Re: Septic death and human ACID genetics?

[Guest guest]

relatedly,

" Association of hypo-responsive toll-like receptor 4 variants with

risk of myocardial infarction "

http://eurheartj.oupjournals.org/cgi/content/full/25/16/1447

[Guest guest]

> This idea does nothing to explain trends this centruy, such as the

> fact that inflammatory bowel disease, for instance, has evidently

> increased in incidence substantially in the US since 1940.

Or does it?

In sepsis, the optimal host strategy is to respond as aggressively as

is possible without causing irreversible damage or death. In septic

situations, mammals whose immune response immediately pushes into the

red zone will have a large chance of victory, but a large chance of

death from immune-mediated shock. On the other hand, mammals bearing a

variant hypofunctional protein such as the Crohns NOD2 variant or

perhaps a TLR4 variant face a smaller chance of abrupt death from

drastic septic shock, but face a larger chance of failing to clear the

infection and spiraling down into death several days or weeks later.

The " red zone " approach would be better in some septic scenarios, and

the conservative approach would be better in others. If the pathogen

is not really that skillful but happened to get out of control due to

circumstances, its much better for the mammal to combat it

conservatively. In such a case it would be pointless to risk death

with an extremely radical immune response. But on the other hand, if

the pathogen is some sort of a total badass like the Black Plauge,

then it is much better for the mammal to push into the red zone

immediately, despite the risk of death, because the mammal's chances

of ever clearing the black death are going down literally every 10

minutes.

As I was speculating last night, the survival advantage bestowed by eg

hypofunctional NOD2 alleles, in *some* septic situations, might cause

them to be retained in the gene pool at low frequency. Enter

penicillin, c. 1945. Now the chances of eventually clearing an acute

infection approach 100% - penicillin will do the job in a few days.

Now, when a human comes down with septic bacterial infection within

reach of a doctor, a life-risking immune response is a *terrible* idea

in *almost every* case; nothing is gained by a red zone immune

response, because penicillin will soon eradicate the infection anyway.

" Red zoners " have their survival somewhat improved by penicillin; on

the other hand carriers of alleles like hypofunctional NOD2, who have

a more conservative immune response to sepsis, now *almost always*

survive. These alleles become more common. Also more common are humans

carrying more than one such allele, and these are vulnerable to

diseases like Crohns which IMO are likely to be simple chronic

infections. Ergo, the incidence of Crohns increases severalfold.

This account is very speculative. It predicts the existence of other

immune system variant alleles which confer both suceptibility to ACIDs

and insuceptibility to septic shock death. The Crohns NOD2 alleles are

currently the only alleles in this category.

It also predicts that the ACID epidemic will level off in rich

countries, but that the increase curve will be delayed in countries

where penicillin was not commonplace for some years after 1945. The

incidence of inflammatory bowel disease has now leveled off in the US

and is still growing in many poor countries; I dont know whether the

advent of widespread penicillin was actually decades behind in those

countries, compared to the US and Western Europe (where, I get the

impression, the rapid adoption of the drug was catalyzed by its

widespread use in getting sick soldiers back to the war).

A major limitation of this theory is that the history may not quite

fit the curve of the ACID epidemic. See for instance Fig 2 in

http://gut.bmjjournals.com/cgi/content/full/46/3/336

Other factors that could factor into the increased ACID incidence:

- the rise of essentially new pathogens able to infect a fairly broad

range of human immuno-phenotypes (lyme could fit this description?)

- the " miracle " of corticosteroids, c. 1950, which probably frisked

up the reproductive lives of ACID victims a little, thus perhaps

increasing the distribution of various suceptibility alleles?

- and theres the hygeine hypothesis

- modern lifestyle/environmental factors, etc