I am afraid to say that Janeway's theory of discrimination of
non-infectious self from infectious nonself is 100% incorrect. First let
me restate his theory (so that if you disagree you may claim that I
misunderstand him) and then provide the reasons he is wrong.
Janeway believes that the acquired immune system (i.e. lymphocytes)
borrowed pattern recognition receptors (i.e. for mannans, glycans, LPS,
poly I:C) from the natural immune system and employed them as inducers of
costimulatory signals on antigen presenting cells. As an example, LPS
induces the expression of B7-2 on B cells, and activated B cells are
potent stimulators of naive T cells. The experimental evidence he
provides for this is from a paper authored by himself and Yang Liu, where
they looked at the ability of B cells activated by LPS, poly I:C, and
perhaps other stimuli to serve as costimulatory APCs for the anti-CD3
mediated activation of CD45Rhi (naive) T cells. This paper shows that
such stimuli effectively turn B cells into good stimulators.
There are two reasons why Janeway is wrong. One is theoretical, and the
other is experimental. I will focus upon LPS as an inducer of
costimulatory signals.
1) LPS is derived from gram-negative bacteria. T cells have nothing to
do with the defense against gram-negative bacteria (as any AIDS patient
should gratefully attest to). If anything, the overstimulation of the
immune system by endotoxin is advantageous for the bacterium, not the host.
2) I and Polly Matzinger have shown that activated B cells expressing the
male antigen, H-Y, induce tolerance in naive, H-Y specific T cells.
We contend that Janeway's experimental mistake was to assume that CD45Rhi
T cells are naive.
You may now say that it is not sufficient to shoot down someone else's
theory, that you must provide one of your own (if only Bill Clinton would
take that attitude toward deficit reduction: OOPS, wrong newsgroup!).
For that I refer to Polly's nice presentation of our theory that the
immune system does not discriminate self from nonself, but is alerted by
non-physiologic cell death.
Ephraim Fuchs
ejf at welchlink.welch.jhu.edu
