Mast Cells in Tuberculosis: Immune Regulation, Allergic Environments, and Pathological Mechanisms

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The subject of this article, the role of mast cells (MCs) in TB immunopathogenesis, could be very interesting, and it is indeed timely to have an updated perspective on this topic. I find the potential of MC-targeted host-directed therapies (HDTs) as novel adjunctive strategies in TB management, as well as the broader importance of personalized medicine approaches, to be highly relevant areas of research. I also appreciate that the authors have used clear and easy to understand language throughout the manuscript, making the topic accessible to a broader audience.

The main focus of the present review is to explore how factors associated with Th2 inflammations (environmental, genetics and immunological factors) affect MCs function in pathogenesis of TB, for which Th1-mediated immune response are essential to control the infection.   The topic is relevant to the field, because it addresses the antagonizing function of MCs to Th1-mediated immune responses to TB and the host directed therapies to target mast cells. Figures and tables are OK.   The authors need to use appropriate references to support their claimed conclusions. Unless it is absolutely essential, authors should cite ORIGINAL research articles and avoid citing other review articles.   Since in some instances inappropriate references was used (I provide some examples in my comments to the authors), conclusions are not entirely consistent with the evidence shown.   some examples:

1. Reference No. 14 does not support the stated conclusion in line 70-72. 

In fact, in this article authors have not assessed if allergic individuals are more prone to TB infection or have worse TB outcomes. This study explored whether tuberculosis (TB) infection in childhood reduces the later risk of asthma or allergy.

2. Reference No. 15 does not support the stated conclusion in line 73-75. 

The article is about how early-life infections may protect against allergies.
It does not discuss genetic cytokine polymorphisms, IL-4/IL-13, TB susceptibility, or Th1/Th2 genetic balance.

3. References No. 16 and 17 do not provide primary evidence for the stated conclusion in line 85-88.

I recommend that the authors cite original research articles that directly investigate the issue in question, rather than referencing review articles.

4.  References No. 9 and 10 do not provide primary evidence for the stated conclusion in line 76-84.

I highly recommend that the authors cite original research articles that directly investigate the issue in question, rather than referencing review articles.

- I have now checked some of the references (mainly 9, 10, 13-17), and they do not provide evidence for the claimed conclusion. Moreover, some of these references are Review articles rather than Original research Articles.
 Given that checking each an every inference is very time consuming, I cannot confirm the suitability of other cites articles for the claimed conclusion.

Author Response

Response to Reviewer #1 

We thank Reviewer #1 for their thoughtful and constructive comments. We appreciate the recognition of our manuscript’s clarity, relevance, and timeliness, as well as the encouragement regarding mast cell–targeted host-directed therapies in tuberculosis (TB). Below, we provide a point-by-point response to the reviewer’s concerns, along with a summary of the changes made to the manuscript. 

 

Comments 1 

Reference No. 14 does not support the stated conclusion in line 70–72. This study explored whether tuberculosis infection in childhood reduces the later risk of asthma or allergy, not whether allergic individuals are more prone to TB. 

Response 1 

We thank the reviewer for pointing out this important discrepancy. We agree that the previously cited Reference No. 14 did not appropriately support the conclusion regarding the increased susceptibility of allergic individuals to tuberculosis (TB). In response, we have revised the text accordingly and replaced the reference with more appropriate studies that directly address the relationship between Th2-skewed immune responses—common in allergic diseases—and impaired immunity against Mycobacterium tuberculosis (Mtb). 

The revised text now reads: 

“In allergic individuals, the situation becomes more complex. Allergic diseases, such as asthma, allergic rhinitis, and atopic dermatitis, are characterized by a T-helper Type 2 (Th2)-biased immune environment that favors the production of interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-13 (IL-13), and immunoglobulin E (IgE). This Th2 dominance can suppress Th1 responses, which are essential for controlling intracellular pathogens like Mtb [9, 10]. Several studies have shown that patients with chronic allergic conditions or Th2-skewed environments exhibit impaired macrophage activation and altered granuloma formation, which may predispose them to TB infection or exacerbate disease progression [11].” 

 

The new references (now listed as [9]–[11]) are: 

• Ashenafi et al. (2014) [9], which demonstrates that progression of clinical TB is associated with a Th2-type immune response. 

• Teles et al. (2013) [10], which discusses how Type I interferons can suppress protective Th1 responses against Mtb. 

