Polymorphonuclear Neutrophils in Rheumatoid Arthritis and Systemic Lupus Erythematosus: More Complicated Than Anticipated

Round 1

Reviewer 1 Report

Dr Ahmad and colleagues wrote a comprehensive review on a very intersting and complex subjet. The review is globally clear and well written.

My main suggestions would be:

-since the review is very exhaustive, the physiological picture that emerges is very complex. A recapitulative figure for each disease (lupus and RA) would much help readers to apprehend the subject.

-many neutrophils dysfonctions, and in particular excess of NETs formation have been described in a very wide range of diseases. Maybe the authors could emphasize more on what is specific to lupus or RA

-while there is no major mistakes, style and fluidity could be improved by English editing services.

Specific comments:

line 49: CD66b is not expressed on basophils, so this is imprecise.

line 50: it should be stated that if indeed CD66b has been used as a neutrophil marker, it is incorrect to do so in some situations without using another marker to exclude eosinophils since the distinction can be important.

line 53: The word naïve should be used only for T and B lymphocyte to avoid confusion. The expression "naive activated" doesn't make much sense per se, it should be explained what is meant here.

line 87 a word is missing after "a source of"

line 112: I'm not sure one can say that RA is "characterized" by ACPA since 30% of patients don't have any

line 125 "Insight of PMN": strange. Check style

line 129 "The results" Not sure what the authors are talking about here. Litterature data? Check and reformulate

line 262: I would add "putative" to autoantigen as the mechanism is not proven, at least in humans

line 290: typo "immunosupressive"

Author Response

Reviewer: 1

 

Comments to the Author

 

Dr Ahmad and colleagues wrote a comprehensive review on a very intersting and complex subjet. The review is globally clear and well written.

 

General reply:

 

We thank the reviewer for his interesting comments, which helped improving the quality of the manuscript.

 

My main suggestions would be:

 

Point 1: since the review is very exhaustive, the physiological picture that emerges is very complex. A recapitulative figure for each disease (lupus and RA) would much help readers to apprehend the subject.

 

Reply: two figures have been included, as suggested. They depict the involvement of PMN, and NET, in agreement with comments of reviewer 2.

 

Point 2: many neutrophils dysfonctions, and in particular excess of NETs formation have been described in a very wide range of diseases. Maybe the authors could emphasize more on what is specific to lupus or RA.

 

Reply: it is not clear which mechanisms are disease-specific and thus not easy to describe them as such. This was mentioned in the conclusion. Several dysfunctions, activities or mechanisms involving PMN and/or NET are observed both in SLE and RA, as well as in other diseases. We believe that those events are finely regulated by stimuli which are disease specific through e.g. inducing NET with slightly different composition. This is better explained in the revised manuscript and discussed in the conclusion.

 

Point 3: while there is no major mistakes, style and fluidity could be improved by English editing services.

 

Reply: the text has been improved as suggested.

 

Specific comments:

 

Point 4: line 49: CD66b is not expressed on basophils, so this is imprecise.

 

Reply: the text has been changed.

 

Point 5: line 50: it should be stated that if indeed CD66b has been used as a neutrophil marker, it is incorrect to do so in some situations without using another marker to exclude eosinophils since the distinction can be important.

 

Reply: there is no perfectly specific marker for eosinophils. Because the percentage of blood eosinophils is very low in comparison to the percentage of blood neutrophils, CD66b is used as a neutrophil marker for blood neutrophils. Nevertheless, eosinophils can be excluded by gating out CD16-negative cells by performing multicolor staining, and this is mentioned in the revised manuscript.

 

Point 6: line 53: The word naïve should be used only for T and B lymphocyte to avoid confusion. The expression "naive activated" doesn't make much sense per se, it should be explained what is meant here.

 

Reply: the text has been modified to reflect the original publication.

 

Point 7: line 87 a word is missing after "a source of".

 

Reply: the text has been corrected.

 

Point 8: line 112: I'm not sure one can say that RA is "characterized" by ACPA since 30% of patients don't have any.

 

Reply: actually ACPA define RA. Reciprocally, some people suggest that ACPA-negative RA patients develop a slightly different disease. However, the text has been modified for clarity.

 

Point 9: line 125 "Insight of PMN": strange. Check style.

 

Reply: style has been changed.

