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kinetic proofreading mechanisms [10-12] during the scanning of APC ligands.
Although, strong discrimination can be achieved during an intercellular interaction,
this is likely insufficient in establishing a reliable and safe discrimination of self and
nonself.
Broadly, there are usually two points of view regarding how a binary response to
a pattern can result in a functional immune system: Either that this discrimination
may be imperfect [2, 8, 9] and hence killing self cells happens at a certain rate,
even in the absence of antigen, or that alternatively it is assumed that a certain
pattern (which can even be the ubiquity of certain peptides) allows perfect
discrimination. Both these approaches raise questions that only future research may
clarify. For instance, the notion that some cells are killed 'by mistake' is inefficient
and requires a continuous supply of new cells. This in turn requires functional
selection of, for example, T cells throughout adult lifetime, perhaps using the adult
thymus. It remains uncertain how adult thymus involution can be compatible with
this (discussed further in [2]). The notion that patterns can perfectly define self and
non-self is not easily reconcilable with evidence that pathogens can often mimic self
patterns. In addition it is unclear how immune cells would robustly coordinate their
responses and minimize the existence of holes in shape space (that is, regions of non-
self peptide sequences not covered by any immune cell) [8, 9, 13], while keeping
autoimmunity to a minimum.
Here, motivated by some recent experimental findings in immunology and a recent
theoretical work in evolutionary biology, we derive a new conceptual framework to
understand how an adaptive immune system could work. Self and nonself emerges as
a whole system property: the self is defined as the set of cells that can keep short lived
intercellular contacts, without ever mounting an immune reaction. Our assumptions
require the introduction of a new concept, cellular frustration. Cellular frustration
enables accomplishing two apparently incompatible tasks, namely, a highly specific
and sensitive reaction against nonself, together with the possibility of maintaining
absolute tolerance in the absence of the antigen.
2 What Is Cellular Frustration?
Frustration can be simply understood through the following example: Can one be
friends of two mutual enemies? Frustration arises because no stable configuration
exists that simultaneously satisfies all the elements interacting in the system.
Consequently, the system fluctuates among several possible configurations. Frustration
has already been studied in the context of immunology by Bersini and Calenbuhr [14,
15], who showed that a frustrated idiotypic network could display rich dynamics with
chaotic behavior, and that frustration in these systems helped maintain tolerance after
antigen detection.
In the present work frustration operates in a different way and with a different
purpose. The mechanism we propose received inspiration from a work discussing the
origin of species [16]. These authors showed that robust reproductive barriers emerge
especially when no barriers exist at the level of individual mating rules. This
apparently paradoxical result resulted from the existence of a complex (competitive)
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