-Abstract-
Bullous pemphigoid(BP) is an autoimmune blistering skin disease which is
characterized by the presence of circulating autoantibodies against hemidesmosomal
molecules, including two major antigens, 230 kDa BP (BPAGI) and 180 kDa BP antigens
(BPAG2). Molecular genetic studies revealed that BPAG2 is a transmembrane protein,
NC16a domain of which is the major epitope of 90% patient sera. However, the
pathophysiology of blistering after autoantibodies bind to the antigens is not clear. One
possibility is that complement activation by anti-BPAG2 antibody leads to release C5a,
which causes migration of neutrophils and inflammation leading to dermoepidermal
separation. This possibility is rather well accepted at the present time.
However, we have been proposing another explanation for a past few years. The
BPAG2 is distributed on the lateral-apical (as a pool) and ventral (as hemidesmosomes)
cell membranes of basal cells and monolayer cultured keratinocytes. In cell culture
experiments, addition of BP-IgG into culture medium causes the formation of immune
complexes of BPAG2 and BP-IgG on the lated-apical plasma membrane. These immune
complexes are then internalized, leading to inhibition of calcium-induced hemidesmosome
reformation by disturbing the supply of the antigen from the lateral-apical membrane to
the ventral membrane to form hemidesmosomes. This internalization of BPAG2 and
BP-IgG was also observed as intracellular dots in more than half of the lesional and
perilesional biopsy specimens of BP-patients, whereas the BPAG2 was detected on the
whole surface of the basal cells without its internalization (dot-formation) in skin
biopsies from normal individuals. These results suggest that binding of BP-IgG on the
lateral-apical cell surface of basal cells causes internalization of BPAG2 in situ in the
epidermis of BP patients and that this internalization of immune complexes may play an
important part in blister formation in BP.
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