Intersections Between Allergic Diseases and Multiple Sclerosis: Mechanisms, Clinical Implications, and Hypersensitivity Reactions to Therapy
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThis is a very thorough and comprehensive review of possible mutual dependencies of MS and allergic disease.
The introduction provides a satidfactory overview of the topic and acquaints even the reader less familiar with the field with the baseline of the review topic. The Authors also succeeded in presenting key differences in immunopathology of the Th1 and Th2-dependent immune response and their possible role in elicitng and promoting the development of MS and allergy. Additionally, the reasons for coexistence of the two diseases are convincingly presented.
From the allergological point of view, a big advantage of the review is the presentation and discussion of the issue of hypersensitivity reactions to treatment agents used i MS, including biologics.
The references are proeprly selected and the conclusions of the review are justified and accordingly outline the knowledge gaps and future research directions.
Please find below some remarks to this review manuscript:
Lines 58-60: I’d suggest giving exapmples of geographical regions where MS and allergy coexist and waht are the frequencies or assessment of prevalence of either disease.
Line 142 – similarly, more detailed description and examples of genetic predispositions and environmental exposures contributing to coexistence of MS and allergy would make a valuable addition
The Authors may also consider adding a figure to graphically present the overlapping immunopathogenesis of MS and allergy. The thorough description os provided but the graphic explanation would be valuable and render the review more readable.
Author Response
Response to Reviewer 1 Comments
- Summary
We sincerely thank Reviewer 1 for the detailed and insightful evaluation of our manuscript. We truly appreciate your recognition of the strengths of our review, including the clarity of the introduction, the comparative analysis of Th1- and Th2-mediated immunopathology, and the emphasis on hypersensitivity reactions to MS therapies. Your suggestions have helped us refine and enrich the manuscript further. All suggested modifications have been implemented in the revised version and are highlighted in red.
- Point-by-point response to Comments and Suggestions for Authors
Comment 1:
Lines 58–60: I’d suggest giving examples of geographical regions where MS and allergy coexist and what are the frequencies or assessment of prevalence of either disease.
Response 1:
Thank you for this helpful suggestion. We have expanded the relevant paragraph in the Introduction (now page 2, paragraph 3) to include specific data on the prevalence of MS and allergic diseases in various industrialized regions. This addition provides a clearer epidemiological context for the coexistence of both conditions.
Updated manuscript excerpt:
“For instance, the global prevalence of multiple sclerosis is estimated at approximately 35.9 per 100,000 inhabitants, but this figure exceeds 150–200 per 100,000 in North America and Western Europe [10], while allergic diseases—particularly asthma, allergic rhinitis, and atopic dermatitis—affect a substantial proportion of the population, with asthma prevalence exceeding 15% and atopic dermatitis affecting up to 30% of children [9].”
Comment 2:
Line 142 – similarly, more detailed description and examples of genetic predispositions and environmental exposures contributing to coexistence of MS and allergy would make a valuable addition.
Response 2:
We appreciate this important recommendation. Accordingly, we have expanded the section on shared immunogenetic mechanisms (Section 2, page 4). We now describe specific genes such as IL2RA, IL7RA, BACH2, CLEC16A, and IKZF3, which have been identified in both allergic diseases and MS via genome-wide association studies. We have also included examples of environmental exposures—namely tobacco smoke and vitamin D deficiency—that have been associated with increased risk for both disease types.
Updated manuscript excerpt:
“The observed co-occurrence of MS and allergic diseases in certain geographic regions further challenges the classical Th1/Th2 paradigm, which posited mutual exclusivity between autoimmune and allergic responses. This overlap may reflect shared genetic predispositions and common environmental exposures. Recent large-scale sequencing studies, particularly genome-wide association studies (GWAS), have begun to identify loci potentially shared between the two conditions [36]. Nonetheless, the current evidence remains limited and fragmented, with only a few genes showing replicated associations in both disease contexts. Among the strongest candidates are IL2RA and IL7RA, which encode interleukin receptors involved in T cell development and homeostasis [37-39]; BACH2, a transcription factor critical for the balance between regulatory and effector T cells [36,40]; CLEC16A, implicated in autophagy regulation and antigen-presenting cell function [36-41].; and IKZF3, a lymphoid transcriptional regulator [36,42]. These findings suggest the existence of partially overlapping immunogenetic mechanisms, though they do not yet support definitive conclusions regarding a shared genetic basis. Additionally, certain environmental factors—such as tobacco exposure and low vitamin D levels—have been associated with increased risk of both MS and allergic diseases and may promote immune deviation toward either autoimmune or allergic phenotypes [3,43–44].”
