Re: Oldstone... weak Ab responses

[Guest guest]

> Oldstone showed however that antibodies were

> produced, but they are complexed with the virus. I've wondered

> about this, and why other infections, by contrast, can be detected

> by ELISA. Unfortunately, he doesn't discuss the factors that

> influence this.

Stereochemistry likely holds the explanation. For an antibody to be

effective in setting off an immune system reaction, other parts of the

immune system have to bind to the back of the antibody after it binds to

the virus. There has to be space for this. If an antibody happens to

bind to a part of the virus which is overhung by some neighboring part of

the virus, such that nothing else can bind to the back of the antibody,

then the antibody will be ineffective.

[Guest guest]

>

> Anyway, if these viruses can express antigen on the cell surface,

a

> solid frame, perhaps something similar might occour.

I hadn't heard about how plasma cells regulate their production of

Ig. Very intesting. It does suggest an active effort on the part

of the pathogen to subvert that B cell feedback mechanism.

LCMV is not cytopathic, so it should display its glycoprotein on the

surface of infected cells for extended periods. This would be the

same glycoprotein(s) that would have to be the target of

antibodies. I'm guessing that could get the infected cell killed,

but maybe not if the cell was an IL-10-producing DC. Even if some

infected cells were killed by a paucity of antibody, I think the

persisting LCMV enjoys reasonable titers and could easily infect new

cells.

> Here's a separate idea. While I don't know how Treg clones are

> raised/established (you probably do),

I'm still learning the complexities. " Natural " Tregs leave the

thymus good to go. " Induced " Tregs are coaxed into the regulatory

phenotype after the fact, apparently by TGFb. Then there's Th3

cells, and another subset called, I think, Trl. I think maybe IL-10

can help generate one or both of the latter two subsets, but I'm not

sure. Presumably the infected DCs do more than just secrete IL-10,

but it probably hasn't been investigated much beyond that. The DCs

might have a tolerogenic phenotype generally, and might promote the

development of the iTregs. Surely it is one or more of the Treg

family that are hypnotizing the anti-LCMV T cells. I know

essentially nothing about the influence Tregs have over B cells,

though it seems to happen:

http://tinyurl.com/3xagng

it also seems like (totally

> speculating) both auto-Ags like TSHr and congenital viruses might

> reasonably be targets of Treg clones. Perhaps the activation of

some

> Th2 clone which is inhibited but not quite abolished by a cognate

> Treg, could result in a positive but very low activity of that

clone.

> Inadequate Th2 help might then result in cognate B cells putting

out

> a weak amount of Ab that gets completely adsorbed to Ag and is not

> properly replenished.

>

I still don't get the role that Th cells play in B cell help. Not

that I've looked very hard. Don't Th2 cells promote class switching

from something like IgG/IgM to IgA? Perhaps that's one way to

reduce the output of humoral antibodies--switch them to mucosal

antibodies. Just as there was a gap in the Th1/Th2 dichotomy, so

too does there appear to be a gap in this B cell help business,

though I'm not informed enough to justifiably advance such rumors.

Maybe the newly appreciated Th17 cells fill in the gap. I haven't

heard Boo about Th17s and B cells, but it's still early days.

[Guest guest]

That's an interesting theory. My question, though, is not on

efficacy, but abundance. Why aren't there enough surplus anti-LCMV

antibodies in a persistent infection to allow for the usual

detection? The antibodies that exist are complexed with virus

particles. What makes LCMV different in this respect? Different

enough to warrant the special, nearly obsessive interest that

immunologists seem to have for this mouse virus? The inability of

an antibody to neutralize a virus (what you're addressing) involves

pathogenesis. What I'm concerned about is clinical detection. Are

there infections in the human population that don't generate humoral

responses that would be observed by the casually constructed ELISA?

How prevalent would such infections be, and does LCMV serve as a

model for an intelligent guesstimate?

The ability of persistant strains of LCMV to infect DCs and render

them tolerogenic is so poetic that it would nearly demand, in my

mind, the existence of other examples. But what kind of fingerprint

would such pathogens leave? How would an investigator locate them?

You could turn the problem on its head and immunoprecipitate

putative virus particles. But how would you go about identifying

the viruses when you don't even know the family? Randomly prime

cDNAs, shotgun clone them and sequence en masse?

>

> > Oldstone showed however that antibodies were

> > produced, but they are complexed with the virus. I've wondered

> > about this, and why other infections, by contrast, can be

detected

> > by ELISA. Unfortunately, he doesn't discuss the factors that

> > influence this.

