Autoimmune Autonomic Dysfunction Syndromes: Potential Involvement and Pathophysiology Related to Complex Regional Pain Syndrome, Fibromyalgia, Chronic Fatigue Syndrome, Silicone Breast Implant–Related Symptoms and Post-COVID Syndrome

Round 1

Reviewer 1 Report

In general nice review concerning autoimmunity and autonomic dysfunction syndromes presenting a clear hypothesis.

I have only few comments:

line 204 - decreased memory? better impaired memory

line 235 - the sentence '..... highly permeable to SARS-CoV-2 in contrast to SARS-CoV ......' necessitate rewriting

line 248 'The autoantibodies isolated were shown to disturb immune function ..." are they not a result of disturbed immune function ?   

Finally - it would be nice to write take home massage in the conclusion section - how to diagnosed and treat nowadays the autoimmune autonomic dysfunction.  

Author Response

Thank you for your comments.

Here are our changes based on your recommendations:

line 204 - decreased memory? better impaired memory - corrected!

line 235 - the sentence '..... highly permeable to SARS-CoV-2 in contrast to SARS-CoV ......' necessitate rewriting - we meant by SARS-CoV, the virus responsible for the SARS outbreak in 2002. So we added a sentence after the virus name.

line 248 'The autoantibodies isolated were shown to disturb immune function ..." are they not a result of disturbed immune function ?  - True, but were found to disturb "further" the immune function. Thus, the word "further" was added.

Finally - it would be nice to write take home massage in the conclusion section - how to diagnosed and treat nowadays the autoimmune autonomic dysfunction. - We aimed to shed light on the pathophysiological aspects of the diseases/syndromes mentioned and not to focus on diagnosis and treatment. As those diseases differ in terms of their diagnostic criteria as well as treatment we did not write a take home message about that. If the reviewer still thinks we should add, we would do it. 

Reviewer 2 Report

Minor revisions

1.      It would be good if you could write the type of current study (e.g. review, experimental study, etc.) in the both abstract and materials & methods sections.

Major revisions

1.      Abstract is not well-explained. It is unclear what your main goals are and what are your main outcomes! Please clarify these items in the abstract.  

2.      It would be well if you could show the process of papers’ selection, selection criteria by which you have chosen articles for the study.

3.      Creating tables summarizing experimental studies and results for each section is mandatory. In another word, you could make a table for each pathophysiology in which studies and the outcomes are summarized.

4.      Creating some figures to show mechanisms of each pathophysiology would be great.

5.      English editing of the manuscript is necessary.

6.      This manuscript seems to be a mini-review.   

Author Response

Thank you for your comments.

Here are our answers:

Minor revisions

1. It would be good if you could write the type of current study (e.g. review, experimental study, etc.) in the both abstract and materials & methods sections. - added to line 28 in the abstract, and line 72 in the introduction.

Major revisions

1. Abstract is not well-explained. It is unclear what your main goals are and what are your main outcomes! Please clarify these items in the abstract. - the abstract was re-edited. 
2. It would be well if you could show the process of papers’ selection, selection criteria by which you have chosen articles for the study. - all papers addressing the syndromes included with autoimmune aspects were included and summarized to support our proposed notions. As this is a review without material and methods sections, a sentence was added in line 77 of the introduction.
3. Creating tables summarizing experimental studies and results for each section is mandatory. In another word, you could make a table for each pathophysiology in which studies and the outcomes are summarized. - a table was added with the references cited. As I could not integrate it in the edited manuscript, I attached it as a separate file.
4. Creating some figures to show mechanisms of each pathophysiology would be great. - as all share, as proposed, autoantibodies directed against ANS, no interesting mechanistic figures or various mechanisms could be illustrated, that's why we did not add a figure, except the chart concluding the idea.
5. English editing of the manuscript is necessary. - re-edited.
6. This manuscript seems to be a mini-review. - as mentioned in point one of minor revision.

Reviewer 3 Report

Current review article is going to introduce a new term“autoimmune autonomic dysfunction syndromes” for complex regional pain syndrome, fibromyalgia, chronic fatigue syndrome, silicone breast implants related symptoms, and post-COVID syndrome. Please conduct the concerns below.

