This is a timely review on the prevalence, pathophysiology and clinical implications of anti-type I Interferons. The author has done a good job in summarizing the literature on this topic, and also in proposing an interesting hypothesis on how genetic and constitutional (age, sex, thymic involution, autoimmune conditions) may intersect with environmental exposures (acute or chronic viral infections) in facilitating the development of such autoantibodies.

The review could be improved in multiple ways. In particular:

1) the same concepts are repeated multiple times, and in different parts of the review. I recommend streamlining the message, avoiding duplications. The review could be shortened substantially if this is done, and the message would be even more clear;

2) - line 60. Ref 12 is cited along with refs. 10-13 when describing the presence of anti-type I autoAbs in patients with autoimmune diseases. However, ref. 12 described the presence of such autoantibodies in patients with RAG deficiency. The author has missed the mechanism underlying their presence in this disease. It has been shown that patients with RAG mutations have a disorganized thymus with lack of AIRE+ medullary thymic epithelial cells (Cavadini et al., JCI 2005; de Ravin et al., Blood 2010). thus, throughout the manuscript, reference to the presence of these autoantibodies in patients with RAG deficiency should be linked to the defect of central tolerance;

3) lines 192-200. The message here is unclear. First, patients with APS-1 are not particularly prone to viral infections. The author could argue that even common viral infections might trigger the development of anti-type I IFN autoAb in such patients. However, against such hypothesis is the fact that these autoantibodies are not found in patients with severe thymic defects, including severe forms of DiGeorge syndrome and other similar conditions. This point needs to be discussed. The author also proposes that older individuals undergoing thymus dysfunction with time would be less likely to experience high IFN-inducing acute infections because of the presence of antibodies against pathogens. However, there is little evidence in favor of this hypothesis, and on the other hand it is true that anti-type I IFN antibodies are more common among elderly individuals. Multiple factors, from thymus aging to Treg dysfunction, may contribute to this.

3) lines 220-223. Although low levels of anti-type I FN autoAbs have been reported in mice and rats, this occurs very rarely. For example, Aire-/- mice do not develop such autoantibodies. It is important to highlight this key difference between humans and mice, where both age and genetic factors (including strain specificity, when it comes to mice) may play a role

4) The last paragraph, pertaining to potential therapeutic and preventive modalities to reduce the risk of severe viral infections in subjects with neutralizing anti-type I IFN autoAbs, should be expanded to include agents targeting plasma cells (daratumumab, bortezomib) and B cells (rituximab). Experience with such treatments in patients with severe COVID-19 should be cited

5) revision of the English language is recommended. For example, throughout the manuscript "viral infections" would be better than "virus infection". Also, at lines 116, 137 and 288, the authors uses "with regards XXX". This is not correct. The English would prefer "with regard to XXX"

The authors have adequately revised the manuscript and addressed the reviewers' comments.

There is one point that needs attention, and that can be fixed when checking the proofs:
1) in the abstract, gene names should be in Italic