🚀 go-pugleaf

Just to expand into another grey area that was talked about in the past 
in the idea of danger and non-danger.  Polly Matzinger hypothesis is that 
 dying cells release compounds which would activate dendritic cells in 
the case of danger and wouldn't in the lack of danger. That activation, 
if her model is correct, may play a role in controlling responsivity. 
This idea could be approximated to include bacteria. However, by binding 
bacteria the phagocyte is promoted to engulf it. the other posts have 
talked about how this process is mechanically controlled (opsinization 
with C' and/or AB.  Sialic residues can initiate binding to macs as 
well.  However, phagocytosis and antigen presentation are NOT 
self/nonself discrimination.  All peptides from degraded proteins are 
presented (to one extent or another) self and non-self.

Axel Boldt wrote:
> 
> Hi,
> 
> I've asked this question here before, I didn't quite understand the
> answers, was advised to read a good immunology book and did just
> that. However, every book I get my fingers on seems to gloss over the
> (from my perspective) most important point about the whole immune
> system.
> 
> Neither B- nor T-cells nor anybody else will take any action unless a
> new antigen has been engulfed, processed and presented by a macrophage
> (let's talk about thymus-dependant antigens only for now); so the most
> central question of all should be: how do macrophages know what to
> engulf? 

If antibodies are stuck to it, the macrophage can use Fc receptors (tail
end of the antibody, as it were) to "know" they should engulf it.  There
is no need for the macrophage to choose between "self" and
"non-self".... most *everything* should be taken in, digested and
presented. It is then up to the repertoire of T-cells (selected in the
thymic education stages of T-cell development) to be able to tell
"non-self" from "self".  So there really isn't a problem for the
macrophage in terms of choice here, as I see it.


>Which soluble proteins, which free viruses, which bacteria?
> How do THEY distinguish self from non-self?  And, given this huge
> evolutionary pressure, why are there not more pathogens who can
> circumvent this macrophage detection mechanism and thereby bypass the
> whole immune defense? Why does everybody talk about the wonders of
> gene rearrangement and somatic mutation which account for the
> specificity of antibody, when the genes that tell macrophages what to
> do are much more important?

You should read up a bit on the recent findings about dendritic cells -
nox *these* guys seem to have a few roles to play in the initiation of
immune response, and perhaps in the long-term memory aspects.

> 
> Thanks for any reply that could help clear this up for me.
> 
> Cheers,
>   Axel

(signed) marc

.

Marc Buhler <mbuhler@STOP_SPAMmail.usyd.edu.au> said:

Axel> Neither B- nor T-cells nor anybody else will take any action unless a
Axel> new antigen has been engulfed, processed and presented by a macrophage
Axel> (let's talk about thymus-dependant antigens only for now); so the most
Axel> central question of all should be: how do macrophages know what to
Axel> engulf? 

Marc> If antibodies are stuck to it, the macrophage can use Fc receptors (tail
Marc> end of the antibody, as it were) to "know" they should engulf
Marc> it. 

At this point, we don't have antibodies. Before the B-cell can produce
antibodies, it has to be stimulated by a Th cell, which has to find
something on a macrophage surface. So the macrophage must know what to
eat without the help of antibodies.

Marc> is no need for the macrophage to choose between "self" and
Marc> "non-self".... most *everything* should be taken in, digested and
Marc> presented.

That would be a possibility of course, but wouldn't that mean that
macrophages chew on the good stuff all day and destroy valuable
proteins and cells along the way?

Axel

I'll post a more formal and detailed announcement later, but for thosoe
who must plan early for a trip to New York City, let me alert you to
the New York Neuropsychology Group's 19th annual conference (joint
meeting with the Psychology Section of The New York Academy of
Sciences): "Neuropsychology and the Neuroimmune Dialogue"

At NYU Medical Center, Saturday, May 2.

PROBABLY will offer CE (psychol) & CME credits (applications pending).

