The Immunobiology of Dry Eye Disease: A Review of the Pathogenesis, Regulation and Therapeutic Implications

Reviewer summary

This manuscript provides an extensive literature survey on the immunobiology of DED, and the authors' efforts in tracking the cutting-edge progress in this field are evident. A particular strength of the article is its in-depth exploration of complex topics such as adaptive immunity, especially T-cell subsets, and the emerging field of neuro-immune interactions. In terms of academic depth and novelty, this manuscript demonstrates significant potential to become a highly impactful review.

However, the manuscript currently suffers from fundamental deficiencies in several key areas. The core issue is that the paper reads more like a linear catalog of research findings rather than a synthesis guided by a central thesis or a critical integration of existing knowledge. This structural looseness, compounded by severe flaws in the presentation of figures, collectively undermines the manuscript's persuasive power and academic contribution. Therefore, I recommend Major Revision, which will require the authors to undertake a thorough reconceptualization and restructuring of the entire paper.

Reviewer comment

Response

Change

The manuscript is missing a core argument. It describes in detail what has been discovered but fails to deeply address why these findings are crucial and how they collectively point to a more profound pathological mechanism. This absence of a central thesis confines the paper to the level of an information compilation.

We thank the reviewer for this insightful comment. It was critical to understand that the core argument of the article was not apparent to the reader. We have made changes to emphasize the role of immune homeostasis in DED and to highlight the complexity of the disease pathology.

Introduction – introducing the central thesis

Section 5.1, 5.2 – linking microbiome and ageing to immune dysregulation.

Section 6 – overview paragraph at the beginning and linking sentences in Section 6.2.

Conclusion

The paper also tends to accept the conclusions of cited literature at face value, without demonstrating the necessary academic scepticism. For instance, contradictions between different studies, the gap between animal models and clinical reality, and the implications of key clinical trial failures are topics of great value for a review, yet they are scarcely addressed here.

We thank the reviewer for this useful comment. We have added more discussion on the conflicts and pitfalls of the data presented

Section 5.2 – final paragraph.

Section 6.1

Section 6.2 – final paragraph

Section 7.4

Section 8

Section 10

Section 12

Furthermore, the current modular structure—treating innate, adaptive, and neuro-immune systems as separate entities—does not effectively illustrate the complex, dynamic interplay between these systems. The manuscript's structure is loose and fails to convey that the "vicious cycle" of DED is a dynamic process. The review also gives almost no attention to the roles of B-cells and the ocular surface microbiome in the immune regulation of DED, which significantly compromises its comprehensiveness.

We thank the reviewer for bringing this to our attention. Additional linking sentences between the major sections have been added in an effort to demonstrate the dynamic nature of each arm of the immune system without compromising clarity of the script. Moreover, we have dedicated two subsections to B cells and the microbiome to help increase comprehensiveness.

Section 5.2 - Microbiome

Section 7.4 – B cells and humoral dysfunction

The quality of Figure 2 is entirely unacceptable. The figure is not only visually chaotic and overcrowded but, more critically, it is provided with no legend whatsoever.

We thank the reviewer for this comment. The figure has been amended and a legend added.

Figure 2

While Table 1 is information-rich, its current format resembles a raw database, limiting its practical utility. The authors need to process this information further; for example, biomarkers could be categorized by function (e.g., cytokines, chemokines) or clinical relevance (e.g., core biomarkers, candidate biomarkers). By adding annotations and classifications, this "data list" could be transformed into a truly instructive "knowledge map."

We thank the reviewer for this suggestion. We categorized the biomarkers by function to make the table more informative and to increase its utility for future reference.

Table 1

Reviewer summary

The review done by Saram et al. provides a comprehensive overview of the immunobiology of dry eye disease. Specifically, the review highlights the complex interplay of molecular mechanisms of innate and adaptive immune activation, neuroimmune-mediated inflammation, and emerging molecular and cellular biomarkers in dry eye disease. Although the authors have done a good job of systematically reviewing the available literature, some aspects can be improved to make the review even better.

Reviewer comment

Response

Change

In the introduction, the authors have mentioned “This review synthesizes the key literature on the biological processes underlying immune dysregulation in DED. Please make it as summarize instead of synthesizes.

We thank the reviewer for this comment. We have made the amendment as suggested.

Section 1.

It would be ideal if authors could provide a flow chart depicting their methodology.

We thank the reviewer for this suggestion. We agree that a flow chart can be a useful tool for presenting the methodology in a systematic review. However, as our manuscript is a narrative review, we believe that the current methodology section adequately serves its intended purpose.

N/A

The authors rely heavily on a few sources, particularly references 2 and 3, which are cited repeatedly.

We thank the reviewer for highlighting this point. We agree that references 2 and 3 are particularly relevant to the scope of this review and have been cited frequently. However, we ensured that our review is comprehensive, having included over 100 references.

Reference list

Providing a short description of the figures in the figure legends would be ideal.

We appreciate the reviewer’s thoughtful remark. We have added descriptions to each of the figures.

