Fab fragments directed against laminin 5 induce subepidermal blisters in neonatal mice

Patients with one form of cicatricial pemphigoid have IgG autoantibodies di rected against laminin 5 (alpha 3 beta 3 gamma 2), an adhesion protein in e pidermal basement membrane. Anti-laminin 5 autoantibodies are not found in patients with other skin or mucosal diseases and hence serve as a specific marker for this autoimmune blistering disorder, The demonstration that expe rimental and patient anti-laminin 5 IgG are pathogenic in animal models ind icated that such autoantibodies are central to disease pathophysiology, To investigate further the role of antibody valence and complement in triggeri ng lesion formation in vivo rabbit anti-laminin 5 (or normal, control) Fab fragments were passively transferred to neonatal BALB/c mice. Mice receivin g anti-laminin 5 Fab fragments developed, in a dose-related fashion, circul ating anti-basement membrane antibodies, deposits of immunoreactive rabbit IgG (but not murine C3) in epidermal basement membranes, and subepithelial blisters of skin and mucous membranes, Such alterations were not observed i n mice treated with equivalent concentrations of normal rabbit Fab fragment s. These studies demonstrated that neither complement activation nor cross- Linking of laminin 5 in epidermal basement membranes was required for induc tion of subepidermal blister formation in this animal model of a human auto immune bullous disease. (C) 2000 Academic Press.