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A degraded/dysfunctional immune system appears to be the main determinant of serious/fatal reaction to viral infection (for COVID-19, SARS, and influenza alike). There are four major approaches being employed or considered presently to augment or strengthen the immune system, in order to reduce adverse effects of viral exposure. The three approaches that are focused mainly on augmenting the immune system are based on the concept that pandemics/outbreaks can be controlled/prevented while maintaining the immune-degrading lifestyles followed by much of the global population. The fourth approach is based on identifying and introducing measures aimed at strengthening the immune system intrinsically in order to minimize future pandemics/outbreaks. Specifically, the four measures are: 1) restricting exposure to virus; 2) providing reactive/tactical treatments to reduce viral load; 3) developing vaccines to prevent, or at least attenuate, the infection; 4) strengthening the immune system intrinsically, by a) identifying those factors that contribute to degrading the immune system, then eliminating/reducing them as comprehensively, thoroughly, and rapidly as possible, and b) replacing the eliminated factors with immune-strengthening factors. This paper focuses on vaccine safety. A future COVID-19 vaccine appears to be the treatment of choice at the national/international level. Vaccine development has been accelerated to achieve this goal in the relatively near-term, and questions have arisen whether vaccine safety has been/is being/will be compromised in pursuit of a shortened vaccine development time. There are myriad mechanisms related to vaccine-induced, and natural infection-induced, infections that could adversely impact vaccine effectiveness and safety. This paper summarizes many of those mechanisms., Competing Interests: The authors report no declarations of interest., (© 2020 The Author(s).)

Premature ovarian insufficiency (POI) refers to a continuum of decreasing ovarian function in women before the age of 40. To date, the cause of POI in the majority of cases remain unresolved. Many cases has been linked to genetic, toxic, infections, enzymatic and iatrogenic causes. A key function of the immune system is to identify and differentiate "self" and "non self" i.e. tolerance. Loss of self-tolerance results in an immune response against self-tissues and thus autoimmunity. Various investigations have highlighted the role of autoimmunity and its pertinence to POI. Several potential immune antigenic targets in the ovary have been reported to be involved in autoantibody induced autoimmune attack. The presence of lymphocytic oöphorits in ovarian samples of patients with POI provides histopathological evidence of autoimmune ovarian involvement. Finally, POI is strongly associated with other autoimmune conditions including for instance Addison disease, autoimmune polyglandular syndrome (APS) -1, APS-4, hypothyroidism, and diabetes mellitus among other autoimmune diseases. Taken together, these lines of evidence provide strong basis that support the role of autoimmunity as a potential cause of disease etiopathogenesis. Continuing research is increasingly providing more insight into the complex disease process. The aim of this review is to summarize the current literature related to the autoimmune nature of POI., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)

Purpose of Review: To give an overview of molecular and immunologic data that link hepatitis C virus (HCV) infection to rheumatic diseases in the human host., Recent Findings: A high level of peptide sharing exists between immunopositive HCV epitopes and human proteins that, when altered, associate with rheumatic manifestations., Summary: The findings suggest the involvement of HCV infection in the induction of most rheumatic diseases via a mechanism of autoimmune cross-reactivity.

Background: Although cross-reactions between Epstein-Barr virus (EBV) and human systemic lupus erythematosus (SLE) autoantigens occur, a complete analysis of the potential EBV peptide cross-reactome has not been performed., Objectives: To analyze the whole EBV proteome searching for peptides common to SLE-related proteins and endowed with an immunological potential., Methods: Fifty-one SLE-related proteins were analyzed for hexapeptide sharing with EBV proteome using publicly available databases., Results: An extremely high number of hexapeptides are shared between 34 human SLE autoantigens and EBV proteins. The peptide sharing mostly occurs with complement components C4 and Interleukin-10 (IL-10)., Conclusions: This study thoroughly describes the EBV vs. SLE autoantigens peptide overlap and powerfully supports cross-reactivity as a major mechanism in EBV-associated SLE etiopathogenesis.

Analyses of the peptide sharing between five common human viruses (Borna disease virus, influenza A virus, measles virus, mumps virus and rubella virus) and the human proteome highlight a massive viral vs. human peptide overlap that is mathematically unexpected. Evolutionarily, the data underscore a strict relationship between viruses and the origin of eukaryotic cells. Indeed, according to the viral eukaryogenesis hypothesis and in light of the endosymbiotic theory, the first eukaryotic cell (our lineage) originated as a consortium consisting of an archaeal ancestor of the eukaryotic cytoplasm, a bacterial ancestor of the mitochondria and a viral ancestor of the nucleus. From a pathologic point of view, the peptide sequence similarity between viruses and humans may provide a molecular platform for autoimmune crossreactions during immune responses following viral infections/immunizations.

