The Role of Exposomes in the Pathophysiology of Autoimmune Diseases I: Toxic Chemicals and Food

Round 1

Reviewer 1 Report

The manuscript titled: "The Role of Exposomes in the Pathophysiology of Autoimmune Diseases I" by Vojdani and Vojdani submitted for publication is a work aiming to discuss the role of exposomes in the pathophysiology of diseases. The paper is extensive and very well-written with good structure and good flow. There is a wealth of information and extensively referenced. The reviewer would like to offer the following points for manuscript improvement.

1. Consider including a PRISM flow illustrating the selection of literature to be included in the manuscript.
2. Consider including a summary table of the referenced studies according to the diseases discussed.
3. Consider including a specific explicit section on strengths and limitations.

Author Response

1. Consider including a PRISM flow illustrating the selection of literature to be included in the manuscript. We appreciate the suggestion, but upon examination of the article, previous submissions, and due reflection, we don't believe that a PRISMA diagram would substantially improve the manuscript.
2. Consider including a summary table of the referenced studies according to the diseases discussed. We have added a summary table on page 23 and hope it is satisfactory.
3. Consider including a specific explicit section on strengths and limitations. We have added a Strengths and Limitations section after the table, on page 24.
4. An amended copy of the entire manuscript is attached.

Author Response File: Author Response.docx

Reviewer 2 Report

With interest, I read the manuscript pathophysiology-1469995. Huge, impressive work.

I have only a few, mostly facultative comments:

1. The whole article is on exposome. It is clear that the pathogens will be presented in the second part. Still, it is striking that hygiene hypothesis is not mentioned even once. It is applicable not only to allergies but also to other diseases, including autoimmune disorders, psychiatric disorders, etc. (PMID: 33815389, 33584703). I suggest mentioning it.

2. Likewise, similarly to allergies, also autoimmune disorders are typical gene x environment diseases, with at least part oft he effects being mediated be epigenetic mechanisms (PMID: 28322581, 34223997). In this article, only DANN methylation is very shortly mentioned (lines 138-141). It would be good to mention the role of epigenetics in gene x environment disorders more widely.

3. All abbreviations used in the figures should be explained in the respective legends.

Author Response

1. The whole article is on exposome. It is clear that the pathogens will be presented in the second part. Still, it is striking that hygiene hypothesis is not mentioned even once. It is applicable not only to allergies but also to other diseases, including autoimmune disorders, psychiatric disorders, etc. (PMID: 33815389, 33584703). I suggest mentioning it. We have added a rather substantial amount of text regarding the hygiene hypothesis starting on page 20.

2. Likewise, similarly to allergies, also autoimmune disorders are typical gene x environment diseases, with at least part oft he effects being mediated be epigenetic mechanisms (PMID: 28322581, 34223997). In this article, only DANN methylation is very shortly mentioned (lines 138-141). It would be good to mention the role of epigenetics in gene x environment disorders more widely. Additional text concerning epigenetic modification and its mechanisms have been added in the middle of page 21 in the same long paragraph about the hygiene hypothesis.

3. All abbreviations used in the figures should be explained in the respective legends. This has been implemented. Thank you for the suggestion.

Author Response File: Author Response.docx