed (16). The findings of Trautmann et al. (2) indicate an additional role for this cytokine in inducing keratinocyte cell death during the manifestation (elicitation) phase of this disease. Interestingly, ACD responds favorably to phototherapy with ultraviolet-B radiation (UVB). Although the mechanism remains unclear, we have observed that UVB can block the biological effects of IFN-γ by inhibiting the phosphorylation of the STAT1 protein (17). STAT1, which is critically involved in the signal transduction pathway of IFN-γ, must be tyrosine-phosphorylated to become active. In light of the present findings (2) that IFN-γ is crucial for manifesting ACD, it may be that UVB improves ACD through its inhibitory effect on IFN-γ signaling.
Another established treatment for both AD and ACD is the application of immunosuppressive drugs, such as steroids or cyclosporin A, which primarily target inflammatory cells (14). These drugs are very effective but are associated with side effects, so there is great demand for alternative therapeutic concepts. Here, too, the observations of Trautmann et al. (2) may be of value. One of the major factors perpetuating eczematous dermatitis is the disruption of the epidermal barrier. If, as proposed, Fas-mediated apoptosis of keratinocytes is the key event in this process, pharmacologic inhibitors of apoptosis should be of benefit. Such drugs would also be promising candidates to treat other disorders involving excess apoptosis, such as Alzheimer’s disease, cerebral stroke, and acute hepatic failure.湿疹性皮炎包括一组异质性炎性皮肤病，其特征在于典型的形态反应模式。在急性期，典型的临床特征包括瘙痒，发红，丘疹和与渗出有关的囊泡。湿疹反应的两个最常见原因是特应性皮炎（AD）和过敏性接触性皮炎（ACD）。尽管AD和ACD在性质上完全不同并且在病原学上不相关，但是两种急性期疾病都具有共同的形态特征，尤其是囊泡形成，其最终导致表皮屏障的破坏。失去该防护罩可使微生物，化学或物理来源的其他外部有害物质进入皮肤，并加剧和延续该疾病。因此，囊泡形成和随后的表皮屏障丧失是急性湿疹反应中的关键事件。
在组织病理学上，湿疹反应的特征是单核细胞浸润并伴有细胞间表皮水肿，这种疾病称为海绵状变。严重的海绵状变性导致角质形成细胞的细胞间附着破裂，被认为是急性湿疹性皮炎产生囊泡的罪魁祸首（1）。在JCI的这一期中，Trautmann等人。 （2）提供了证据，即另一条途径，即通过激活Fas受体系统诱导角质细胞凋亡，也破坏了表皮屏障，他们认为渗透的T淋巴细胞是通过这种新途径导致角质细胞死亡的直接原因。
细胞凋亡导致的细胞死亡是一个严格调控的过程，可以去除不必要的，老化的或受损的细胞。在细胞凋亡期间，开始执行复杂的死亡程序，该程序最终导致细胞分裂，最终将其分解为被巨噬细胞吞噬的膜封闭体。由于它不涉及炎性介质的释放，因此与坏死形成鲜明对比的是，凋亡通常不会引起炎性反应。不过，炎症可以诱导局部细胞凋亡，在病毒性肝炎，桥本氏（Hashimoto’s）甲状腺炎以及湿疹性皮炎等疾病中，可以发现与凋亡相关的炎症。