>

> Stereochemistry likely holds the explanation. For an antibody to

be

> effective in setting off an immune system reaction, other parts of

the

> immune system have to bind to the back of the antibody after it

binds to

> the virus. There has to be space for this. If an antibody

happens to

> bind to a part of the virus which is overhung by some neighboring

part of

> the virus, such that nothing else can bind to the back of the

antibody,

> then the antibody will be ineffective.

>

[Guest guest]

I guess I've been assuming that the body has some sort of mechanism for

increasing the number of antibodies when those antibodies successfully

find targets, and that if antibodies sort of disappear from view, the

body can get disappointed and give up on making more. I don't know what

such a mechanism might involve, though.

On Mon, Mar 26, 2007 at 03:38:19AM -0000, phagelod wrote:

>That's an interesting theory. My question, though, is not on

>efficacy, but abundance. Why aren't there enough surplus anti-LCMV

>antibodies in a persistent infection to allow for the usual

>detection? The antibodies that exist are complexed with virus

>particles. What makes LCMV different in this respect? Different

>enough to warrant the special, nearly obsessive interest that

>immunologists seem to have for this mouse virus? The inability of

>an antibody to neutralize a virus (what you're addressing) involves

>pathogenesis. What I'm concerned about is clinical detection. Are

>there infections in the human population that don't generate humoral

>responses that would be observed by the casually constructed ELISA?

>How prevalent would such infections be, and does LCMV serve as a

>model for an intelligent guesstimate?

>

>The ability of persistant strains of LCMV to infect DCs and render

>them tolerogenic is so poetic that it would nearly demand, in my

>mind, the existence of other examples. But what kind of fingerprint

>would such pathogens leave? How would an investigator locate them?

>You could turn the problem on its head and immunoprecipitate

>putative virus particles. But how would you go about identifying

>the viruses when you don't even know the family? Randomly prime

>cDNAs, shotgun clone them and sequence en masse?

>

>

>

>>

>> > Oldstone showed however that antibodies were

>> > produced, but they are complexed with the virus. I've wondered

>> > about this, and why other infections, by contrast, can be detected

>> > by ELISA. Unfortunately, he doesn't discuss the factors that

>> > influence this.

>>

>> Stereochemistry likely holds the explanation. For an antibody to be

>> effective in setting off an immune system reaction, other parts of the

>> immune system have to bind to the back of the antibody after it binds

>> to the virus. There has to be space for this. If an antibody happens

>> to bind to a part of the virus which is overhung by some neighboring

>> part of the virus, such that nothing else can bind to the back of the

>> antibody, then the antibody will be ineffective.

>>

>

>

[Guest guest]

> I guess I've been assuming that the body has some sort of mechanism

for

> increasing the number of antibodies when those antibodies successfully

> find targets, and that if antibodies sort of disappear from view, the

> body can get disappointed and give up on making more.

It's basically like that. But it doesn't involve recovery or detection

of released antibody bound to antigen. It involves antigen capture by

special membrane-bound antibodies present on the surface of the B cell.

Diversity in the hypervariable region of the antibody (which accounts

for its specific binding to a certain stereochemical epitope) is

generated by random alteration of the DNA. Every B cell unergoes its

own unique random DNA alterations, then posts a copy of the resulting

antibody on its surface to see if there is anything out there that

sticks to it. If something does, then the B cell starts secreting

antibody. But in order that autoantibodies not be generated, the B cell

first has to get permission from a Th2 cell, usually.

I think there may also be some special antibodies that pre-exist in the

genome and aren't produced by this random DNA alterations. I forget.

The adaptive immune system is pretty breathtaking. Imagine how hard it

must have been for this to (presumably) evolve. Yet, Mtb or some other

primative piece of crap hands you some molecule that causes you to

manufacture excess IL-10, and you rot like a log in the woods... so

there you go... nice adaptive immune system you've got there, quite

decorative and entertaining.

