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February 2000

Levels of Antibodies to BP180 Correlate With Disease Activity in Bullous Pemphigoid

Arch Dermatol. 2000;136(2):253-254. doi:10.1001/archderm.136.2.253

THE ARTICLE by Schmidt et al1 in this issue of the ARCHIVES is interesting and may have relevance to our clinical practice in the future. In order to make valuable the interpretation of their data and to understand the biological significance of their findings, it is important to highlight the milestones in the research on bullous pemphigoid (BP) during the last 15 years. Unlike patients with pemphigus in whom there is a direct correlation between disease activity and pemphigus antibody titers as detected by standard indirect immunofluorescence, studies have shown no correlation between disease activity and level of anti–basement membrane antibodies in BP.2,3 This finding is intriguing in a putatively autoimmune bullous disorder. Another interesting finding is the absence of detectable antibodies by indirect immunofluorescence in approximately 30% of patients with BP. Since all patients with BP had anti–basement membrane antibodies in their skin (as detected by direct immunofluorescence), the negative indirect immunofluorescence findings were interpreted to indicate low levels of antibodies that fell below the sensitivity threshold of indirect immunofluorescence. Many tests were later found to have higher sensitivities than standard indirect immunofluorescence for the detection of circulating BP antibodies. These include indirect immunofluorescence on salt-split human skin, skin explant culture,4 Western blotting, immunoprecipitation, and enzyme-linked immunosorbent assay (ELISA).5,6 It is now clear that all patients with BP have anti–basement membrane antibodies. These antibodies are heterogeneous in their binding sites within the basement membrane area (intracellular hemidesmosomal plaque vs lamina lucida)7,8 as well as the antigenic molecules they recognize (BP230 and BP180).8 Bullous pemphigoid 230 antibodies recognize a molecule that is intracellular within the basal cell hemidesmosomal plaque. Bullous pemphigoid 180 antibodies recognize a transmembrane molecule that has domains within the hemidesmosomal plaque, basal cell membrane, and lamina lucida (and probably the lamina densa).9,10 Bullous pemphigoid 230 antibodies are responsible for most if not all of the binding to the basement membrane as detected by indirect immunofluorescence.11,12 The antibodies detected in the lamina lucida in the skin of patients with BP (by direct immunofluorescence and direct immunoelectron microscopy) are directed against BP180. The majority of antibodies to BP180 recognize a noncollagenous domain (NC16A) just outside the basal cell membrane in the outer lamina lucida.13 Finally, the passive transfer of antibodies to murine BP180 results in skin lesions in mice that are similar to those occurring in human BP.14 It is not surprising that antibodies to BP180 are pathogenic since the extracellular domain of BP180 is accessible to circulating antibodies, unlike BP230 which is completely intracellular. It is presently believed that antibodies to BP230 are secondary, nonpathogenic, and result from "epitope spreading," an event that occurs in several autoimmune disorders in which an immune response to a specific epitope is slowly followed by an immune response to a neighboring epitope or molecule. The proximity of BP230 to BP180 is consistent with this hypothesis. It is interesting that other molecules within the hemidesmosomal–lamina lucida area (including integrins) do not appear to be involved in this phenomenon.