• Parasa et al. (2014) [11], which models granuloma formation in a human lung tissue system, showing how immune dysregulation may affect TB pathology. 

We believe this revision more accurately supports the statement and provides mechanistic insight into the impact of allergic immune profiles on TB susceptibility. 

 

Comments 2 

Reference No. 15 does not support the stated conclusion in line 73–75. The article discusses the hygiene hypothesis and early infections in allergy, not genetic polymorphisms related to Th1/Th2 balance or TB. 

 

Response 2 

We appreciate the reviewer’s careful examination of our references and agree that the previously cited Reference No. 15 was not appropriate to support the statement regarding genetic polymorphisms in cytokine genes and susceptibility to tuberculosis (TB). In response to this comment, we have replaced the reference with a more relevant and up-to-date study that directly addresses this issue. 

The revised sentence now reads: 

“Furthermore, genetic polymorphisms in cytokine genes, including IL-4 and IL-13, which drive Th2 responses and mast cell activation, have been associated with increased susceptibility to TB and reduced capacity to mount an effective Th1-mediated immune response [12].” 

The new references (now listed as [12]) is: 

• Zhen et al. (2023) [12], is a meta-analysis that investigates the association between IL-4 gene polymorphisms and the risk of TB, offering strong and specific support for our statement. This study provides direct evidence that variations in genes driving Th2 immune responses are linked to increased TB susceptibility, aligning well with the context of Th1/Th2 balance discussed in this section. 
   

We thank the reviewer again for helping us improve the scientific accuracy of the manuscript. 

 

Comments 3 

References No. 16 and 17 do not provide primary evidence for the stated conclusion in line 85–88. 

Response 3 

We thank the reviewer for highlighting the issue regarding the appropriateness of References No. 16 and 17. We agree that the previously cited references did not provide direct primary evidence to support the specific immunological mechanisms described in this sentence. Accordingly, we have revised the text and replaced the references with more suitable and mechanistic studies that demonstrate the effects of PM2.5 and diesel exhaust particles on mast cell (MC) activation and macrophage dysfunction, respectively. 

 

The revised passage now reads: 

“Environmental exposures common in allergic individuals, such as air pollution, cigarette smoke, and airborne allergens, may further exacerbate this immunological imbalance. Pollutants like Particulate Matter ≤ 2.5 µm (PM2.5) have been shown to activate mast cells via ROS/JNK signaling, promoting IgE-mediated degranulation and cytokine release [13]. Additionally, diesel exhaust particles impair macrophage function—reducing phagocytosis and cytokine production (e.g., TNFα, IL8, IL1β), and compromising antimycobacterial defense in vitro and in vivo [14].” 

 

The new references (now listed as [13]–[14]) are: 

• Wang et al. (2021) [13], which demonstrates that PM2.5 induces ROS-dependent activation of the JNK pathway, leading to mast cell degranulation and enhanced release of allergic cytokines. 

• Rodríguez-Fernández et al. (2024) [14], which provides in vitro and in vivo evidence that diesel exhaust particles impair macrophage immune function, reducing their ability to control Mycobacterium bovis BCG infection. 

We believe these updated references now accurately support the immunological mechanisms being discussed and address the reviewer’s concern regarding the specificity and primary nature of the supporting literature. 

 

Comments 4 

References No. 9 and 10 do not provide primary evidence for the stated conclusion in line 76–84. Reviewer recommends citing original research articles rather than review articles.  

 

Response 4 

We thank the reviewer for this valuable suggestion. We agree that the previously cited references were review articles and did not provide direct experimental evidence for the dual role of mast cells (MCs) in TB pathogenesis. In response to this comment, we have replaced these references with appropriate original research studies that directly support the described phenomena in murine models and human tissue analyses. 

The revised paragraph now reads: 

“The concept of MCs acting as immunological ‘double agents’ in TB pathogenesis—capable of both promoting host defense and contributing to immune dysregulation—is supported by evidence from both murine models and human post-mortem lung studies. For example, transfer of Toll-Like Receptor 2 (TLR2)-expressing MCs into TLR2-deficient mice has been shown to rescue granuloma formation, normalize myeloid cell recruitment, and restore Th1 cytokine production, ultimately improving bacterial control [7]. Conversely, MCs residing at the periphery of necrotic granulomas and within fibrotic tissue express pro-fibrotic mediators such as transforming growth factor-beta (TGF-β) and chymase, potentially contributing to lung tissue remodeling and long-term sequelae of TB [8].” 