诱导凋亡的一种方法是触发一个称为死亡受体的跨膜蛋白家族（3），其中Fas蛋白（CD95）可能是最重要的（4），因为Fas诱导的凋亡似乎与多种凋亡相关。桥本氏（Hashimoto’s）甲状腺炎和幽门螺杆菌引起的胃炎等疾病（5、6）。通过激动性抗体或其同源配体FasL触发Fas诱导细胞凋亡。配体结合导致Fas的三聚化，并且三聚化的细胞质区域通过募集衔接子分子FADD（具有死亡结构域的Fas相关蛋白）来转导信号。 FADD通过募集半胱氨酸蛋白酶caspase-8负责下游信号转导。随后，级联的下游胱天蛋白酶执行凋亡细胞死亡（4）。
受此凋亡途径影响的细胞中，研究得最好的是淋巴细胞。 Fas及其配体对于正常的淋巴系统稳态至关重要，正如Fas系统的缺陷导致淋巴结病，脾肿大或自身免疫时所见（7）。该途径也与肿瘤的进展有关，因为表达高水平FasL的肿瘤细胞已显示出通过杀死带有Fas的淋巴细胞而逃避了免疫反应（8）。 Trautmann等人的论文。 （2）现在将角质细胞鉴定为Fas诱导的细胞凋亡的另一个靶点，并提供证据表明这种细胞死亡形式与湿疹性皮炎的发病机理有关。角质细胞通常表达低水平的Fas，但IFN-γ会上调这些细胞上的Fas（9，10）。作者表明，与自体活化的T淋巴细胞共孵育后，培养的角质细胞被驱动凋亡。加入封闭的Fas-Fc片段可抑制细胞凋亡，表明角质细胞死亡是由于触发了Fas系统。 T淋巴细胞分泌IFN-γ可促进Fas在角质细胞中的上调，是该途径中至关重要的早期步骤。因此，在这种情况下，角质细胞的凋亡仅与炎症反应有关。但重要的是要提到炎症浸润不是后果，而是细胞凋亡的原因。类似的机制可能适用于乙型肝炎病毒相关的肝硬化，其中T淋巴细胞使用Fas系统杀死肝细胞（11）。桥本氏（Hashimoto’s）甲状腺炎中，炎症介质IL-1β似乎是通过上调这些细胞上的Fas来引发甲状腺细胞死亡的（5）。
Fas介导的角质细胞死亡最近已证明与另一种皮肤病，毒性表皮坏死溶解症（TEN）有关（12）。 TEN是威胁生命的药物诱发的皮肤反应，具有广泛的表皮破坏作用。与AD和ACD不同，TEN中的角质细胞通过表达FasL杀死自身，因此不需要淋巴细胞的帮助。尽管尚不清楚杀伤配体的上调机制，但通过应用中和的Fas抗体抑制Fas途径似乎是一种有前途的治疗方法（12）。
角质细胞凋亡的临床意义
从病理生理学的角度来看，有趣的是，AD和ACD表现出相同的机制，因为这些皮肤病通常被认为是互斥的，AD是由T辅助2介导的（Th2介导的）和ACD是Th1介导的过程（13）。 Th2细胞优先释放IL-4，IL-5和IL-10，但不释放IFN-γ。由于IFN-γ会促进Th1应答，因此IFN-γ甚至已经在AD中进行了治疗，不幸的是未获得很大的成功（14）。但是，Grewe等。最近的研究表明，Th2细胞仅在AD的初始阶段才重要，而向Th1反应的转变则在稍后发生，并导致病变中IFN-γ的高表达（15）。这些作者推测，通过上调粘附分子ICAM-1的IFN-γ表达有助于炎症细胞的后续积累。与此建议一致，目前的发现（2）暗示IFN-γ的高表达还通过表皮屏障的破坏传播了炎症过程。有趣的是，在AD和ACD病变的组织学切片中，大多数凋亡的角质细胞不是在海绵状区域，而是在保留了正常表皮细胞凝聚力的区域。因此，可以推测凋亡发生在海绵状细胞形成之前，而且，角质细胞的凋亡性死亡通过使细胞外液流入表皮而促进了海绵状细胞 （spongiosis ）形成。
ACD一直被认为是Th1驱动的免疫反应，而Th1细胞因子IFN-γ的关键作用，尤其是在诱导（敏化）阶段，仍然是无可争议的（16）。 Trautmann等人的发现。 （2）表明该细胞因子在该疾病的表现（诱导）阶段诱导角质细胞死亡中的另外作用。有趣的是，ACD对使用紫外线B辐射（UVB）的光疗反应良好。尽管机理尚不清楚，但我们观察到UVB可以通过抑制STAT1蛋白的磷酸化来阻断IFN-γ的生物学作用（17）。 STAT1关键参与IFN-γ的信号转导途径，必须将酪氨酸磷酸化才能激活。根据当前的发现（2），IFN-γ对于ACD的表达至关重要，可能是UVB通过抑制IFN-γ信号传导来改善ACD。
AD和ACD的另一种确立的治疗方法是应用免疫抑制药物，例如类固醇或环孢菌素A，其主要靶向炎症细胞（14）。 这些药物非常有效，但有副作用，因此对替代治疗概念有很高的需求。 在这里，也是Trautmann等人的观察。 （2）可能有价值。 维持湿疹性皮炎的主要因素之一是表皮屏障的破坏。 如所提出的，如果Fas介导的角质细胞凋亡是此过程中的关键事件，则凋亡的药理抑制剂应是有益的。 这种药物也有望成为治疗其他涉及过度凋亡的疾病的有前途的候选药物，例如阿尔茨海默氏病，脑中风和急性肝衰竭。No eczema without keratinocyte death
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC314367/
J Clin Invest. 2000 Jul;.
