Behçet’s Disease: A Comprehensive Review on the Role of HLA-B*51, Antigen Presentation, and Inflammatory Cascade
Round 1
Reviewer 1 Report
Comments and Suggestions for Authors
This is a detailed review of the role HLA-B*51 and inflammation in Behcet's Disease. While most of the major papers are covered it would be helpful to include;
Papers on KIR3D1 allotypes associated with BD - Petrushkin H et al J Immunol 2019 203;1629; Erer B et al Genes and Immunity 2016 17;396 (both for NK section) and Ombrello M. et al Proc Natl Acad Sci 2104 11;8867 (on protective HLA alleles.
Secondly, a more detailed assessment of ERAP Hap 10/ HLA-B*51 risk. While this combination is a clear rsik factor for BD it only occurs in a small number of patients. This should be made more clear.
Finally, some discussion about the fact that most patients with BD do not express HLA-B*51 should be included.
Author Response
Dear Editor,
We would like to thank you and the reviewers for the stimulating and helpful comments to the manuscript entitled “Behçet’s Disease: A Comprehensive Review on the Role of HLA-B*51, Antigen Presentation, and Inflammatory Cascade”.
We are grateful for all the inspiring suggestions which we incorporated into the revised version of the manuscript. To facilitate the review, we prepared a list of the reviewers' comments and the according to answers and explanations below. Proposed changes have been respected, and they can be seen in the revised manuscript in track changes mode in red color.
Response to the reviewers’ comments
Reviewer 1
- This is a detailed review of the role HLA-B*51 and inflammation in Behcet's Disease. While most of the major papers are covered it would be helpful to include;
Papers on KIR3D1 allotypes associated with BD –
- Petrushkin H et al J Immunol 2019 203;1629;
- Erer B et al Genes and Immunity 2016 17;396 (both for NK section)
- Ombrello M. et al Proc Natl Acad Sci 2104 11;8867 (on protective HLA alleles).
We thank the reviewer for this valuable comment. We added a subsection to include KIR3D1 association with BD and included the articles the reviewer recommended. We also added a subsection on other HLA Class I alleles and discussed Ombrello article and other linked articles in this subsection.
- Secondly, a more detailed assessment of ERAP Hap 10/ HLA-B*51 risk. While this combination is a clear risk factor for BD it only occurs in a small number of patients. This should be made more clear.
We thank the reviewer for this comment. We wrote a more detailed assessment of ERAP-HLAB51 risk. We added that majority of patients do not have this combination of genes and further discussed this. We also added a functional study on herpes-induced mice with heterozygous ERAP variant showing that low activity ERAP results in increased IL-17 expression and inflammation.
- Finally, some discussion about the fact that most patients with BD do not express HLA-B*51 should be included.
We elaborated the discussion this topic and added that although this risk gene is important it is not present in majority of patients and included other HLA Class I allotypes associated with BD (risk factor or protective).
Reviewer 2 Report
Comments and Suggestions for Authors
The manuscript entitled " Behçet’s Disease: A Comprehensive Review on the Role of HLA-B*51, Antigen Presentation, and Inflammatory Cascade " is a very detailed review of the topic.
I have several recommendations to the authors:
1. Write the abstract according to the usual sections: background, aim, material and methods, results.
2. Include in the systematic review - Search strategy, number of selected articles, number of eliminated articles, PRISMA flowchart of the process. You should include material and methods section.
3. In the next sentence " Among the thousands of HLA class I alleles identified, only a few are linked to certain 79 diseases, including HLA-B*51for BD, HLA-B27 for ankylosing spondylitis (AS), HLA-80 C06:02 for psoriasis, and HLA-A29:02 for birdshot chorioretinopathy." - HLA B 27 is very common to the family of spondyloarthritis ( psoriatic arthritis). It is better to include this clarification in the text.
4. "In Turkey, the prevalence of the HLA-B*51 allele in BD patients is high, ranging from 50% to 70%, whereas in the general population, around 25% of individuals are HLA-B*51positive 115 [25, 26]." - You can include the prevalence in Turkish population the gene mutation in MEFV gene. Recently a couple of articles were published on that topic. You can also include information about the association of MEFV mutation and neuro-BD.
5. Shorten the conclusion and remove figure 2 from it and put it in the body of manuscript.
6. Recheck the references.
The manuscript is well-written, some corrections according to the structure and inclusion of material and methods section are needed, but otherwise it is very detailed and interesting.
Comments on the Quality of English Language
The English language is on sufficient level.
Author Response
Dear Editor,
We would like to thank you and the reviewers for the stimulating and helpful comments to the manuscript entitled “Behçet’s Disease: A Comprehensive Review on the Role of HLA-B*51, Antigen Presentation, and Inflammatory Cascade”.