The new references (now listed as [7]–[8]) are: 

• Tait Wojno et al. (2019) [7], which provides experimental evidence of TLR2-dependent MC function in modulating Th1 responses and granuloma architecture in TB models. 

• Wang et al. (2025) [8], which examines the presence of MC-derived mediators like TGF-β and chymase in fibrotic TB lesions and discusses their role in tissue remodeling and immune dysregulation. 

We believe these original research articles better support the mechanistic insights presented and reflect the reviewer’s recommendation for greater scientific rigor. Thank you again for your thoughtful feedback. 

 

In addition to the changes outlined above, we have carefully re-evaluated all citations throughout the manuscript. As a result, we have revised, replaced, or supplemented other references as necessary to ensure that each citation accurately supports the corresponding statements and reflects the most relevant and up-to-date primary literature. 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This is a very well-written and comprehensive review covering an interesting topic of the role of mast cells in tuberculosis with special Focus on the context of allergic environment. The goals of the review are clearly stated and covered in the text. Immunologic mechanisms of Th1/17 and Th2-skewed response are sufficiently described and presented in the context of the main topic of the review. The manuscript is accompanied by tables and figures that add a lot to its readability and make it more appealing to the readership.

Please find below my minor suggestions and remarks to be considered:

1. SInce the Th1/Th17-dependent mechanisms are mentioned, did the Authors consider to discuss the role of alarmins in the mutually dependent allergy/TB response mechanisms? These are the mediators that have gained wide recognition in non-type-2 inflammation in asthma and became therapeutical targets for biologics. The literaturę regarding alarmins in TB is not abundant, but the Authors may consider adding some speculative sentences and their views.
2. In table 1 – last line: Cytokine modulators, in the „Allergic disease” column, the Authors may consider adding IL-5-targeted and TSLP-targeted treatments to give broader picture of therapeutic modalities in allergic disease.
3. On Figure 2: please correct: „polymorphisms” instead of „Polymophismohisms”
4. Apart from TLR2 – have other innate immunity receptors been studied on mast cells and their role in the MTB response considered?

These minor suggestions do not decrease the overall high quality of the manuscript, consider them at your discretion.

Author Response

Response to Reviewer #2 

We sincerely thank Reviewer #2 for the kind and encouraging evaluation of our manuscript. We are especially grateful for the recognition of the manuscript’s scientific value, clarity, and comprehensiveness, and for the constructive minor comments provided to further improve the work. 

 

Comments 1 

Since the Th1/Th17-dependent mechanisms are mentioned, did the Authors consider to discuss the role of alarmins in the mutually dependent allergy/TB response mechanisms? These are the mediators that have gained wide recognition in non-type-2 inflammation in asthma and became therapeutical targets for biologics. The literaturę regarding alarmins in TB is not abundant, but the Authors may consider adding some speculative sentences and their views. 

 

Response 1 

We thank the reviewer for this insightful and forward-looking comment. We agree that alarmins—particularly IL-33 and TSLP—represent a mechanistically relevant yet underexplored component in the immunological intersection between allergy and tuberculosis (TB). In response to this suggestion, we have incorporated a speculative but evidence-informed discussion at the end of the Conclusion section to highlight potential roles of alarmins in mast cell (MC) activation and TB immunopathogenesis. 

The added text reads: 

“Recent findings also suggest that alarmins such as IL-33 and TSLP—epithelial-derived cytokines involved in type 2 and innate inflammation—may influence MC activation in the context of TB. Although direct evidence is limited, IL-33 has been shown to prime human mast cells for enhanced responsiveness to mycobacterial stimuli, and co-administration of IL-33 with TB DNA vaccines augments Th1-type responses in murine models [43, 44]. These observations highlight the need for further research into how alarmin–MC interactions may shape the immune landscape of TB, particularly in allergic individuals.” 

To support this addition, we have cited: 

• Salimi et al. (2013) [43], which details IL-33-driven MC and ILC2 activation in type 2 inflammation. 

• Villarreal et al. (2015) [44], which demonstrates that IL-33 enhances TB-specific immune responses in animal models. 

