Molecular mapping of the major epitopes of BP180 recognized by herpes gestationis autoantibodies

Herpes gestationis (HG) is an autoantibody-mediated subepidermal bullous dermatosis associated with pregnancy. The primary target of HG autoantibodies is BP180, a 180-kDa hemidesmosomal glycoprotein. We previously showed that autoantibodies and autoimmune T lymphocytes from HG patients recognize the MCW-1 antigenic site (AA 507-520), which is located in the membrane-proximal noncollagenous domain (NC16A) of BP180. Here, we analyzed the sera of 37 HG patients to further define the sites on BP180 that are targeted by autoantibodies. All of the HG sera, but none of the control sera, were immunoreactive with sec180e, a 120-kDa recombinant protein encompassing the entire BP180 extracellular domain. HG sera depleted of reactivity to NC16A no longer reacted with sec180e, indicating that the major HG-associated epitopes on BP180 are restricted to the NC16A domain. The vast majority of the HG sera (34 of 37) reacted with a 7 amino acid peptide corresponding to the N-terminal half of MCW-1 (MCW-1A). Eleven HG sera (including the 3 that failed to react with MCW-1A) recognized one or more of three antigenic sites located within a 15 amino acid stretch immediately downstream of MCW-1A. In summary, we have identified four major HG-associated epitopes clustered within a 22 amino acid region of the BP180 ectodomain. These findings support the hypothesis that an autoimmune response to the BP180 NC16A domain is a crucial step in the pathogenesis of HG.