We are grateful for all the inspiring suggestions which we incorporated into the revised version of the manuscript. To facilitate the review, we prepared a list of the reviewers' comments and the according to answers and explanations below. Proposed changes have been respected, and they can be seen in the revised manuscript in track changes mode in red color.
Response to the reviewers’ comments
Reviewer 2
- Write the abstract according to the usual sections: background, aim, material and methods, results.
We thank the reviewer for making this point, because the journal guidelines does not allow subsections as the reviewer suggested we revised only the flow of the abstract so that it starts with the background followed by aim, methods etc.
- Include in the systematic review - Search strategy, number of selected articles, number of eliminated articles, PRISMA flowchart of the process. You should include material and methods section.
We thank the reviewer for this comment. We only had 10 days for the review revisions. We still partially did the systematic review using ‘GWAS, HLA B51, HLA, MHC Class I and Behçet’s disease keywords and included all the relevant studies on the HLA B51 association and Behçet’s disease. Flowchart and a table of the summary of the associated studies are included in the article.
- In the next sentence " Among the thousands of HLA class I alleles identified, only a few are linked to certain 79 diseases, including HLA-B*51for BD, HLA-B27 for ankylosing spondylitis (AS), HLA-80 C06:02 for psoriasis, and HLA-A29:02 for birdshot chorioretinopathy." - HLA B 27 is very common to the family of spondyloarthritis (psoriatic arthritis). It is better to include this clarification in the text.
We completely agree, and we thank the reviewer. We revised the appropriate part in the manuscript as follows: “Among the thousands of HLA class I alleles identified, only a few are linked to certain diseases, including HLA-B*51 for BD, HLA-B27 for spondylarthritis family (ankylosing spondylitis (AS), psoriatic arthritis, reactive arthritis, arthritis associated with inflammatory bowel disease (IBD)), HLA-C06:02 for psoriasis, and HLA-A29:02 for birdshot chorioretinopathy.”
- "In Turkey, the prevalence of the HLA-B*51 allele in BD patients is high, ranging from 50% to 70%, whereas in the general population, around 25% of individuals are HLA-B*51positive 115 [25, 26]." - You can include the prevalence in Turkish population the gene mutation in MEFV gene. Recently a couple of articles were published on that topic. You can also include information about the association of MEFV mutation and neuro-BD.
We thank the reviewer for this valuable comment. We added a subsection of the role of MEFV gene mutations in Behçet’s disease in the article. We added related references including two of the three references suggested by the reviewer.
- Ishikawa H, Shindo A, Ii Y, Kishida D, Niwa A, Nishiguchi Y, Matsuura K, Kato N, Mizutani A, Tachibana K, Hirata Y, Matsuyama H, Ogawa-Ito A, Taniguchi A, Tomimoto H. MEFV gene mutations in neuro-Behçet's disease and neuro-Sweet disease. Ann Clin Transl Neurol. 2019 Dec;6(12):2595-2600. doi: 10.1002/acn3.50937. Epub 2019 Nov 4. PMID: 31682063; PMCID: PMC6917328.
- Kirino Y, Zhou Q, Ishigatsubo Y, Mizuki N, Tugal-Tutkun I, Seyahi E, Özyazgan Y, Ugurlu S, Erer B, Abaci N, Ustek D, Meguro A, Ueda A, Takeno M, Inoko H, Ombrello MJ, Satorius CL, Maskeri B, Mullikin JC, Sun HW, Gutierrez-Cruz G, Kim Y, Wilson AF, Kastner DL, Gül A, Remmers EF. Targeted resequencing implicates the familial Mediterranean fever gene MEFV and the toll-like receptor 4 gene TLR4 in Behçet disease. Proc Natl Acad Sci U S A. 2013 May 14;110(20):8134-9. doi: 10.1073/pnas.1306352110. Epub 2013 Apr 30. PMID: 23633568; PMCID: PMC3657824.
- Shorten the conclusion and remove figure 2 from it and put it in the body of manuscript.
We thank the reviewer, and we completely agree, we removed Figure 2 from the conclusion section and moved it to “Exploring the involvement of diverse immune cells in Behçet's Disease” section. We have also shortened to conclusion to make it more concise.
- Recheck the references.
We double checked the references.
Hocam MEFV geni ve Neuro-BD hakkında sadece bu 3 makaleyi bulabildim
Round 2
Reviewer 2 Report
Comments and Suggestions for Authors
The manuscript is significantly improved. Major revision was done by the authors according to all of my recommendations. I can recommend this manuscript for publication.
