Dnase1 Family in Autoimmunity

Round 1

Reviewer 1 Report

The review "DNase1 family in Autoimmunity" by Engavale M et al. it clearly and sufficiently extensively describes both the chemistry of the mechanism of action of DNase1 family and it's suggested involvement in autoimmune disorders such as SLE, HUVS, skin diseases. References are appropriate and consistent with the topic.

Author Response

We thank the reviewer for this assessment of our manuscript.

Reviewer 2 Report

This review is highly important and very timely since during the last years numerous applications of DNase were experimentally shown.
In my opinion, already in the abstract it is needed to include the fingings of DNase1 and DNase1L3 cooperating on the degradation of ecDNA
I would suggest to exoand the part on the pro-inflammatory nature of ecDNA. This is a crucial point for the importance of DNases.
The substrate specificity of DNase 1 and DNase 1L3 should be described in more detail, especially with regard to their cooperation in vivo
I would mention the therapeutic use in sepsis models and in hepatorenal injury.
It is important to point towards the mechanism of immunothrombosis mediated by ecDNA as DNases could be crucial in their prevention. this requires more than just one sentence.
Also, it would be good to include the recent effeorts to use DNases for the treatment of severe Covid to clear NETs and to prevent thrombosis.
I would suggest to organize the manuscript a bit more - the mutational analysis of the DNase genes should be in one subchapter, the physiology in another... pathophysiology etc...
also I would like to see the information on the evolution of DNases in one standalone subchapter as well.

Author Response

This review is highly important and very timely since during the last years numerous applications of DNase were experimentally shown.

We thank the reviewer for this assessment of our manuscript.

In my opinion, already in the abstract it is needed to include the fingings of DNase1 and DNase1L3 cooperating on the degradation of ecDNA

We thank the reviewer for this suggestion. We have added a line to the abstract about their cooperation in degrading extracellular DNA.

I would suggest to exoand the part on the pro-inflammatory nature of ecDNA. This is a crucial point for the importance of DNases.

We thank the reviewer for this suggestion. We have expanded this section.

The substrate specificity of DNase 1 and DNase 1L3 should be described in more detail, especially with regard to their cooperation in vivo

We thank the reviewer for this suggestion. We have added this on lines 108-118.

I would mention the therapeutic use in sepsis models and in hepatorenal injury.

We thank the reviewer for this suggestion. We have added this to the clinical section.

It is important to point towards the mechanism of immunothrombosis mediated by ecDNA as DNases could be crucial in their prevention. this requires more than just one sentence.

We thank the reviewer for this suggestion. We have expanded on this in both the clinical section and in the NET clearance section.

Also, it would be good to include the recent effeorts to use DNases for the treatment of severe Covid to clear NETs and to prevent thrombosis.

We thank the reviewer for this suggestion. This has been added to the section on NET clearance.

I would suggest to organize the manuscript a bit more - the mutational analysis of the DNase genes should be in one subchapter, the physiology in another... pathophysiology etc…

We thank the reviewer for this suggestion. We have restructured the manuscript to place the clinical/experimental uses of Dnases after the ‘diseases’ section which has been renamed ‘The Pathophysiology of the Dnase1 family.’

also I would like to see the information on the evolution of DNases in one standalone subchapter as well.

We thank the reviewer for this suggestion. The evolutionary information is concentrated in Section 1.2, which is now named “Evolution of Dnases”