185 results on '"Kanduc D"'
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2. Molecular Mimicry between Meningococcal B Factor H-Binding Protein and Human Proteins.
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Kanduc D
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This study calls attention on molecular mimicry and the consequent autoimmune cross reactivity as the molecular mechanism that can cause adverse events following meningococcal B vaccination and warns against active immunizations based on entire antigen., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)
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- 2023
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3. Epigenetics of Hypogonadotropic Hypogonadism: Molecular Mimicry between Severe Acute Respiratory Syndrome Coronavirus 2 and KISSR.
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Kanduc D
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This study analyzed KISS1 and its receptor KISSR for peptide sharing with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was found that SARS-CoV-2 shares numerous minimal immune pentapeptide determinants with KISSR only. The peptide sharing has a high immunologic potential since almost all the common peptides are present in 101 SARS-CoV-2-derived immunoreactive epitopes. Data are in favor of configuring molecular mimicry as an epigenetic factor that can alter KISSR thus causing the hypogonadotropic hypogonadism syndrome with which altered KISSR associates., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)
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- 2023
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4. Exposure to SARS-CoV-2 and Infantile Diseases.
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Kanduc D
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Background and Aim Immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in newborns and children after prophylactic immunization is currently a relevant research topic. The present study analyzes the issue by examining the possibility that the anti-SARS-CoV-2 immune responses are not uniquely directed against the virus but can-via molecular mimicry and the consequent cross-reactivity-also hit human proteins involved in infantile diseases. Methods Human proteins that-if altered-associate with infantile disorders were searched for minimal immune pentapeptide determinants shared with SARS-CoV-2 spike glycoprotein (gp). Then, the shared pentapeptides were analyzed for immunologic potential and immunologic imprinting phenomena. Results Comparative sequence analysis shows that: (1) numerous pentapeptides (namely, 54) are common to SARS-CoV-2 spike gp and human proteins that, when altered, are linked to infantile diseases; (2) all the shared peptides have an immunologic potential since they are present in experimentally validated SARS-CoV-2 spike gp-derived epitopes; and (3) many of the shared peptides are also hosted in infectious pathogens to which children can have already been exposed, thus making immunologic imprint phenomena feasible. Conclusion Molecular mimicry and the consequent cross-reactivity can represent the mechanism that connects exposure to SARS-CoV-2 and various pediatric diseases, with a fundamental role of the immunologic memory and the history of the child's infections in determining and specifying the immune response and the pathologic autoimmune sequela., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)
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- 2023
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5. Molecular Mimicry between Respiratory Syncytial Virus F Antigen and the Human Proteome.
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Kanduc D
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This study examined respiratory syncytial virus (RSV) F glycoprotein (gp) antigen for molecular mimicry with the human proteome. It was found that the viral antigen presents an impressive number of pentapeptides (namely, 525 out of 570) in common with the human proteome, with viral sequences widely and repeatedly distributed among 3,762 human proteins implicated in crucial fundamental cellular functions. The data can have implications for anti-RSV vaccines. Indeed, the high level of molecular mimicry can lead to cross-reactivity and autoimmunity, and invites to follow safer vaccinal protocols based on pentapeptide sequences uniquely present in the viral antigen., Competing Interests: Conflicts of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)
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- 2023
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6. Modifiable contributing factors to COVID-19: A comprehensive review.
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Kostoff RN, Briggs MB, Kanduc D, Dewanjee S, Kandimalla R, Shoenfeld Y, Porter AL, and Tsatsakis A
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- Humans, SARS-CoV-2, Inflammation, Immune System, COVID-19
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The devastating complications of coronavirus disease 2019 (COVID-19) result from an individual's dysfunctional immune response following the initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Multiple toxic stressors and behaviors contribute to underlying immune system dysfunction. SARS-CoV-2 exploits the dysfunctional immune system to trigger a chain of events ultimately leading to COVID-19. The current study identifies eighty immune system dysfunction-enabling toxic stressors and behaviors (hereafter called modifiable contributing factors (CFs)) that also link directly to COVID-19. Each CF is assigned to one of the five categories in the CF taxonomy shown in Section 3.3.: Lifestyle (e.g., diet, substance abuse); Iatrogenic (e.g., drugs, surgery); Biotoxins (e.g., micro-organisms, mycotoxins); Occupational/Environmental (e.g., heavy metals, pesticides); Psychosocial/Socioeconomic (e.g., chronic stress, lower education). The current study shows how each modifiable factor contributes to decreased immune system capability, increased inflammation and coagulation, and increased neural damage and neurodegeneration. It is unclear how real progress can be made in combatting COVID-19 and other similar diseases caused by viral variants without addressing and eliminating these modifiable CFs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
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- 2023
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7. The Role of Codon Usage, tRNA Availability, and Cell Proliferation in EBV Latency and (Re)Activation.
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Kanduc D
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Epstein-Barr nuclear antigen 1 (EBNA1) protein synthesis is inhibited during Epstein-Barr virus (EBV) latency and is resumed in EBV (re)activation. In analyzing the molecular mechanisms underpinning the translation of EBNA1 in the human host, this article deals with two orders of data. First, it shows that the heavily biased codon usage of the EBNA1 open reading frame cannot be translated due to its noncompliance with the human codon usage pattern and the corresponding tRNA pool. The EBNA1 codon bias resides in the sequence composed exclusively of glycine and alanine, i.e., the Gly-Ala repeat (GAR). Removal of the nucleotide sequence coding for GAR results in an EBNA1 codon usage pattern with a lower codon bias, thus conferring translatability to EBNA1. Second, the data bring cell proliferation to the fore as a conditio sine qua non for qualitatively and quantitatively modifying the host's tRNA pool as required by the translational needs of EBNA1, thus enabling viral reactivation. Taken together, the present work provides a biochemical mechanism for the pathogen's shift from latency to (re)activation and confirms the role of human codon usage as a first-line tool of innate immunity in inhibiting pathogens' expression. Immunologically, this study cautions against using codon optimization and proliferation-inducing substances such as glucocorticoids and adjuvants, which can (re)activate the otherwise quiescent, asymptomatic, and innocuous EBV infection. Lastly, the data pose the question whether the causal pathogenic role attributed to EBV should instead be ascribed to the carcinogenesis-associated cellular proliferation., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)
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- 2022
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8. SARS-CoV-2: The Self-Nonself Issue and Diagnostic Tests.