Sudden cardiac death (SCD) is an unexpected death due to cardiac causes that occurs in a short time period (generally within 1 h of symptom onset) in a person with known or unknown cardiac disease. Patients with cardiomyopathies, myocarditis, ischemic heart disease and cardiac channelopathies are at risk of SCD. However, a certain percentage of autopsy-negative cases of SCD in the young (<35 years) remain unexplained even after a post-mortem genetic testing. Autoantibodies against cardiac proteins may be potentially involved in the pathogenesis of different heart diseases and in the occurrence of unexplained SCD. In this review we analyze clinical and animal studies that elucidate the prevalence of these autoantibodies in patients with different cardiac diseases and their pathophysiological relevance. We propose a classification of the autoantibodies associated with heart diseases and focus on their molecular and cellular effects. Anti-beta adrenergic receptor antibodies and anti-muscarinic acetylcholine receptor antibodies affect myocardial electrophysiological properties and were reported to be the independent predictors of SCD in patients with different heart diseases. Autoimmune mechanism is proposed for cardiac-related adverse reactions following human papillomavirus (HPV) vaccination. The pentapeptid sharing between HPV's antigens, adrenergic receptors and muscarinic acetylcholine receptors supports this assumption. The dysregulating effects of the autoantibodies against calcium and potassium ion channels can be the basis for autoimmune phenocopies of genetic cardiac channelopathies, which are also associated with SCD., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: To define the cross-reactivity potential and the consequent autoimmunity intrinsic to viral versus human peptide sharing., Methods: Using human papillomavirus (HPV) infection/active immunization as a research model, the experimentally validated HPV L1 epitopes catalogued at the Immune Epitope DataBase were analyzed for peptide sharing with the human proteome., Results: The final data show that the totality of the immunoreactive HPV L1 epi-topes is mostly composed by peptides present in human proteins., Conclusions: Immunologically, the high extent of peptide sharing between the HPV L1 epitopes and human proteins invites to revise the concept of the negative selection of self-reactive lymphocytes. Pathologically, the data highlight a cross-reactive potential for a spectrum of autoimmune diseases that includes ovarian failure, systemic lupus erythematosus (SLE), breast cancer and sudden death, among others. Therapeutically, analyzing already validated immunoreactive epitopes filters out the peptide sharing possibly exempt of self-reactivity, defines the effective potential for pathologic autoimmunity, and allows singling out peptide epitopes for safe immunotherapeutic protocols., (© 2019 S. Karger AG, Basel.)

Background: Anti-ovarian cancer vaccines based on minimal immune determinants uniquely expressed in ovarian cancer biomarkers appear to promise a high level of sensitivity and specificity for ovarian cancer immunodiagnostics, immunoprevention, and immunotherapy., Methods: Using the Pir Peptide Match program, three ovarian cancer biomarkers - namely, sperm surface protein Sp17, WAP four-disulfide core domain protein 2, and müllerian-inhibiting substance - were searched for unique peptide segments not shared with other human proteins. Then, the unique peptide segments were assembled to define oligopeptides potentially usable as synthetic ovarian cancer antigens., Results and Conclusion: This study describes a methodology for constructing ovarian cancer biomarkerderived oligopeptide constructs that might induce powerful, specific, and non-crossreactive immune responses against ovarian cancer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background and Objective: HCMV infection may cause neurodevelopmental disorders, including intellectual disability, hearing loss, cortical malformations, and calcifications. Theorizing about the still unknown molecular basis of HCMV-related diseases, this study analyzes the peptide sharing between HCMV, strains AD169 and Merlin, and human proteins, searching for shared sequences that might lead to crossreactive autoimmune injuries in the brain during immune responses following HCMV infection., Method: HCMV proteins were analyzed for peptides shared with the human proteome using the Pir Peptide Match resource., Result: Numerous HCMV peptides (ranging from 9 to 13 mer in length) are disseminated through hundreds of human proteins. The peptide sharing mostly involves crucial neurodevelopmental antigens such as PITX3, implicated in the differentiation of meso-diencephalic dopaminergic neurons; SIX3, which controls proper anterioposterior patterning of the diencephalon and formation of the rostral diencephalon during forebrain development; and ZIC2, which plays a fundamental role in the early stage of organogenesis of the central nervous system., Conclusion: This study describes a HCMV vs human peptide overlap that may represent a crossreactive platform linking the pathologic sequelae of HCMV infection to the immune anti-HCMV response. The data could inform development of effective and safe immune therapeutic/preventive approaches against HCMV infections., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Purpose of Review: Systemic lupus erythematosus (SLE) is a well known, widespread autoimmune disease, involving multiple organ systems, with a multifaceted, widely unmapped etiopathogenesis. Recently, a new aspect of morbidity has been described among SLE patients: infection with human papilloma virus (HPV). We set out to review data regarding the intricate relationship between the two and attempt to determine whether HPV may pose as a contributing factor to the development of SLE., Recent Findings: We relate to epidemiological, molecular and clinical data. We have found evidence in all these fields suggesting HPV to be involved in the pathogenesis of SLE: increased prevalence of HPV infection among SLE patients; vast molecular homology between viral peptides and human proteins associated with SLE; several reports of SLE development post-HPV vaccination. Our findings suggest a possible involvement of HPV infection in the induction of SLE, via a mechanism of immune cross-reaction due to molecular homology., Summary: We review clinical, epidemiological and molecular data suggesting involvement of HPV infection in the pathogenesis of SLE. We suggest that these findings may justify the development of new HPV vaccines containing viral peptides that bear no homology to the human proteome, in order to avoid possible adverse immune cross-reactivity.

