Killer Immunoglobulin-Like Receptor 2DL4 (CD158d) Regulates Human Mast Cells both Positively and Negatively: Possible Roles in Pregnancy and Cancer Metastasis

Round 1

Reviewer 1 Report

This is a very interesting, actual and complete review about the functionality of mast cells and their important role in healthy and disease people, in different circumstances by secreting many mediators expressed in the secretion of many cytokines. Mast cells are distributed in many tissues and organs in the body modulating many functions related to allergic processes, inflammation. So, activated mast cells located in the gastrointestinal tract increase the fluid secretion, the smooth muscle contraction, increasing the peristalsis and producing diarrhea in different pathologic circumstances. In the airway induce airway muscle contractions, increase mucous production and edema and repetitive cough accesses. Finally, in the activated skin, they induce urticaria and angioedema repeated episodes. By consequence, mast cells are a major effector in many allergic diseases, including several types of food allergy, asthma, allergic rhinitis, atopic dermatitis and anaphylaxis, and all these diseases are very well explained by these authors about the pathogenetic mechanisms up-regulated by the mast cells. Also, they play a relevant contribution in relevant autoimmune and cardiovascular diseases. These functions are mainly mediated by the high-affinity receptor for IgE and KIT receptor signaling pathways.

The regulation of KIT mediated signal pathways, would be a promising route to control mast-cell mediated allergic reactions. Therefore the HIR2DL4 should be an useful antibody therapy for alergia diseases. This is w promisión tool not yet confirmed in humans actually.

Reduced numbers of decidual Tregs were observed in some women with spontaneous repeated abortions. Thus the human decidual mast cells participante in the stablishment of pregnancy also via KIR2DL4

HLA-G is expressed in several tumors and his presence is related to a poor prognosis. A role for mast cells in tumor progresión is actually under discussion.

The KIR2DL4 is a potential target because may increase the NK effect against virus infections and may enhance the infertilty treatment in many women

Congratulaciones to the authors for this very interesting contribution

 

Author Response

We appreciate your comments.

Reviewer 2 Report

Kataoka, et al. provide a valuable review of emerging literature on KIR2DL4 expression and function on mast cells. It is of note that most of the key studies originate from their lab.

 

The authors provide a brief standard summary of the hallmark receptors on MC (FceRI and CD117) as well some inhibitory signals, and then contextualize this with their work on KIR2DL4 in mastocytosis, embryo implantation, and breast cancer.

 

In general, this review will be a useful contribution to the field since there is compelling evidence that KIR2DL4 fulfills an important and context-specific role for MC – especially with respect to pregnancy.

 

I have some minor comments that should be addressed in order of importance:

It would help consistency to synthesize any literature on HLA-G in IgE-mediated disorders. Also for consistency, discussion of the role of LIF in tumor biology, as this seems to be a critical downstream factor in pregnancy. I think the authors could make a more clear synthesis statement at the end of section 6. Something along the lines of: so while MC deficiency leads to pregnancy and parturition disorder, and KIR2DL4 downregulation is associated with infertility, it is the selective KIR2DL4-induced production of LIF and MMP-9 from MC that may illustrate the critical context-specific role of MC in pregnancy. It seems that KIR2DL4 can affect MC independent of FceRI and CD117 activities, in addition to important influence over those receptors. Therefore, it would be interesting to see this receptor contextualized with other important MC receptors, namely the IL-33/ST2 axis and MRGPRX2 if such literature exists. Can the authors comment/speculate on the importance of KIR2DL4 causing both “weak cytotoxicity and cytokine secretion”? What is the impact of this combination (death + cytokines) physiologically? Additionally, what are the specific signals transduced (Line 162) This might be at odds with the commentary later, especially starting with Line 201 about KIR2DL4 inhibitory effects on MC. On lines 66 and 67 the authors attribute MC dysfunction to IgE and SCF signaling. Certainly for IgE-mediate allergic disorders this is the case; however this may not necessarily be the case for many IBDs. FceRI and CD117 just seems to be the most heavily studied. Line 317: nasophageal should be nasopharyngeal The paper requires additional copyediting for English language, especially the following: Lines: 49, 55, 74-76, 120, 133, 134-136 (the meaning of this sentence is not clear), 139-156, 189, 216, 225-235, 258-260, 273, and 350.

Author Response

It would help consistency to synthesize any literature on HLA-G in IgE-mediated disorders.

- We found the paper on association of HLA-G and IgE-mediated allergic diseases, and added the mention in lines 252 - 254 (Ref. 61).

 

Also for consistency, discussion of the role of LIF in tumor biology, as this seems to be a critical downstream factor in pregnancy.

- We found the paper on association of LIF and tumor biology (tumorigenesis and metastasis), and added the mention in lines 311 - 313 (Ref. 79).

 

I think the authors could make a more clear synthesis statement at the end of section 6. Something along the lines of: so while MC deficiency leads to pregnancy and parturition disorder, and KIR2DL4 downregulation is associated with infertility, it is the selective KIR2DL4-induced production of LIF and MMP-9 from MC that may illustrate the critical context-specific role of MC in pregnancy.

- We added the above-mentioned sentences (lines 319 – 322).

 

It seems that KIR2DL4 can affect MC independent of FceRI and CD117 activities, in addition to important influence over those receptors. Therefore, it would be interesting to see this receptor contextualized with other important MC receptors, namely the IL-33/ST2 axis and MRGPRX2 if such literature exists.

- We do not have any data on the KIR2DL4 effects on IL-33/ST2 axis and MRGPRX2. We should study on this, and mentioned in lines 402 - 405.

 

Can the authors comment/speculate on the importance of KIR2DL4 causing both “weak cytotoxicity and cytokine secretion”? What is the impact of this combination (death + cytokines) physiologically?

- No, we are not ready to comment on this. This should be studied on both NK and mast cells. We mentioned in lines 176 - 178

 

Additionally, what are the specific signals transduced (Line 162) This might be at odds with the commentary later, especially starting with Line 201 about KIR2DL4 inhibitory effects on MC.

- We rewrote the sentences on the signal transductions in lines169 – 182 and lines 209 – 215.

 

On lines 66 and 67 the authors attribute MC dysfunction to IgE and SCF signaling. Certainly for IgE-mediate allergic disorders this is the case; however this may not necessarily be the case for many IBDs. FceRI and CD117 just seems to be the most heavily studied.

- We agree this, and rewrote the sentences (lines 66 – 68).

 

Line 317: nasophageal should be nasopharyngeal

- We amended this typo (line 328).

 

The paper requires additional copyediting for English language, especially the following: Lines: 49, 55, 74-76, 120, 133, 134-136 (the meaning of this sentence is not clear), 139-156, 189, 216, 225-235, 258-260, 273, and 350.

- These sentences have been checked by an English consult

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.