The Involvement of Alarmins in the Pathogenesis of Sjögren’s Syndrome

Round 1

Reviewer 1 Report

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This mauscript, a review by Dr. Sarrand et al. that provides an extensive overview of the current literature, addresses the potential roles that various molecular factors defined as ¨alarmins¨might play in the pathology of Sjogren´s Syndrome (SS). The presentation is divided into a discussion of alarmins based on cellular compartmentation. Although not directly pointed out in the paper, it appears that a common element in immune activations involves the NF-kb pathway…a pathway identified as critical in SS disease development. Overall, the manuscript is a comprehensive description of the topic that should be a nice reference for the field.  However, a couple of issues should be addressed:

• The Introductory paragraph requires a better description of what exactly is an alarmin, especially in light of its long-term evolutionary changes in the field.  This point is clearly evident in reading the third paragraph of the Introduction.  The sentence (lines 59-60) is totally unclear, furthermore it suggests that SS is a microbial-induced disease, which is still debatable.
• The last two sentences of the Introduction suggests that this review focuses on the role of different types of alarmins in the pathogenesis of SS, but really is a review of various alarmins that have been reported to be dysregulated in SS and what/how they may contribute to or correlate with the SS pathology.
• Although there are two figures shown in the text, neither is actually referenced in the text and neither has a figure legend. Furthermore, is there a reason not to present a similar figure for annexins and defensins?
• While the manuscript is well-written, the verb usage requires review. Multiple times the verbs are wrongly singular vs plural.

Author Response

Dear Reviewer, 

Thank you for reviewing our manuscript . 

1. we have accordingly updated the introductory section on alarmins.
2. The text has been modified accordingly to review.. and figures have been referenced throughout the text. 
3. We have added new figures including defenses and decorins.

Thank you again for your review.

Kind regards

Reviewer 2 Report

It is a lack of basic introduction to primary Sjögren's syndrome. Primary SS is related to multiple factors. The genetic locus most significantly associated with primary SS is the major histocompatibility complex/human leukocyte antigen region. Environmental factors, such as glandular viral infection, could prompt epithelial cells to activate the HLA-independent innate immune system through toll-like receptors. Epithelial cells in Sjögren's syndrome lesions are active participants in the induction and perpetuation of the inflammatory process. Typical SS ANA patterns are SSA/Ro and SSB/La, of which anti-SSB/La is far more specific; anti-SSA/Ro is associated with numerous other autoimmune conditions. Dysregulation of apoptosis (programmed cell death) is believed to play a role in the pathogenesis of a variety of autoimmune diseases,

The information is scattered and not well understood. It needs an overall graph about alarmins pathway and multifactorial interactions about pSS.

Author Response

Dear reviewer, 

The work is scaffolded following extra cellular and intra cellular alarmins . I am confused when you underline that it is scattered and not well understood. I am very sorry for that . 

We have included new figures and added a graph as demanded

Kind regards