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Kanduc D
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Objective At present, false negatives/positives have been reported in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) diagnostics. Searching for the molecular basis of such tests' unreliability, this study aimed at defining how specific are the sequences used in serological and polymerase chain reaction (PCR) tests to detect SARS-CoV-2. Materials and Methods Analyses were performed on the leading SARS-CoV-2 biomarker spike glycoprotein (gp). Sharing of peptide sequences between the spike antigen and the human host was analyzed using the Peptide Search program from Uniprot database. Sharing of oligonucleotide sequences was investigated using the nucleotide Basic Local Alignment Search Tool (BLASTn) from National Center for Biotechnology Information (NCBI). Results Two main points stand out: (1) a massive pentapeptide sharing exists between the spike gp and the human proteome, and only a limited number of pentapeptides (namely 107) identify SARS-CoV-2 spike gp as nonself when compared with the human proteome, and (2) the small phenetic difference practically disappears at the genetic level. Indeed, almost all of the 107 pentadecameric nucleotide sequences coding for the pentapeptides unique to SARS-CoV-2 spike gp are present in human nucleic acids too. Conclusion The data are of immunological significance for defining the issue of the viral versus human specificity and likely explain the fact that false positives can occur in serological and PCR tests for SARS-CoV-2 detection., Competing Interests: Conflicts of Interest None declared., (The Indian Association of Laboratory Physicians. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)
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- 2022
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9. SARS-CoV-2-Induced Immunosuppression: A Molecular Mimicry Syndrome.
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Kanduc D
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Background Contrary to immunological expectations, decay of adaptive responses against severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) characterizes recovered patients compared with patients who had a severe disease course or died following SARS-CoV-2 infection. This raises the question of the causes of the virus-induced immune immunosuppression. Searching for molecular link(s) between SARS-CoV-2 immunization and the decay of the adaptive immune responses, SARS-CoV-2 proteome was analyzed for molecular mimicry with human proteins related to immunodeficiency. The aim was to verify the possibility of cross-reactions capable of destroying the adaptive immune response triggered by SARS-CoV-2. Materials and Methods Human immunodeficiency-related proteins were collected from UniProt database and analyzed for sharing of minimal immune determinants with the SARS-CoV-2 proteome. Results Molecular mimicry and consequent potential cross-reactivity exist between SARS-CoV-2 proteome and human immunoregulatory proteins such as nuclear factor kappa B (NFKB), and variable diversity joining V(D)J recombination-activating gene (RAG). Conclusion The data (1) support molecular mimicry and the associated potential cross-reactivity as a mechanism that can underlie self-reactivity against proteins involved in B- and T-cells activation/development, and (2) suggest that the extent of the immunosuppression is dictated by the extent of the immune responses themselves. The higher the titer of the immune responses triggered by SARS-CoV-2 immunization, the more severe can be the cross-reactions against the human immunodeficiency-related proteins, the more severe the immunosuppression. Hence, SARS-CoV-2-induced immunosuppression can be defined as a molecular mimicry syndrome. Clinically, the data imply that booster doses of SARS-CoV-2 vaccines may have opposite results to those expected., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)
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- 2022
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10. Nucleotide Sequence Sharing between the Human Genome and Primers for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Detection.
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Kanduc D
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This study shows that oligonucleotide sequences are shared between the human genome and primers that have been proposed/used for SARS-CoV-2 detection by polymerase chain reaction (PCR). The high level of sharing (namely, up to 19mer with a maximum number of gaps equal to 2) might bear implications for the diagnostic validity of SARS-CoV-2 detection by PCR., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)
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- 2022
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11. Retraction notice to "Why are we vaccinating children against COVID-19?" [Toxicol. Rep. 8 (2021) 1665-1684].
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Kostoff RN, Calina D, Kanduc D, Briggs MB, Vlachoyiannopoulos P, Svistunov AA, and Tsatsakis A
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[This retracts the article DOI: 10.1016/j.toxrep.2021.08.010.]., (© 2022 The Authors.)
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- 2022
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12. Contributing factors common to COVID‑19 and gastrointestinal cancer.
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Kostoff RN, Briggs MB, Kanduc D, Shores DR, Kovatsi L, Drakoulis N, Porter AL, Tsatsakis A, and Spandidos DA
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- COVID-19 etiology, COVID-19 immunology, Gastrointestinal Neoplasms etiology, Gastrointestinal Neoplasms immunology, Humans, Risk Factors, SARS-CoV-2 physiology, Socioeconomic Factors, COVID-19 epidemiology, Gastrointestinal Neoplasms epidemiology
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The devastating complications of coronavirus disease 2019 (COVID‑19) result from the dysfunctional immune response of an individual following the initial severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection. Multiple toxic stressors and behaviors contribute to underlying immune system dysfunction. SARS‑CoV‑2 exploits the dysfunctional immune system to trigger a chain of events, ultimately leading to COVID‑19. The authors have previously identified a number of contributing factors (CFs) common to myriad chronic diseases. Based on these observations, it was hypothesized that there may be a significant overlap between CFs associated with COVID‑19 and gastrointestinal cancer (GIC). Thus, in the present study, a streamlined dot‑product approach was used initially to identify potential CFs that affect COVID‑19 and GIC directly (i.e., the simultaneous occurrence of CFs and disease in the same article). The nascent character of the COVID‑19 core literature (~1‑year‑old) did not allow sufficient time for the direct effects of numerous CFs on COVID‑19 to emerge from laboratory experiments and epidemiological studies. Therefore, a literature‑related discovery approach was used to augment the COVID‑19 core literature‑based 'direct impact' CFs with discovery‑based 'indirect impact' CFs [CFs were identified in the non‑COVID‑19 biomedical literature that had the same biomarker impact pattern (e.g., hyperinflammation, hypercoagulation, hypoxia, etc.) as was shown in the COVID‑19 literature]. Approximately 2,250 candidate direct impact CFs in common between GIC and COVID‑19 were identified, albeit some being variants of the same concept. As commonality proof of concept, 75 potential CFs that appeared promising were selected, and 63 overlapping COVID‑19/GIC potential/candidate CFs were validated with biological plausibility. In total, 42 of the 63 were overlapping direct impact COVID‑19/GIC CFs, and the remaining 21 were candidate GIC CFs that overlapped with indirect impact COVID‑19 CFs. On the whole, the present study demonstrates that COVID‑19 and GIC share a number of common risk/CFs, including behaviors and toxic exposures, that impair immune function. A key component of immune system health is the removal of those factors that contribute to immune system dysfunction in the first place. This requires a paradigm shift from traditional Western medicine, which often focuses on treatment, rather than prevention.
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- 2022
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13. Molecular mimicry between SARS-CoV-2 and the female reproductive system.
