Re: Inflammation and Evolution

> There seem to exist two distinct types of inflammatory
> response on the local level. The type II response,
> directed towards clean up of damaged tissue, is inhibited by
> the type I response, directed towards destruction of bacteria.
> The two types of response are based on the coordinated activity
> of two separate cell types, neutrophils and macrophages.

Not exactly. It's more like an "early" verses "late" response. In
nearly all cases of inflammation you'll get both the bacterial and
tissue cleaning types of inflammation. The bacterial-clearing immunity
always occurs first. Once the pathogen is cleared (or, in the case of
an injury, the tissue damage is stopped and crudely "fixed") the
anti-bacterial inflammation begins to resolve. Upto this point much of
the healing process has been put on hold; once the anti-bacterial
inflammation stops the healing processes are allowed to proceed. The
process by which macrophage "clean up" damaged tissue is on-going, it's
only unregulated during inflammation to deal with the increased amount
of damaged tissue which is around. Normally, this macrophage activity
is limited to the bare minimum required to remove the cells which are
constantly dieing in our bodies.

As for the cell types involved, it is a lot more complex then just
macrophage and neutrophils. These are the main cells involved in
anti-bacterial immunity, but many other cell types are also involved
(especially when long-lasting infections are present). Other important
immune cells consists of B-cells (make antibodies), T-cells (identify
and destroy pathogen-containing cells), NK cells (like T-cells, but
different), eosinophils and mast cells (kill large pathogens like
worms, give us asthma and allergies), and dendritic cells (sentinels
which look out for pathogens).

> Only one question: you said, or seemed to imply that extremely
> rarely, neutrophils are not a major part of the initial
> influx of immune cells. Can you say what a specific
> case is, in which that happens?

There are lots of cases. For example, neutrophils cannot do a lot in
the event of a viral infection, so they are rarely recruited to the
sites of viral infection. Neutrophil also rarely enter the brain, even
when bacteria are present. This is because neutrophils are essentially
our immune systems version of a hand grenade; and you never set off
hand grenades in sensitive areas. There are also some autoimmune
diseases where there is a great deal of inflammation, but the cells
entering the inflamed site are largely macrophage and T-cells (diabetes
for example). IN the case of diseases like HIV neutrophils are
dysfunctional, and will not be recruited to any site of inflammation -
even if under normal circumstances they would go to that site by the
millions.

> So it looks like the need to fight potentially rapidly
> multiplying bacteria quickly before things get out of control
> is paramount, simply because the outcome could be much more
> dire. The extra damage caused in case of an error is seemingly
> less of a problem for survival on average, and mechanisms do
> exist to eventually mitigate and repair such damage.

Exactly. Some bacteria can replicate in our bodies once every 20
minutes or so. This means that in a single day a single infecting
bacteria can result in the production of ~20 BILLION offspring (in
theory). This doesn't happen in the real word (because there isn't
enough food for them), but still, bacteria can divide extremely quickly
in our bodies. As such the primary role of inflammation is to limit
this at all costs - a little localized tissue damage is a small price
to pay.

Just as an example of how important this is, you need look no farther
then patients with leukocyte adhesion deficiency (LAD). This is an
inherited genetic trait, in which patients cannot recruit neutrophils
to the site of infection. Without a bone marrow transplant (which
repairs the defect), these patients almost always die within weeks of
being born - even if they're put into a sterile bubble.

> Very interesting: so a dedicated immune system apparently
> is needed only at a higher level of organization,

As a general rule, the more complex an organism, the more complex their
responses to pathogens. Also, you need to keep in mind that a
dedicated immune system is extremely energy-intensive. So in the case
of many smaller organisms, their is more of an evolutionary benefit to
do without the immune system, and replicate more often, then it is to
have dedicated immune system. In fact, even among animals with
dedicated immune systems, you tend to see a shutting down of the immune
system after the organisms reproductive peak.

For example, in humans, the immune system starts to weaken in the late
20's. By the time women reach menopause (and men the equivalent
reproductive age), the immune system is somewhat compromised. Within
the bone marrow (where immune cells are made) this decreasing immunity
directly correlates with the amount of fat in the marrow - as you age
fat replaces the immune cells. This is why the elderly have so much
trouble fighting off even minor viral infections.

And this isn't limited to humans. For example, the immune system of
mice begins to crap out at about 1 year in age, which also happens to
be "old age" for a wild mouse.

> themselves against
> bacteria by secreting the anti-bacterial molecules, which if
> I understand it, are also possibly very damaging to self-cells?

In general they are damaging to our own cells. The main issue is that
bacteria and us are made of the same building blocks, so things that
tend to damage bacteria also damage us. It's also very difficult to
direct some of these molecules only to bacteria, as some (like
oxidants) simply leak non-directionally out of the cells which produce
them. Many other immune cells have toxic granules which are released
in response to bacteria - although the release of these granules is
often in the direction of the bacteria, diffusion carries them
throughout the surrounding tissue.

As much as we'd like otherwise, biology cannot trump the laws of
physics...

> So basically: it seems as if plant cells retained such mechanisms
> to defend themselves against bacteria as their ancestors may have
> already had when they were single celled, but the fact that plant
> cells surround themselves thick walls of cellulose means that physical
> barriers are much more effective than in animals,

Not so much more effective as possible. You cannot put thick, rigid
walls around cells in an organism which is supposed to be motile.
Where animals can put in place thick walls, they do. Your skin being
an excellent example of this.

> and a coordinated
> immune response is unnecessary.

Although a plants immune system is simple in comparison to ours, it is
far from uncoordinated. In many ways, plants are more sophisticated
then us. For example, many plants will release hormone-like chemicals
into the environment when they are "sick". This warns other plants of
danger, often resulting in increased production of anti-bacterial
products by the uninfected plants. No species of animal has been
observed with an equivalent "population" immune response. And when you
take into consideration that plants often respond to these cues
cross-species, this form of immune regulation is even more admirable.

Likewise, within an infected plant there is a great deal of
coordination - all tissues in the plant will upregulate their
anti-bacterial proteins. But the cells closer to the site of infection
will actually act to block off the area of infection, such that
bacteria cannot spread any further. The infected cells themselves may
even commit suicide to prevent further infection. Of these processes,
only the last one is used by all animals. The process of blocking off
and shedding infected portions is, AFAIK, limited to plants.

> Thanks for spending the time I know it must have taken to
> make this truly excellent post, and thanks too for dealing
> very patiently with all of my questions.

No problem - I enjoy these kinds of discussion. So much better then
the name calling which is the norm on usenet...

Bryan

.

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