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 adhering 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 desmoglein 1 and bullous pemphigoid antigen 2 which interact with components of, respectively, the desmosomal and hemidesmosomal plaques. Computer modeling of F12 showed that the GSSG sequence protudes inside the antigen-combining site and thus might be involved in antigen interactions. 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 produced during the course of an autoimmune disease can behave as adhesion molecules, through the molecular mimicry of the motif involved in protein/protein adhesion, and to propose a new self-antigen binding mechanism for some autoantibodies.
Gilbert
D
D
IFR23, Faculté Mixte de Médecine et de Pharmacie, Centre Hospitalier Universitaire Charles-Nicolle, Rouen, France.
Courville
P
P
Brard
F
F
Joly
P
P
Petit
S
S
Bernardi
E
E
Schoofs
A R
AR
Lauret
P
P
Tron
F
F
D000595:Amino Acid Sequence; D001323:Autoantibodies / Q000276:immunology*; D001483:Base Sequence; D001666:Binding Sites, Antibody / Q000187:drug effects; D001667:Binding, Competitive / Q000276:immunology; D002460:Cell Line; D003198:Computer Simulation; D003429:Cross Reactions; D003598:Cytoskeletal Proteins / Q000276:immunology*; D051183:Desmoglein 1; D051182:Desmogleins; D051180:Desmoplakins; D003896:Desmosomes / Q000276:immunology*; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000378:metabolism*; D018448:Models, Immunological; D008958:Models, Molecular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D010391:Pemphigoid, Bullous / Q000276:immunology; D010455:Peptides / Q000276:immunology*
D001323:Autoantibodies; D003598:Cytoskeletal Proteins; C495297:DSG1 protein, human; D051183:Desmoglein 1; D051182:Desmogleins; D051180:Desmoplakins; D007135:Immunoglobulin Variable Region; D010455:Peptides