A hypothesis concerning a potential involvement of ceramide in apoptosis and acantholysis induced by pemphigus autoantibodies

Abstract

Autoimmune diseases affect more than 50 million Americans, resulting in significant healthcare costs. Most autoimmune diseases occur sporadically; however, endemic pemphigus foliaceus (EPF) is an autoimmune skin disease localized to specific geographic loci. EPF, and the related diseases pemphigus vulgaris (PV) and pemphigus foliaceus (PF), are characterized by skin lesions and autoantibodies to molecules found on epidermal keratinocytes. A variant of EPF in patients from El Bagre, Colombia, South America, has recently been reported to be distinct from previously described loci in Brazil and Tunisia epidemiologically and immunologically. As in PF and EPF, El Bagre EPF patients exhibit autoantibodies towards desmoglein-1, a cell adhesion molecule critical for maintaining epidermal integrity. An association of El Bagre EPF with sun exposure has been detected, and ultraviolet irradiation also exacerbates symptoms in PV, PF and EPF. Our hypothesis is that: (1) the autoantibodies generate pathology through an alteration in ceramide metabolism in targeted keratinocytes, resulting in apoptosis and/or cell death and acantholysis, but only when the cell's ability to metabolize ceramide is exceeded, and (2) apoptosis in response to this altered ceramide metabolism is initiated and/or exacerbated by other agents that increase ceramide levels, such as cytokines, ultraviolet irradiation, and senescence.

Figure 1

Ceramide Metabolism. Ceramide is produced de novo via serine palmitoyltransferase (SPT) and ceramide synthase (CerS), or from sphingomyelin via sphingomyelinase (SMase), and induces apoptosis. In turn, ceramide is metabolized via multiple mechanisms, including glucosylceramide synthase (GCS), ceramidase (CDase) sphingosine kinase (SphK), and sphingomyelin synthase (SMS), with this metabolism of ceramide allowing cell survival.

Figure 2

Sphingomyelin synthase. The reaction catalyzed by sphingomyelin synthase (SM synthase) results in a reduction in ceramide and an increase in diacylglycerol and sphingomyelin levels. The reported phosphatidylcholine-specific phospholipase C inhibitor D609 also inhibits sphingomyelin synthase activity.

Figure 3

Hypothesized Involvement of Sphingolipid Metabolism in the Keratinocyte Response to Pemphigus Autoantibodies. Our hypothesis is that pemphigus autoantibodies binding to Dsgs results in the activation of sphingomyelinase (SMase) to produce ceramide and phosphorylcholine. In an attempt to survive, keratinocytes activate sphingomyelin synthase (SM synthase). The result is an increase in phosphorylcholine and diacylglycerol levels and a reduction in phosphatidylcholine. Stimuli that overwhelm the ability of the cell to metabolize ceramide, such as cytokines or ultraviolet (UV) light (or senescence), which increase ceramide levels, are proposed to allow manifestation of pathologic skin lesions. Note that UV light increases ceramide in at least two ways: first, by activation of both SMase-mediated [35] and de novo ceramide production [19] and second, by decreasing ceramidase activity/expression [60]. Ceramidases are key in the response of keratinocytes to UV light because (1) they metabolize ceramide and decrease its levels and (2) they generate sphingosine, which can be converted to S1P (which allows cell survival) by the action of sphingosine kinase. Indeed, knocking down sphingosine kinase sensitizes keratinocytes to UV-induced apoptosis [60]. In addition, ceramide and its metabolites can activate cytosolic phospholipase A2 and cyclooxygenase-2, suggesting that eicosanoids might be elevated and potentially contribute to the pemphigus disease process (reviewed in [56]).