Role of Peripheral Immune Cells in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

Round 1

Reviewer 1 Report

This review article attempts to summarize current knowledge of the immune system in the pathogenesis of MS/EAE. While the authors have mentioned many types of immune cells which have a role in MS, I felt that the manuscript mostly describes basic immunology text-book knowledge and does not provide any interesting insights into MS pathogenesis or into our current understanding of the immune system in MS/neuroinflammation, and the crosstalk between the adaptive and innate immune cells in MS/EAE. It rather provided some week evidence that the cells which are mentioned in the text are found in MS/EAE but how do they contribute to the pathophysiology of the disease is missing.

Additional minor points:

1. Figure 1 is confusing to follow and would benefit from reorganization.
2. PRMS has been removed from the MS criteria in 2013, though some may still use it. CIS has been introduced as an early event of the disease and might be worth mentioning 

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

The abstract is a bit vague. It could be more to the point highlighting the review.

Generally the review is well written. It provides a reasonable, general approach to issues in multiple sclerosis. One issue is that the sub-dural lymphatic web is not considered. The web allows for immune cells to migrate into and out of the CNS without crossing the blood-brain-barrier. This is a fairly significant oversight.

The CD8 section is vague.

Author Response

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Reviewer 3 Report

This is a well written narrative review on multiple sclerosis pathophysiological mechanisms and the experimental model usually investigated to address the acute aspects of the disease, i.e. autoimmune encephalomyelitis in mice. Interestingly, authors mainly addressed the role of peripheral cells in causing inflammation. I have the following comments:

• Maybe, the title could clearly indicate that peripheral immune cells are the focus of the review.
• The abstract should end with a conclusive statement.
• In line 57, “Stress…” is too generic and should be defined.
• Chapter 2.3 is interesting but it should be discussed in relation to the disease severity. Vainchtein et al. (2014, in Glia) showed that macrophages are progressively more involved with increasing severity of autoimmune encephalomyelitis in mice. Moreover, macrophages appeared to be highly immune activated. This should be mentioned by authors.
• Some description of autoimmune encephalomyelitis in mice should be provided.
• Line 243, BBB was already introduced as abbreviation in the previous sentences.
• It is unclear the mention of melatonin in lines 314-317. Several other endogenous molecules were protective in models of multiple sclerosis (for instance, allopregnanolone, Noorbakhsh et al. 2014 in Front. Cell. Neurosci., or ghrelin, Liu et al. 2019, in Front. Pharmacol.), but are not mentioned by authors.

Author Response

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Round 2

Reviewer 1 Report

The revised manuscript has significantly improved. The new figures are nice. However, I felt that the sections on the roles of CD4 and CD8 T cells still need much improvement. These sections are vague and do not highlight much of the functions of CD4 and CD8 T cells in EAE/MS, while these cells have been extensively investigated in MS and EAE. For instance, CD8 T cells were proposed to have immunoregulatory functions in EAE, this is not mentioned in the text at all (reviewed by Sinha S. et al. 2015; DOI: 10.3389/fimmu.2015.00619). CD8 T cells also promote progressive EAE disease and exacerbate EAE induced by CD4 T cells, some of these studies are mention, but many others are not. Similarly, B cells were also reported to have immunoregulatory roles in EAE/MS, and this is also not mentioned (reviewed by Negron A. et el. 2019; DOI: 10.1016/j.cellimm.2018.10.006). If the authors do not want to describe the immunoregulatory roles of immune cells (B cells and CD8 T cells), then a more appropriate title should be provided. 

CD4 T cells are perhaps the most critical cells for EAE development, and thus the functions of CD4 T cells in EAE/MS have been extensively investigated. For instance, CD4 T cells promote CNS damage via the expression of inflammatory mediators (e.g. TNF, IL-17, IFN-g), but none of these functions are being discussed. Additionally, a description of how do CD4 T cells promote neuroinflammation (e.g. via expression of CCL2 to recruit neutrophils and monocytes) and demyelination and neuronal death (e.g. via expression of IL-17, TNF, and CXCL13) is also not provided. If the authors think that too many details would be outside the scope of the current review, the authors should then refer to other review articles that would provide a more comprehensive overview of T cell functions in EAE/MS.

Author Response

We thank the reviewer for the comments. We have revised the manuscript according to the reviewer's suggestions (marked in yellow). Also, we added new references, as requested by the reviewer (marked in yellow).  

Author Response File: Author Response.docx

Reviewer 3 Report

All my questions have been addressed and the manuscript is definitely improved.

Author Response

We thank the reviewer for the comments.

Round 3

Reviewer 1 Report

The authors have adequately addressed all of my concerns