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Dotan A, Kanduc D, Muller S, Makatsariya A, and Shoenfeld Y
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- Epitopes, Female, Humans, Molecular Mimicry, Oogenesis genetics, SARS-CoV-2 genetics, Spike Glycoprotein, Coronavirus genetics
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Introduction: Oogenesis, the process of egg production by the ovary, involves a complex differentiation program leading to the production of functional oocytes. This process comprises a sequential pathway of steps that are finely regulated. The question related to SARS-CoV-2 infection and fertility has been evoked for several reasons, including the mechanism of molecular mimicry, which may contribute to female infertility by leading to the generation of deleterious autoantibodies, possibly contributing to the onset of an autoimmune disease in infected patients., Objective: The immunological potential of the peptides shared between SARS-CoV-2 spike glycoprotein and oogenesis-related proteins; Thus we planned a systematic study to improve our understanding of the possible effects of SARS-CoV-2 infection on female fertility using the angle of molecular mimicry as a starting point., Methods: A library of 82 human proteins linked to oogenesis was assembled at random from UniProtKB database using oogenesis, uterine receptivity, decidualization, and placentation as a key words. For the analyses, an artificial polyprotein was built by joining the 82 a sequences of the oogenesis-associated proteins. These were analyzed by searching the Immune Epitope DataBase for immunoreactive SARS-CoV-2 spike glycoprotein epitopes hosting the shared pentapeptides., Results: SARS-CoV-2 spike glycoprotein was found to share 41 minimal immune determinants, that is, pentapeptides, with 27 human proteins that relate to oogenesis, uterine receptivity, decidualization, and placentation. All the shared pentapeptides that we identified, with the exception of four, are also present in SARS-CoV-2 spike glycoprotein-derived epitopes that have been experimentally validated as immunoreactive., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2021
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14. From Genetics to Epigenetics: Top 4 Aspects for Improved SARS-CoV-2 Vaccine Designs as Paradigmatic Examples.
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Kanduc D
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This literature review described the genetic and biochemical factors that may have been overlooked in the formulation of vaccines and that most likely underlie possible issues with mass vaccination., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)
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- 2021
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15. MTADV 5-MER peptide suppresses chronic inflammations as well as autoimmune pathologies and unveils a new potential target-Serum Amyloid A.
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Hemed-Shaked M, Cowman MK, Kim JR, Huang X, Chau E, Ovadia H, Amar KO, Eshkar-Sebban L, Melamed M, Lev LB, Kedar E, Armengol J, Alemany J, Beyth S, Okon E, Kanduc D, Elgavish S, Wallach-Dayan SB, Cohen SJ, and Naor D
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- Animals, Anti-Inflammatory Agents therapeutic use, Autoimmunity, Cells, Cultured, Computational Biology, Cytokines metabolism, Disease Models, Animal, Humans, Inflammation Mediators metabolism, Mice, Mice, Knockout, Peptides therapeutic use, Serum Amyloid A Protein genetics, Arthritis, Rheumatoid immunology, Hyaluronan Receptors genetics, Inflammation immunology, Inflammatory Bowel Diseases immunology, Multiple Sclerosis immunology, Peptides genetics, Serum Amyloid A Protein immunology
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Despite the existence of potent anti-inflammatory biological drugs e.g., anti-TNF and anti IL-6 receptor antibodies, for treating chronic inflammatory and autoimmune diseases, these are costly and not specific. Cheaper oral available drugs remain an unmet need. Expression of the acute phase protein Serum Amyloid A (SAA) is dependent on release of pro-inflammatory cytokines IL-1, IL-6 and TNF-α during inflammation. Conversely, SAA induces pro-inflammatory cytokine secretion, including Th17, leading to a pathogenic vicious cycle and chronic inflammation. 5- MER peptide (5-MP) MTADV (methionine-threonine-alanine-aspartic acid-valine), also called Amilo-5MER, was originally derived from a sequence of a pro-inflammatory CD44 variant isolated from synovial fluid of a Rheumatoid Arthritis (RA) patient. This human peptide displays an efficient anti-inflammatory effects to ameliorate pathology and clinical symptoms in mouse models of RA, Inflammatory Bowel Disease (IBD) and Multiple Sclerosis (MS). Bioinformatics and qRT-PCR revealed that 5-MP, administrated to encephalomyelytic mice, up-regulates genes contributing to chronic inflammation resistance. Mass spectrometry of proteins that were pulled down from an RA synovial cell extract with biotinylated 5-MP, showed that it binds SAA. 5-MP disrupted SAA assembly, which is correlated with its pro-inflammatory activity. The peptide MTADV (but not scrambled TMVAD) significantly inhibited the release of pro-inflammatory cytokines IL-6 and IL-1β from SAA-activated human fibroblasts, THP-1 monocytes and peripheral blood mononuclear cells. 5-MP suppresses the pro-inflammatory IL-6 release from SAA-activated cells, but not from non-activated cells. 5-MP could not display therapeutic activity in rats, which are SAA deficient, but does inhibit inflammations in animal models of IBD and MS, both are SAA-dependent, as shown by others in SAA knockout mice. In conclusion, 5-MP suppresses chronic inflammation in animal models of RA, IBD and MS, which are SAA-dependent, but not in animal models, which are SAA-independent., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2021
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16. COVID-19: adrenal response and molecular mimicry.
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Churilov LP, Kanduc D, and Ryabkova VA
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- Adrenal Glands immunology, Adrenal Glands virology, Humans, Inflammation Mediators immunology, Receptors, Angiotensin immunology, Receptors, Corticotropin immunology, SARS-CoV-2 physiology, Post-Acute COVID-19 Syndrome, Adrenal Insufficiency etiology, Adrenal Insufficiency immunology, Adrenal Insufficiency virology, Autoimmunity immunology, COVID-19 complications, COVID-19 immunology, Molecular Mimicry immunology
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- 2021
17. From Anti-SARS-CoV-2 Immune Response to the Cytokine Storm via Molecular Mimicry.
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Kanduc D
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The aim of this study was to investigate the role of molecular mimicry in the cytokine storms associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human proteins endowed with anti-inflammatory activity were assembled and analyzed for peptide sharing with the SARS-CoV-2 spike glycoprotein (gp) using public databases. It was found that the SARS-CoV-2 spike gp shares numerous pentapeptides with anti-inflammatory proteins that, when altered, can lead to cytokine storms characterized by diverse disorders such as systemic multiorgan hyperinflammation, macrophage activation syndrome, ferritinemia, endothelial dysfunction, and acute respiratory syndrome. Immunologically, many shared peptides are part of experimentally validated epitopes and are also present in pathogens to which individuals may have been exposed following infections or vaccinal routes and of which the immune system has stored memory. Such an immunologic imprint might trigger powerful anamnestic secondary cross-reactive responses, thus explaining the raging of the cytokine storm that can occur following exposure to SARS-CoV-2. In conclusion, the results support molecular mimicry and the consequent cross-reactivity as a potential mechanism in SARS-CoV-2-induced cytokine storms, and highlight the role of immunological imprinting in determining high-affinity, high-avidity, autoimmune cross-reactions as a pathogenic sequela associated with anti-SARS-CoV-2 vaccines.
