Immune Checkpoints and the Immunology of Liver Fibrosis

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is a very comprehensive review; however, a few additional points should be included:

 

 

Balance Between Pro-Inflammatory and Anti-Inflammatory Cytokines:

Expand on how pro-inflammatory cytokines like IL-1β, TNF-α, and IL-6 initiate and sustain fibrosis through immune cell activation and hepatic stellate cell (HSC) transformation. Conversely, anti-inflammatory cytokines like IL-10 and TGF-β contribute to immune tolerance but can also exacerbate fibrosis under chronic conditions. This balance is crucial in determining disease progression (PMID: 28853443).

 

 

Relative to Section 3.3.2: "LSECs as Gatekeepers of Innate and Adaptive Immunity":

It is crucial to mention that LSEC fenestrations are required for T cells to recognize intravascular antigens through cellular protrusions crossing the fenestrations. This mechanism is abolished by liver fibrosis and capillarization, reducing the effector function of antigen-specific T cells (PMID: 26188075).

Author Response

REVIEWER 1

We thank the reviewer for the comments on our paper. Changes have been highlighted in yellow.

This is a very comprehensive review; however, a few additional points should be included:

 

1.Balance Between Pro-Inflammatory and Anti-Inflammatory Cytokines:

Expand on how pro-inflammatory cytokines like IL-1β, TNF-α, and IL-6 initiate and sustain fibrosis through immune cell activation and hepatic stellate cell (HSC) transformation. Conversely, anti-inflammatory cytokines like IL-10 and TGF-β contribute to immune tolerance but can also exacerbate fibrosis under chronic conditions. This balance is crucial in determining disease progression (PMID: 28853443).

            The role of TNFa in fibrosis was pointed out. Moreover, the roles of TGF and IL-10 in chronic conditions as mediators of cell exhaustion were expanded.

 

 

2.Relative to Section 3.3.2: "LSECs as Gatekeepers of Innate and Adaptive Immunity":

It is crucial to mention that LSEC fenestrations are required for T cells to recognize intravascular antigens through cellular protrusions crossing the fenestrations. This mechanism is abolished by liver fibrosis and capillarization, reducing the effector function of antigen-specific T cells (PMID: 26188075).

             It has been done

Reviewer 2 Report

Comments and Suggestions for Authors

The article offers a thorough analysis of the interconnections between liver fibrosis and immunological factors across three domains, demonstrating structural coherence. The individual sub-sections are meticulously detailed. It synthesizes the relationship between liver fibrosis and immunology, offering foundational insights and clinical immunological assessments pertinent to clinical liver fibrosis. The references section is robust, featuring numerous high-quality articles, predominantly published within the last five years, underscoring the article's scholarly merit. Below are several suggestions and observations for improvement:

1. The article, titled "Liver Fibrosis: Immune Checkpoints and Immunology," should primarily concentrate on elucidating the immune cells and systems associated with liver fibrosis. However, the article tends to overly elaborate on certain points, such as hepatic stellate cells (HSC) and microRNA-related descriptions.

2. The section addressing the origin of macrophages, along with the related discussion on hepatic stellate cells in section 2.2, could benefit from reducing the quantity of content in favor of enhancing the quality of the description.

3. Figure 1.2 lacks sufficient detail and aesthetic appeal. It would be beneficial to improve the clarity and visual quality of the illustrations.

4. In the section titled "3. Immunology of Liver Fibrosis," a more focused and comprehensive description is required. Instead of providing a superficial list of liver immune-related cells, it would be advantageous to explore the connection between the liver immune system and liver fibrosis in greater depth.

5. "CONCLUSIONS" The current description lacks complexity and depth. It could be enhanced by elaborating on the interrelationships among various immune cells within the liver and their roles in liver fibrosis, as well as detailing the methodologies employed in immunologic testing. Furthermore, it should encompass an analysis of contemporary applications of immunological checkpoints and explore prospective advancements in this field.

6. Considering that some of the referenced literature includes studies related to Chinese pharmacology, it would be beneficial to incorporate insights from a Traditional Chinese Medicine (TCM) perspective regarding its connection to immunology and liver fibrosis.

Author Response

REVIEWER 2

We thank the reviewer for the comments on our paper. Changes have been highlighted in yellow.

The article offers a thorough analysis of the interconnections between liver fibrosis and immunological factors across three domains, demonstrating structural coherence. The individual sub-sections are meticulously detailed. It synthesizes the relationship between liver fibrosis and immunology, offering foundational insights and clinical immunological assessments pertinent to clinical liver fibrosis. The references section is robust, featuring numerous high-quality articles, predominantly published within the last five years, underscoring the article's scholarly merit. Below are several suggestions and observations for improvement:

1. The article, titled "Liver Fibrosis: Immune Checkpoints and Immunology," should primarily concentrate on elucidating the immune cells and systems associated with liver fibrosis. However, the article tends to overly elaborate on certain points, such as hepatic stellate cells (HSC) and microRNA-related descriptions.

Although we agree with you, we felt that a more elaborate presentation of the mechanisms of liver fibrosis would probably help the non-expert reader. However, we made reductions in micro-RNAs descriptions.

2. The section addressing the origin of macrophages, along with the related discussion on hepatic stellate cells in section 2.2, could benefit from reducing the quantity of content in favor of enhancing the quality of the description.

We reduced the quantity of information in section 2.2 as suggested.

3. Figure 1.2 lacks sufficient detail and aesthetic appeal. It would be beneficial to improve the clarity and visual quality of the illustrations.

We tried to improve the quality of the illustrations in the final text

4. In the section titled "3. Immunology of Liver Fibrosis," a more focused and comprehensive description is required. Instead of providing a superficial list of liver immune-related cells, it would be advantageous to explore the connection between the liver immune system and liver fibrosis in greater depth.

We feel that analyzing the immune papticipation of individual cells in liver fibrosis and summarizing their role in table 2 and Fig 2 could be clearer to the reader of this very complex mechanism.

5. "CONCLUSIONS" The current description lacks complexity and depth. It could be enhanced by elaborating on the interrelationships among various immune cells within the liver and their roles in liver fibrosis, as well as detailing the methodologies employed in immunologic testing. Furthermore, it should encompass an analysis of contemporary applications of immunological checkpoints and explore prospective advancements in this field.

The conclusions have been modified.

6. Considering that some of the referenced literature includes studies related to Chinese pharmacology, it would be beneficial to incorporate insights from a Traditional Chinese Medicine (TCM) perspective regarding its connection to immunology and liver fibrosis.

An appropriate comment and references have been added in subsection 2.3