Pathogenicity of IgG subclass autoantibodies to type VII collagen: induction of dermal-epidermal separation.
In different autoimmune diseases, tissue damage is mediated by the Fc portion of autoantibodies. These include autoimmunity to type VII collagen, a major hemidesmosomal skin constituent, where autoantibodies activate both complement and leukocytes, leading to separation within the dermal-epidermal junction. Fc-dependent effector functions differ among IgG subclasses. To elucidate the still controversial role of IgG subclasses in the pathogenesis of autoimmunity to type VII collagen, we generated a unique set of V gene-matched recombinant chimeric anti-type VII collagen autoantibodies of the four human IgG subclasses. Binding specificities and avidities of all four autoantibodies were comparable. Using ex vivo models, our results demonstrate that a monoclonal autoantibody is sufficient to activate complement and to induce dermal-epidermal separation. However, only IgG1 and IgG3, but not IgG2 and IgG4 against type VII collagen, were pathogenic in our ex vivo model systems. To our knowledge, this is the first time that a full-length recombinant disease-related human autoantibody has been investigated. Our results demonstrate the usefulness of recombinant antibody technology to dissect the contribution of F(ab')(2) and Fc portions of autoantibodies to their biological effects. These findings may eventually contribute to novel diagnostic tools for monitoring disease and to the development of more specific therapies in autoantibody-mediated diseases, i.e. the generation of subclass-specific adsorbers, used for extracorporal immunoapheresis, or the shifting of the autoimmune response to production of non-pathogenic autoantibodies.
Recke
Andreas
A
Department of Dermatology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany. Andreas.Recke@uk-sh.de <Andreas.Recke@uk-sh.de>
Sitaru
Cassian
C
Vidarsson
Gestur
G
Evensen
Mirja
M
Chiriac
Mircea T
MT
Ludwig
Ralf J
RJ
Zillikens
Detlef
D
D000818:Animals; D001323:Autoantibodies; D015551:Autoimmunity; D024143:Collagen Type VII / Q000276:immunology*; D020405:Dermis / Q000473:pathology*; D004817:Epidermis / Q000473:pathology*; D006801:Humans; D007128:Immunoglobulin Fragments; D007074:Immunoglobulin G / Q000276:immunology*; D051379:Mice; D015202:Protein Engineering; D011994:Recombinant Proteins
D001323:Autoantibodies; D024143:Collagen Type VII; D007128:Immunoglobulin Fragments; D007074:Immunoglobulin G; D011994:Recombinant Proteins