Clinical and Molecular Characterization of Autoimmune Bullous Diseases

Abstract

Tremendous advances have been made in the past decades in characterizing the autoantigens of the major autoimmune bullous skin diseases, which provide a direct relationship among distinct clinical phenotypes, the nature and distribution of the targeted autoantigens, and the molecular mechanisms of the immune pathogenesis of these disorders. Pemphigus encompasses a group of life-threatening autoimmune diseases with extensive blistering of the mucous membranes and the skin, that is characterized by intraepidermal loss of adhesion caused by autoantibodies against components of desmosomes that confer adhesion between epidermal keratinocytes. Anhalt et al. (1982) were the first to provide direct evidence that immunoglobulin G (IgG) autoantibodies from pemphigus sera cause epidermal loss of adhesion when injected into neonatal mice. Amagaiet al. (1991) successfully cloned the cDNA encoding a 130 kDa protein that was recognized specifically by pemphigus sera and was identified as a novel desmosomal adhesion protein, named desmoglein 3 (Dsg 3). Stanley et al. (1986) identified another desmosomal cadherin, Dsg 1, which had many structural homologies with Dsg 3 and turned out to be the autoantigen of pemphigus foliaceus, a related disorder characterized by extensive superficial erosions of the skin. Moreover, Stanley and co-workers (Mahoney et al., 1999) provided the pathogenic explanation as to why distinct autoantibody profiles cause a distinct clinical phenotype in pemphigus. The so-called compensation hypothesis is based on the concept that Dsg 1 and Dsg 3 compensate each other’s loss of function upon binding of pemphigus autoantibodies in tissues where they are equally expressed. In pemphigus foliaceus, IgG against Dsg 1 causes superficial cutaneous blisters because Dsg 1 is exclusively expressed in the stratum granulosum of stratified squamous epithelia and is thus not substituted by Dsg 3. In pemphigus vulgaris, anti-Dsg 3 IgG autoantibodies cause suprabasilar loss of adhesion of noncornified squamous epithelia (that is mucous membranes) where Dsg 3 is exclusively expressed and cannot be substituted by Dsg1. The relevance of the adhesive function of desmosomal cadherins for epidermal integrity was demonstrated by Koch et al. (1997), who generated Dsg3-deficient mice, which showed blisters of the oral mucosa and snout due to the loss of adhesion between epidermal keratinocytes. Finally, a most elegant study by Amagai et al. (2000) showed that blistering due to a loss of adhesive function of Dsg 1 is also an inherent feature of bullous impetigo and staphylococcal scalded skin syndrome, two disorders that are caused by Staphylococcus aureus infection of the skin. Staphylococcal exfoliative toxin is a serine protease that specifically cleaves the extracellular portion of Dsg 1 that harbors the major antigenic sites targeted by pathogenic autoantibodies in pemphigus. Lymphatic tumors, drugs containing thiols and nonthiol components, and various infectious agents have all been implicated as triggering factors in the loss of immunological tolerance against Dsg, leading to the etiopathogenesis of pemphigus. Diaz and colleagues suggested that an endemic variant of pemphigus foliaceus, fogo selvagem, which occurs in restricted areas of central South America, may be triggered by local factors such as infections (Warren et al., 2000). They reported a high prevalence of individuals with IgG antibodies against Dsg 1 in these restricted areas who later developed full-blown fogo selvagem. Immunologically, the patients’ autoantibodies targeted epitopes of Dsg 1 (namely its N terminus) that were different from the nonpathogenic epitopes (located in the C terminus of Dsg1) found in the healthy residents of this endemic area (Li et al., 2003). These findings support the concept that a shifted epitope recognition of human autoantigens precedes the clinical outcome of an overt autoimmune disease. Ongoing research strongly suggests that the production of autoantibodies is tightly controlled by Dsg-specific autoaggressive T cells, which are critical for the induction, perpetuation, and immune surveillance of the autoimmune response against Dsg 3 and Dsg 1 (reviewed in Hertl et al., 2006). Immunobullous subepidermal blistering diseases are characterized by autoantibodies to cell–matrix adhesion molecules of the dermal–epidermal junction (DEJ). Stanley et al. (1981) were the first to characterize a constituent of the DEJ as the target of autoantibodies. They identified a