Human anti-laminin 5 autoantibodies induce subepidermal blisters in an experimental human skin graft model. J Invest Dermatol 2000 Jan;114(1):178-84
Date
01/05/2000Pubmed ID
10620135DOI
10.1046/j.1523-1747.2000.00829.xScopus ID
2-s2.0-0034120523 (requires institutional sign-in at Scopus site) 82 CitationsAbstract
Patients with one form of cicatricial pemphigoid have IgG antibasement membrane autoantibodies against laminin 5 (alpha3beta3gamma2). Although passive transfer of rabbit anti-laminin 5 IgG to neonatal mice has been shown to induce subepidermal blisters that mimic those in patients, it has not been possible to directly assess the pathogenic activity of human autoantibodies in this animal model because the latter do not bind murine skin. To address this question, a disease model in adult mice as well as SCID mice bearing human skin grafts was developed. Adult BALB/C mice challenged with rabbit anti-laminin 5 IgG developed, in a concentration-related fashion, erythema, erosions, and crusts surrounding injection sites, histologic evidence of noninflammatory, subepidermal blisters, and deposits of rabbit IgG and murine C3 in epidermal basement membranes. Anti-laminin 5 IgG also induced subepidermal blisters in: adult complement-, mast cell-, and immuno-deficient mice; adult BALB/C mice pretreated with dexamethasone; and human skin grafts on SCID mice. Alterations did not develop in matching controls challenged with identical amounts of purified normal rabbit IgG or bovine serum albumin. Using this adult mouse model, human skin grafts on SCID mice were challenged with purified IgG from patients with alpha subunit-specific, anti-laminin 5 autoantibodies, or normal controls. Patient (but not control) IgG induced epidermal fragility as well as noninflammatory, subepidermal blisters in grafted human (but not adjacent murine) skin. Moreover, whereas all mice that received patient autoantibodies had anti-laminin 5 IgG in their circulation, deposits of human IgG were present only in the epidermal basement membranes of grafts. Interestingly, these in situ and circulating autoantibodies were predominately of the IgG4 subclass. These studies demonstrate that human anti-laminin 5 autoantibodies are pathogenic in vivo and describe an animal model that can be used to define disease pathomechanisms and biologically important domains within this autoantigen.
Author List
Lazarova Z, Hsu R, Yee C, Yancey KBMESH terms used to index this publication - Major topics in bold
AnimalsAutoantibodies
Blister
Cell Adhesion Molecules
Disease Models, Animal
Epidermis
Humans
Immunoglobulin G
Mice
Mice, Inbred BALB C
Mice, SCID
Rabbits
Skin Transplantation
Transplantation, Heterologous
