A COMPLEMENTARITY-DETERMINING REGION PEPTIDE OF AN ANTI-DESMOSOME AUTOANTIBODY MAY INTERACT WITH THE DESMOSOMAL PLAQUE THROUGH MOLECULAR MIMICRY WITH A CYTOPLASMIC DESMOGLEIN-1 SEQUENCE

The sera of patients with pemphigus, a group of autoimmune blistering skin diseases, contain autoantibodies directed against components of a dhering junctions termed desmosomes. F12, a human monoclonal antibody derived from a pemphigus patient, recognizes an unknown polypeptide of the desmosomal and hemidesmosomal plaques. The third complementarity- determining region of the F12 heavy chain (VH-CDR3) was shown to share a four-amino-acid sequence (GSSG) with the intracellular domains of d esmoglein 1 and bullous pemphigoid antigen 2 which interact with compo nents of, respectively, the desmosomal and hemidesmosomal plaques. Com puter modeling of F12 showed that the GSSG sequence protudes inside th e antigen-combining site and thus might be involved in antigen interac tions. The GSSG sequence is essential to F12 function, since a peptide containing the VH-CDR3 inhibited its binding to target antigens while VH-CDR3 peptides with specific modifications of the GSSG sequence did not. These data allow us to hypothesize that certain autoantibodies p roduced during the course of an autoimmune disease can behave as adhes ion molecules, through the molecular mimicry of the motif involved in protein/protein adhesion, and to propose a new self-antigen binding me chanism for some autoantibodies.