Etiology, pathogenesis, and immunology of systemic lupus erythematosus (SLE) form a complex, still undeciphered picture that recently has been further made complicated by a new factor of morbidity: human papillomaviruses (HPVs). Indeed, a prevalence of HPV infections has been reported among SLE patients. Searching for molecular mechanisms that might underlie and explain the relationship between HPV infection and SLE, we explored the hypothesis that immune responses following HPV infection may crossreact with proteins that, when altered, associate with SLE. Analyzing HPV L1 proteins and using Epstein-Barr virus (EBV) and human retrovirus (HERV) as controls, we found a vast peptide overlap with human proteins comprehending lupus Ku autoantigen proteins p86 and p70, lupus brain antigen 1 homolog, lupus antigen expressed in neurons and muscles, natural killer cell IgG-like receptors, complement proteins C4-A and C4-B, complement receptor CD19, and others. The multitude and heterogeneity of peptide overlaps not only further support the hypothesis that crossreactivity can represent a primum movens in SLE onset, but also provide a molecular framework to the concept of SLE as "an autoimmune mosaic syndrome." Finally, once more, it emerges the need of using the principle of peptide uniqueness as a new paradigm for safe and efficacious vaccinology.

Aiming at the molecular definition of the relationship(s) between prenatal infections and fetal microcephaly and using pentapeptides as minimal immune determinants, we analyzed the peptide matching between proteins from infectious agents involved in microcephalic syndromes (namely Zika virus, human Cytomegalovirus, and Toxoplasma gondii) and human proteins that, when altered, have been specifically associated with microcephaly. We report that an unexpected high number of epitopic pentapeptides (ie, 34) are common to the three fetopathogenic agents and repeatedly occur throughout an important number of microcephaly-related human proteins. The data introduce the issue of multiple cross-reactivity into the etiology on ZIKV-associated pathologies. Indeed, the commonality of immune determinants might lead to a sequence of boostered immune responses if the host undergoes different fetopathogenic infections, thus temporally scanning a potential clinical progression toward brain malformations. At this juncture, the past history of maternal infections/vaccinations might dictate the fetal pathologic outcome., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Restriction of protein synthesis characterizes human cytomegalovirus (HCMV) latency in the human host. In analyzing the molecular factors that hinder HCMV expression, the present study shows that HCMV genes frequently use 6 rare codons, i.e., GCG (Ala), CCG (Pro), CGT (Arg), CGC (Arg), TCG (Ser), and ACG (Thr). In some instances, the rare host codons are clustered along viral nucleotide sequences and represent the majority in sequences encoding short alanine and proline repeats. Given the positive correlation between codon usage, tRNA content, and protein production, the results support the hypothesis that HCMV usage of rare human codons might hinder HCMV protein synthesis, in this way leading to HCMV latency., (© 2017 S. Karger AG, Basel.)

