BULLOUS PEMPHIGOID AND CICATRICIAL PEMPHIGOID AUTOANTIBODIES REACT WITH ULTRASTRUCTURALLY SEPARABLE EPITOPES ON THE BP180 ECTODOMAIN - EVIDENCE THAT BP180 SPANS THE LAMINA-LUCIDA

The BP180 antigen is a hemidesmosomal glycoprotein that is recognized by autoantibodies associated with three autoimmune disorders, bullous pemphigoid (BP), herpes gestationis (HG), and cicatricial pemphigoid ( CP), BP and HG sera have been shown to recognize a common extracellula r site located near the membrane-spanning domain of this protein, wher eas CP sera react predominantly with a distinct Site near the C termin us, In the current study, the main immunogenic sites on the BP180 ecto domain were ultrastructurally localized using six BP sera, four CP ser a, and two rabbit antisera. The immunolocalization pattern of BP sera was largely restricted to the upper lamina lucida region immediately s ub-jacent to the epidermal hemidesmosome and closely resembled that of a rabbit antiserum directed against the NC16A (membrane-proximal) dom ain of BP180, CP sera, on the other hand, exhibited a lower lamina luc ida/lamina densa labeling pattern that was strikingly similar to that of rabbit antibodies to the BP180 C-terminal region, Finally, antibodi es to the BP180 C-terminal region co-localized with an anti-laminin-5 antibody in the anchoring filament zone, These findings strongly sugge st that the BP180 extracellular domain exists in an extended conformat ion, with the C terminus of this protein projecting into the lamina de nsa, These data support the hypothesis that BP180 contributes to the s tructure and function of the anchoring filaments, Differences in the u ltrastructural mapping of BP and CP autoantibodies appear to correlate with epitope mapping data, which, together, may help to explain the c linical heterogeneity observed in this group of bullous disorders.