Evidence linking atopy and staphylococcal superantigens to the pathogenesis of lymphomatoid papulosis, a recurrent CD30+ cutaneous lymphoproliferative disorder

Marshall E. Kadin; Robert G. Hamilton; Eric C. Vonderheid

doi:10.1371/journal.pone.0228751

Peer Review History

Original SubmissionAugust 5, 2019
11 Dec 2019 Decision Letter - Lucienne Chatenoud, Editor Transfer Alert This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present. PONE-D-19-22149 Evidence linking atopy and staphylococcal superantigens to the pathogenesis of lymphomatoid papulosis, a recurrent CD30+ cutaneous lymphoproliferative disorder PLOS ONE Dear Professor Kadin, First of all we would like to apologize for our late response due to difficulties in securing the adequate number of reviewers. We thank you for submitting your manuscript to PLOS ONE. After careful consideration, the content was considered very interesting and sound. Therefore, we decided yo accept the manuscript for publication provided you agree to address the minor comments raised by one of the reviewers. We would appreciate receiving your revised manuscript by Jan 25 2020 11:59PM. 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Unfortunately, this does not meet our data sharing requirements. PLOS does not permit references to inaccessible data. We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository. Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession numbers that may be used to access these data. Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data. 5. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. Additional Editor Comments (if provided): [Note: HTML markup is below. Please do not edit.] 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: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't Know Reviewer #2: Yes ****** 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). 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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: This is an interesting manuscript suggesting that an atopic diathesis may contribute to the pathogenesis of LyP. If indeed atypical CD30+ cells directly promoting IgE production one should expect that patients with high burden of disease will have higher IgE levels - have you correlated number of LyP lesions with IgE levels? Reviewer #2: The study is well performed and technically sound with high quality figures and tables. The manuscript is well-read and the conclusions justified. The study builds on previous on previous findings on a putative link between atopy and LyP and provides new interesting data strengthening such an association and a possible role of staphylococcal aureus superantigens in the pathogenesis. I have no major suggestions for changes of this excellent and interesting study. A minor point which might be of interest to touch in the Discussion is concerning the role of Staphylococcus aureus superantigens in the pathogenesis. The authors propose a mechanism that SSAg may induce apoptosis in malignant CD30+ T cells in LyP patient and thus hypothetically contribute to the hig.h apoptotic index and benign course of the disease. This is naturally one interesting hypothesis. However, at the same time the authors refer to Dr. Vonderheids observations that antibiotics have a beneficial effect in some patients, suggesting the possibility, that bacteria may a negative clinical effect. Therefore, it could be of interest to know whether or not presence of anti-SSAg of IgE type is associated with regression, progression, or neither (if the authors might have followed these patients for a sufficiently long observation time). Of notice, Lindahl et al (Blood 2019) recently reported that antibiotics inhibited both clinical disease activity and the fraction of malignant T cells in situ in a smal cohort of patients of mycosis fungoides/Sezary syndrome colonised by SSAg producing Staph aureus which is in line with Dr Vonderheids observations and may be worth discussing in relation to LyP. ****** 6. 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 #1: No Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0228751.r001
Revision 1
21 Jan 2020 Author Response Editor’s comment: In ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records used in your retrospective study. Specifically, please ensure that you have discussed whether all data were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data from their medical records used in research, please include this information. Response: This study was conducted in accordance with the Declaration of Helsinki Principles. Clinical data were obtained from a cutaneous lymphoma registry approved by the Institutional Review Board at Johns Hopkins University. IgE measurements were performed on de-identiﬁed frozen sera. The ethics committee waived the requirement for informed consent. Editor’s comment: We note that you have included the phrase “data not shown” in your manuscript. Unfortunately, this does not meet our data sharing requirements. PLOS does not permit references to inaccessible data. We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository. Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession numbers that may be used to access these data. Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data. Response: We deleted the sentence ending “data not shown” because it is not essential to our results or conclusion. Response to Reviewers Reviewer #1: This is an interesting manuscript suggesting that an atopic diathesis may contribute to the pathogenesis of LyP. If indeed atypical CD30+ cells directly promoting IgE production one should expect that patients with high burden of disease will have higher IgE levels - have you correlated number of LyP lesions with IgE levels? Reply to reviewer 1: Unfortunately, because this was a retrospective study, we cannot provide specific information about the number of LyP lesions or extent of body surface involvement. For this reason, we used soluble CD30 levels from a previous study as measure of the total CD30+ cell mass. As stated in the paper, no correlation was found between the level of sCD30 and IgE-t. Reviewer #2: The study is well performed and technically sound with high quality figures and tables. The manuscript is well-read and the conclusions justified. The study builds on previous on previous findings on a putative link between atopy and LyP and provides new interesting data strengthening such an association and a possible role of staphylococcal aureus superantigens in the pathogenesis. I have no major suggestions for changes of this excellent and interesting study. A minor point which might be of interest to touch in the Discussion is concerning the role of Staphylococcus aureus superantigens in the pathogenesis. The authors propose a mechanism that SSAg may induce apoptosis in malignant CD30+ T cells in LyP patient and thus hypothetically contribute to the hig.h apoptotic index and benign course of the disease. This is naturally one interesting hypothesis. However, at the same time the authors refer to Dr. Vonderheids observations that antibiotics have a beneficial effect in some patients, suggesting the possibility, that bacteria may a negative clinical effect. Therefore, it could be of interest to know whether or not presence of anti-SSAg of IgE type is associated with regression, progression, or neither (if the authors might have followed these patients for a sufficiently long observation time). Of notice, Lindahl et al (Blood 2019) recently reported that antibiotics inhibited both clinical disease activity and the fraction of malignant T cells in situ in a smal cohort of patients of mycosis fungoides/Sezary syndrome colonised by SSAg producing Staph aureus which is in line with Dr Vonderheids observations and may be worth discussing in relation to LyP. Reply to reviewer 2: We are aware of Lindahl’s work that SSAgs from S aureus intensify skin inflammation and have a tumor promoting effect in patients with mycosis fungoides/Sezary syndrome. However, these patients (as well as atopic dermatitis) have chronic skin lesions that are prone to bacterial colonization. This differs from patients with LyP where lesions come and go, often with intervals where no lesions are present. For this reason, the pathogenic role of SSAg, if any, in LyP may be different. In other words, the eruptive nature of LyP (and the closely related pityriasis lichenoides) more closely resembles eruptive guttate psoriasis than Sezary syndrome. Accordingly we have modified the discussion to clarify this point. Reviewer 2 ’s comment also refers to this sentence in the discussion: “Although overt clinical infection by S. aureus is not typical of LyP lesions, it is intriguing that LyP sometimes improves on oral antibiotics (particularly tetracycline/minocycline in Dr. Vonderheid’s experience).” If S. aureus is producing SSAgs that stimulate initial expansion if atypical CD30+ cells, then anti-Staphylococcal antibiotics might in principle inhibit the development of new lesions and eventually promote complete clearing. The rationale to administer antibiotics for LyP and Dr. Vonderheid’s experience with long-term tetracycline-type antibiotics as a suppressive therapy has been clarified in the discussion. Attachments Attachment Submitted filename: Response to reviewers.docx https://doi.org/10.1371/journal.pone.0228751.r002
23 Jan 2020 Decision Letter - Lucienne Chatenoud, Editor Evidence linking atopy and staphylococcal superantigens to the pathogenesis of lymphomatoid papulosis, a recurrent CD30+ cutaneous lymphoproliferative disorder PONE-D-19-22149R1 Dear Dr. Kadin, We are pleased to inform you that the revised version of your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements. Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication. Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. With best regards, Lucienne Chatenoud Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0228751.r003
Formally Accepted
3 Feb 2020 Acceptance Letter - Lucienne Chatenoud, Editor PONE-D-19-22149R1 Evidence linking atopy and staphylococcal superantigens to the pathogenesis of lymphomatoid papulosis, a recurrent CD30+ cutaneous lymphoproliferative disorder Dear Dr. Kadin: I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. For any other questions or concerns, please email plosone@plos.org. Thank you for submitting your work to PLOS ONE. With kind regards, PLOS ONE Editorial Office Staff on behalf of Prof. Lucienne Chatenoud Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0228751.r004

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