We appreciate the reviewer’s suggestion to include this emerging area of investigation, which we believe adds depth to the discussion and points to important avenues for future research. 

 

Comments 2 

In table 1 – last line: Cytokine modulators, in the „Allergic disease” column, the Authors may consider adding IL-5-targeted and TSLP-targeted treatments to give broader picture of therapeutic modalities in allergic disease. 

 

Response 2 

We thank the reviewer for this helpful suggestion. In response, we have revised the last row of Table 1 under the "Allergic Diseases" column to include IL-5–targeted and TSLP–targeted treatments, thereby presenting a more comprehensive overview of cytokine modulators used in allergic conditions. 

The updated entry now reads: 

“Target IL-4/IL-13, IL-5, and TSLP (e.g., dupilumab, polizumab, tezepelumab)*” 

In addition, we have added the following footnote for clarification: 

* Dupilumab (anti–IL-4Rα), mepolizumab and benralizumab (anti–IL-5), and tezepelumab (anti–TSLP) are biologics used in the treatment of severe type 2 asthma and other allergic conditions. 

 

These modifications are now reflected in the revised version of Table 1, as shown in the updated manuscript. We appreciate the reviewer’s input, which has improved the clinical completeness and translational relevance of this summary table. 

 

Comments 3 

On Figure 2: please correct: „polymorphisms” instead of „Polymophismohisms” 

 

Response 3 

We have corrected the typographical error in Figure 2 by replacing “Polymophismohisms” with the correct term “Polymorphisms.” Additionally, to improve visual clarity and enhance accessibility, we have adjusted the font across all figure elements and slightly repositioned some icons for improved information flow. We believe these changes improve the overall professionalism and visual presentation of the manuscript. 

The updated figure 2 : 

 

Comments 4 

Apart from TLR2 – have other innate immunity receptors been studied on mast cells and their role in the MTB response considered? 

 

Response 4 

We sincerely thank the reviewer for raising this important and thought-provoking point. In response, we reviewed the literature on other pattern recognition receptors (PRRs), such as TLR4, NOD2, and Dectin-1, which are known to be expressed on mast cells and to contribute to innate immune signaling in various infectious and inflammatory contexts. 

Although TLR4 and NOD2 have been shown to modulate mast cell activation and cytokine production in response to bacterial components, we found a lack of direct experimental evidence linking these receptors to mast cell-mediated responses in Mycobacterium tuberculosis (Mtb) infection specifically. Given the limited scope of current studies directly addressing this interaction in the TB context, we have decided not to include detailed discussion on this point in the present version of the manuscript to maintain scientific accuracy and clarity. 

Nonetheless, we fully agree that this represents a valuable and understudied area of research, and future investigations into PRRs beyond TLR2 may provide important insights into the diverse roles of mast cells in TB pathogenesis. 

Once again, we thank the reviewer for this excellent suggestion, which has helped us further reflect on gaps in the current literature and avenues for future exploration. 

 

We sincerely thank Reviewer #2 once again for the thoughtful and constructive comments. We have carefully reviewed and addressed each point raised, incorporating the suggested revisions into the manuscript. We hope that the changes made align with your intentions and expectations, and that they have contributed to strengthening the clarity, scientific rigor, and overall impact of our work. 

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

This is a well written narrative review focusing on mast cells and immune activity in Tb infection.

Infection and immunity are a very interesting hot topic, seeing that can lead to host direct therapies and more personalised medicine.

I have a very limited remarks: 

1/ There are on few occasions repetitions in text, here are 3 examples (these are not the only ones):

• Lines 228-232 with 238-240
• Lines 464 -468 with 284-287
• Lines 344- 346 with 492 segment

But I don’t find them particularly bothering. It can be less narrative text in general, but that is my subjective opinion.

 

2/ Overall, I find limited number of references used for this relative long narrative review and a very interesting, but not very new topic. Less investigated in general, but not new. I think there can be more evidence used.

 

3/ Future research suggestions I find it practical and well incorporated. 

 

Author Response

Response to Reviewer #3 

We sincerely thank Reviewer #3 for their kind and encouraging evaluation of our manuscript, and for recognizing its relevance, clarity, and scientific interest in the context of mast cell biology and tuberculosis immunity. We also greatly appreciate the reviewer’s careful reading and constructive comments. Thanks to these thoughtful suggestions, we were able to revise the manuscript in a more refined and organized manner. Below, we address each point raised in detail. 

