Re: Inflammation and Evolution

Bryan Heit wrote:
> >Thanks for your extensive response and your detailed
> >explanations, which I found edifying.
>
> For some reason Google groups screwed up whom I was replying to - the
> reply should have been to the original posters question...
>

Never mind ... I think it worked out better for me
this way.

> >I'm interested in your claim that the main role of
> >inflammation is in response to (mainly) bacterial
> >invasions, that the main purpose is to `clean up'
> >damaged tissues.
>
> That point of view comes from my job (as a scientist who studies
> inflammation). During an inflammatory response, regardless of the
> stimuli (tissue damage, bacteria, autoimmunity), certain types of cells
> are recruited into the injured site. Neutrophils are almost always a
> part of this influx of immune cells - especially in the case of a joint
> injury. Neutrophils only have one biologically significant function -
> to kill bacteria. Their role in wound healing is minimal, and once
> healing is initiated, neutrophils must be removed for healing to
> complete.
>
> The presence of neutrophils in inflamed tissues tells us that
> inflammation is orientated towards bacterial clearance for several
> reasons. Notably:
>
> 1) Neutrophil produce large amounts of anti-bacterial substances when
> they are in an inflamed tissue. This includes superoxides (reactive
> chemicals, including the same chemical found in bleach), defensins
> (punch holes in cells) and proteases (which chew up proteins). These
> anti-bacterial substances are also highly damaging to your own tissues,
> as they are indiscriminant in the cells which they target. As such the
> large influx of neutrophils causes, rather then fixes, tissue damage.
>
> 2) Neutrophils are phagocytic cells, which means that they can engulf
> and destroy particles. But unlike macrophage, they cannot engulf
> damaged cells, and instead can only target bacteria and immune
> complexes (antibody coated particles). As such, neutrophils are unable
> to aid in the "cleanup" of damaged tissues.
>
> 3) Neutrophils skew the immune responses within the inflamed tissue
> away from healing, and towards an anti-bacterial response. This is
> done through the release of immune mediators such as TNF, IL-8, LTB4,
> IL-6 and GM-CSF. The effect of these chemicals is to alter the way
> other cells in a tissue function. For example, macrophage, which
> normally clean up cell debris, will switch to an anti-bacterial
> function when they see these molecules. As a result, the macrophage
> will begin to produce a lot of anti-bacterial products, many of which
> damage our own tissues. Likewise, other cells which are involved in
> healing (ex. fibroblasts) are shut down by these chemicals, presumably
> so they don't interfere with the bacterial clearance process.
>
> 4) Finally, during inflammation the body goes into what is termed the
> acute phase response. Basically, in response to the inflammation, your
> liver begins to produce a variety of molecules which it secretes into
> your blood. These molecules consist entirely of anti-bacterial
> compounds, including compliment molecules (which "tag" bacteria for
> destruction), defensins, and c-reactive protein (which directly lyses
> bacteria). Associated with this acute response is increased production
> of antibacterial cells by the bone marrow.
>
> These events occur regardless of what the inflammatory stimuli is -
> infection, damage (i.e. a sprain), burns or other. And in all cases
> the inflammatory response is exquisitely designed to destroy bacteria.
> Ironically, this same inflammatory response inhibits the healing
> process - that is, until the inflammation begins to resolve. Once the
> inglammation begins to resolve, the immune cells will produce the
> chemicals required to initiate the repair process (chemicals such as
> TGF, FGF, VEGF). Once this stage is reached some of the inflammatory
> cells (almost entirely macrophage) begin to repair the tissue - the
> remaining inflammatory cells (i.e. neutorphils) are simply removed.
> However, upto this point the inflammation is almost entirely devoted to
> the removal of bacteria. And in most cases the inflammation increases,
> rather then limits, tissue damage.
>

Thanks very much, that is beautifully clear and detailed.

Cumulatively this certainly looks to me like convincing
evidence for your point of view. I didn't have anything
like such a clear picture of the order of events before.