Will NOT involve the impressivbe level of detail some of you show (e.g.
in the thread re macrophages); rather, for neuropsychologists, a primer
and exposition of dimensions they have so far not considered well, and
perhaps for immunologists some ideas regarding so-far unexploited
possibilities for explanations of clinical/cognitive/behavioral
phenomena, involving neural-immune-behavioral interactions at a more
systemic level.

Pending post of more formal announcements, details by FAX or snail
mail, from:

F. Frank LeFever, Ph.D.          FAX (914) 786-4978
Helen Hayes Hospital            voice(914) 786-4110
West Haverstraw, NY 10993       flefeverr@ix.netcom.com

In article <xzqafbxz9s1.fsf@dali.uni-paderborn.de>,
Axel Boldt <axel@uni-paderborn.de> wrote:
>
>central question of all should be: how do macrophages know what to
>engulf? Which soluble proteins, which free viruses, which bacteria?
>How do THEY distinguish self from non-self?  And, given this huge

I think the most general answer is "they don't".  I think that macrophages
will phagocytose almost anything under a certain size.  However, some
things are phagocytosed more efficiently than others.  Particulate
material of a certain size range, for example (and I don't know what that
range is) will get sucked up pretty well, while free proteins are less
efficiently taken up (mostly by fluid-phase pinocytosis, as a background
process), and so forth.  Others have pointed out that there are various
triggers, including (as I recall, and this is just from the memory of
someone who doesn't work in the field) particular membrane components only
found on bacteria, and other membrane components only seen on apoptotic
cells.  And of course there's complement, which similarly 'sees' abnormal
stuff. 

So even before any specific component kicks in and provides antibody for
the Fc receptors or cytokines, you have multiple levels of efficiency and
redundancy, I think. You have things with 'foreign' markers (membrane
components, eg), which are phagocytosed really fast.  You have particulate
material, which is taken up less efficiently.  You have free protein,
which is slowly and inefficiently taken up.  And so on.  

But even at the low end of efficiency, there's still a low level of
phagocytosis, and if and when this happens to turn up a genuine non-self,
then you get massive amplification of the response because it cranks up
all the specific stuff.  At the low-efficiency end, the macrophages as a
group probably depend on a positive feedback.

Hope this helps.

Ian

-- 
    Ian York   (iayork@panix.com)  <http://www.panix.com/~iayork/>
    "-but as he was a York, I am rather inclined to suppose him a
     very respectable Man." -Jane Austen, The History of England

Axel Boldt wrote:
> 
> Marc Buhler <mbuhler@STOP_SPAMmail.usyd.edu.au> said:
> 
> Axel> Neither B- nor T-cells nor anybody else will take any action unless a
> Axel> new antigen has been engulfed, processed and presented by a macrophage
> Axel> (let's talk about thymus-dependant antigens only for now); so the most
> Axel> central question of all should be: how do macrophages know what to
> Axel> engulf?
> 
> Marc> If antibodies are stuck to it, the macrophage can use Fc receptors (tail
> Marc> end of the antibody, as it were) to "know" they should engulf
> Marc> it.
> 
> At this point, we don't have antibodies. Before the B-cell can produce
> antibodies, it has to be stimulated by a Th cell, which has to find
> something on a macrophage surface. So the macrophage must know what to
> eat without the help of antibodies.
> 
> Marc> is no need for the macrophage to choose between "self" and
> Marc> "non-self".... most *everything* should be taken in, digested and
> Marc> presented.
> 
> That would be a possibility of course, but wouldn't that mean that
> macrophages chew on the good stuff all day and destroy valuable
> proteins and cells along the way?
> 
> Axel