Thank you for pointing out the instances of partial repetition within the manuscript. Although the duplicated segments did not disrupt the readability, we agree that reducing redundancy can improve the overall flow. Therefore, we carefully revised the text in the following areas: 

 

Comments 1 

Occasional textual repetition (e.g., Lines 228–232 with 238–240; Lines 464–468 with 284–287; Lines 344–346 with 492 segment)  

Response 1 

We appreciate the reviewer’s attention to detail in identifying these instances of textual repetition. We have carefully revised each of the indicated segments to reduce redundancy while preserving the scientific content and narrative coherence. 

• Lines 228–240 (Future Therapeutic Strategies section): 
  Two nearly identical sentences describing gut–lung axis interventions (e.g., probiotic supplementation, high-fiber diet) appeared in close succession. We have removed the redundant sentence and retained a single, consolidated version in the earlier portion of the paragraph. The revised text maintains the original message while improving clarity. No other changes were made to this section in order to preserve the surrounding structure and references. 

• The updated text : 

 

Furthermore, interventions involving the gut–lung axis, such as probiotic supplementation or high-fiber dietary modifications, may support systemic immune modulation and reduce allergic inflammation, potentially enhancing pulmonary defenses against Mtb [25–27]. Future clinical trials are warranted to investigate the synergistic benefits of these adjunctive therapies in TB patients with comorbid allergic conditions. 

Finally, personalized medicine approaches incorporating cytokine profiling, MC activity assays, and genotyping of immune-related polymorphisms (e.g., IL-4 −589C/T, IL-13 R130Q, IFN-γ +874T/A) could help stratify patients by risk and optimize treatment selection [12, 33]. A precision immunology framework tailored to the allergic–TB spectrum would not only improve individual outcomes but also inform more cost-effective public health interventions. 

 

• Lines 284–287 with 464–468 (TLR2-related experimental evidence): 
  These passages discussed similar findings from adoptive transfer experiments involving TLR2+/+ mast cells in TLR2−/− mice. To avoid verbatim repetition, we rephrased and differentiated the two sections according to their respective contexts: 

• Section 3.2 now emphasizes mast cell–specific mechanisms. 

3.2. TLR2-Mediated Mast Cell Activation: A Crucial Defense Axis 

Recent murine studies have demonstrated that MCs can directly sense Mtb components via pattern recognition receptors, particularly TLR2. TLR2-deficient (TLR2−/−) mice infected with Mtb exhibit defective immune responses characterized by impaired recruitment of myeloid cells, poorly organized granulomas, and reduced levels of key cytokines (e.g., IL-1β, TNF-α, IL-6). Notably, restoration of mast cell function via adoptive transfer of TLR2-competent bone marrow-derived mast cells (BMMCs) reestablishes protective immunity, including improved granuloma structure and CD8+ T cell localization in the lungs [6]. These findings suggest that TLR2-dependent MC activation is essential for orchestrating both innate and adaptive responses during TB infection. 

Furthermore, Mtb engages additional MC surface molecules, such as CD48, a GPI-anchored receptor involved in microbial recognition. Studies have shown that CD48 ligation by Mtb leads to intracellular calcium flux and MC degranulation, accompanied by the release of TNF-α, IL-6, and leukotriene B4, which are critical for neutrophil recruitment and early granuloma formation [2, 16]. However, excessive release of these mediators may also amplify inflammation and tissue injury, especially in sensitized individuals with allergic backgrounds [4, 9]. 

 

• Section 6.1 revisits the findings from a broader innate immune signaling perspective. 

6.1. Innate Immune Recognition and MC Activation 

MCs express multiple pattern recognition receptors (PRRs), including TLR2, which recognize Mtb-derived ligands such as 19-kDa lipoproteins, lipomannan, and phosphatidylinositol mannosides. Activation via TLR2 promotes the release of key pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6, which are essential for recruiting neutrophils and monocytes to infection sites. Studies using TLR2-deficient mice have underscored the receptor’s critical role in host defense against TB, revealing heightened bacterial burden and disrupted granulomatous responses. Complementation with TLR2-expressing mast cells partially reverses these defects, enhancing cytokine output and lymphocyte trafficking to infected lung tissue [6]. These findings highlight the essential role of TLR2-dependent MC activation in establishing a protective immune milieu capable of controlling Mtb infection [2, 6, 16]. 