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- 2021
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18. From Anti-Severe Acute Respiratory Syndrome Coronavirus 2 Immune Response to Cancer Onset via Molecular Mimicry and Cross-Reactivity.
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Kanduc D
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Background and Objectives Whether exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may predispose to the risk of cancer in individuals with no prior cancers is a crucial question that remains unclear. To confirm/refute possible relationships between exposure to the virus and ex novo insurgence of tumors, this study analyzed molecular mimicry and the related cross-reactive potential between SARS-CoV-2 spike glycoprotein (gp) antigen and human tumor-suppressor proteins. Materials and Methods Tumor-associated proteins were retrieved from UniProt database and analyzed for pentapeptide sharing with SARS-CoV-2 spike gp by using publicly available databases. Results An impressively high level of molecular mimicry exists between SARS-CoV-2 spike gp and tumor-associated proteins. Numerically, 294 tumor-suppressor proteins share 308 pentapeptides with the viral antigen. Crucially, the shared peptides have a relevant immunologic potential by repeatedly occurring in experimentally validated epitopes. Such immunologic potential is of further relevancy in that most of the shared peptides are also present in infectious pathogens to which, in general, human population has already been exposed, thus indicating the possibility of immunologic imprint phenomena. Conclusion This article described a vast peptide overlap between SARS-CoV-2 spike gp and tumor-suppressor proteins, and supports autoimmune cross-reactivity as a potential mechanism underlying prospective cancer insurgence following exposure to SARS-CoV-2. Clinically, the findings call for close surveillance of tumor sequelae that possibly could result from the current coronavirus pandemic., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)
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- 2021
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19. Human Codon Usage: The Genetic Basis of Pathogen Latency.
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Kanduc D
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Infectious diseases pose two main compelling issues. First, the identification of the molecular factors that allow chronic infections, that is, the often completely asymptomatic coexistence of infectious agents with the human host. Second, the definition of the mechanisms that allow the switch from pathogen dormancy to pathologic (re)activation. Furthering previous studies, the present study (1) analyzed the frequency of occurrence of synonymous codons in coding DNA, that is, codon usage, as a genetic tool that rules protein expression; (2) described how human codon usage can inhibit protein expression of infectious agents during latency, so that pathogen genes the codon usage of which does not conform to the human codon usage cannot be translated; and (3) framed human codon usage among the front-line instruments of the innate immunity against infections. In parallel, it was shown that, while genetics can account for the molecular basis of pathogen latency, the changes of the quantitative relationship between codon frequencies and isoaccepting tRNAs during cell proliferation offer a biochemical mechanism that explains the pathogen switching to (re)activation. Immunologically, this study warns that using codon optimization methodologies can (re)activate, potentiate, and immortalize otherwise quiescent, asymptomatic pathogens, thus leading to uncontrollable pandemics., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)
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- 2021
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20. Thromboses and Hemostasis Disorders Associated with COVID-19: The Possible Causal Role of Cross-Reactivity and Immunological Imprinting.
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Kanduc D
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By examining the issue of the thromboses and hemostasis disorders associated with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) through the lens of cross-reactivity, it was found that 60 pentapeptides are shared by SARS-CoV-2 spike glycoprotein (gp) and human proteins that- when altered, mutated, deficient or, however, improperly functioning- cause vascular diseases, thromboembolic complications, venous thrombosis, thrombocytopenia, coagulopathies, and bleeding, inter alia. The peptide commonality has a relevant immunological potential as almost all of the shared sequences are present in experimentally validated SARS-CoV-2 spike gp-derived epitopes, thus supporting the possibility of cross-reactions between the viral gp and the thromboses-related human proteins. Moreover, many of the shared peptide sequences are also present in pathogens to which individuals have previously been exposed following natural infection or vaccinal routes, and of which the immune system has stored imprint. Such an immunological memory might rapidly trigger anamnestic secondary cross-reactive responses of extreme affinity and avidity, in this way explaining the thromboembolic adverse events that can associate with SARS-CoV-2 infection or active immunization., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)
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- 2021
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21. The SARS-CoV-2 as an instrumental trigger of autoimmunity.
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Dotan A, Muller S, Kanduc D, David P, Halpert G, and Shoenfeld Y
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- Autoimmunity, COVID-19 Vaccines, Herpesvirus 4, Human, Humans, SARS-CoV-2, Autoimmune Diseases, COVID-19, Epstein-Barr Virus Infections
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Autoimmunity may be generated by a variety of factors by creating a hyper-stimulated state of the immune system. It had been established long ago that viruses are a substantial component of environmental factors that contribute to the production of autoimmune antibodies, as well as autoimmune diseases. Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human immunodeficiency virus (HIV) are viruses that withhold these autoimmune abilities. In a similar manner, SARS-CoV-2 may be counted to similar manifestations, as numerous records demonstrating the likelihood of COVID-19 patients to develop multiple types of autoantibodies and autoimmune diseases. In this review, we focused on the association between COVID-19 and the immune system concerning the tendency of patients to develop over 15 separate types of autoantibodies and above 10 distinct autoimmune diseases. An additional autoimmunity manifestation may be one of the common initial symptoms in COVID-19 patients, anosmia, the complete loss of the ability to sense smell, and other olfactory alterations. We summarize current knowledge on principal mechanisms that may contribute to the development of autoimmunity in the disease: the ability of SARS-CoV-2 to hyper-stimulate the immune system, induce excessive neutrophil extracellular traps formation with neutrophil-associated cytokine responses and the molecular resemblance between self-components of the host and the virus. Additionally, we will examine COVID-19 potential risk on the new-onsets of autoimmune diseases, such as antiphospholipid syndrome, Guillain-Barré syndrome, Kawasaki disease and numerous others. It is of great importance to recognize those autoimmune manifestations of COVID-19 in order to properly cope with their outcomes in the ongoing pandemic and the long-term post-pandemic period. Lastly, an effective vaccine against SARS-CoV-2 may be the best solution in dealing with the ongoing pandemic. We will discuss the new messenger RNA vaccination strategy with an emphasis on autoimmunity implications., (Copyright © 2021 Elsevier B.V. All rights reserved.)
