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closeReferee Comments: Referee 1 (Graham Rook)
Posted by PLOS_ONE_Group on 28 Dec 2007 at 18:43 GMT
Reviewer 1's Review
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This impressive paper provides a mass of data on a crucially important topic, and backs it up with functional studies. I am not competent to comment critically on the methods or statistics. I have three small queries of a more immunological flavour for the authors to consider.
The statement that the reported associations between alleles of various molecules and susceptibility to TB has revealed only weak associations might not be approriate for MCP-1/CCL2, where the association is claimed to be rather strong. A comment might be helpful..
On page 18 where the findings are put into context, the authors do not make sufficiently clearly the point that susceptibility to TB might not be due to the same mechanisms in different populations. There is evidence that TB strains are adapted to different ethnic groups, and also that the immunology of the disease is different in different geographical locations. It might be that the ways in which Mtb overcomes the immune response differ not only for different strains, but also for different human/Mtb combinations.
FInally, perhaps one line where they discuss IL-12 might emphasise the point that the defects in the IL-12/IL-23/IFN-g pathway that still dominate the immunological literature seem more relevant to organisms of low virulence, and BCG, than to Mtb itself (unless very severe defects are involved). The authors imply this because they do not menton Mtb when discussing IL-12 polymorphisms, but perhaps the point needs to be emphasised to help temper the current obsession with Th1!
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N.B. These are the general comments made by the reviewer when reviewing this paper in light of which the manuscript was revised. Specific points addressed during revision of the paper are not shown.