Molecular Linkage between Immune System Disorders and Atherosclerosis

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review of mechanistic relations between immune disorders and atherosclerosis, comprising primary and secondary immunodeficiencies, nutritional deficiencies,, medicinal effects and smoking, is well-written and very informative, but some substantive revisions are necessary.  The Introduction is basically a rewrite of the abstract.  A more thorough Introduction is needed.  Acronyms are undefined before page 4.  A table of abbreviations would be helpful.  In the discussion of atheroprogression on page 2, negative remodeling of the artery at the site of the atheroma should be mentioned as an alternative to stenosis.  Interferon should be abbreviated IFN, not INF.  Lines 87-93 comprise a run-on sentence that is poorly structured.  Neutrophil apoptosis (line 130) needs more explanation.  Activation of the PI3K/Akt pathway by C-peptide should mention ultimate activation of mTOR as the mediator of proliferative effects (line 152).  Lines 157-159 comprise an awkward sentence.  The intermittent use of vascular epithelium to denote endothelium is confusing.  I think the authors mean endothelial in lines 668-669, rather than endometrial.

Comments on the Quality of English Language

Two awkward sentences are mentioned in the comments to the authors, above.

Author Response

Dear Reviewer,
In our work, we tried to draw attention to many aspects of the immune system, especially primary and secondary immunodeficiencies. The article is very extensive and contains as many as 36 pages. Each paragraph could actually be in the form of a single article. Due to the fact that we wanted to cover as many important aspects as possible, we may have omitted some dependencies. Therefore, on behalf of myself and the co-authors of the work, I would like to thank you for your positive opinion and very valuable comments that increased the value of the manuscript.
In the revised version of the manuscript:
- improved introduction
-acronyms added to page 4
- added information about negative artery remodeling
- the nomenclature of endothelium and the abbreviation IFN have been corrected (unfortunately, sometimes the translator changes words automatically, in one of my articles he once translated remote appointment as teleportation?)
Corrections (all reviewers) are marked in red.
I hope that the changes introduced will meet expectations.
With great respect,
Katarzyna Napiórkowska-Baran

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have invested valuable efforts in unraveling the molecular links between immune disease and atherosclerosis. This is important for readers to understand the relationship between them, which might be helpful for subsequent therapeutic development. However, following comments need to be addressed before it could be published.

1.       There are common inflammatory genes which are changed in both atherosclerosis and other immune system disorders, among these is IL6. The authors might add a table to list these factors/cells, and how they have changed in various immune system disorders discussed in this review. This will help the readers grasp the information more quickly. In addition, lipid profile changes in different immune system disorders should also be included in the table.

2.       A section involving the medications currently used in treating autoimmune diseases or other immune system disorders need to be added, such as methotrexate, colchicine, and canakinumab etc. This will increase the impact of digging into the molecular link of immune system disorders and atherosclerosis.

3.       The authors have used epithelium of the vascular system across the text to refer to vascular endothelium, I believe. This needs to be corrected.

4.       In line 403, ‘Sixty-one percent of patients who died from cardiovascular disease were diagnosed with breast, prostate or bladder cancer.’ Needs to be changed to ‘Sixty-one percent of the cancer patients who died from cardiovascular disease were diagnosed with breast, prostate or bladder cancer’.

5.       The authors should modify their references to include more original research articles than other reviews.

Author Response

Dear Reviewer,
In our work, we tried to draw attention to many aspects of the immune system, especially primary and secondary immunodeficiencies. The article is very extensive and contains as many as 36 pages. Each paragraph could actually be in the form of a single article. Due to the fact that we wanted to cover as many important aspects as possible, we may have omitted some dependencies. Therefore, on behalf of myself and the co-authors of the work, I would like to thank you for your positive opinion and very valuable comments that increased the value of the manuscript.
Ad1. Due to the fact that the article is very extensive, we focused, as the title suggests, on the immunological, not genetic, aspects of atherosclerosis. Of course, we are aware that there is a close relationship between them, which is why we added information about the genetic aspects of atherosclerosis in the introduction. The suggested changes are a great idea for a separate, equally extensive article. Regarding changes in the lipid profile in various immune system disorders, it is not simple and clear to present. In different patients with the same diagnosis of one disease, e.g. IEI, the lipid profile may depend on many different factors: manifestation of deficiency (e.g. autoimmunity affecting the gastrointestinal tract or in another location, chronic infections or recurrent sepsis, length of hospitalization, dietary habits or treatment used).
Ad 2. A paragraph regarding indicated drugs has been added. As mentioned earlier, due to the length of the article, we are not able to describe all medications. The aim of the review is to draw attention to the pro-atherogenic effect of drugs and the need to assess the patient in this respect
Ad 3. The nomenclature of vascular endothelium has been corrected.
Ad 4. The sentence in line 403 has been corrected
Ad 5. The literature was modified - from 138 initially to 178
Amendments (by all reviewers) are marked in red font.
With great respect,
Katarzyna Napiórkowska-Baran

Reviewer 3 Report

Comments and Suggestions for Authors

This manuscript presents an interesting subject of molecular linkage between immune disorders and atherosclerosis, suggesting the immune role in atherosclerosis and cardiovascular disease (CVD), as currently known, for at least the last 10 years. There is a growth research evidence emphasizing on chronic inflammatory vascular disease and endothelial dysfunction and the role of genetic factors in its pathogenesis.

The paper is well written, the language is throughout the text correct, and the references are in general up-to-date. 

