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Aims: Measles virus (MV) infection induces a protective immunity that is accompanied by a transient pathologic suppression of the immune system. This immunologic paradox remains unexplained in spite of the numerous hypotheses that have been advanced (i.e., cytokine production, soluble immunosuppressive factor, cell cycle block, signaling lymphocyte activation molecule receptor and MV infection of dendritic cells, among others)., Methods: Searching for molecular link(s) between MV infection and host immunodeficiency, this study used the Immune Epitope DataBase to analyze the peptide sharing between the antigenic MV hemagglutinin (H) protein and human proteins associated with immunodeficiency., Results: It was found that the majority of MVH derived epitopes share several exact pentapeptide sequences with numerous human proteins involved in immune functions and immunodeficiency, such as B- and T-cell antigens, and complement components., Conclusion: The data suggest that crossreactivity might contribute to our understanding of the link between MV immunogenicity and MV-induced immunosuppression, and highlight peptides unique to MV as a basis for developing effective and safe anti-MV vaccines.

The tendency to use the terms homology, similarity, and identity interchangeably persists in comparative biology. When translated to immunology, overlapping the concepts of homology, similarity, and identity complicates the exact definition of the self-nonself dichotomy and, in particular, affects immunopeptidomics, an emerging field aimed at cataloging and distinguishing immunoreactive peptide epitopes from silent nonreactive amino acid sequences. The definition of similar/dissimilar peptides in immunology is discussed with special attention to the analysis of immunological (dis)similarity between two or more protein sequences that equates to measuring sequence similarity with the use of a proper measurement unit such as a length determinant., (Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd.)

The development of vaccines for new and re-emerging pathologies and infections is based on the ability to define immunogenic epitopes. An immunogenic B-cell peptide epitope is a specific restricted antigen region that is capable of eliciting a humoral immune response and of combining with a specific site on antibodies. Using a number of experimental models and based on data from several literature reports, we identified low levels of sequence similarity to the host proteome as one of the main factors modulating the B-cell epitope repertoire in the humoral immune response. In point of fact, a low level of sequence identity to the host proteins is a common denominator unifying the composite, disparate assembly of linear peptide B-cell epitopes that has been experimentally validated and described in the literature. Here, we explore the proteomic similarity of conformational epitopes experimentally validated and described in published reports. Again, discontinuous epitopic structures formed by non-contiguous amino acid residues were found to define peptide sequences with a low level of similarity to the host. The present meta-analysis adds further significance to the immunological low-similarity theory and its clinical implications. Potentially, low-similarity peptide epitopes pave the way for novel effective vaccines in cancer, autoimmunity, and infectious diseases.

In the past decade, renewed efforts have been made toward the development of vaccines against cancers, infectious agents, autoimmune diseases, and allergies. These efforts have led to the accumulation of numerous peptide sequences experimentally validated as epitopes. However, the factors that render a peptide immunogenic and, more generally, the nature of the antigen-antibody recognition process remain unclear. Based on the hypothesis that potential epitopes correspond to rare sequences and/or structures, we analytically review the data on the molecular structure and properties of immunoreactive sequences derived from (or evoked by) Clostridium tetani, Bacillus anthracis, and C. botulinum toxins. A cohesive picture emerges when peptide motifs are absent or scarcely represented in endogenous self proteins as they define a common immune signature of bacterial toxin B-cell immune determinants. Likewise, the scientific literature also shows that the heavy chain third complementarity-determining regions (CDR3s) from antitoxin antibodies are characterized as being formed by rare peptide sequences. The present meta-analysis aims to provide a key to understanding the molecular nature of the immune recognition process and, in turn, to contribute to the development of effective and safe peptide-based diagnostic tools and vaccine applications.

The specific definition of the immunogenic peptide repertoire from tumor-associated-antigens (TAAs) is of crucial importance for designing effective immunotherapeutical treatments. Multiple mechanisms, at different levels and in complementary manners, contribute to the generation of immunogenic peptides. Using as an experimental model the prostate specific antigen (PSA) and a murine monoclonal antibody (MAb) raised against human PSA, the role of PSA peptide 1) similarity to the murine proteome, 2) affinity to H2-Ad/Ed molecules, and 3) proteasomal cleavage pattern were investigated. We report that the core of the interaction between the anti-PSA MAb ER-PR8 and the prostatic antigen is located in the pentapeptide motif PSA(27-31)GGWEC. The pentapeptide motif is characterized by having no sequence similarity to the murine proteome and a low number of potential proteolytic sites.