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- 2021
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22. Lack of Molecular Mimicry between Nonhuman Primates and Infectious Pathogens: The Possible Genetic Bases.
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Kanduc D
- Abstract
Recently, it was found that proteomes from poliovirus, measles virus, dengue virus, and severe acute respiratory syndrome-related Coronavirus 2 (SARS-CoV-2) have high molecular mimicry at the heptapeptide level with the human proteome, while heptapeptide commonality is minimal or absent with proteomes from nonhuman primates, that is, gorilla, chimpanzee, and rhesus macaque. To acquire more data on the issue, analyses here have been expanded to Ebola virus, Francisella tularensis , human immunodeficiency virus-1 (HIV-1), Toxoplasma gondii , Variola virus, and Yersinia pestis . Results confirm that heptapeptide overlap is high between pathogens and Homo sapiens , but not between pathogens and primates. Data are discussed in light of the possible genetic bases that differently model primate phenomes, thus possibly underlying the zero/low level of molecular mimicry between infectious agents and primates. Notably, this study might help address preclinical vaccine tests that currently utilize primates as animal models, since autoimmune cross-reactions and the consequent adverse events cannot occur in absentia of shared sequences., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)
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- 2021
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23. Sjögren's Syndrome Associated with Chikungunya Infection: A Case Report.
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de Carvalho JF, Kanduc D, da Silva FF, Tanay A, Lucchese A, and Shoenfeld Y
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Chikungunya virus (CHIKV) infection is caused by an arbovirus prevalent in various parts of the world. The virus can induce autoantibodies and rheumatic diseases, such as rheumatoid arthritis and spondylarthritis. However, until now, no case of Sjögren syndrome (SS) was described associated with CHIKV. In this article, we describe a 49-year-old female with polyarthralgia and a temporary rash on her trunk and arms. Her physical examination showed polyarthritis of her ankles and wrists. Serologies for CHIKV were interpreted as positive with IgM 6.5 (normal range < 0.8) and negative for IgG. Antinuclear antibodies were positive at a titer of 1:640 as well as anti-Ro/SS-A. The diagnosis of subacute CHIKV infection was determined. The Schirmer test, Rose Bengal, and salivary scintigraphy were positive and the diagnosis of SS was confirmed. She was treated with hydroxychloroquine, methotrexate, and a single dose of betamethasone depot. This is the first report on CHIKV associated with SS. Sequence analysis of the CHIKV proteome versus SS autoantigens showed an extensive peptide sharing between the virus and numerous SS autoantigens, thus supporting the hypothesis that autoimmune cross-reactivity might causally link CHIKV to SS.
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- 2021
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24. The role of proteomics in defining autoimmunity.
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Kanduc D
- Subjects
- Autoantigens, Cross Reactions, Humans, Proteome, Autoimmunity, Proteomics
- Abstract
Introduction: Proteomics, i.e. the study of the set of proteins produced in a cell, tissue, organism, or biological entity, has made possible analyses and contextual comparisons of proteomes/proteins and biological functions among the most disparate entities, from viruses to the human being. In this way, proteomic scrutiny of tumor-associated proteins, autoantigens, and pathogen antigens offers the tools for fighting cancer, autoimmunity, and infections., Areas Covered: Comparative proteomics and immunoproteomics, the new scientific disciplines generated by proteomics, are the main themes of the present review that describes how comparative analyses of pathogen and human proteomes led to re-modulate the molecular mimicry concept of the pre-proteomic era. I.e. before proteomics, molecular mimicry - the sharing of peptide sequences between two biological entities - was considered as intrinsically endowed with immunologic properties and was related to cross-reactivity. Proteomics allowed to redefine such an assumption using physicochemical parameters according to which frequency and hydrophobicity preferentially confer an immunologic potential to shared peptide sequences., Expert Opinion: Proteomics is outlining peptide platforms to be used for the diagnostics and management of human diseases. A Molecular Medicine targeted to obtain healing without paying the price for adverse events is on the horizon. The next step is to take up the challenge and operate the paradigm shift that the current proteomic era requires.
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- 2021
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25. Common contributing factors to COVID-19 and inflammatory bowel disease.
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Kostoff RN, Briggs MB, Kanduc D, Shores DR, Kovatsi L, Vardavas AI, and Porter AL
- Abstract
The devastating complications of coronavirus disease 2019 (COVID-19) result from an individual's dysfunctional immune response following the initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Multiple toxic stressors and behaviors contribute to underlying immune system dysfunction. SARS-CoV-2 exploits the dysfunctional immune system to trigger a chain of events ultimately leading to COVID-19. We have previously identified many contributing factors (CFs) (representing toxic exposure, lifestyle factors and psychosocial stressors) common to myriad chronic diseases. We hypothesized significant overlap between CFs associated with COVID-19 and inflammatory bowel disease (IBD), because of the strong role immune dysfunction plays in each disease. A streamlined dot-product approach was used to identify potential CFs to COVID-19 and IBD. Of the fifty CFs to COVID-19 that were validated for demonstration purposes, approximately half had direct impact on COVID-19 (the CF and COVID-19 were mentioned in the same record; i.e., CF---→COVID-19), and the other half had indirect impact. The nascent character of the COVID-19 core literature (∼ one year old) did not allow sufficient time for the direct impacts of many CFs on COVID-19 to be identified. Therefore, an immune system dysfunction (ID) literature directly related to the COVID-19 core literature was used to augment the COVID-19 core literature and provide the remaining CFs that impacted COVID-19 indirectly (i.e., CF---→immune system dysfunction---→COVID-19). Approximately 13000 potential CFs for myriad diseases (obtained from government and university toxic substance lists) served as the starting point for the dot-product identification process. These phrases were intersected (dot-product) with phrases extracted from a PubMed-derived IBD core literature, a nascent COVID-19 core literature, and the COVID-19-related immune system dysfunction (ID) core literature to identify common ID/COVID-19 and IBD CFs. Approximately 3000 potential CFs common to both ID and IBD, almost 2300 potential CFs common to ID and COVID-19, and over 1900 potential CFs common to IBD and COVID-19 were identified. As proof of concept, we validated fifty of these ∼3000 overlapping ID/IBD candidate CFs with biologic plausibility. We further validated 24 of the fifty as common CFs in the IBD and nascent COVID-19 core literatures. This significant finding demonstrated that the CFs indirectly related to COVID-19 -- identified with use of the immune system dysfunction literature -- are strong candidates to emerge eventually as CFs directly related to COVID-19. As discussed in the main text, many more CFs common to all these core literatures could be identified and validated. ID and IBD share many common risk/contributing factors, including behaviors and toxic exposures that impair immune function. A key component to immune system health is removal of those factors that contribute to immune system dysfunction in the first place. This requires a paradigm shift from traditional Western medicine, which often focuses on treatment, rather than prevention., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)
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- 2021
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26. Erratum to "Why are we vaccinating children against COVID-19?" [Toxicol. Rep. 8C (2021) 1665-1684 / 1193].