Comment 3:
The Authors may also consider adding a figure to graphically present the overlapping immunopathogenesis of MS and allergy. The thorough description is provided but the graphic explanation would be valuable and render the review more readable.
Response 3:
Thank you for this excellent suggestion. In response, we have added a new schematic Figure 1 titled “Shared and Divergent Immunological Pathways in MS and Allergic Diseases”. This figure visually summarizes the principal immune cell types, cytokines, and mediators implicated in both conditions, as well as the zones of overlap and divergence. We believe this graphical representation improves the accessibility and educational value of the review for readers.
Figure location: end of Section 2, page 4.
Author Response File: 
Author Response.docx
Reviewer 2 Report
Comments and Suggestions for AuthorsI had the pleasure of reading the manuscript entitled "Intersections between Allergic Diseases and Multiple Sclerosis: Mechanisms, Clinical Implications, and Hypersensitivity Reactions to Therapy". The article is interesting, well-written and is significant to the field. However, I would highly suggest the author do not miss the occupational risk factors of Multiple Sclerosis, not only environmental ones. This is a recent topic and I recommend the authors include doi: 10.3389/fpubh.2023.1285103. In this article, many variables are well-known potentially allergenic substances such as "shoes and leather workers", "solvents", "pesticides", "animals", "hairdresser", "cleaner", "chemical industry workers". This is crucial and must be included.
Author Response
Response to Reviewer 2 Comments
- Summary
We thank Reviewer 2 for their careful reading of our manuscript and for highlighting the importance of occupational risk factors in the context of multiple sclerosis. We appreciate the constructive suggestion and have addressed it in detail below. The corresponding revisions have been incorporated into the manuscript and are highlighted in red in the re-submitted version.
- Point-by-point response to Comments and Suggestions for Authors
Comment 1:
“However, I would highly suggest the author do not miss the occupational risk factors of Multiple Sclerosis, not only environmental ones. This is a recent topic and I recommend the authors include doi: 10.3389/fpubh.2023.1285103. In this article, many variables are well-known potentially allergenic substances such as ‘shoes and leather workers’, ‘solvents’, ‘pesticides’, ‘animals’, ‘hairdresser’, ‘cleaner’, ‘chemical industry workers’. This is crucial and must be included.”
Response 1:
We appreciate the reviewer’s valuable suggestion. We fully agree that occupational exposures constitute a critical and often underrecognized component of MS environmental risk. Accordingly, we have added a new paragraph to the Epidemiological evidence on allergies and MS risk section (Section 3.1, page 6), discussing recent findings from the recommended meta-analysis (Giussani et al., 2023; DOI: 10.3389/fpubh.2023.1285103). This includes the identification of increased MS risk among workers exposed to pesticides, solvents, and allergenic or irritant substances in occupations such as hairdressing and cleaning. We also emphasize that many of these agents are known sensitizers, reinforcing the potential overlap between allergic and autoimmune triggers. Additionally, this study has been added to Table 1 summarizing epidemiological findings.
“Beyond classic allergic conditions, recent epidemiological research has underscored the potential role of occupational exposures to sensitizing or irritant agents in MS susceptibility. A recent systematic review and meta-analysis, including over 19,000 MS cases and 4 million controls, identified a significantly increased risk of MS among workers exposed to substances such as pesticides or toxic fumes from oil wells, as well as in occupations such as hairdressers, agricultural workers and offshore workers [53]. While these exposures do not constitute allergic diseases per se, many involve contact with agents known to induce allergic sensitization or mucosal irritation. Chronic exposure to such substances may contribute to immune dysregulation by promoting low-grade systemic inflammation and epithelial barrier disruption. These findings highlight the need to consider allergen-rich occupational environments as a potentially underrecognized component of MS environmental risk.”
We thank the reviewer again for this insightful recommendation, which has helped strengthen the manuscript.
Author Response File: Author Response.docx