HBsAg and HPV L1 proteins - the HBV and HPV antigens utilized in current vaccines - share amino acid sequences with human proteins such as cardiomyopathy-associated protein 5, titin, protein-arginine deiminase, E3 ubiquitin-protein ligase RNF19A, bassoon, G-protein coupled receptor for fatty acids, insulin isoform 2, and mitogen-activated protein kinase kinase kinase 10, inter alia. Many shared peptides are also part of immunopositive epitopes. The data 1) support the possibility of crossreactions between the two viral antigens and human proteins that, when altered, may associate with neuropsychiatric, cardiovascular and metabolic diseases such as multiple sclerosis, amyotrophic lateral sclerosis, diabetes, and sudden death; 2) confirm the concept that only vaccines based on sequences unique to pathogens might nullify potential crossreactivity risks in vaccination protocols., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Zika virus (ZIKV) infection during pregnancy may be linked to fetal neurological complications that include brain damage and microcephaly. How the viral infection relates to fetal brain malformations is unknown. This study analyzes ZIKV polyprotein for peptide sharing with human proteins that, when altered, associate with microcephaly and brain calcifications. Results highlight a vast viral versus human peptide commonality that, in particular, involves centriolar and centrosomal components canonically cataloged as microcephaly proteins, i.e., C2CD3, CASC5, CP131, GCP4, KIF2A, STIL, and TBG. Likewise, a search for ZIKV peptide occurrences in human proteins linked to Guillain-Barré-like syndromes also show a high, unexpected level of peptide sharing. Of note, further analyses using the Immune Epitope DataBase (IEDB) resource show that many of the shared peptides are endowed with immunological potential. The data indicate that immune reactions following ZIKV infection might be a considerable source of crossreactions with brain-specific proteins and might contribute to the ZIKV-associated neuropathologic sequelae., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Herpesviruses can remain in their hosts by establishing a latent infection with a low pattern of viral gene expression. Passage from latency to reactivation may occur under particular conditions such as immunosuppressive treatments or during fetal development, and often is accompanied by heavy pathologic sequelae. To investigate the molecular basis underlying herpesvirus latency and (re)activation, codon usage of rat cytomegalovirus was comparatively analyzed with respect to the rat codon usage. Two major points stand out as follows: (i) six codons - GCG (Ala), CCG (Pro), CGG (Arg), CGC (Arg), TCG (Ser), and ACG (Thr) - are rare in rat genes and intensively used in rat cytomegalovirus coding sequences; (ii) in many instances, the codons seldom used by the host are clustered along viral sequences coding for single amino acid repeats such as poly-Ala and poly-Thr stretches. The results indicate that rare host codons and their iteration along viral sequences might represent major constraints that lock rat cytomegalovirus translation in its host during the viral latent phase. Consequently, the data also suggest a link between rat cytomegalovirus quiescence/activation and the functional tRNA coadaptation phenomenon. Indeed, increases in minor tRNA species corresponding to rare rat codons mark rat cell proliferation and might rescue difficult viral translational contexts. Ala isoaccepting-tRNA (CGC) is reported as an example. On the whole, the present findings may contribute to explain how the molecular mechanisms that normally control host gene expression can silence/(re)activate viral gene expression, and might address research toward new approaches in anti-viral therapeutics., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A 13-year-old girl developed immune thrombocytopenic purpura (ITP) and concomitant positive antiphospholipid antibodies (aPL) following vaccination with a quadrivalent human papillomavirus (HPV) vaccine. During the course of a disease, she developed clinical manifestation with bleeding and she was treated with intravenous immunoglobulins. Consequently, the number of her platelets remained critically low and she was put on corticosteroids and rituximab. Since then, her platelet count remain within the normal range, but her aPL are still present., (Published by Elsevier Inc.)

Antigens of infectious agents share amino acid sequences with human proteins. Such a peptide matching may lead to autoimmunity through crossreactivity phenomena following pathogen infection and/or immunotherapeutic approaches. In this framework, we analyzed as a model the primary sequence of human cytomegalovirus (HCMV) glycoprotein B (gB) protein and searched for viral peptide sequences shared with human proteins. We show that the HCMV antigen has a high peptide identity with a large number of human proteins at the penta-, hexa-, and heptapeptide level, with the viral versus human peptide overlap involving host proteins implicated in crucial processes such as embryonic development, spermatogenesis, spatial learning, and hippocampal plasticity, inter alia. This study might help understand the etiology of the pathologic sequela associated with HCMV (re)activation and, in addition, address scientific and clinical research toward the definition of antiviral therapeutics based on non-crossreactive viral sequences.

Background: Two main factors can affect the development of ebolavirus immunotherapeutics: the vast peptide commonality between ebolavirus and human proteins, and the high rate of spontaneous mutation of ebolavirus within its human host. Indeed, the viral versus human peptide overlap may represent a relevant source of autoimmune crossreactions following vaccination, while ebolavirus genome mutations can limit and/or nullify a vaccine response., Methods: Aiming at defining safe and effective peptide-based vaccines to fight ebola disease, this study analyzed a recently described Ebola virus isolate (Hoenen et al., Emerging Infect Dis 2016, 22, 331) for sequences not shared with the human proteome and conserved among ebolaviruses., Results: Using the pentapeptide as a minimal immune determinant, it was found that: 1) only 6.6% of the 4865 pentapeptides present in the Ebola virus isolate proteins are unique to the virus; 2) only 55 of the unique viral pentapeptides are conserved among 251 proteomes derived from the four ebolavirus species that may affect humans; and 3) none of the unique peptide signatures that mark Ebola virus isolate glycoprotein are 100% conserved., Conclusions: The present findings pose the basis for the construction of viral polypeptide antigens able to induce non-crossreactive, specific and broadly protective immune responses against ebolavirus, and warn against immune therapeutic/preventive approaches exclusively focused on glycoprotein epitope(s).