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Kostoff RN, Calina D, Kanduc D, Briggs MB, Vlachoyiannopoulos P, Svistunov AA, and Tsatsakis A
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[This corrects the article DOI: 10.1016/j.toxrep.2021.08.010.]., (© 2021 The Author(s).)
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- 2021
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27. Why are we vaccinating children against COVID-19?
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Kostoff RN, Calina D, Kanduc D, Briggs MB, Vlachoyiannopoulos P, Svistunov AA, and Tsatsakis A
- Abstract
This article examines issues related to COVID-19 inoculations for children. The bulk of the official COVID-19-attributed deaths per capita occur in the elderly with high comorbidities, and the COVID-19 attributed deaths per capita are negligible in children. The bulk of the normalized post-inoculation deaths also occur in the elderly with high comorbidities, while the normalized post-inoculation deaths are small, but not negligible, in children. Clinical trials for these inoculations were very short-term (a few months), had samples not representative of the total population, and for adolescents/children, had poor predictive power because of their small size. Further, the clinical trials did not address changes in biomarkers that could serve as early warning indicators of elevated predisposition to serious diseases. Most importantly, the clinical trials did not address long-term effects that, if serious, would be borne by children/adolescents for potentially decades. A novel best-case scenario cost-benefit analysis showed very conservatively that there are five times the number of deaths attributable to each inoculation vs those attributable to COVID-19 in the most vulnerable 65+ demographic. The risk of death from COVID-19 decreases drastically as age decreases, and the longer-term effects of the inoculations on lower age groups will increase their risk-benefit ratio, perhaps substantially., Competing Interests: The authors declare that they have no competing interests, (© 2021 The Author(s).)
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- 2021
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28. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): Codon Usage and Replicative Fitness.
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Kanduc D
- Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) codon usage, as shown by the polyprotein coding sequence, shows better translation potential in the human host when compared with human coronavirus OC43 (HCoV-OC43) codon usage. Such translational advantage might facilitate SARS-CoV-2 replication, immunogenicity, and pathogenicity, thus also accounting for the less harmful character of HCoV-OC43 infection., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)
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- 2020
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29. Molecular mimicry between SARS-CoV-2 spike glycoprotein and mammalian proteomes: implications for the vaccine.
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Kanduc D and Shoenfeld Y
- Subjects
- Age Factors, Animals, Antigens, Viral chemistry, Antigens, Viral immunology, Betacoronavirus immunology, Betacoronavirus pathogenicity, COVID-19, COVID-19 Vaccines, Cats, Cattle, Coronavirus Infections immunology, Coronavirus Infections virology, Cross Reactions immunology, Drug Development, Humans, Mice, Models, Animal, Peptides chemistry, Peptides immunology, Pneumonia, Viral immunology, Pneumonia, Viral virology, Proteome chemistry, Rabbits, SARS-CoV-2, Spike Glycoprotein, Coronavirus chemistry, Swine, Viral Vaccines therapeutic use, Coronavirus Infections prevention & control, Molecular Mimicry immunology, Pandemics prevention & control, Pneumonia, Viral prevention & control, Proteome immunology, Spike Glycoprotein, Coronavirus immunology, Viral Vaccines immunology
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- 2020
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30. Covid-19 and autoimmunity.
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Ehrenfeld M, Tincani A, Andreoli L, Cattalini M, Greenbaum A, Kanduc D, Alijotas-Reig J, Zinserling V, Semenova N, Amital H, and Shoenfeld Y
- Subjects
- Betacoronavirus chemistry, COVID-19, Coronavirus Infections virology, Humans, Pandemics, Pneumonia, Viral virology, SARS-CoV-2, Autoantibodies immunology, Autoimmune Diseases immunology, Autoimmune Diseases virology, Autoimmunity, Betacoronavirus immunology, Coronavirus Infections immunology, Pneumonia, Viral immunology
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- 2020
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31. From Anti-EBV Immune Responses to the EBV Diseasome via Cross-reactivity.
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Kanduc D and Shoenfeld Y
- Abstract
Sequence analyses highlight a massive peptide sharing between immunoreactive Epstein-Barr virus (EBV) epitopes and human proteins that-when mutated, deficient or improperly functioning-associate with tumorigenesis, diabetes, lupus, multiple sclerosis, rheumatoid arthritis, and immunodeficiencies, among others. Peptide commonality appears to be the molecular platform capable of linking EBV infection to the vast EBV-associated diseasome via cross-reactivity and questions the hypothesis of the "negative selection" of self-reactive lymphocytes. Of utmost importance, this study warns that using entire antigens in anti-EBV immunotherapies can associate with autoimmune manifestations and further supports the concept of peptide uniqueness for designing safe and effective anti-EBV immunotherapies., Competing Interests: Conflict of Interest D.K. declares no conflicts. Y.S. is a medical consultant in vaccine compensation court, United States., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)
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- 2020
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32. Medical, Genomic, and Evolutionary Aspects of the Peptide Sharing between Pathogens, Primates, and Humans.
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Kanduc D and Shoenfeld Y
- Abstract
Comparing mammalian proteomes for molecular mimicry with infectious pathogens highlights the highest levels of heptapeptide sharing between pathogens and human, murine, and rat proteomes, while the peptide sharing level is minimal (or absent) with proteomes from nonhuman primates such as gorilla, chimpanzee, and rhesus macaque. From the medical point of view, the data might be useful to clinicians and vaccinologists to develop and evaluate immunomodulatory and immunotherapeutic approaches. As a matter of fact, primates seem to be unreliable animal models for revealing potential autoimmune events in preclinical testing of immunotherapies. In terms of genomics, the scarce or absent peptide sharing between pathogens and primates versus the massive peptide sharing existing between pathogens and humans lets foresee mechanisms of pathogen sequence insertion/deletion/alteration that have differently operated in mammals over evolutionary timescales. Why and how the human genome has been colonized by pathogen sequences and why and how primates escaped such a colonization appears to be the new scientific challenge in our efforts to understand not only the origin of Homo sapiens but also his autoimmune diseasome., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)
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- 2020
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33. From Anti-SARS-CoV-2 Immune Responses to COVID-19 via Molecular Mimicry.
