PONE-D-20-29792

The pronounced lung lesions developing in LATY136F knock-in mice mimic human IgG4-related lung disease

PLOS ONE

Dear Dr. Waseda,

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Academic Editor

PLOS ONE

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Editor's Comment

Apart from the clarifications requested by the reviewers, please make sure that the paper is edited by a native English speaker or a English editing company to help with fixing all grammar errors that make some areas of this paper unclear.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: Yes

Reviewer #2: No

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The manuscript “The pronounced lung lesions developing in LATY136F knock-in mice mimic human IgG4-related lung disease” by Waseda et al is a concise report that correlated mice that express an alternate form of LAT and the spontaneous lymphoproliferative disorder they develop to human IgG4-related disease. The authors find that these mice exhibit strong Th2 inflammation early in life, followed by fibrosis. This study is quite straight-forward, but would benefit from more detail in many places.

Concerns:

1. This study uses knock-in of LAT in which tyrosine 136 is substituted with a phenylalanine, thereby preventing downstream signaling. This results in drastic lymphoproliferation. Is there any evidence that LAT is involved in human disease? The authors also discuss lung involvement in the introduction and mention clinical characteristics, but these characteristics are not defined. More detail about the clinical observations in this disease and how they correlate to what is seen in the animal model would be helpful.

2. The authors briefly mention the Th2 nature of their observations and the potential link with allergic disease, but there is no follow-up on this in either the experiments or in the discussion. Are there differences in IgE in this model?

3. Figure 1 needs more detail in the results and figure legend, especially regarding the 20 week sections. It seems that the image on the left is H&E staining and the image on the right is not, but this is unclear and the stains for each section needs to be defined.

4. The Ashcroft score needs to be defined.

5. In general, Figures 1-3 would benefit from greater details in the results section.

Reviewer #2: Dr. Wasada et al present a well argued manuscript describing the use of a LAT knock-in mouse as a model of IgG4-RD of the lung. This is a well executed follow-up study of their prior work, published in this journal, establishing this same mouse model in other organs commonly affected by human IgG4 disease. While the authors provide a compelling argument, there are a few minor issues that I suspect, if addressed, would improve the author's argument.

1) Figure 1: you present two LAT 20w x20 figures at the bottom with largely different appearances. Does this speak to the heterogeneity of the results at 20w? If so, would it help to show cumulative data, compiling the fibrosis scores. If this is true heterogeneity, it may be beneficial to add actual datapoints to Figure 3B, 4, and 5 instead of just showing the median.

2) Redundancy: the statement, "In addition, in Lat knock in mice, the score significantly increased over time." This is already shown in the sentence above, just with data re-arranged. I would re-word or eliminate this.

3) I'm assuming you chose to study BALF at 8,9 weeks due to your prior results suggesting peak inflammation occurred between 6-10 weeks. I wonder if you would have found greater cytokine production at an earlier time-point. It would have been interesting to see the composition of the lymphocytes found in the BALF. This could be done fairly easily using flow cytometry and could provide some insight into the unique cytokine pattern you found with bead array.

4) Next steps. Now that you have established this model, how do you intend to study it further?

5) Wording. There are some phrases throughout the manuscript that are hard to follow, or do not seem to add anything to your argument. For example, on page two, "Regarding the lungs, in addition to comprehensive diagnostic criteria, diagnostic criteria unique to the lungs were established, and diagnosis of lung lesions is performed based on the clinical characteristics." The clarity of your message could be improved greatly by a grammatical review focused on reducing redundancy.

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Reviewer #1: No

Reviewer #2: No

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The pronounced lung lesions developing in LATY136F knock-in mice mimic human IgG4-related lung disease

PONE-D-20-29792R1

Dear Dr. Waseda,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Michal A Olszewski, DVM, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: The authors were able to partly answer my comments, but I believe sufficiently to make the manuscript acceptable for publication. It is a bit worrisome when individual datapoints are not shown in figures, especially when analyzing mouse data. This was one of my comments that was not addressed and this remains my only reservation.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No