A number of
autoimmune diseases have been clinically and pathologically characterized. In contrast, target
antigens have been identified only in a few cases and, in these few cases, the knowledge of the exact
epitopic antigenic sequence is still lacking. Thus the major objective of current work in the autoimmunity field is the identification of the
epitopic sequences that are related to autoimmune reactions. Our labs propose that
autoantigen peptide epitopes able to evoke humoral (auto)immune response are defined by the sequence similarity to the host
proteome. The underlying scientific rationale is that
antigen peptides acquire immunoreactivity in the context of their proteomic similarity level. Sequences uniquely owned by a
protein will have high potential to evoke an immune reaction, whereas motifs with high proteomic redundancy should be immunogenically silenced by the tolerance phenomenon. The relationship between sequence redundancy and
peptide immunoreactivity has been successfully validated in a number of experimental models. Here the hypothesis has been applied to
pemphigus diseases and the corresponding
desmoglein autoantigens.
METHODS: Computational analysis led to identifying a linear immunodominant desmoglein-3
epitope highly reactive with the sera from
Pemphigus vulgaris as well as
Pemphigus foliaceous. The
epitopic peptide corresponded to the
amino acid REWVKFAKPCRE sequence, was located in the extreme N-terminal region (residues 49 to 60), and had low redundancy to the human
proteome. Sequence alignment showed that human
desmoglein 1 and 3 share the REW-KFAK-RE sequence as a common motif with 75% residue identity.
CONCLUSION: This study 1) validates sequence redundancy to autoproteome as a main factor in shaping
desmoglein peptide immunogenicity; 2) offers a molecular mechanicistic basis in analyzing the commonality of autoimmune responses exhibited by the two forms of
pemphigus; 3) indicates possible
peptide-immunotherapeutical approaches for
pemphigus diseases.