Immunoglobulin-Related Fibroinflammatory Diseases of Uncertain Etiology—Polarized Isotype Switching Connects an Ancient with a Contemporary Disease

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript of Chi Sing addresses two rare yet clinically significant Ig-related fibroinflammatory diseases, IgG4-related disease (IgG4RD) and Kimura disease (KD). The discussion on their pathogenesis through polarized Ig isotype switching is both novel and essential for advancing our understanding of these conditions. Especially, the manuscript highlights a potential connection between IgG4RD and KD, suggesting a shared mechanism that could open new avenues for research and therapeutic approaches. The exploration of the role of IgG4 and IgE in immune dysfunction adds substantial value to the current knowledge. The review raises intriguing questions about the etiology and immunological mechanisms underlying IgG4RD and KD. By emphasizing the need for further investigation, it provides a strong foundation for future research in immunopathology.

The author provided a clear and concise write-up. The writing is well-structured and effectively communicates complex immunological concepts in a clear manner, making it accessible to a broad scientific audience, including immunologists and clinicians.

However, a discussion on how understanding IgG4 and IgE in these diseases could influence therapeutic strategies (e.g., targeted immunomodulation) would strengthen the manuscript's clinical impact. Besides, details on molecular mechanisms would also be of great strengths. especiallay, while the manuscript introduces polarized Ig heavy chain isotype switching as a central concept, it would be helpful to elaborate on specific molecular pathways or genetic factors that might contribute to this phenomenon.

Overall, the entire manuscript needs close attention to fix typos and grammatical errors .

Comments on the Quality of English Language

See comments to the authors

Author Response

1. A discussion on how understanding IgG4 and IgE in these diseases could influence therapeutic strategies (e.g. targeted immunomodulation) would strengthen the manuscript's clinical impact.     Response 1: New treatment strategies based on increased understanding of the mechanisms of  immunological pathogenesis of the diseases have been included in sections 9 & 10. Specifically, use of anti-IgE, anti-IL4/IL13 and possible targeting of the Erk/MAPK signaling pathway may be useful in KD. The use of JAK inhibitors (with successful reports) and rituximab in treating IgG4RD is also included.
2. Details on molecular mechanisms would also be of great strengths, especially, while the manuscript introduces polarized Ig heavy chain isotype switching as a central concept. It would be helpful to elaborate on specific molecular pathways or genetic factors that might contribute to this phenomenon.  Response 2: Involvement of the JAK/STAT signaling pathway in IgG4RD and the Erk/MAKP pathway in KD is included in the 8, 9 & 10 of the manuscript. Genetic factors and hereditary predisposition in IgG4RD is mentioned under section 7.
3. Overall, the entire manuscript needs close attention to fix typos and grammatical errors.    Response 3: All typos and grammatical errors have been fixed.

Reviewer 2 Report

Comments and Suggestions for Authors

The review provides a thorough and valuable comparison between IgG4RD and KD, offering insights into their overlapping and distinct features.

The discussion on immunoglobulin isotype switching is well-articulated but could be better structured to avoid redundancy.

Some sections could benefit from better logical flow, particularly the sections on genetic predisposition and pathogenesis, which appear scattered.

Some diagrams or schematics summarizing key points (e.g., immunological pathways or comparisons between KD and IgG4RD) would significantly enhance readability.

 

Comments on the Quality of English Language

The manuscript is well-written but contains some awkward phrasing and overly complex sentence structures that could be simplified for better readability.

Minor grammatical and typographical errors are present and should be corrected.

Author Response

1. The discussion on immunoglobulin isotype switching is well-articulated but could be better structured to avoid redundancy.  Response 1: Redundant phrases and sentences have been deleted or merged. The discussion has become concise and readable.
2. Some sections could benefit from better logical flow, particularly the sections on genetic predisposition and pathogenesis, which appear scattered.    Response 2: The sections of etiology and genetic predisposition are merged into the new section 7 of the manuscript.
3.  Some diagrams or schematics summarizing key points (e.g. immunological pathways or comparisons between KD and IGG4Rd) would significantly enhance readability.  Response 3: A new table (Table 1) has been built for easy comparison of salient features of both KD and IgG4RD.