yes

Axel Boldt wrote:
> 
> Marc Buhler <mbuhler@STOP_SPAMmail.usyd.edu.au> said:
> 
> Axel> Neither B- nor T-cells nor anybody else will take any action unless a
> Axel> new antigen has been engulfed, processed and presented by a macrophage
> Axel> (let's talk about thymus-dependant antigens only for now); so the most
> Axel> central question of all should be: how do macrophages know what to
> Axel> engulf?
> 
> Marc> If antibodies are stuck to it, the macrophage can use Fc receptors (tail
> Marc> end of the antibody, as it were) to "know" they should engulf
> Marc> it.
> 
> At this point, we don't have antibodies. Before the B-cell can produce
> antibodies, it has to be stimulated by a Th cell, which has to find
> something on a macrophage surface. So the macrophage must know what to
> eat without the help of antibodies.
> 
> Marc> is no need for the macrophage to choose between "self" and
> Marc> "non-self".... most *everything* should be taken in, digested and
> Marc> presented.
> 
> That would be a possibility of course, but wouldn't that mean that
> macrophages chew on the good stuff all day and destroy valuable
> proteins and cells along the way?
> 
> Axel

If you've read the post in this thread from Ian York, you will see some
good comments on this subject. I agree with him - cells are damaged and
die and as bits are available to be engulfed, so they are.  It's a bit
of a paradox in immunological dogma that the "non-self" pathway of
immune recognition also has to contend with "self" presented in that
way. But *HOW* could the phagocytic cell pcik things apart?? Well - as
Ian and Mark have said, they can't. Hence the t-cell deletion and t-cell
/ b-cell regulation in the development of a "self-deleted" repertoire. 


(signed) marc

In <6c0h5d$kpo@sjx-ixn11.ix.netcom.com> flefever@ix.netcom.com(F. Frank
LeFever) writes: 
>
>I'll post a more formal and detailed announcement later, but for
thosoe
>who must plan early for a trip to New York City, let me alert you to
>the New York Neuropsychology Group's 19th annual conference (joint
>meeting with the Psychology Section of The New York Academy of
>Sciences): "Neuropsychology and the Neuroimmune Dialogue"
>
>At NYU Medical Center, Saturday, May 2.
>
>PROBABLY will offer CE (psychol) & CME credits (applications pending).
>
>Will NOT involve the impressivbe level of detail some of you show
(e.g.
>in the thread re macrophages); rather, for neuropsychologists, a
primer
>and exposition of dimensions they have so far not considered well, and
>perhaps for immunologists some ideas regarding so-far unexploited
>possibilities for explanations of clinical/cognitive/behavioral
>phenomena, involving neural-immune-behavioral interactions at a more
>systemic level.
>
>Pending post of more formal announcements, details by FAX or snail
>mail, from:
>
>F. Frank LeFever, Ph.D.          FAX (914) 786-4978
>Helen Hayes Hospital            voice(914) 786-4110
>West Haverstraw, NY 10993       flefeverr@ix.netcom.com

Yes, CE credits for psychologists WILL be awarded (probably 6 hours);
CME credits likely, but still pending.

earlier, I wrote:


>>I'll post a more formal and detailed announcement later, but for
>thosoe
>>who must plan early for a trip to New York City, let me alert you to
>>the New York Neuropsychology Group's 19th annual conference (joint
>>meeting with the Psychology Section of The New York Academy of
>>Sciences): "Neuropsychology and the Neuroimmune Dialogue"
>>
>>At NYU Medical Center, Saturday, May 2.
>>
>>PROBABLY will offer CE (psychol) & CME credits (applications
pending).
>>
>>Will NOT involve the impressivbe level of detail some of you show
>(e.g.
>>in the thread re macrophages); rather, for neuropsychologists, a
>primer
>>and exposition of dimensions they have so far not considered well,
and
>>perhaps for immunologists some ideas regarding so-far unexploited
>>possibilities for explanations of clinical/cognitive/behavioral
>>phenomena, involving neural-immune-behavioral interactions at a more
>>systemic level.
>>
>>Pending post of more formal announcements, details by FAX or snail
>>mail, from:
>>
>>F. Frank LeFever, Ph.D.          FAX (914) 786-4978
>>Helen Hayes Hospital            voice(914) 786-4110
>>West Haverstraw, NY 10993       flefeverr@ix.netcom.com
>