Oldstone... weak Ab responses

[Guest guest]

> worked with LCMV. When mice are infected in utero or neonatally,

> the virus sets up a persistent infection and for a time

> (historically) it appeared that the virus managed not to provoke a

> humoral response. 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. Some LLMDs claim that anti-borrelia antibodies are

> difficult to detect because they are complexed with borrelia and

I'm

> pretty sure that that rationale can be ultimately traced back to

> Oldstone's work. The Ab-LCMV complexes cause glomerular nephritis

> and arteritis in these persitantly infected mice--which I did not

> know. He says these findings can be extended to other pathogens,

> like HBV, HIV, CMV and EBV, though he didn't give citations for

> this, and commercial ELISAs are available to detect anti-HIV and

> anti-HBV antibodies (if not the others), so I'm not sure if the

> pathogen-detectors are adding some sort of detergent to their

> cocktails to circumvent this problem, or what.

My weak and textbookish understanding is that B cells have an Fc

receptor. If they encounter their specific epitope already in complex

with an Ig, this complex will ligandize both the B cell's membrane-

bound Ig and the B cell's Fc receptor, cross-linking the two

receptors, and that this cross linking inhibits Ig secretion. So if

there are free antigen particles out there unbound by Ig, and there

are appropriate B cell clones, the B cells should be induced to pump

up their Ig secretion (assuming the Th2 help works out fine,

something I know nothing about). Presumably this homeostasis is

tilted a bit towards excess Ig secretion. Ideally this should ensure

that there is plenty of free Ig out there to get the job done, rather

than all the Ig being adsorbed. Something must be messing up that

ideal.

I've mentioned that the agonist Abs against acetylcholine-R

(myasthenia gravis) and TSHr (Graves') are missing in the fluids of 5-

10% of patients, and that adsorption of all the Ab onto said Ags has

been put forward as an excuse for this. In this case, this may be

very sensible, because these epitopes are found on a solid frame, the

cell surface. I think B cells are supposed to be inhibited when they

bind an antigen fixed to a solid frame. I don't know if that happens

only in negative selection, or can perhaps also factor into the level

of ergia and proliferation a clone experiences after it has already

passed through negative selection (as the activated clones against

actylcholine-r and TSHr obviously have). If so, frame-fixed antigen

may be able to take up Ab without contributing to the stimulation of

further Ab synthesis. Perhaps this could lead to weak Ab levels. (In

fact, you have to wonder how TSHr would ever end up solubilized at

all. Perhaps it's some different, cross-reactive epitope that

stimulates the anti-TSHr Ab?)

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

solid frame, perhaps something similar might occour. Somehow, though,

I vaguely sense there is probably going to be a problem somewhere

with this excuse, in the case of viruses, though maybe it's a good

excuse for the anti-TSHr case...

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

raised/established (you probably do), 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.