To try to summarize roughly, and you may well disagree:

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.

Both cell types are phagocytic, but neutrophils act phagocytically
only against bacteria or against antibody marked complexes, not
against self-cells, while macrophages act phagocytically against
ostensibly damaged self-cells, but not against bacteria.

When neutrophils are active, which initially is almost
always the case in inflammatory responses, so that almost
all such responses are initially type I, they secrete
many factors damaging both to bacteria and to self-cells.
Additionally, neutrophils secrete immune mediators which
cause macrophages to switch to an antibacterial role.

If a type I response persists, then wider systemic
resources eventually become recruited for fighting what
apparently is an out of control invasion by bacteria.

However, in the absence of neutrophils, or at least when
some decline in the activity of the neutrophils begins
to take place, macrophages switch over to a role of
cleaning up debris from damaged self-cells, which is
what I presumptively called an inflammatory process of
type II. In addition, as the inflammation finally resolves,
certain other immune system cells begin to secrete factors
that promote cell growth and tissue repair, and macrophages
aid in that repair.

It's an extremely interesting picture.

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?

> >I'm not quite clear whether bacterial invasion is the
> >major source of tissue damage
>
> This is a complex question. Firstly, bacteria can enter the body
> through injured sites, or through non-injured sites. So sometimes it's
> the injury which leads to infection, and sometimes its infection which
> leads to injury. Secondly, the way in which bacteria injure tissues is
> extremely variable. Some bacteria release toxins which cause an
> incredible amount of tissue damage. These toxins can lyse cells,
> suppress the immune system, and in some cases even "eat" away our
> tissues. But on the other end of the spectrum are the bacteria which
> try to minimize damage to our body. These bacteria prefer to hide away
> in our body, and simply feed off of our bodies without causing damage.
> These bacteria also release toxins, but these toxins tent to be
> orientated towards hiding from the immune system, rather then towards
> damaging tissue.
>
> The one thing which unifies these different types of infections is that
> our immune system tends to cause a lot of damage in trying to clear
> these bacteria. As I mentioned above, numerous toxic and tissue
> damaging molecules are produced by inflammatory cells. These molecules
> are very good at killing bacteria, but because they are indiscriminant
> on what they target, they also do a very god job of killing our own
> cells. So in many cases it is our immune system, not the infecting
> bacteria, which is responsible for the majority of the tissue damage
> which occurs during an infection. This is on top of any damage which
> may have resulted in the infection (i.e. a cut).
>

Fascinating, so apparently the problem of the excess damage is
less severe on the whole than the problem of an out of control
bacterial invasion. This, together with the fact that there
may be a bacterial invasion without significant initial external
injury, but which later leads to internal injury makes it difficult
to detect, initially, whether the injury is due to bacteria or
contains bacteria. So the great majority of responses are simply
initially directed against bacteria which may potentially be present.

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.

> > whether bacterial
> > invasion more often occurs subsequent to damage to
> > epithelial cells that would, naively, seem to provide the
> > first, physical lines of immune defense against infectious
> > agents generally.
>
> As I said above, this is a tough question. Some bacteria (called
> opportunistic pathogens) will only infect our bodies if damage has
> already occurred, and provided a passage for the bacteria past our
> epithelial barriers. In contrast, many bacteria have mechanisms to get
> past the epithelium without injury. In most cases these bacteria
> "trick" the epithelium into internalizing the bacteria. Once inside
> the epithelium the bacteria can kill the endothelial cell, or escape
> out the other side. Either way, the bacteria enters our body without
> requiring a pre-injury to the epithelium. Nearly all of the bacteria
> which cause food poisoning enter in this manner.
>

I was thinking more about it yesterday, and it occurred
to me that some bacteria may well have evolved ways to slip
past the epithelium. It's interesting to hear that that was
a correct guess. But the first part of your answer clarifies
the question enough, I think.