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Kanduc D
- Abstract
Aim: To define the autoimmune potential of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection., Methods: Experimentally validated epitopes cataloged at the Immune Epitope DataBase (IEDB) and present in SARS-CoV-2 were analyzed for peptide sharing with the human proteome., Results: Immunoreactive epitopes present in SARS-CoV-2 were mostly composed of peptide sequences present in human proteins that-when altered, mutated, deficient or, however, improperly functioning-may associate with a wide range of disorders, from respiratory distress to multiple organ failure., Conclusions: This study represents a starting point or hint for future scientific-clinical investigations and suggests a range of possible protein targets of autoimmunity in SARS-CoV-2 infection. From an experimental perspective, the results warrant the testing of patients' sera for autoantibodies against these protein targets. Clinically, the results warrant a stringent surveillance on the future pathologic sequelae of the current SARS-CoV-2 pandemic.
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- 2020
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34. On the molecular determinants of the SARS-CoV-2 attack.
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Kanduc D and Shoenfeld Y
- Subjects
- Amino Acid Sequence, Antibodies, Viral chemistry, Antibodies, Viral genetics, Betacoronavirus pathogenicity, COVID-19, Coronavirus 229E, Human immunology, Coronavirus Infections genetics, Coronavirus Infections pathology, Coronavirus Infections virology, Coronavirus OC43, Human immunology, Cross Reactions, Epitopes chemistry, Epitopes genetics, Epitopes immunology, Gene Expression, Host-Pathogen Interactions genetics, Host-Pathogen Interactions immunology, Humans, Oligopeptides chemistry, Oligopeptides genetics, Oligopeptides immunology, Pandemics, Pneumocystis carinii pathogenicity, Pneumonia, Pneumocystis genetics, Pneumonia, Pneumocystis pathology, Pneumonia, Pneumocystis virology, Pneumonia, Viral genetics, Pneumonia, Viral pathology, Pneumonia, Viral virology, Protein Binding, Pulmonary Surfactant-Associated Proteins genetics, Pulmonary Surfactant-Associated Proteins immunology, Pulmonary Surfactants immunology, Pulmonary Surfactants metabolism, SARS-CoV-2, Sequence Homology, Amino Acid, Spike Glycoprotein, Coronavirus genetics, Spike Glycoprotein, Coronavirus immunology, Betacoronavirus immunology, Coronavirus Infections immunology, Pneumocystis carinii immunology, Pneumonia, Pneumocystis immunology, Pneumonia, Viral immunology, Pulmonary Surfactant-Associated Proteins chemistry, Pulmonary Surfactants chemistry, Spike Glycoprotein, Coronavirus chemistry
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- 2020
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35. Hydrophobicity and the Physico-Chemical Basis of Immunotolerance.
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Kanduc D
- Subjects
- Humans, Peptides immunology, Receptors, Antigen, B-Cell immunology, Hydrophobic and Hydrophilic Interactions, Immune Tolerance, Peptides chemistry, Receptors, Antigen, B-Cell chemistry, Static Electricity
- Abstract
This study analyzes the primary electrostatic interaction between the membrane-bound B-cell receptor and antigen peptide determinants, and identifies peptide frequency and hydrophobicity as the main factors that govern and shape immunotolerance versus immunoreactivity., (© 2020 S. Karger AG, Basel.)
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- 2020
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36. Vaccine- and natural infection-induced mechanisms that could modulate vaccine safety.
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Kostoff RN, Kanduc D, Porter AL, Shoenfeld Y, Calina D, Briggs MB, Spandidos DA, and Tsatsakis A
- Abstract
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).)
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- 2020
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37. Insights into the autoimmune aspect of premature ovarian insufficiency.
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Sharif K, Watad A, Bridgewood C, Kanduc D, Amital H, and Shoenfeld Y
- Subjects
- Addison Disease complications, Addison Disease diagnosis, Addison Disease immunology, Addison Disease therapy, Autoantibodies analysis, Autoantibodies blood, Autoimmune Diseases diagnosis, Autoimmune Diseases therapy, Female, Humans, Primary Ovarian Insufficiency diagnosis, Primary Ovarian Insufficiency therapy, Autoimmunity physiology, Primary Ovarian Insufficiency etiology, Primary Ovarian Insufficiency immunology
- Abstract
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.)
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- 2019
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38. From hepatitis C virus immunoproteomics to rheumatology via cross-reactivity in one table.
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Kanduc D
- Subjects
- Cross Reactions immunology, Hepatitis C complications, Hepatitis C virology, Humans, Rheumatic Diseases immunology, Rheumatic Diseases virology, Autoimmunity, Hepacivirus immunology, Hepatitis C immunology, Hepatitis C Antibodies immunology, Proteomics methods, Rheumatic Diseases etiology, Rheumatology methods
- Abstract
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.
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- 2019
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39. Proteome-Wide Epstein-BarrVirus Analysis of Peptide Sharing with Human Systemic Lupus Erythematosus Autoantigens.
- Author
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Kanduc D
- Subjects
- Complement C4 immunology, Cross Reactions immunology, Databases, Factual, Herpesvirus 4, Human immunology, Humans, Interleukin-10 immunology, Autoantigens immunology, Epstein-Barr Virus Infections immunology, Lupus Erythematosus, Systemic immunology, Peptides immunology, Proteome
- Abstract
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.
- Published
- 2019
40. The comparative biochemistry of viruses and humans: an evolutionary path towards autoimmunity.
- Author
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Kanduc D
- Subjects
- Amino Acid Sequence, Humans, Autoimmunity, Borna disease virus immunology, Influenza A virus immunology, Measles virus immunology, Mumps virus immunology, Peptides immunology, Rubella virus immunology
- Abstract
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.
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- 2019
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41. Lethal immunoglobulins: Autoantibodies and sudden cardiac death.
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Ryabkova VA, Shubik YV, Erman MV, Churilov LP, Kanduc D, and Shoenfeld Y
- Subjects
- Arrhythmias, Cardiac etiology, Arrhythmias, Cardiac mortality, Autoantibodies immunology, Autoimmune Diseases complications, Autoimmune Diseases diagnosis, Autoimmune Diseases mortality, Cardiomyopathies immunology, Cardiomyopathies mortality, Genetic Testing, Humans, Myocarditis complications, Myocarditis immunology, Myocarditis mortality, Myocardium immunology, Myocardium pathology, Phenotype, Autoantibodies adverse effects, Death, Sudden, Cardiac etiology, Immunoglobulins adverse effects
- Abstract
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.)
