Di Zenzo and colleagues have undertaken a multicenter prospective study to clarify the epitope profile for IgG anti-BP180 and BP230 antibodies in 35 patients with bullous pemphigoid (BP). Both intra- and intermolecular epitope spreading events were observed, in which epitopes shifted exclusively from extracellular to intracellular domains. The presence of IgG antibodies to the BP180 C-terminal domain and BP230, in addition to the BP180-NC16A domain, correlated with disease severity and activity, suggesting specific pathogenic relevance for anti-BP230 antibodies. Epitope spreading was found in both T- and B-cell recognition. IgA anti LAD-1 antibodies are frequently found in patients with BP; these antibodies appear to follow the development of IgG antibodies to BP180 and BP230 by epitope spreading. These observations provide direction for future studies of the pathogenesis of and treatments for BP.