 

Point 10: line 129 "The results" Not sure what the authors are talking about here. Litterature data? Check and reformulate.

 

Reply: the text has been changed.

 

Point 11: line 262: I would add "putative" to autoantigen as the mechanism is not proven, at least in humans.

 

Reply: the text has been modified accordingly.

 

Point 12: line 290: typo "immunosupressive".

 

Reply: the text has been corrected.

 

Reviewer 2 Report

In this review article, the authors discuss what is known about neutrophilic extracellular traps (NETs) in SLE and RA. The review is logical and easy to follow and the discussion is sound and generally well-articulated, although a few sentences need a second look (see below).

This reviewer believes that the manuscript will benefit tremendously by having a model figure depicting the role(s) or NETs in SLE and RA, accompanying the conclusion. This figure should include known stimuli acting on NET producing cells as well as the functions of NETs as possible inducers or disease, amplification factors, or pathogenic components. 

Specific linguistic comments and suggestions:

lines 195-201: the use of "similarly" and  "reciprocally" does not make sense here. Please re-read and update.

lines 315-316: please change "whereas" to "and".

lines 329-332: These two sentences should be combined into one, as the latter part of the first sentence and the second sentence overlap significantly.

lines 348-351: These two sentences should also be combined.

line 354: remove "to".

line 361 and line 425: the use of "thus" here does not make sense. Maybe change to "for example" or "for instance"

line 374: change "in" to "into"l

line 430-432: please combine these two sentences into one.

line 446: remove "and"

line 448: replace "but also" with "as well as" or "in addition to"

 

 

 

 

Author Response

Reviewer: 1

 

Comments to the Author

 

In this review article, the authors discuss what is known about neutrophilic extracellular traps (NETs) in SLE and RA. The review is logical and easy to follow and the discussion is sound and generally well-articulated, although a few sentences need a second look (see below).

 

General reply:

 

We thank the reviewer for his interesting comments that we took into account to improve the quality of the manuscript.

 

Point 1: This reviewer believes that the manuscript will benefit tremendously by having a model figure depicting the role(s) or NETs in SLE and RA, accompanying the conclusion. This figure should include known stimuli acting on NET producing cells as well as the functions of NETs as possible inducers or disease, amplification factors, or pathogenic components.

 

Reply: two figures have been included, as suggested. They depict the involvement of NET, and PMN, in agreement with comments of reviewer 1.

 

Specific linguistic comments and suggestions:

 

Point 2: lines 195-201: the use of "similarly" and  "reciprocally" does not make sense here. Please re-read and update.

 

Reply: we used “similarly” because NET are composed of DNA and proteins, and antimicrobial activities have been reported for both. Nevertheless, the text has been modified. “Reciprocally” refers to the defense mechanism developed by bacteria against NET. NET attack bacteria and reciprocally bacteria attack NET. The text has been modified.

 

Point 2: lines 315-316: please change "whereas" to "and".

 

Reply: the text has been changed.

 

Point 3: lines 329-332: These two sentences should be combined into one, as the latter part of the first sentence and the second sentence overlap significantly.

 

Reply: actually, data are complementary but not really overlapping. Indeed, in the latter part of the first sentence we focus on PMN activated by immune complexes and the consequences on PBMC, whereas in the second sentence we focus on PMN activated by autoantibodies and the consequences on pDC. We fear that mixing in the same sentence different target cells with different stimuli may be confusing for the reader. However, if absolutely required, the modification would be done. Eventually, as an alternative, the first part of the first sentence could be combined with the second sentence, but this would also lead to two independent sentences with the latter part of the first sentence alone.

 

Point 4: lines 348-351: These two sentences should also be combined.

 

Reply: sentences have been combined.

 

Point 5: line 354: remove "to".

 

Reply: has been removed.

 

Point 6: line 361 and line 425: the use of "thus" here does not make sense. Maybe change to "for example" or "for instance".

 

Reply: the text has been changed as suggested.

 

Point 7: line 374: change "in" to "into"l

 

Reply: the text has been changed.

 

Point 8: line 430-432: please combine these two sentences into one.

 

Reply: sentences have been combined.

 

Point 9: line 446: remove "and".

 

Reply: done.

 

Point 10: line 448: replace "but also" with "as well as" or "in addition to".

 

Reply: has been replaced as suggested.