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- 2019
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42. Human Papillomavirus Epitope Mimicry and Autoimmunity: The Molecular Truth of Peptide Sharing.
- Author
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Kanduc D and Shoenfeld Y
- Subjects
- Capsid Proteins genetics, Cross Reactions, Epitopes genetics, Epitopes immunology, Humans, Oncogene Proteins, Viral genetics, Peptides genetics, Proteome, Autoimmunity, Capsid Proteins immunology, Molecular Mimicry immunology, Oncogene Proteins, Viral immunology, Papillomaviridae immunology, Peptides immunology
- Abstract
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.)
- Published
- 2019
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43. Oligopeptides for Immunotherapy Approaches in Ovarian Cancer Treatment.
- Author
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Kanduc D
- Subjects
- Female, Humans, Immunotherapy, Oligopeptides therapeutic use, Anti-Mullerian Hormone chemistry, Antigens, Neoplasm chemistry, Biomarkers, Tumor chemistry, Calmodulin-Binding Proteins chemistry, Membrane Proteins chemistry, Ovarian Neoplasms therapy, WAP Four-Disulfide Core Domain Protein 2 chemistry
- Abstract
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.)
- Published
- 2019
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44. Cytomegalovirus Infection: The Neurodevelopmental Peptide Signatures.
- Author
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Lucchese G and Kanduc D
- Subjects
- Calcinosis metabolism, Cytomegalovirus metabolism, Deafness metabolism, Humans, Cytomegalovirus Infections metabolism, Neurodevelopmental Disorders metabolism, Peptides metabolism, Viral Proteins metabolism
- Abstract
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.)
- Published
- 2018
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45. Human papilloma virus and lupus: the virus, the vaccine and the disease.
- Author
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Segal Y, Calabrò M, Kanduc D, and Shoenfeld Y
- Subjects
- Autoantigens immunology, Cross Reactions immunology, Humans, Lupus Erythematosus, Systemic immunology, Papillomaviridae immunology, Papillomavirus Infections immunology, Papillomavirus Infections prevention & control, Papillomavirus Vaccines therapeutic use, Prevalence, Risk Factors, Viral Proteins immunology, Lupus Erythematosus, Systemic epidemiology, Papillomavirus Infections epidemiology
- Abstract
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.
- Published
- 2017
- Full Text
- View/download PDF
46. HPV and systemic lupus erythematosus: a mosaic of potential crossreactions.
- Author
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Segal Y, Dahan S, Calabrò M, Kanduc D, and Shoenfeld Y
- Subjects
- Antibodies, Viral blood, Antigens, CD19 genetics, Antigens, CD19 immunology, Autoimmunity, Capsid Proteins genetics, Capsid Proteins immunology, Complement C4 genetics, Complement C4 immunology, Cross Reactions, Epitope Mapping, Humans, Ku Autoantigen genetics, Ku Autoantigen immunology, Lupus Erythematosus, Systemic immunology, Oncogene Proteins, Viral genetics, Oncogene Proteins, Viral immunology, Papillomavirus Infections immunology, Peptide Fragments genetics, Peptide Fragments immunology, Receptors, Natural Killer Cell genetics, Receptors, Natural Killer Cell immunology, Antigens, CD19 metabolism, Capsid Proteins metabolism, Complement C4 metabolism, Ku Autoantigen metabolism, Lupus Erythematosus, Systemic virology, Oncogene Proteins, Viral metabolism, Papillomaviridae immunology, Papillomavirus Infections virology, Papillomavirus Vaccines immunology, Peptide Fragments metabolism, Receptors, Natural Killer Cell metabolism
- Abstract
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.
- Published
- 2017
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47. Minimal immune determinants connect Zika virus, human Cytomegalovirus, and Toxoplasma gondii to microcephaly-related human proteins.
- Author
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Lucchese G and Kanduc D
- Subjects
- Antibodies, Viral metabolism, Autoantibodies metabolism, Autoantigens immunology, Epitopes, B-Lymphocyte immunology, Female, Humans, Immunity, Humoral, Infant, Newborn, Infant, Newborn, Diseases epidemiology, Infectious Disease Transmission, Vertical, Microcephaly epidemiology, Pregnancy, Zika Virus Infection epidemiology, Cross Reactions, Cytomegalovirus immunology, Cytomegalovirus Infections immunology, Infant, Newborn, Diseases immunology, Microcephaly immunology, Pregnancy Complications, Infectious virology, Toxoplasma immunology, Toxoplasmosis immunology, Zika Virus immunology, Zika Virus Infection immunology
- Abstract
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.)
- Published
- 2017
- Full Text
- View/download PDF
48. Rare Human Codons and HCMV Translational Regulation.
- Author
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Kanduc D
- Subjects
- Base Sequence, Gene Expression Regulation, Genes, Viral genetics, Genome, Human, Humans, RNA, Transfer genetics, Viral Proteins genetics, Viral Proteins metabolism, Virus Latency physiology, Codon, Cytomegalovirus genetics, Host-Pathogen Interactions genetics, Protein Processing, Post-Translational
- Abstract
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.)
- Published
- 2017
- Full Text
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49. From HBV to HPV: Designing vaccines for extensive and intensive vaccination campaigns worldwide.
- Author
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Kanduc D and Shoenfeld Y
- Subjects
- Amino Acid Sequence, Antigens, Viral chemistry, Capsid Proteins chemistry, Capsid Proteins immunology, Cross Reactions, Epitopes chemistry, Hepatitis B Surface Antigens chemistry, Hepatitis B Vaccines adverse effects, Hepatitis B Vaccines chemistry, Humans, Immunization Programs, Oncogene Proteins, Viral chemistry, Oncogene Proteins, Viral immunology, Papillomavirus Vaccines adverse effects, Papillomavirus Vaccines chemistry, Vaccination, Viral Envelope Proteins chemistry, Viral Envelope Proteins immunology, Antigens, Viral immunology, Hepatitis B Surface Antigens immunology, Hepatitis B Vaccines immunology, Papillomavirus Vaccines immunology
- Abstract
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.)
- Published
- 2016
- Full Text
- View/download PDF
50. Reply concerning the article "Zika virus and autoimmunity: From microcephaly to Guillain-Barré syndrome, and beyond".
- Author
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Lucchese G and Kanduc D
- Subjects
- Autoimmunity, Guillain-Barre Syndrome, Humans, Zika Virus Infection, Microcephaly, Zika Virus
- Published
- 2016
- Full Text
- View/download PDF
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