Molecular Mimicry between SARS-CoV-2 and Human Endocrinocytes: A Prerequisite of Post-COVID-19 Endocrine Autoimmunity?
Round 1
Reviewer 1 Report
The present manuscript provides a good historical perspective on molecular mimicry. The authors offer examples of this mechanism used by pathogens to induce autoimmunity. They proposed that SARS-CoV-2 infection can cause endocrinopathies due to the presence of 14 peptides in the S-protein of the virus that shares remarkable similarity with autoantigens that are produced by the thyroid gland, pituitary gland, adrenal cortex, and Langerhans’ islets beta-cells. The authors cited several studies supporting their hypothesis. The authors included two tables in the results section where the sequence of the identified peptides is displayed along with the corresponding endocrine antigen.
Comments:
- Given that the approach is computational, molecular models must be included showing the location of the identified peptides. Include a figure showing the sequence similarity between the identified peptides and the antigens.
- The article will significantly benefit by including figures.
Author Response
The present manuscript provides a good historical perspective on molecular mimicry. The authors offer examples of this mechanism used by pathogens to induce autoimmunity. They proposed that SARS-CoV-2 infection can cause endocrinopathies due to the presence of 14 peptides in the S-protein of the virus that shares remarkable similarity with autoantigens that are produced by the thyroid gland, pituitary gland, adrenal cortex, and Langerhans’ islets beta-cells. The authors cited several studies supporting their hypothesis. The authors included two tables in the results section where the sequence of the identified peptides is displayed along with the corresponding endocrine antigen.
Comments:
Given that the approach is computational, molecular models must be included showing the location of the identified peptides. Include a figure showing the sequence similarity between the identified peptides and the antigens.
The article will significantly benefit by including figures.
Thanks for advise. The figures of molecular models included.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
In this article, the authors very elegantly summarize molecular mimicry through peptide sharing between SARS-CoV-2 spike protein and human endocrinocytes which are involved in autoimmune endocrinopathies. The clinical importance of their findings is mainly related to the association between COVID-19 and endocrinopathies involving autoantigens such as thyroid, pituitary, adrenal cortex, islet cells of Langerhans, and more.
From a historical point of view, it would be very interesting for the readers of the journal to learn more about the origins and birthplace of the concept of molecular mimicry.
I believe that due to some kind of glitch in the automatic reference citation program, reference #7 is cited for all references in the Introduction, Materials & Methods, Results and Discussion sections. Reference #8 is also cited in the Discussion section.
Line 93 - After the paragraph dealing with the cross-reaction between cow's milk and human insulin, I would recommend adding a reference about the contributions of milk and EBV to multiple sclerosis through mimicry
Bjornevik K et al. Longtitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science 375, 296-301, 2022.
as well as this
Chunder R et al. Antibody cross-reactivity between casein and myelin-associated glycoprotein results in central nervous system demyelination with implications for the immunopathology of multiple sclerosis. PNAS 119(10), dot: 10.1073/pnas.2117034119, 2022.
Since it is well-established that autoimmune polyendocrinopathy syndrome is characterized by hypoparathyroidism, hypothyroidism, type 1 diabetes, adrenal insufficiency and candidiasis, the authors are encouraged to discuss the contributions of yeast infection to this disorder, and how it would be possible to differentiate between yeast infection and SARS-CoV-2 contributions to polyendocrinopathy.
Ferre EMN et al. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Frontiers in Pediatrics, doi: 10.3389/fped.2021.723532, 2021.
Vojdani A et al. Immunological cross-reactivity between Candida albicans and human tissue. J Clin Lab Imunol, 48, 1-15, 1996.
Comments for author File: Comments.pdf
Author Response
In this article, the authors very elegantly summarize molecular mimicry through peptide sharing between SARS-CoV-2 spike protein and human endocrinocytes which are involved in autoimmune endocrinopathies. The clinical importance of their findings is mainly related to the association between COVID-19 and endocrinopathies involving autoantigens such as thyroid, pituitary, adrenal cortex, islet cells of Langerhans, and more.
From a historical point of view, it would be very interesting for the readers of the journal to learn more about the origins and birthplace of the concept of molecular mimicry.
I believe that due to some kind of glitch in the automatic reference citation program, reference #7 is cited for all references in the Introduction, Materials & Methods, Results and Discussion sections. Reference #8 is also cited in the Discussion section.
Thanks, reference numbers corrected.