 
This approach maintains scientific precision while enhancing structural clarity. 

• Lines 344–346 with 492 (Dual roles of mast cell mediators): 
  We identified partial redundancy in the discussion of context-dependent effects of mast cell mediators such as LTB4, tryptase, and chymase. Accordingly, we revised both sections as follows: 

• Section 3.6 now highlights the functional roles of individual mediators in TB pathophysiology. 

3.6. Dual Roles of Mast Cell-Derived Mediators in TB Immunopathology 

MC-derived mediators exhibit dual roles in TB, often exerting protective or pathological effects depending on the context. Histamine, released from activated MCs, suppresses IFN-γ synthesis by T cells and NK cells, thereby hindering macrophage activation and intracellular killing of Mtb [28, 38]. Elevated histamine levels also promote vasodilation and vascular leakage, potentially facilitating bacterial dissemination [28].  

Leukotriene B4 (LTB4), another MC product, contributes to neutrophil recruitment required for granuloma formation, but excessive levels may drive tissue damage and lung pathology [6]. Similarly, tryptase and chymase promote extracellular matrix (ECM) turnover during inflammation, yet their sustained release has been linked to pulmonary fibrosis and structural remodeling in TB [1, 4]. 

 

• Section 6.4 focuses on the therapeutic implications and regulatory strategies based on these dual roles. 

6.4. Context-Dependent Mediator Release 

The dual role of MC activation is especially relevant in the therapeutic context. While MC-derived TNF-α and IL-6 promote granuloma stability and immune cell recruitment, overproduction of proteases such as tryptase and chymase, or cytokines like TGF-β, can lead to fibrosis and structural lung damage [1, 3, 4, 5]. Likewise, excessive leukotrienes, including LTB4, may aggravate inflammation and compromise granuloma integrity [4, 40]. These observations highlight the importance of context-aware modulation of MC activity. Rather than indiscriminate suppression, tailored interventions that balance their beneficial and harmful outputs could preserve host defense while minimizing immunopathology in TB. 

 
This clarification strengthens the distinction between mechanistic discussion and translational interpretation. 

We hope these revisions address the reviewer’s concerns and contribute to a clearer and more concise manuscript. 

 

 

Comments 2 

Overall, I find limited number of references used for this relative long narrative review and a very interesting, but not very new topic. Less investigated in general, but not new. I think there can be more evidence used. 

 

Response 2 

We sincerely appreciate the reviewer’s observation regarding the limited number of references relative to the length and breadth of the review. In response, we conducted a thorough and comprehensive re-evaluation of the literature cited across the entire manuscript. As a result of this process, we: 

• Added several new primary research articles to strengthen mechanistic explanations and support underdeveloped sections 

• Replaced several secondary sources (review articles) with more appropriate original experimental or clinical studies 

• Updated citations that were previously too indirect or outdated, ensuring better alignment with the statements they support 

• Adjusted sentence structures or expressions where needed to accommodate the newly added references with clarity and precision 

As a result, the number of references has increased from 31 to 43, reflecting a more robust and evidence-based foundation for the arguments presented throughout the review. Particular attention was paid to incorporating less-cited but high-quality experimental studies to support key claims, especially those related to mast cell–TB interactions and immunomodulatory pathways. 

We believe these revisions substantially improve the scientific depth, accuracy, and credibility of the manuscript, and we thank the reviewer for prompting this valuable enhancement. 

 

Comments 3 

Future research suggestions I find it practical and well incorporated.  

 

Response 3 

We are grateful for the reviewer’s positive assessment of our proposed future research directions. We aimed to highlight clinically relevant, yet underexplored, avenues of investigation—including cytokine modulation, microbiota-based interventions, and precision immunology—to support further translational work in the allergic–TB spectrum. Your encouragement confirms the value of this approach. 

 

Once again, we sincerely thank Reviewer #3 for their thoughtful and constructive feedback. Each comment was carefully considered, and we have revised the manuscript accordingly to enhance clarity, scientific rigor, and completeness. We hope that our revisions meet your expectations and that the updated manuscript now better reflects the complexity and translational relevance of mast cell–mediated immunity in tuberculosis. Your input was instrumental in improving the quality of this review. 

 

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The newly added references that replaced the older ones are more appropriate addressing the issue in question.