However, there is no information about molecules of extracellular matrix (ECM) and arterial basement membranes (BMs) degradation. There are two recent papers in the area:1. Matrix Gelatinases in Atherosclerosis and Diabetic Nephropathy:Progress and Challenges. Curr Vasc Pharmacol 2017;15(6):557-565 and 2. PHhysiological Properties, Functions, and Trends in Inflammation-Mediated Human Diseases. Curr Med Chem 2023;30(18):2075-2112.

In kidney disease (glomerular BM, GBM) and vascular disease, damage is due to BM incresed degradation. Matrix metalloproteinases (MMPs) -2 and -9, for example, are both considered as the main enzymes that degrade collagen type-IV, the key component of ECM, that constitutes the architectural structure of vessels. Inflammation and oxidative stress represent the major pathways of endothelial dysfunction. These molecules and several other agents of adipose tissue active products such as MMPs-2 and -9, TIMPs-1 and -2, VEGF-A, TGFβ-1, FGF-21 and -23, ox-lDL, IL-6, hsCRP, Isoprostane-8 and -15 might be mentionedrepresenting therapeutic targets that could regress vascular disease and atherosclerosis in each stage of disease progression. I would like to see incorporated comments in this review using the above recent papers for better approach current knowledge and improve this clinical model.

Author Response

Dear Reviewer,
In our work, we tried to draw attention to many aspects of the immune system, especially primary and secondary immunodeficiencies.
On behalf of myself and the co-authors of the work, I would like to thank you for your positive opinion and very valuable comments that increased the value of the manuscript.
We have added a section on the degradation of extracellular matrix molecules and arterial basement membranes as well as suggested articles.
I hope that the changes introduced will meet expectations.
Amendments (by all reviewers) are marked in red font.
With great respect,
Katarzyna Napiórkowska-Baran

Reviewer 4 Report

Comments and Suggestions for Authors

Dear Authors, I have read your manuscript with interest.

The current manuscript titled: "Molecular Linkage between Immune System Disorders and Atherosclerosis" represents an important analysis of evolving field of Immunology.

 

In my opinion, these are the adjustments which should be made to increase the value of your manuscript:

1.       In Introduction chapter, please, add the review aim.

2.       Please, add abbreviation for “INF-γ”, “IL”, etc.

3.       In chapters 2 and 3, please, add images reflecting the physiopathological mechanisms of the described processes.

4.       In autoimmune diseases, please, add information about Sjögren's syndrome and antiphospholipid syndrome.

5.       In Obesity chapter, please, add information about obesity paradox.

6.       In Vitamin D chapter, please, add more detailed information and consider this holistic article https://doi.org/10.1155/2021/9782994.

7.       Please, add chapter with particularities in COVID-19.

8.       Please, add future perspectives.

9.       In Conclusions section please highlight the practical implications of this review and its relevance to real clinical practice.

10.   The manuscript contains some punctuation errors, please revise the text.

Comments on the Quality of English Language

Minor editing of English language required.

Author Response

Dear Reviewer,
In our work, we tried to draw attention to many aspects of the immune system, especially primary and secondary immunodeficiencies.
On behalf of myself and the co-authors of the work, I would like to thank you for your positive opinion and very valuable comments that increased the value of the manuscript.
Ad.1. The purpose of the review was added to the introduction.
Ad.2. Added abbreviations for "INF-γ", "IL", etc.
Ad.3. In chapters 2 and 3, images reflecting the physiopathological mechanisms of the described processes have been added. Figure 2 connects chapters 3 and 4 because there is a relationship between them.
Ad.4. In autoimmune diseases, information on Sjögren's syndrome and antiphospholipid syndrome has been added.
Ad.5. Information about the obesity paradox has been added to the Obesity chapter.
Ad.6. In the Vitamin D chapter, more detailed information has been added and a valuable article has been suggested
Ad.7. A section has been added with detailed information regarding COVID-19.
Ad.8. Future perspectives added.
Ad.9. The Conclusions section highlights the practical implications of this review and its relevance to real-world clinical practice.
Ad.10. Attempts have been made to correct punctuation errors in the manuscript.
I hope that the changes introduced will meet expectations.
Amendments (by all reviewers) are marked in red font.
With great respect,
Katarzyna Napiórkowska-Baran

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The added section in 4.1.5 on the obesity paradox does not have any immune aspects.  Can anything be added?

Comments on the Quality of English Language

In line 30, it should be "vessels, thereby...."  In line 337, the word should be "architecture," not "architectonics."  On page 8, there are two instances of improperly used colons.  Replace them with commas.  Lines 360-361 are not a sentence.  Line 373 should read ", and connective tissue...."  The text in lines 1228-1229 can be worded better.  Line 1418 should read "issue, not....."  In line 1421, I suggest "This review not only elucidates...."

 

Author Response

Dear Reviewer,
On behalf of ourselves and the other co-authors of the work, we would like to thank you once again for the positive review of our manuscript and valuable comments. We are very pleased that the corrections met your expectations.

Suggested further fixes are also highlighted in red.

We wish you all the best, above all good health.
Best regards,
Katarzyna Napiórkowska-Baran

Reviewer 4 Report

Comments and Suggestions for Authors

I agree with the changes made, which significantly improve the quality of the manuscript.

Comments on the Quality of English Language

Minor editing of English language required

Author Response

Dear Reviewer,
On behalf of ourselves and the other co-authors, we would like to thank you once again for the positive review of our manuscript and valuable comments.
We wish you all the best, above all good health.
Best regards,
Katarzyna Napiórkowska-Baran