cells bearing receptors that bind to self-
antigens at a certain level of affinity or
above are eliminated. This is known as
negative selection. At the end of this
process any receptors that remain can
only be activated by foreign pathogens
[1,14].
This is a classical reductionist theory
that is extremely elegant and simple. It
explains how we create a repertoire,
which on the one hand can identify
pathogens and yet does not react falsely
with our body’s molecular patterns. It is
also a very mechanistic way of viewing
the workings of the immune system.
One major implication of this theory is
that autoimmunity—the reaction of im-
mune receptors to self antigens—is
something that exists only as a pathol-
ogy and never in a properly functioning
immune system or a healthy body. Even
if we were not about to show that the
immune system works like a cognitive
system, there is a major problem with
this theory. The elimination of self-
repertoire completely ignores other
functions of the immune system that
are essentially involved with self, such
as wound healing and combating
cancer [2,15].
Several generally known aspects of
immune detection, agreed on even by
the most ardent supporters of the clonal
selection theory, seem to imply that the
immune system is working as a cogni-
tive system: First, the need for costimu-
lation of B cells and T cells for immune
reaction [12], and second, the fact that
B cells are reacting to extracellular in-
formation, whereas T cells react to in-
tracellular information. Together these
appear to imply an immune reaction to
patterns and context.
Treating the immune system as a
cognitive system, the idea of building a
repertoire in the way suggested by the
clonal selection theory becomes less
plausible. The immune system’s envi-
ronment is built completely of cells
both endogenous and exogenous,
which at the time of encounter are re-
siding in the body. Also, all of this cel-
lular and viral life is built of similar
building blocks. There is no intrinsic
molecular signal that differentiates be-
tween the organic substances of our
body and those of other organisms. Re-
moving all receptors to self amounts to
removing all receptors to all of the
things that are common to all cellular
life. Building a system that needs to rec-
ognize the important aspects of this en-
vironment but is blind to the general
properties (which are those things that
are ubiquitous in the environment) is
like building a human visual system
that can not become aware of edges.
We are suggesting a model of the im-
mune system as a cognitive system.
This implies several things about the
way the immune system is primed and
how it detects its environment (see Fig-
ure 1). As we showed for vision and lan-
guage, the priming of the system and
building of the achieved set of represen-
tations starts by fulfilling innate sys-
temic biases or tendency. In this case,
this would probably be a genetically
transferred tendency to present certain
protein examples that are used to build
the receptor repertoires. These useful
examples would, as in vision and lan-
guage, be examples of the general prop-
erties of the living molecular environ-
ment. They should, therefore, be ex-
amples of self that cause a positive
selection of receptors with at least some
minimal affinity to these examples.
We would, therefore, expect to find
that, from the first randomly generated
stock of receptors, the adult repertoire
of immune receptors are created by a
combination of positive and negative
selection using specific molecular ex-
amples of self.
Part of the reason that the clonal se-
lection theory is being forced to change
is that positive selection is apparently
important for the creation of the mature
repertoires in both B cells and T cells
[16,17]. This is especially evident in T
cells. One form of positive selection is
agreed on for T cells, even by the clonal
selection theory. T cells must have a
minimal affinity for at least one self an-
tigen—MHC receptors—if they are to
function. However it appears that the
recognition of self-MHCs is not the only
kind of self-recognition that is neces-
sary for proper T-cell development, in
fact the proteins nested in the MHCs,
while selection is in process, affect the
positive selections outcome [18]. Fur-
ther, it has been shown, using genetic
engineering techniques, that an im-
mune system built with fewer kinds of
fragments presented by MHCs, within
the context of positive selection, will
have a less diverse T-cell repertoire [18].
The selection of T cells within certain
boundaries of affinity to MHC receptors
and the fact that MHC receptors only
present the fragments of certain pro-
teins [11], together show a possible
mechanism by which the immune sys-
tem creates an important bias toward a
certain population of examples while
creating the repertoire of receptors.
What are the “useful examples” pre-
sented by the MHCs bias? The exact
types of proteins, fragments of which
are presented by MHC, have not yet
been characterized. However, let us
consider, given a tendency, what would
constitute the useful examples that are
corroborated, and what is the environ-
ment for which they create an achieved
set? As we mentioned before, the envi-
ronment of the immune system is the
body’s cellular life. Candidates for “use-
ful examples” would have to have the
following properties: they would have
to be part of every cell; they would have
to have been there all through the his-
tory of the development of the immune
system for them to be such a major part
of its function; they should be relevant
in times of stress (or otherwise they
cannot serve extreme conditions usu-
ally common in immune response).
Indeed, it is possible to find such a
set. The set corresponds to a group of
antigens Cohen has named “homuncu-
lar antigens” [2], and all belong to a
group called housekeeping or mainte-
nance proteins. Housekeeping proteins
are essential in all cells, because they
are responsible for ongoing energy me-
tabolism, protein construction, and ba-
sic genetic manipulations.
One group of housekeeping proteins
of special interest is called heat shock
proteins (HSPs). HSPs are part of a
larger group of proteins called chaper-
ones, which are essential in correct pro-
tein construction and folding. HSPs
help cells maintain the proper form
(and function) of proteins in various
© 2001 John Wiley & Sons, Inc.
CO M PLEXITY
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