1.      Autoantibodies against each specific antigen were required for autoimmune. How to link with autonomic nervous system (ANS) shall be explained in detail.

2.      In this speculation,“chronic fatigue syndrome” (CFS) may associate with ANS without autoimmune although one reference 50^th has been cited.

3.      The autoantibodies might play an immunomodulatory role in the pathogenesis of disorders mentioned in current review. Therefore, potential evidence is required.

4.      The autoantibodies increased in patients with COVID-19 or others may be an indicator. However, the involvement of autoimmune factors in the pathogenesis of disorders belonged to complicated. Therefore, application of each evidence in this speculation shall be careful.

5.      Conclusion of autoimmune autonomic dysfunction to the disorders mentioned in current speculation needs solid data to support.

6.      Limitation(s) of the current report shall be added.

Author Response

Thank you for your comments.

Here are our answers:

1. Autoantibodies against each specific antigen were required for autoimmune. How to link with autonomic nervous system (ANS) shall be explained in detail - absolutely true. We have highlighted this through our manuscript. Line 74 in the introduction, GPCR as antigens. Line 135 ANS receptors in CRPS. Line 158 regarding Goebel's work. Line 220 the entire paragraph regarding ANS receptors as antigens. Line 258 regarding the same receptors as target of autoantibodies.  
2. In this speculation,“chronic fatigue syndrome” (CFS) may associate with ANS without autoimmune although one reference 50^th has been cited. - We do definitely agree. The pathogenetic role of autoantibodies produced in CFS needs further investigation. However, autoantibodies against neurotransmitter, as the paper states, were described in CFS. In fact, this is the goal behind our suggested term, to serve as a base for better approach of the investigations needed in the diseases and syndromes listed, i.e. the pathogenetic role of the autoantibodies detected particularly as the pathophysiology in these syndromes remains unclear.   
3. The autoantibodies might play an immunomodulatory role in the pathogenesis of disorders mentioned in current review. Therefore, potential evidence is required. - Very important comment, as the others, indeed. the role is not clearly understood. Our group is still working about this, it was explained by Halpert and colleagues in their article cited, reference number 54. We did not address these aspects as they are still under investigations.
4. The autoantibodies increased in patients with COVID-19 or others may be an indicator. However, the involvement of autoimmune factors in the pathogenesis of disorders belonged to complicated. Therefore, application of each evidence in this speculation shall be careful. Absolutely, this is what we summarized. First there are plenty of autoantibodies in COVID-19 as described by many papers. Some described the same receptors GPCR addressed earlier in patients with long COVID, especially patients with neurological manifestations. There is no doubt that this domain remains to be investigated and we believe that there are more to come in this field. 
5. Conclusion of autoimmune autonomic dysfunction to the disorders mentioned in current speculation needs solid data to support. - we do agree, but as mentioned earlier, it is a proposal based in previous works, and aimed to serve as a base for further research as concluded in our article: [The term “autoimmune autonomic dysfunction syndromes” could serve as a base for directed research, through a detailed animal model-based experiments initially, followed by appropriately designed clinical studies. The results will doubtlessly improve the diagnosis of the syndromes and provide targeted treatment options]. 
6. Limitation(s) of the current report shall be added. - as our manuscript is a review article based on many studies including experimental animal, clinical, case series, and review articles among others, we could not point out general limitations of this review which are true to all the studies included. The need for further research highlighted throughout our paper indicates how investigations are needed in this domain.

Round 2

Reviewer 2 Report

Dear Editor,

The authors responded my comments; however, I couldn't find all revisions in the manuscript.

Regards,

Author Response

Thank you for your comments.

The changes were made in track changes and they were included in the manuscript submitted. The table was submitted separately as the manuscript uploaded for changes by the journal did not permit reference editing made by EnNote.

I'll contact the journal to make sure the changes are shown.

Reviewer 3 Report

Table did not add in the revised version. Please improve it before publication.

Author Response

Thank you for your comment.

The table was added as a separate file, as the manuscript uploaded by the journal, did not permit changes in regard to the references cited in the table.

I'll contact the journal to check if the the table was added in the text accordingly.