Epstein-Barr virus (EBV) infects B-, T-, and NK cells and has been associated not only with a wide range of lymphoid malignancies but also with autoimmune diseases such as lupus erythematosus, rheumatoid arthritis and, in particular, multiple sclerosis. Hence, effective immunotherapeutic approaches to eradicate EBV infection might overthrow cancer and autoimmunity incidence. However, currently no effective anti-EBV immunotherapy is available. Here we use the concept that protein immunogenicity is allocated in rare peptide sequences and search the Epstein-Barr nuclear antigen 1 (EBNA1) sequence for peptides unique to the viral protein and absent in the human host. We report on a set of unique EBV EBNA1 peptides that might be used in designing peptide-based therapies able to specifically hitting the virus or neutralizing pathogenic autoantibodies.

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 concept according to which unique, rare and common sequences may define immunogenicity, immunopathogenicity and immunotolerance, respectively, is graphically illustrated using a melanoma-associated antigen, Melan-A/Mart-1, as a model. The final picture is consolidated by experimentally validated data from the scientific literature and may represent a concrete prelude to effective immunotherapies exempt from collateral autoimmune reactions.

Background: Although rare, adverse events may associate with anti-poliovirus vaccination thus possibly hampering global polio eradication worldwide., Objective: To design peptide-based anti-polio vaccines exempt from potential cross-reactivity risks and possibly able to reduce rare potential adverse events such as the postvaccine paralytic poliomyelitis due to the tendency of the poliovirus genome to mutate., Methods: Proteins from poliovirus type 1, strain Mahoney, were analyzed for amino acid sequence identity to the human proteome at the pentapeptide level, searching for sequences that (1) have zero percent of identity to human proteins, (2) are potentially endowed with an immunologic potential, and (3) are highly conserved among poliovirus strains., Results: Sequence analyses produced a set of consensus epitopic peptides potentially able to generate specific anti-polio immune responses exempt from cross-reactivity with the human host., Conclusion: Peptide sequences unique to poliovirus proteins and conserved among polio strains might help formulate a specific and universal anti-polio vaccine able to react with multiple viral strains and exempt from the burden of possible cross-reactions with human proteins. As an additional advantage, using a peptide-based vaccine instead of current anti-polio DNA vaccines would eliminate the rare post-polio poliomyelitis cases and other disabling symptoms that may appear following vaccination.

In order to define poliovirus (PV) neurovirulence at the molecular level, we comparatively analyze the primary amino acid sequence of Mahoney, a neurovirulent PV strain, versus (i) Sabin, an attenuated PV strain, and (ii) IS1, a PV isolate obtained in temporal association to a paralysis event from a polio vaccinated subject. We identify and describe 12 pentapeptides that, originally present in the Mahoney sequence, are changed in the non-neurovirulent Sabin strain, and, successively, restored in IS1 strain., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Epidemiologic data suggest that maternal microbial infections may cause fetal neurodevelopmental disorders, potentially increasing susceptibility to heavy psychopathologies such as schizophrenia, schizophreniform disorder, autism, pervasive developmental disorders, bipolar disorders, psychosis, epilepsy, language and speech disorders, and cognitive impairment in adult offspring. However, the molecular pathomechanisms underlying such a relationship are not clear. Here we analyze the potential role of the maternal immune response to viral infection in determining fetal brain injuries that increase the risk of neurological disorders in the adult. We use influenza infection as a disease model and human axon guidance pathway, a key process in the formation of neural network during midgestation, as a potential fetal target of immune insults. Specifically, we examined influenza A H1N1 hemagglutinin (HA), an antigenic viral protein, for amino acid sequence similarity to a random library of 188 axon guidance proteins. We obtain the results that (1) contrary to any theoretical expectations, 45 viral pentapeptide matches are distributed throughout a subset of 36 guidance molecules; (2) in 24 guidance proteins, the peptide sharing with HA antigen involves already experimentally validated influenza HA epitopes; and (3) most of the axon guidance vs HA peptide overlap is conserved among influenza A viral strains and subsets. Taken together, our data indicate that immune cross-reactivity between influenza HA and axon guidance molecules is possible and may well represent a pathologic mechanism capable of determining neurodevelopmental disruption in the fetus.

This study documents that mumps virus shares several peptide sequences with human proteins that, when altered, may be involved in oligospermia/azoospermia, sterility and testicular atrophy. Examples are sperm flagellar protein 2 and spermatogenesis and centriole-associated protein 1. The data invite to further investigate crossreactivity as a potential mechanism linking anti-mumps immune responses, alterations of spermatogenesis-associated antigens and male fertility disorders.