Figure 1 and Figure 2

Please use either the word beta; or its symbol consistently throughout, e.g., IL-1β

We thank the reviewer for this observation and have made the necessary changes to the manuscript.

Throughout the manuscript

Here, "SP may also be implicated in the promotion and maintenance of memory Th17 cells [81]. In vitro studies have shown increased conversion of effector T cells to memory Th17 cells when cultured with SP [81]. Further, when cultured with Th17 memory cells, SP continued to preserve the cells [81]." Consider consolidating the repeated citation [81] at the end of the paragraph instead of after each sentence. These similar trends were noted across several locations.

We are grateful to the reviewer for this helpful observation. We have made requested changes.

Throughout the manuscript

Since the complement system is a component of the innate immune system and has been

implicated in DED, it would be preferable to summarise the relevant studies of the

complement system in DED in a single paragraph in the review.

We are grateful to the reviewer for highlighting this important aspect of DED pathology. We have made the requested changes.

Section 6.2

Please proofread to correct the spacing issues.

We thank the reviewer for this valuable suggestion, which we have now addressed in the revised manuscript

Throughout the manuscript

Reviewer summary

I am pleased to review the work of Sarah Jacqueline Saram and colleagues: The Immunobiology of Dry Eye Disease: A Review of the Pathogenesis, Regulation and Therapeutic Implications. Their study presents the alterations of ocular surface immune function and molecular biomarkers related to dry eye disease, along with a limited discussion on therapeutic approaches. I have only two minor comments:

Reviewer comment

Response

Change

In Section 3. OS Immune Homeostasis, the authors mention the contribution of lacrimal gland-related functions to ocular surface homeostasis. However, my concern is that the authors only dedicate one or two sentences to describe the lacrimal gland and tear film, without properly elaborating on the role of the lacrimal gland in ocular surface homeostasis, and this aspect is also neglected in the rest of the manuscript. In fact, lacrimal gland damage can induce corneal neovascularization and corneal surface roughness/dryness (10.1167/iovs.63.3.14), thereby altering corneal homeostasis. When the lacrimal gland is absent (10.3791/67317), aqueous deficiency dry eye disease will result in related ocular surface changes, including corneal inflammation. Moreover, other publications (10.4103/IJO.IJO_2981_22) have also highlighted the contribution of tear-related biomarkers in dry eye. I recommend that the authors incorporate these references and expand this discussion to enrich the manuscript

We thank the reviewer for this comment. We agree that the lacrimal gland plays an important role in DED, which could warrant a separate review on the subject. We have added additional information that fits within the scope of this work, and the suggested reference has been included in Table 1

Section 3.

Table 1.

The Methodology section lacks inclusion/exclusion criteria.

We thank the reviewer for this suggestion and have made the requested changes.

Section 2.

The Therapeutic Implications section is incomplete. To my knowledge, Diquafosol (10.1167/iovs.19-27872) should be included, especially as it has been recommended by TFOS DEWS II. In addition, it is uncertain whether pranoprofen (10.1080/08923973.2024.2390449) should also be considered in this work. The authors are encouraged to further refine this section to cover other potential therapeutic agents.

We appreciate the reviewer’s point. We have included additional information that aligns with the scope of this work.

Section 10.

Reviewer summary

This is a well-organized and comprehensive narrative review that synthesizes a broad body of literature on the immunopathogenesis of dry eye disease (DED). The manuscript thoroughly covers both innate and adaptive immune pathways, integrates neuroimmune mechanisms, and discusses emerging therapeutic targets. The scope is appropriate for IJMS, and the manuscript is timely given the increasing interest in immunomodulatory strategies for DED. However, few aspects require clarification, and better structuring to improve its impact and readability.

Reviewer comment

Response

Change

The review is very dense, and several sections (especially innate vs adaptive immunity) repeat similar concepts without clear transitions. Consider reorganizing Section 6–7 and maybe 8 to first present overview diagrams or summary tables of immune pathways.

We thank the reviewer for the insightful feedback. We have revised several sections of the manuscript to enhance the clarity and organization of the information presented.

Section 5.1

Section 5.2,

Section 6.1,

Section 6.2,

Section 6.3

Section 7.5.

The manuscript mentions age as a risk factor but does not fully integrate how aging alters immune regulation (e.g., Treg plasticity, macrophage polarization) and neuroimmune homeostasis. Given the growing evidence linking aging to increased DED severity, this should be explicitly discussed, ideally in a dedicated subsection.

We appreciate the reviewer’s thoughtful comment and have added a section addressing the topic of the influence of ageing and immune dysregulation in DED.

Section 5.1

Figure 1 (tear film) is useful, but additional schematic diagrams showing the immunopathogenic cascade (“vicious cycle”) and the innate–adaptive–neuroimmune interactions would help readers visualize complex mechanisms.

We thank the reviewer for this comment. We have amended Figure 2 which illustrates neuroimmune interactions and added a legend.

Figure 2.