[Guest guest]

lol! Yeah, It's great to be Goliath, until you get hit with a little rock. :-) penny <usenethod@...> wrote: > I guess I've been assuming that the body has some sort of mechanism for> increasing the number of antibodies when those antibodies successfully> find targets, and that if antibodies sort of disappear from view, the> body can get disappointed and give up on making

more. It's basically like that. But it doesn't involve recovery or detection of released antibody bound to antigen. It involves antigen capture by special membrane-bound antibodies present on the surface of the B cell.Diversity in the hypervariable region of the antibody (which accounts for its specific binding to a certain stereochemical epitope) is generated by random alteration of the DNA. Every B cell unergoes its own unique random DNA alterations, then posts a copy of the resulting antibody on its surface to see if there is anything out there that sticks to it. If something does, then the B cell starts secreting antibody. But in order that autoantibodies not be generated, the B cell first has to get permission from a Th2 cell, usually.I think there may also be some special antibodies that pre-exist in the genome and aren't produced by this random DNA alterations. I forget.The adaptive immune

system is pretty breathtaking. Imagine how hard it must have been for this to (presumably) evolve. Yet, Mtb or some other primative piece of crap hands you some molecule that causes you to manufacture excess IL-10, and you rot like a log in the woods... so there you go... nice adaptive immune system you've got there, quite decorative and entertaining.

[Guest guest]

On Tue, Mar 27, 2007 at 04:07:13AM -0000, wrote:

>

>> I guess I've been assuming that the body has some sort of mechanism for

>> increasing the number of antibodies when those antibodies successfully

>> find targets, and that if antibodies sort of disappear from view, the

>> body can get disappointed and give up on making more.

>

>It's basically like that. But it doesn't involve recovery or detection

>of released antibody bound to antigen. It involves antigen capture by

>special membrane-bound antibodies present on the surface of the B cell.

>

>Diversity in the hypervariable region of the antibody (which accounts

>for its specific binding to a certain stereochemical epitope) is

>generated by random alteration of the DNA. Every B cell unergoes its

>own unique random DNA alterations, then posts a copy of the resulting

>antibody on its surface to see if there is anything out there that

>sticks to it. If something does, then the B cell starts secreting

>antibody. But in order that autoantibodies not be generated, the B cell

>first has to get permission from a Th2 cell, usually.

Part of that permission has to do with cells that have phagocytized

intruders passing information about those intruders to T helper cells.

Isn't it more likely for an intruder to be phagocytized if it has

antibodies sticking to it?

[Guest guest]

> Part of that permission has to do with cells that have phagocytized

> intruders passing information about those intruders to T helper cells.

> Isn't it more likely for an intruder to be phagocytized if it has

> antibodies sticking to it?

Yes... opsonization they call it... from the Greek meaning to prepare

something as a meal or something like that. Some phagocytosis can

generally occur without opsonization. Some varmints have a

polysaccharide capsule that makes them highly refractory to

phagocytosis without opsonization, but I don't know if that can push

the phagocytosis down far enough to impair T cell response.

Plus, there are certain circumstances under which B cells can produce

Ab in a " T cell independent " fashion. I think this is especially likely

to work against very abundant surface antigens.

Also, there are certain Abs in most peoples' blood that will hit

pathogens they've never been exposed to. I think some of them are low-

specificty... and some might be germ-line encoded (again, I forget)...

or they may be cross-reactive ones from prior infections, as

polysaccharides and peptidoglycans etc from different bacterial

miscreants tend to have certain similarities.

[Guest guest]

On Tue, Mar 27, 2007 at 07:32:49PM -0000, wrote:

>

>> Part of that permission has to do with cells that have phagocytized

>> intruders passing information about those intruders to T helper cells.

>> Isn't it more likely for an intruder to be phagocytized if it has

>> antibodies sticking to it?

>

>Yes... opsonization they call it... from the Greek meaning to prepare

>something as a meal or something like that. Some phagocytosis can

>generally occur without opsonization. Some varmints have a

>polysaccharide capsule that makes them highly refractory to

>phagocytosis without opsonization, but I don't know if that can push

>the phagocytosis down far enough to impair T cell response.

Sorry, I didn't complete the thought there. What I'm driving at is that

this seems to give a feedback loop: antibody finds target, target gets

eaten, eater digests target and presents its antigens to T helper cells,

and T helper cells tell B cells to make more antibodies. If the loop

were interrupted by antibodies sticking to a target in a place that

phagocytic cells could not see, then there might be few antibodies made,

total -- few enough that all the ones made might end up stuck to targets

without being effective.

[Guest guest]

Ah yes, now I see what you mean.

> Sorry, I didn't complete the thought there. What I'm driving at is

that

> this seems to give a feedback loop: antibody finds target, target gets

> eaten, eater digests target and presents its antigens to T helper

cells,

> and T helper cells tell B cells to make more antibodies. If the loop

> were interrupted by antibodies sticking to a target in a place that

> phagocytic cells could not see, then there might be few antibodies

made,

> total -- few enough that all the ones made might end up stuck to

targets

> without being effective.

>