Sequence matching analyses show that Clostridium tetani neurotoxin shares numerous pentapeptides (68, including multiple occurrences) with 42 human proteins that, when altered, have been associated with epilepsy. Such a peptide sharing is higher than expected, nonstochastic, and involves tetanus toxin-derived epitopes that have been validated as immunopositive in the human host. Of note, an unexpected high level of peptide matching is found in mitogen-activated protein kinase 10 (MK10), a protein selectively expressed in hippocampal areas. On the whole, the data indicate a potential for cross-reactivity between the neurotoxin and specific epilepsy-associated proteins and may help evaluate the potential risk for epilepsy following immune responses induced by tetanus infection. Moreover, this study may contribute to clarifying the etiopathogenesis of the different types of epilepsy.

Aim: Notwithstanding a renewed interest in the application of immunotherapy as an alternative to chemotherapy and radiotherapy for the treatment of ovarian cancer (OC), and in spite of the available knowledge about ovarian tumor-associated-antigens, the search for a vaccine against OC remains a scientific and clinical challenge. Likewise, immunodiagnostics can detect only a late stage of the disease. Thus, the development of new therapeutic and diagnostic options is highly desirable., Methods: Based on the low-similarity hypothesis, which supports the concept that immunogenicity is preferentially associated to sequences with no/low-similarity to the host proteome, and using Protein Information Resource peptide match program, we searched the ovarian tumor antigen CA125 for amino acid sequences unique to CA125 and absent in the remaining human proteins., Results & Conclusion: We identified a set of 159 pentapeptides unique to CA125 that might be used to design specific and effective immunological tools for diagnosis and treatment of OC.

We report on a high level of octapeptide matching between HCV, HIV-2, MPV, MUV, EBV, HHV-6, and CMV, and human brain antigens that, when altered, have been specifically associated with neuropathologies such as amyotrophic lateral sclerosis, spinocerebellar ataxia, frontotemporal degeneration, Huntington disease, Parkinson disease, cognitive impairment, aphasia and oculomotor apraxia. Quantitatively, the extent of the viral octapeptide sharing with neurodegeneration- associated proteins is in excess when analyzed in a stochastic expectation context. Qualitatively, two main features characterize the peptide matching: 1) many common sequences are single amino acid repeats, and 2) mostly, the shared octapeptides are part of experimentally validated epitopes, thus suggesting an immune crossreactive potential of the viral peptides shared with brain antigens involved in neurodegeneration. The present study may have relevance for peptidebased therapeutic approaches to block potential autoimmune crossreactions in neurological diseases and dysfunctional behavior.

Epstein-Barr virus proteins were examined for amino acid sequence matching to human proteins at the decapeptide level. We report that numerous EBV peptides of different length (from 10- to 13-mer) are present in 28 human proteins. The viral vs. human peptide overlap mainly involves the glycine-rich region allocated in the NH2 terminus of Epstein-Barr nuclear antigen 1 protein and host cellular components that play crucial roles in basic biochemical pathways, such as chromatin remodeling, RNA splicing, transmission across chemical/electrical synapses, and neurogenesis, and that, when altered, may characterize various pathologies such as immunodeficiency, systemic lupus erythematosus, myelination, and speech disorders. The present results might contribute to understand and define the (physio) pathological relationships and interactions occurring between EBV and the human host., (© 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.)

The primary amino acid sequence of West Nile virus (WNV) polyprotein, GenBank accession number M12294, was analyzed by computional biology. WNV is a mosquito-borne neurotropic flavivirus that has emerged globally as a significant cause of viral encephalitis in humans. Using pentapeptides as scanning units and the perfect peptide match program from PIR International Protein Sequence Database, we compared the WNV polyprotein and the human proteome. WNV polyprotein showed significant sequence similarities to a number of human proteins. Several of these proteins are involved in embryogenesis, neurite outgrowth, cortical neuron branching, formation of mature synapses, semaphorin interactions, and voltage dependent L-type calcium channel subunits. The biocomputional study suggest that common amino acid segments might represent a potential platform for further studies on the neurological pathophysiology of WNV infections., (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Aim: To explore the molecular basis of the relationship between Bordetella pertussis infection and sudden death., Methods: B. pertussis proteins were analyzed for amino acid sequence identity to a set of 67 human proteins that, when altered, have been associated with sudden death., Results: More than 82,000 pentapeptides are shared between B. pertussis proteins and sudden death-associated antigens., Conclusion: Results suggest that a possible link between B. pertussis infection and sudden death might be represented by potential immunological cross-reactions occurring between B. pertussis proteins and human proteins associated to sudden death.