Line 93 - After the paragraph dealing with the cross-reaction between cow's milk and human insulin, I would recommend adding a reference about the contributions of milk and EBV to multiple sclerosis through mimicry
Bjornevik K et al. Longtitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science 375, 296-301, 2022.
as well as this
Chunder R et al. Antibody cross-reactivity between casein and myelin-associated glycoprotein results in central nervous system demyelination with implications for the immunopathology of multiple sclerosis. PNAS 119(10), dot: 10.1073/pnas.2117034119, 2022.
We included one of recommended references,
Chunder R, Weier A, Mäurer H, Luber N, Enders M, Luber G, Heider T, Spitzer A, Tacke S, Becker-Gotot J, Kurts C, Iyer R, Ho PP, Robinson WH, Lanz TV, Kuerten S. Antibody cross-reactivity between casein and myelin-associated glycoprotein results in central nervous system demyelination. Proc Natl Acad Sci U S A. 2022 Mar 8;119(10):e2117034119. doi: 10.1073/pnas.2117034119.
another one was not included because it does not deal with milk antigens.
Since it is well-established that autoimmune polyendocrinopathy syndrome is characterized by hypoparathyroidism, hypothyroidism, type 1 diabetes, adrenal insufficiency and candidiasis, the authors are encouraged to discuss the contributions of yeast infection to this disorder, and how it would be possible to differentiate between yeast infection and SARS-CoV-2 contributions to polyendocrinopathy.
Ferre EMN et al. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Frontiers in Pediatrics, doi: 10.3389/fped.2021.723532, 2021.
Vojdani A et al. Immunological cross-reactivity between Candida albicans and human tissue. J Clin Lab Imunol, 48, 1-15, 1996.
The suggested note is included with both references.
Author Response File: Author Response.pdf
Reviewer 3 Report
The work presents 5mer peptide-sharing between SARS-CoV-2 spike protein and human endocrinocytes, as a pre-requisite for molecular mimicry-based autoimmunity in susceptible individuals. The work also has a very comprehensive and informative introduction section and an extensive discussion section. I have only few comments, as detailed below.
1-) It is written in the abstract that "peptide sharing is not a guarantee, but just a prerequisite of autoimmunity..." It means that there can be peptide sharing without autoimmunity but there cannot be autoimmunity without peptide sharing. I think revising the term autoimmunity as molecular mimicry-based autoimmunity might be better.
2-) It is written at page 2, lines 62-64 that "Much more often there occurs a cross-reaction between sequential determinants of autoantigens and alien antigens because the evolutionary diversity of primary structures in these polypeptides is not so great, as for spatial tertiary conformations." What is the length range of those peptides, can you comment on their approximate length range?
3-) Last but not the least, reference numbering seems to have stucked at 7. Something might have gone wrong at the editorial manager system, which might need you to contact them, if that is the case. I also saw some typos. For instance, it is written anf instead of and at page 3, line 102, and debut instead of debute at page 6, line 194, if that was what you meant to write. Also, please close the parenthesis after S-protein at page 1, line 15.
Author Response
The work presents 5mer peptide-sharing between SARS-CoV-2 spike protein and human endocrinocytes, as a pre-requisite for molecular mimicry-based autoimmunity in susceptible individuals. The work also has a very comprehensive and informative introduction section and an extensive discussion section. I have only few comments, as detailed below.
1-) It is written in the abstract that "peptide sharing is not a guarantee, but just a prerequisite of autoimmunity..." It means that there can be peptide sharing without autoimmunity but there cannot be autoimmunity without peptide sharing. I think revising the term autoimmunity as molecular mimicry-based autoimmunity might be better.
Agree, corrected.
2-) It is written at page 2, lines 62-64 that "Much more often there occurs a cross-reaction between sequential determinants of autoantigens and alien antigens because the evolutionary diversity of primary structures in these polypeptides is not so great, as for spatial tertiary conformations." What is the length range of those peptides, can you comment on their approximate length range?
Agree, added.
3-) Last but not the least, reference numbering seems to have stucked at 7. Something might have gone wrong at the editorial manager system, which might need you to contact them, if that is the case. I also saw some typos. For instance, it is written anf instead of and at page 3, line 102, and debut instead of debute at page 6, line 194, if that was what you meant to write. Also, please close the parenthesis after S-protein at page 1, line 15.
Corrected with gratitude.
Author Response File: Author Response.pdf