T cell-mediated Fas-induced keratinocyte apoptosis plays a key pathogenetic role in eczematous dermatitis
1Swiss Institute of Allergy and Asthma Research (SIAF), Davos, Switzerland.
Clinical and histologic similarities between various eczematous disorders point to a common efferent pathway. We demonstrate here that activated T cells infiltrating the skin in atopic dermatitis (AD) and allergic contact dermatitis (ACD) induce keratinocyte (KC) apoptosis. KCs normally express low levels of Fas receptor (FasR) that can be substantially enhanced by the presence of IFN-gamma. KCs are rendered susceptible to apoptosis by IFN-gamma when FasR numbers reach a threshold of approximately 40,000 per KC. Subsequently, KCs undergo apoptosis induced by anti-FasR mAb's, soluble Fas ligand, supernatants from activated T cells, or direct contact between T cells and KCs. Apoptotic KCs show typical DNA fragmentation and membrane phosphatidylserine expression. KC apoptosis was demonstrated in situ in lesional skin affected by AD, ACD, and patch tests. Using numerous cytokines and anti-cytokine neutralizing mAb's, we found no evidence that cytokines other than IFN-gamma participate in this process. In addition, apoptosis-inducing pathways other than FasR triggering were ruled out by blocking T cell-induced KC apoptosis by caspase inhibitors and soluble Fas-Fc protein. Responses of normal human skin and cultured skin equivalents to activated T cells demonstrated that KC apoptosis caused by skin-infiltrating T cells is a key event in the pathogenesis of eczematous dermatitis.
T cell-mediated Fas-induced keratinocyte apoptosis plays a key pathogenetic role in eczematous dermatitis - PubMed
https://pubmed.ncbi.nlm.nih.gov/10880045/
Targeting keratinocyte apoptosis in the treatment of atopic dermatitis and allergic contact dermatitis.
Trautmann A, Akdis M, Schmid-Grendelmeier P, Disch R, Bröcker EB, Blaser K, Akdis CA.
J Allergy Clin Immunol. 2001 Nov;108(5):839-46. doi: 10.1067/mai.2001.118796.
PMID: 11692113
Cytokine network and dysregulated apoptosis in atopic dermatitis.
Akdis M, Trautmann A, Klunker S, Blaser K, Akdis CA.
Acta Odontol Scand. 2001 Jun;59(3):178-82. doi: 10.1080/000163501750266783.
PMID: 11501888 Review.
Decisive role of tumor necrosis factor-α for spongiosis formation in acute eczematous dermatitis.
Kerstan A, Bröcker EB, Trautmann A.
Arch Dermatol Res. 2011 Nov;303(9):651-8. doi: 10.1007/s00403-011-1149-5. Epub 2011 May 8.
PMID: 21553284
Keratinocytes in Atopic Eczema | SpringerLink
https://link.springer.com/chapter/10.1007/3-540-29856-8_33
Giustizieri ML, Mascia F, Frezzolini A, De Pità O, Chinni ML, Giannetti A, Girolomoni G, Pastore S (2001) Keratinocytes from patients with atopic dermatitis and psoriasis show a different chemokine production profile in response to T cell-derived cytokines.
Cited by: 2
Publish Year: 2006
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