Defining the minimal protein determinants of enzymic reactions, biological interactions, and immune recognition is at the core of biochemistry, pathology and therapeutics. Indeed, short peptide sequences are involved in physiological processes such as cell growth and apoptosis, and in pathological phenomena such as amyloid protein fibrillogenesis and tumor cell migration. An active peptide may exert more powerful activity than the entire parent protein and, in immunology, use of short peptides may improve immunotherapies and avoid the potential hazards of using full-length protein antigens. This review illustrates the concept that a peptide sequence only 5-residues long may be used as a basic functional unit in cell biology and immunology, underlines the crucial biological roles played by minisequences and emphasizes the multifold applications of short peptides as therapeutic agents.

West Nile virus (WNV) infection may be associated with fever, neurologic disorders, and acute flaccid paralysis as a final clinical outcome. In spite of the numerous WNV infection outbreaks in Africa, Eurasia, Australia, and North America and notwithstanding an intense research effort for developing effective anti-WNV vaccines, currently no immunopreventive or therapeutic approaches are available. Moreover, antigenic cross-reactivity among flaviviruses can make difficult WNV serodiagnosis. Here we analyze the primary sequence of WNV polyprotein searching for peptide modules that might be utilized to design targeted diagnostic tools and anti-WNV vaccines for use in humans. To this aim, we applied the low-similarity hypothesis, according to which rare peptide sequences are more likely immunogenic than frequent peptide sequences. We report on a set of peptide sequences unique to the WNV, the immunogenic potential of which appears to be confirmed by immunological data cataloged at the Immune Epitope Data Base resource.

Gene expression profiling can be useful for phenotypic classification, investigation of functional pathways, and to facilitate the search for disease risk genes through the integration of transcriptional data with available genomic information. To enhance our understanding of the genetic and molecular basis of basal cell carcinoma (BCC) we performed global gene expression analysis to generate a disease-associated transcriptional profile. A gene signature composed of 331 differentially expressed genes (DEGs) was generated from comparing 4 lesional and 4 site-matched control samples using Affymetrix Human Genome U95A microarrays. Hierarchical clustering based on the obtained gene signature separated the samples into their corresponding phenotype. Pathway analysis identified several significantly overrepresented pathways including PPAR-γ signaling, TGF-β signaling and lipid metabolism, as well as confirmed the importance of SHH and p53 in the pathogenesis of BCC. Comparison of our microarray data with previous microarray studies revealed 13 DEGs overlapping in 3 studies. Several of these overlapping genes function in lipid metabolism or are components of the extracellular matrix, suggesting the importance of these and related pathways in BCC pathogenesis. BCC-associated DEGs were mapped to previously reported BCC susceptibility loci including 1p36, 1q42, 5p13.3, 5p15 and 12q11-13. Our analysis also revealed transcriptional 'hot spots' on chromosome 5 which help to confirm (5p13 and 5p15) and suggest novel (5q11.2-14.3, 5q22.1-23.3 and 5q31-35.3) disease susceptibility loci/regions. Integrating microarray analyses with reported genetic information helps to confirm and suggest novel disease susceptibility loci/regions. Identification of these specific genomic and/or transcriptional targets may lead to novel diagnostic and therapeutic modalities.

In a companion paper, we reported that pentapeptides from human poliovirus 1, Mahoney strain, occur repeatedly in human proteins for a total of more than 18,000 overlaps. In the present study, we describe the distribution of the polio pentapeptides throughout biochemical pathways and networks characterizing functions and tissues in the human host. The present study might be of help to better define the poliovirus-host relationships as well as for designing peptide modules with anti-polio activity.

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.)

Recent numerous studies have demonstrated that an extensive peptide identity platform characterizes entities spanning the entire evolutionary arc from viruses to humans and establishes an immune cross-reactivity potential among viruses and bacteria, as well as between microbial organisms and humans. This peptide commonality presents obstacles to diagnostics, burdens therapeutic vaccinology with harmful collateral effects, and can result in autoimmune diseases. The present study 1) recapitulates the significance of cross-reactivity from the molecular mimicry hypothesis to the phenomenon of microbial immunoevasion; 2) analyzes the implications of cross-reactivity for the self-nonself discrimination issue; 3) highlights the negative role exerted by cross-reactions in translating immunology to effective vaccines; 4) outlines the vicious circle connecting peptide commonality, microbial immune escape, adjuvanted vaccines and autoimmune cross-reactions; and 5) conclusively indicates sequence uniqueness as a basic criterion for designing effective vaccines exempt from autoimmune cross-reactions.

In the present study, we analyze the peptide commonality between poliovirus polyprotein and the human proteins. We report on the following findings: (1) the extent of polio peptide overlap on the human proteome is high, and involves the entire viral polyprotein; (2) viral peptide matching affects human proteins linked to fundamental cellular functions. The data may help to further our understanding of the relationships between poliovirus and the human host.

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.