> > [...] can be put through a blender,
> > and still manage to reorganize themselves afterwards,
> > so it's clear that they have at least a rudimentary
> > response to injury!
>
> This is not equivalent to our response to injury. The reformation of
> these simple organisms is little more then the developmental process in
> reverse, and as you can imagine, the structure of these organisms is
> nothing compared to what our tissues look like. Plus, as far as I
> know, these animals lack a dedicated immune system. For most simple
> organisms like this (including the single-celled ones) their "immune
> system" consists of little more then the production of anti-bacterial
> molecules. Keep in mind that many of these simple organisms "eat"
> bacteria, so their "immune response" is simply to eat. The smallest
> animal I know of with a dedicated immune system is c. elegans (which
> has a single macrophage). This animal has ~1000 cells.
>

Very interesting: so a dedicated immune system apparently
is needed only at a higher level of organization, perhaps when
a larger number of the basic cell types have specialized and
possibly lost some of the ability to defend themselves against
bacteria by secreting the anti-bacterial molecules, which if
I understand it, are also possibly very damaging to self-cells?

> As for plants, "immunity" is very different then in animals. Plants do
> not have an immune system, or cells dedicated to the killing of
> pathogens. Rather, plant immunity is largely based on anti-bacterial
> and anti-viral proteins produced by every cell, the physical structure
> of the plant, and containment.
>
> A plants first line of defense is the structure of the cell - plant
> cells are surrounded by a thick wall of cellulose. This wall is
> extremely hard to break through, making it difficult for bacterial to
> enter. In addition, the surface of most plants is covered with a waxy
> substance which further limits bacterial entry. Plants also produce a
> large number of anti-bacterial and anti-viral proteins. These proteins
> work in a variety of ways, including direct killing and interference
> with growth. Lastly, plants limit infection by limiting the spread of
> bacteria/viruses. All plant cells are connected together by small
> channels through the cell wall. These channels are too small for most
> bacteria to pass though, so even if one cell gets infected there is no
> guarantee that the bacteria will be able to spread to other cells.
> Plants can also undergo a scarring process which acts to block off
> areas which become infected. This results in the blemishes you often
> see on fruit.
>

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, and a coordinated
immune response is unnecessary. Clearly they couldn't have
a system based on some sort of motile cells in any case, since
the structure prevents long range motion. That should have
been clear.

> > I also read there that there seems to be no evidence for
> > acquired or adaptive immunity in invertebrates. So apparently
> > some relatively new mechanisms of dealing with infection,
> > bacterial and otherwise have evolved.
>
> This is true. The "simplest" animal which appears to have an adaptive
> immune system is sharks. They can produce simple antibodies, but
> that's about it. As you move to more "advanced" vertebrates more and
> more complex adaptive immunity is found. Mammals have, by any measure,
> the most complex adaptive immune system. What is mystifying though, is
> that there doesn't seem to be much of a link between the animals with
> non-adaptive and adaptive immune systems. You look one step down from
> sharks and there is nothing. So whether the first steps were formed by
> a now extinct line of animals, or if sharks spent a lot of time
> evolving the basic mechanism is not clear. But from sharks on up, the
> continuing complexity of the adaptive immune system is well
> established.
>
> Bryan
>
> PS: In case you're wondering, I study how inflammatory cells
> (predominantly neutrophils) navigate through tissues to find bacteria.
> I also study how certain diseases (sepsis, HIV) impact on this process,
> and look at the net effect of these diseases on how well we can mount
> an inflammatory response. I also have an interest in how these
> processes mediate disease progression during autoimmunity -
> particularly during multiple sclerosis and autoimmune hepatitis. In
> the case of the lab where I work, we research almost all aspects of
> inflammation - from how inflammatory cells are recruited from the
> blood into tissues, to how inflammatory cells function during a variety
> of diseases, to how inflammation is resolved once an infection is
> cured. Lately, we've been concentrating a lot on finding ways to
> limit inflammation during autoimmune diseases.

It sounds like absolutely fascinating work, and hopefully
with some benefits for medical science too.

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.


David

.

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