Reviewer 3 Report

Comments and Suggestions for Authors

In the review manuscript titled "Immunoglobulin-Related Fibroinflammatory Diseases of Uncertain Etiology - Polarized Isotype Switching Connects an Ancient with A Contemporary Disease ” by Sing Ng et. al. the authors reviewed the immune functions and characteristics of IgG4 and IgE and highlighted their role in immunity. In this review the authors analyzed two rare chronic fibroinflammatory diseases, IgG4-related disease (IgG4RD) and Kimura disease (KD), which involve IgG4- or IgE-positive plasma cells in affected tissues.  Further, the review explores the unknown underlying causes of these diseases and suggests that their pathogenesis may be linked through polarized Ig heavy chain isotype switching and associated cellular and cytokine interactions. It's an interesting review. However, there are major concerns apart from poor English language and writing that need to be addressed before the manuscript could be considered for publication. 1. The authors must keep all fonts the same throughout the text of the manuscript, it looks like paragraphs written using different fonts are merged together. 2. The authors must include at least 5 keywords for a quick understanding of the subject content of the review.  3. Very poorly written and awkwardly phrased paragraphs for eg. "The accompanying associated cellular, cytokine and chemotaxin interactions ensue in tissue inflammation and fibrosis". The authors must improve their English language and writing skills. 4. The first paragraph is an introduction while the second is B cell development. There is absolutely no connection between the two paragraphs. Authors should correlate the introduction to the other paragraphs for ease of understanding, enhanced readability and clarity. 5. Line 59,  The authors wrote a statement (which occurs in the spleen in mice, but unclear in humans)" is misleading. In humans, isotype switching occurs in germinal centers of secondary lymphoid organs, including lymph nodes and spleen so they must rewrite the literature. 6. Line 73: The sentence "switching of the heavy chain (HC) class from IgD or IgM of mature plasma cells to IgA, G or E" is incorrect. Infact plasma cells do not undergo class switching, CSR occurs at the activated B cell stage before differentiation into plasma or memory B cells. 7. Line 78: CD40L is incorrectly mentioned in the TI pathway—CD40-CD40L interaction is exclusive to the T-dependent (TD) response. 8. High affinity IgE is produced under influence of IL-13; and low affinity IgE produced under influence of IL-4 (as occurring in IgG4RD). The language used is non-scientific. The authors should use other phrases instead of "under the influence of" 9.  The review lacks information on the diseases and their etiology especially in the context of auto-immune disease and cancer. The authors must cite the following literature pmid   25187664, 37339207. In similar contexts cite 31341075, 37153623 and the research 37703975 to further enrich the literature and make it more suitable for publication. 10. Lines 146-151 are highlighted and look like they have been copied from another source and pasted. The authors must keep all fonts the same and make necessary changes. 11. Further, the authors should discuss the latest developments in the etiology of the KD and IgG4RD.

Comments on the Quality of English Language

Needs lot of improvement!

Author Response

1. The authors must keep all fonts the same throughout the text of the manuscript, it looks like paragraphs written using different fonts are merged together.   Response 1: The fonts of the manuscript is unified to be Calibri.
2. The authors must include at least 5 keywords for a quick understanding of the subject content of the review.    Response 2: Five keywords have been provided following the Abstract.
3. Very poorly written and awkwardly phrased paragraphs, e.g. "The accompanying associated cellular, cytokine and chemotaxin interactions ensue in tissue inflammation and fibrosis". The authors must improve their English language and writing skills.   Response 3: The English language and writing of the entire manuscript has bee facelifted and revamped. Redundant phrases or sentences have been merged or removed. Excessively long sentences have been broken into shorter more easy to understand sentences.
4.  The first paragraph is an introduction while the second is B cell development. There is absolutely no connection between the two paragraphs. Authors should correlate the introduction to the other paragraphs for ease of understanding, enhanced readability and clarity.   Response 4: The last sentence in the introduction is the lead to the subsequent paragraphs of the manuscript. 
5. Line 59. The authors wrote a statement (which occurs in the spleen in mice, but unclear in humans) is misleading. In humans, isotype switching occurs in germinal centers of secondary lymphoid organs, including lymph nodes and spleen so they must rewrite the literature.    Response 5: This sentence has been removed from the manuscript.
6. Line 73. The sentence "switching of heavy chain (HC) class from IgD or IgM of mature plasma cells to IgA, G or E is incorrect. In fact plasma cells do not undergo class switching, CSR occurs at the activated B cell stage before differentiation into plasma or memory  B cells.   Response 6: The words plasma cells have been replaced by activated B cells.
7. Line 68. CD40L is incorrectly mentioned in the TI pathway - CD40-CD40L interaction is exclusive to the T-dependent (TD) response.      Response 7: The sentence on involvement of CD40L in the TI pathway has been removed. 
8. High affinity IgE is produced under influence of IL-13; and low affinity IgE produced under influence of IL-4 (as occurring in IgG4RD). The language used is non-scientific. The authors should use other phrases instead of "under the influence of".     Response 8: The phrase "under the influence of" has been replaced by "under the control of".
9. The review lacks information on the diseases and their etiology especially in the context of autoimmune disease and cancer. The authors must cite the following literature pmid 25187664, 37339207. In similar contexts cite 31341075, 37153623, and the research 37703975 to further enrich the literature and make it more suitable for publication.   Response 9: The paper on PD-1 in human leprosy (PMID 37153623) has been cited (new reference 23) in the section 3 on CSR. The remaining reference are not directly related to KD or IgG4RD. However, taking reference from these works and correlating the researched immunological markers and processes with KD and IgG4RD, several relevant references have been discovered. These are the new references 20, 21, 22, 55,56, 86 & 87, with relevant text inserted in sections on pathogenesis (section 8) and clinicopathologic features of IgG4RD and KD (sections 9& 10). The newly inserted references and text relate to pathogenesis and new treatment strategies based on increased understanding of the immunological pathogenesis of these diseases. 
10. Lines 146-151 are highlighted and look like they have been copied from another source and pasted.  The authors must keep all fonts the same and make necessary changes.  Response 10: The highlighting was used at the manuscript drafting stage and inadvertently left intact when the paper was submitted. The highlighting has been removed. All fonts are Calibri (please see Response 1).
11. The authors should discuss the latest developments in etiology of KD and IgG4RD.   Response 11: New developments in the etiology of these diseases are included in sections 7, and new references 55,& 60 added.

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

The authors have addressed all my concerns and have made suggested changes in the manuscript. I, therefore, recommend the manuscript suitable for publication in its revised form.