What types of amino acid substitutions are functionally tolerated in an epitope? This question is of importance because the immunogenicity, pathogenicity, and therapeutic potential of a peptide can be determined by a single amino acid change. As an example, a single amino acid change in the encephalitogenic myelin oligodendrocyte glycoprotein WYRSPFSRVV peptide confers the capacity to ameliorate and reverse experimental autoimmune encephalomyelitis. Currently, no rule is available to predict/explain the functional outcomes of amino acid changes. To address this issue, we examined the role of single amino acid changes in immune responses by applying proteomic similarity analyses to available data. We found that the loss or gain of immunological information in a peptide epitope following an amino acid substitution often is related to a gain or loss in the proteomic similarity. Rare, but significant epitopic sequences become immunologically insignificant when an amino acid change makes them common, repeated sequences. This study confirms that low similarity to the host proteome is a major factor in modulating the immune epitope repertoire.

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.

This paper defines potential peptide cross-reactivity between HIV-1 and the human host. Specifically, the amino acid primary sequence of HIV-1, isolate CDC-451, was analyzed for potential immunopathological relationships with the human proteome. The results revealed that: 1) HIV-1 shares 50 heptapeptides and three octapeptides with the human proteome; 2) 34 of the 50 shared heptapeptides are experimentally validated epitopes targeted by immune responses following HIV-1 infection; 3) the viral heptapeptide epitopes are present in human proteins that, when altered, are associated with disease characteristics of acquired immunodeficiency syndrome (AIDS) such as CD4+ cell loss, encephalopathy, schizophrenia, myopathy, cardiovascular disorders, hypertension, corneal diseases, diarrhea, lymphoma, and bladder cancer; 4) at the pentapeptide level, the viral-versus-human overlap is extensive (14,227 matches), with the viral pentapeptides disseminated throughout 10,312 human proteins. The findings are discussed in relationship to HIV-1 escape from immune surveillance, adjuvant-induced HIV-1 immunogenicity, autoimmune cross-reactions following human hyperimmune responses against HIV-1, and AIDS.

We describe the pentapeptides shared between the Corynebacterium diphtheria toxin and the human proteins associated with fundamental neural functions. We report that diphtheria toxin pentapeptides are spread among human antigens such as tuberous sclerosis proteins 1 and 2, reelin, contactin-4, neuroligins, semaphorin-5A, sodium channel protein type 1 subunit α, Williams-Beuren syndrome chromosomal region 1 protein, Williams-Beuren syndrome chromosomal region 20A protein. Williams-Beuren syndrome chromosomal region 8 protein, Bardet-Biedl syndrome 9 protein, Bardet-Biedl syndrome 10 protein, oligodendrocyte-myelin glycoprotein, neurofibromin-2, and periaxin. The data are discussed in relation to the bacterial immune escape phenomenon, and in the context of potential cross-reactions in diagnostic tests and immune therapies.

An inspection of the sequence similarity between the hepatitis C virus (HCV) polyprotein and human proteins revealed a high level of peptide sharing, with a limited number of motifs unique to the virus (i.e., with no counterpart in the human proteome). Using pentapeptide matching, only 214 motifs out of a total of 3,007 (7.11%) identified HCV as nonself compared to the Homo sapiens proteome. However, this virus-versus-human phenetic difference disappeared at the genetic level. Indeed, a BLAST analysis of pentadecameric oligodeoxynucleotide sequences corresponding to the 214 pentapeptides unique to HCV revealed that almost all of them are present in the human genome, located in the non-coding strand, introns, and/or pseudogenes, thus being, as such, untranslatable. The present data warn against using DNA-based vaccines to fight HCV infection and emphasize peptide uniqueness as the molecular basis for designing effective anti-HCV immunotherapeutic approaches.

Although B19 erythrovirus infection may be associated with severe clinical outcomes, especially in early infancy, pregnancy and in immunocompromised or hemolytic subjects, no vaccine is currently available. Using the concept that effective immune responses to an infectious agent may be restricted to the specific peptidome unique to that agent, we analyzed primary amino acid sequence of B19 erythrovirus, searching for peptide motifs to be used in vaccine formulations. Here, we identify and describe a set of unique viral peptides that may guarantee both high efficacy and practically no cross-reactive autoimmune responses in anti-B19 immunotherapeutic approaches.

We explore the pentapeptide overlapping between human immunodeficiency virus (HIV) proteins and the human proteome. Our intent was to define viral peptides to be used in vaccines effective against different HIV strains, vaccines that are able to overcome the difficulties posed by the tendency of HIV to mutate, and that are also exempt from harmful collateral cross-reactions, as well as being repeatedly administrable to the global population. Analysis of HIV-1 envelope glycoprotein 160 (Env gp160) sequences revealed a set of 15 pentapeptides highly conserved among a number of retroviral sequences, and absent in the human proteome, thus representing unique molecular retroviral signatures. Use of these short viral peptide modules may represent the first concrete step toward the goal of a universal, safe and effective anti-HIV vaccine.