Autoimmune bullous diseases (ABDs) are organ-specific
autoimmune diseases, in which
blisters on the skin and mucous membranes develop through binding of pathogenic
autoantibodies to target
antigens. There are two major ABD groups: the
pemphigus group, showing
autoantibodies to desmosomal components; and the subepidermal ABD group, showing
autoantibodies to hemidesmosomal components in the epidermal basement membrane zone. Recent immunological, biochemical and molecular biological studies revealed many new
autoantigens, including
desmocollins, various plakin family
proteins and
integrins. A revised ABD classification includes new disease entities such as paraneoplastic
pemphigus,
IgA pemphigus and anti-
laminin γ1
pemphigoid. In addition to systemic
corticosteroids and various
immunosuppressive agents, various adjuvant
therapies for ABDs have developed. Among them,
intravenous immunoglobulin (
IVIG) is a promising
therapy, although the therapeutic mechanisms are still unknown. Various disease models for ABDs have developed, particularly for
pemphigus vulgaris,
bullous pemphigoid and
epidermolysis bullosa acquisita (EBA), and these have provided insights into the pathogenesis of various ADBs that suggest possible new treatment strategies. However, the fundamental mechanisms in disruption of immune-tolerance are still unknown. EBA shows autoimmunity to
type VII collagen, the major component of anchoring fibrils, and EBA pathogenesis has been studied in various disease models. Previous studies suggested that, following binding of
autoantibodies to
type VII collagen, activation of
complement,
cytokine release, neutrophil migration, Fcγ receptors (FcgRs) and
metalloproteinases play important roles in induction of subepidermal
blisters. In this issue of the Journal of Pathology, Kasperkiewicz and colleagues reveal important roles of activating FcgRIV and inhibitory FcgRIIB in EBA pathogenesis that were recognized by conducting elegant studies using both genetic analysis and functional animal model methods. The expression equilibrium of the activating and inhibitory FcgRs can be modulated towards the inhibitory FcgRIIB by
IVIG therapy, resulting in beneficial clinical effects of
IVIG in EBA and other autoimmune skin-blistering diseases.