Our labs are focused on identifying amino acid sequences having the ability to react specifically with the functional binding site of a complementary antibody. Our epitopic definition is based on the analysis of the similarity level of antigenic amino acid sequences to the host proteome. Here, the similarity profile to the human proteome of an HCV E1 immunodominant epitope, i.e. the HCV E1(315-328)HRMAWDMMMNWSPT sequence, led to i) characterizing the immunoreactive HCV E1 315-328 region as a sequence endowed with a low level of similarity to human proteins; ii) defining 2 contiguous immunodominant linear determinants respectively located at the NH(2) and COOH terminus of the conserved viral antigenic sequence. This study supports the hypothesis that low sequence similarity to the host's proteome modulates the pool of epitopic amino acid sequences in a viral antigen, and appears of potential value in defining immunogenic viral peptide sequences to be used in immunotherapeutic approaches for HCV treatment.

Short amino acid motifs, either linear sequences or discontinuous amino acid groupings, can interact with specific protein domains, so exerting a central role in cell adhesion, signal transduction, hormone activity, regulation of transcript expression, enzyme activity, and antigen-antibody interaction. Here, we analyze the literature for such critical short amino acid motifs to determine the minimal peptide length involved in biologically important interactions. We report the pentapeptide unit as a common minimal amino acid sequence critically involved in peptide-protein interaction and immune recognition. The present survey may have implications in defining the dimensional module for peptide-based therapeutical approaches such as the development of novel antibiotics, enzyme inhibitors/activators, mimetic agonists/antagonists of neuropeptides, thrombolitic agents, specific anti-viral agents, etc. In such a therapeutical context, it is of considerable interest that low molecular weight peptides can easily cross biological barriers, are less susceptible to protease attacks, and can be administered at high concentrations. In addition, small peptides are a rational target for strategies aimed at antigen-specific immunotherapeutical intervention. As an example, specific short peptide fragments might be used to elicit antibodies capable of reacting with the full-length proteins containing the peptide fragment's amino acid sequence, so abolishing the risk of cross-reactivity.

An efficient strategy is presented for the identification of antigenic sequences in the context of given MHC molecules of interest. The proteomic analysis of the antigenic peptide repertoire is described and demonstrated by using high-molecular weight melanoma-associated antigen. The identification of the epitopic sequence of a monoclonal antibody raised against the 250 kDa tumor associated antigen was reached by using only seven short synthetic peptide fragments, instead of the 155 non-overlapping 15-mer peptides theoretically necessary as minimum screening library. The present result has been obtained by applying as driving criteria the analysis of the peptide affinity to MHC class II molecules and the non-self discrimination concept.

A proteomics-based approach was exploited in order to individuate peptide sequences having the immunogenic potential to evoke humoral response. The epitope search utilized two parameters: the similarity level of the peptide sequence to the host's proteins, and the peptide capability to bind to the major histocompatibility complex class II molecules. By this approach, the human papillomavirus 16 E7(49-63) RAHYNIVTFCCKCDS peptide was individuated as the immunogenic epitope recognized by an anti-HPV16 E7 monoclonal antibody raised against the full-length viral oncoprotein. In this report, two-dimensional nuclear magnetic resonance spectroscopic experiments unequivocally probe the HPV16 E7 epitope individuation.

With the aid of computational biology, we have studied the possibility of predicting the peptides able to evoke humoral immune response by using as experimental model the human HER-2/neu breast cancer-associated antigen. We already demonstrated that HER-2/neu peptides, that are the target of humoral human and mouse immune responses, correspond to those sequences having a low degree of sequence similarity to host's proteome. Here we report that the linear peptide determinant of the anti-HER-2/neu MAb-3 is characterized by a low degree of sequence similarity to mouse proteome in combination with high binding potential to specific MHC II molecule.

We applied computational biology to identify the linear amino acid sequence recognized by a mouse monoclonal antibody raised against the full length HPV16 E7 oncoprotein. Computer-assisted search for the epitopic peptide used two parameters: the capability of E7 peptides to bind to MHC class II molecules, and the similarity level of the oncoprotein sequence to the mouse proteome. We report that anti-E7 mAb recognized the peptide having both high binding potential to MHC II molecules and low level of molecular mimicry to mouse proteome. Peptide ability to bind to MHC II molecules appears a necessary but not sufficient condition to determine peptide immunodominance, by needing to be supported by a low degree of peptide similarity to the host's proteome.