No studies have been reported that characterized structures of the lipid bilayer at intercellular spaces in the SC of AD lesional skin, and only structures in nonlesional SC have been investigated. The long-periodicity phase in the lipid bilayer in the nonlesional SC was found to be slightly but significantly reduced in the repeat distance or repeat quantity compared to healthy SC (Janssens et al. 2012). Regarding the lateral lipid packing, it was found that the nonlesional SC of AD patients has an increased percentage of hexagonal lattice, gel phase, compared to healthy skin which is characterized by a larger presence of orthorhombic packing, crystalline phase (Pilgram et al. 2001; Janssens et al. 2012, 2013). These differences could be interpreted as originating from the lipid abnormalities, such as a lower level of total CER, an altered CER composition, and/or CER species with shorter chain lengths.

The diminished level of total CER in the SC of AD skin had a negative correlation with transepidermal water loss (TEWL), which is an index of impaired barrier function (Ishikawa et al. 2010). Also, there was a significantly negative correlation of the TEWL value versus the level of each CER subclass other than CER[AS] and CER[NS]. The subclass of CER[AS] had a significantly positive correlation with TEWL (Ishikawa et al. 2010). Only the subclass CER[AS] seems to have a different nature in terms of the involvement with the barrier function in AD skin. An effect of chain lengths of CER species on the TEWL has also been revealed. Thus, the more abundant the CER species with shorter chain lengths are, the higher the TEWL values (Ishikawa et al. 2010; Joo et al. 2010; Janssens et al. 2012). Since the level of C34 CER species sounds strongly correlated with TEWL (Ishikawa et al. 2010; Janssens et al. 2012), it may be a characteristic marker for the diagnosis of AD. Janssens et al. (2013) showed that the change in tendency in the lateral packing is correlated with the TEWL value. That correlation could be interpreted by the physicochemical nature that the hexagonal lattice is a less-packed structure in the lateral direction, where water can be less disturbed through the lipid bilayer.

The structure of the lipid bilayer in the SC of AD skin is likely to be changed into a bilayer with the reduced repeat distance or repeat quantity in the long-periodicity phase and with an increase in the hexagonal lattice, which may be due to the lipid abnormalities. This change in structure would cause a higher TEWL value corresponding to the impaired barrier function of AD skin.

An ultrastructural study of AD skin versus healthy skin indicated the immature formation of lipid lamellae at the border between the stratum granulosum and the SC of AD skin (Fartasch et al. 1992). Thus, in AD skin, lamellar body-discs remained undelivered and were found even within the horny cells, in contrast to healthy skin where the body-discs completely disappeared. This suggested an abnormal keratinization coming from the unusual lipid metabolism in AD skin. The deficiency of CER in the SC of patients with AD can be explained by the extraordinary upregulation of glucosylceramide sphingomyelin deacylase (GSDase), which hydrolyzes glucosylceramide (GlcCER) or sphingomyelin (SM) at an acyl site to yield sphingosylphosphorylcholine (SPC) or glucosylsphingosine (GSP), respectively, instead of CER (Imokawa 2009), as illustrated in Reaction 1 of Fig. 24.2. The substantiality of the enzyme is supposed to be the β-subunit of acid ceramidase (CDase) based on a study using rat skin (Nogami-Itoh et al. 2010). At first, it was found that in the skin of patients with AD, the activities of three sphingolipid hydrolysis enzymes, β-glucocerebrosidase, sphingomyelinase (SMase), and CDase were not changed (Jin et al. 1994; Murata et al. 1996) whereas SM hydrolysis was increased with the occurrence of SPC as a reaction product and this hitherto undiscovered enzyme was tentatively termed SM deacylase (Murata et al. 1996; Hara et al. 2000). In a subsequent study, this enzyme was then termed GSDase because it hydrolyzes not only SM but also GlcCER in AD skin (Higuchi et al. 2000). The fact that the levels of SPC and GSP were both significantly higher in the epidermis of AD patients (Okamoto et al. 2003; Ishibashi et al. 2003), as listed in Table 24.1, corroborates the mechanism that the upregulation of GSDase generates the CER deficiency.

Other possible mechanisms underlying the diminished level of CER were proposed regarding reduced SMase activity (Reaction 2 of Fig. 24.2) and the involvement of bacterial CDase (Reaction 3 of Fig. 24.2). Acid SMase as well as neutral SMase, which produce CER from SM in the epidermis, were decreased both in the lesional and nonlesional skin from AD patients compared to control healthy skin (Jensen et al 2014). The involvement of bacteria secreting CDase by which CER would be decomposed in the SC of AD skin was proposed (Ohnishi et al. 1999). Those mechanisms might be responsible in part for the diminished level of total CER. However, the altered CER composition cannot be explained only by the SMase activity or bacterial CDase because CER[NS] and CER[AS] are derived in part from the corresponding SM precursors while other subclasses such as EO-containing CER are derived only from GlcCER (Uchida et al. 2000; Hamanaka et al. 2002). Those mechanisms are not enough to explain the altered CER composition in the selective changes in the balances of CER[EOS], other EO-containing CER subclasses, and CER[NP].

Macheleidt et al. (2002) compared the de novo synthesis of GlcCER and CER in lesional AD skin with healthy skin using a metabolic labeling technique, which revealed remarkable decreases of newly biosynthesized ClcCER and CER in lesional AD skin. An experimental system using a reconstructed human epidermal keratinization model suggested that the Th2 type of inflammation evoked in AD skin may be one factor involved in the downregulated biosynthesis of CER, which results in the reduced levels of CER in the SC (Sawada et al. 2012). Therefore, the deficiency of CER in the SC of AD skin is likely to be caused not only by the abnormal pathway from GlcCER and SM to CER, such as the upregulation of GSDase (Reaction 1 of Fig. 24.2), but also reduced the de novo synthesis of CER skeletons themselves (Reaction 4 of Fig. 24.2). As for the chain length, elongases in the epidermis seem to be involved. Although the results were obtained in an experimental system using mice but not humans, some elongases that synthesize very-long-chain FFA were downregulated in a hapten-induced AD model (Park et al. 2012). It could be assumed that the downregulated elongases resulted in the decreased levels of CER species with longer -chain lengths (Bleck et al. 1999; Ishikawa al. 2010; Janssens et al. 2012)very-long-chain FFA (Macheleidt et al. 2002).

Based on evidence accumulated to date, the mechanism underlying the lipid abnormalities for the SC in AD skin can most probably be explained by a combination of events, as follows: (1) the lower level of total CER would be caused by both the upregulation of GSDase and the reduced de novo synthesis of CER in the epidermis of AD skin, (2) the altered CER composition might be ascribed to changes in activities of enzymes relevant to the production of CER in the SC although this remains to be clarified, and (3) CER species with shorter chain lengths might originate from downregulated elongases although that also remains to be elucidated.