LAD-1 Is Absent in a Subset of Junctional Epidermolysis Bullosa Patients

Abstract

The anchoring filament protein LAD-1 has been recently identified as the target of autoantibodies in the acquired blistering disorder linear IgA bullous dermatosis. Because this protein appears to be involved in the process of dermal-epidermal cohesion, this study sought to determine the involvement of LAD-1 in the pathology of junctional epidermolysis bullosa (JEB). To this end, 44 patients with a variety of subtypes of JEB were analyzed by indirect immunofluorescence microscopy with antibodies to LAD-1, BP180, and laminin-5. We found that only patients with generalized atrophic benign epidermolysis bullosa (GABEB) contained LAD-1 defects. Of the 16 GABEB patients studied, 13 showed absent or greatly reduced expression of LAD-1 (including 2 patients with a peculiar interrupted staining pattern) and 3 patients showed defects of laminin-5 expression with normal LAD-1 expression. Patients who showed LAD-1 defects also showed abnormal expression of BP180. Keratinocytes were cultured from the skin of two GABEB patients and analyzed by indirect immunofluorescent microscopy. One culture demonstrated defects of BP180 and LAD-1 expression (which was also verified by radioimmunoprecipitation assay), and one culture showed decreased laminin-5 expression but normal BP180 and LAD-1 expression. Thus, these studies demonstrate that: (i) LAD-1 and BP180 are normally expressed in all subtypes of JEB except GABEB, (ii) the majority of GABEB patients show absent or near absent expression of both LAD-1 and BP180 but normal expression of laminin-5, and (iii) a smaller subset of GABEB patients show normal LAD-1 and BP180 expression but express persistent but reduced levels of laminin-5.

Patients with Bullous Pemphigoid and Linear IgA Disease show a Dual IgA and IgG Autoimmune Response to BP180

“…This 120 kDa LAD antigen was found to be also recognized by IgG autoantibodies in a large number of BP sera [18,19]. The close relationship between BP180 and LAD-1 was supported by the observation that BP180-deficient tissues from patients with generalized atrophic benign epidermolysis bullosa show abnormally low or no expression of LAD-1 and do not secrete this protein into the culture medium [18,20]. Recent peptide sequence analysis and biochemical studies suggested that LABD97 and LAD-1 are generated as proteolytic cleavage products of the extracellular domain of BP180 [21][22][23].…”

IgA Autoimmune Disorders: Development of a Passive Transfer Mouse Model

“…They noted that linear IgA disease antibodies reacted with this antigen (Marinkovich et al, 1996). Further work showed that patients with generalized atrophic benign epidermolysis bullosa, who were de¢cient in BP180, also failed to show reactivity to this linear IgA disease antigen (Marinkovich et al, 1997). This suggested that this antigen is the same as BP180; however, the lack of immunoreactivity of sera with the intact BP180 antigen on immunoblot was not yet understood.…”

Revertant mosaicism: partial correction of a germ-line mutation in COL17A1 by a frame-restoring mutation

“…In a recently documented form of mosaicism called revertant mosaicism (4), mutant cells undergo a second genetic event that restores protein function or expression, generating normal-appearing cells on a background of mutant cells. Although the occurrence of such revertant cells has been reported in multiple patients with Duchenne muscular dystrophy (5), tyrosinemia type I (6), Fanconi's anemia (7), Bloom's syndrome (8), and generalized atrophic benign epidermolysis bullosa (GABEB) (4,(9)(10)(11)(12)(13), the molecular basis of this mosaicism has been defined only rarely.…”