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Proteomic definition of a desmoglein linear determinant common to Pemphigus vulgaris and Pemphigus foliaceous.

Lucchese A, Mittelman A, Tessitore L, Serpico R, Sinha AA, Kanduc D - J Transl Med (2006)

Bottom Line: The relationship between sequence redundancy and peptide immunoreactivity has been successfully validated in a number of experimental models.Computational analysis led to identifying a linear immunodominant desmoglein-3 epitope highly reactive with the sera from Pemphigus vulgaris as well as Pemphigus foliaceous.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dept of Odontostomatology, University of Bari, Italy. alucchese@hotmail.com

ABSTRACT

Background: 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: Desmoglein 3 sequence similarity analysis to the human proteome followed by dot-blot/NMR immunoassays were carried out to identify and validate possible epitopic sequences.

Results: 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.

No MeSH data available.


Related in: MedlinePlus

Immunoreactivity of PV, PF or prostate cancer human sera towards EC Dsg3 peptides. Sera: A) control sera from prostate cancer patients; B) Pemphigus foliaceous sera; C) Pemphigus vulgaris sera. Immunoreactivity of each serum was assayed by dot-blot as described under Methods. Indirect IF titer is reported for each PF and PV serum. Antigens: Dsg3, recombinant EC Dsg 3 protein; peptides with low redundancy to the human proteins: Dsg336–44EEMTMQQAK and Dsg349–60 REWVKFAKPCRE; peptide with high affinity to DRB*0402: Dsg3190–204LNSKIAFKIVSQEPA; control peptides: Dsg3373–380QVINVREG and Dsg3518–525NRYTGPYT.
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Figure 3: Immunoreactivity of PV, PF or prostate cancer human sera towards EC Dsg3 peptides. Sera: A) control sera from prostate cancer patients; B) Pemphigus foliaceous sera; C) Pemphigus vulgaris sera. Immunoreactivity of each serum was assayed by dot-blot as described under Methods. Indirect IF titer is reported for each PF and PV serum. Antigens: Dsg3, recombinant EC Dsg 3 protein; peptides with low redundancy to the human proteins: Dsg336–44EEMTMQQAK and Dsg349–60 REWVKFAKPCRE; peptide with high affinity to DRB*0402: Dsg3190–204LNSKIAFKIVSQEPA; control peptides: Dsg3373–380QVINVREG and Dsg3518–525NRYTGPYT.

Mentions: Fig. 3 shows that the non-redundant Dsg349–60REWVKFAKPCRE peptide was immunoreactive with all sera from PV. The Dsg3373–380QVINVREG sequence showed some faint reactivity. The DRB1*0402 binding and T cell epitope Dsg3190–204LNSKIAFKIVSQEPA peptide [32] did not react with any of the human sera used in this study. Interestingly Fig. 3 illustrates that the non-redundant Dsg349–60REWVKFAKPCRE peptide was immunoreactive with AAbs from PF too.


Proteomic definition of a desmoglein linear determinant common to Pemphigus vulgaris and Pemphigus foliaceous.

Lucchese A, Mittelman A, Tessitore L, Serpico R, Sinha AA, Kanduc D - J Transl Med (2006)

Immunoreactivity of PV, PF or prostate cancer human sera towards EC Dsg3 peptides. Sera: A) control sera from prostate cancer patients; B) Pemphigus foliaceous sera; C) Pemphigus vulgaris sera. Immunoreactivity of each serum was assayed by dot-blot as described under Methods. Indirect IF titer is reported for each PF and PV serum. Antigens: Dsg3, recombinant EC Dsg 3 protein; peptides with low redundancy to the human proteins: Dsg336–44EEMTMQQAK and Dsg349–60 REWVKFAKPCRE; peptide with high affinity to DRB*0402: Dsg3190–204LNSKIAFKIVSQEPA; control peptides: Dsg3373–380QVINVREG and Dsg3518–525NRYTGPYT.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1590053&req=5

Figure 3: Immunoreactivity of PV, PF or prostate cancer human sera towards EC Dsg3 peptides. Sera: A) control sera from prostate cancer patients; B) Pemphigus foliaceous sera; C) Pemphigus vulgaris sera. Immunoreactivity of each serum was assayed by dot-blot as described under Methods. Indirect IF titer is reported for each PF and PV serum. Antigens: Dsg3, recombinant EC Dsg 3 protein; peptides with low redundancy to the human proteins: Dsg336–44EEMTMQQAK and Dsg349–60 REWVKFAKPCRE; peptide with high affinity to DRB*0402: Dsg3190–204LNSKIAFKIVSQEPA; control peptides: Dsg3373–380QVINVREG and Dsg3518–525NRYTGPYT.
Mentions: Fig. 3 shows that the non-redundant Dsg349–60REWVKFAKPCRE peptide was immunoreactive with all sera from PV. The Dsg3373–380QVINVREG sequence showed some faint reactivity. The DRB1*0402 binding and T cell epitope Dsg3190–204LNSKIAFKIVSQEPA peptide [32] did not react with any of the human sera used in this study. Interestingly Fig. 3 illustrates that the non-redundant Dsg349–60REWVKFAKPCRE peptide was immunoreactive with AAbs from PF too.

Bottom Line: The relationship between sequence redundancy and peptide immunoreactivity has been successfully validated in a number of experimental models.Computational analysis led to identifying a linear immunodominant desmoglein-3 epitope highly reactive with the sera from Pemphigus vulgaris as well as Pemphigus foliaceous.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dept of Odontostomatology, University of Bari, Italy. alucchese@hotmail.com

ABSTRACT

Background: 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: Desmoglein 3 sequence similarity analysis to the human proteome followed by dot-blot/NMR immunoassays were carried out to identify and validate possible epitopic sequences.

Results: 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.

No MeSH data available.


Related in: MedlinePlus