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also suffer from fragility as a trade-off. This may seem contradictory, but robustness
in this sense means stability in the face of reasonable changes. For example, the
complex autopilot system of a passenger airplane maintains a given flight path while
being robust against changes in atmospheric conditions. The system is inherently
fragile, however, to unexpected extreme events such as complete engine failure
(Kitano 2004). The same applies to biological systems where robustness allows
buffering against environmental changes and perhaps more importantly against small
variations in genotype representing interindividual differences. Therefore, inter-
individual variations will not necessarily
they are catastrophic defects, for example deficiency in the enzyme adenosine
deaminase leading to Severe Combined Immunodeficiency (SCID) in children, or
unless they affect the dynamics of the system, for example susceptibility to
mycobacterial and
Salmonella
infections in individuals with defects in the IL-12
receptor. Both types of events can therefore define disease (Kitano 2004)
Systems control consists of a number of principles of which positive and negative
feedback mechanism are well known in the immune system. Negative feedback is the
main method of control that enables a robust response buffered against noise and
perturbations. From this point of view, DCs sensing PAMPs might exhibit negative
feedback control to buffer against differences in PAMP signaling intensity and strength
allowing maintenance of a fixed time-dependent maturation program. Positive
feedback contributes to a robust system by amplifying stimuli and often results in the
phenomenon of bistability. This occurs in signal transduction/transcription settings
when for a given range of input stimuli only a modest increase in transcription occurs,
but for a different, higher range of input positive feedback results in a large increase in
transcription. This in effect produces a bistable switch (Fig. 4). The modeling of T
H
1
and T
H
2 stimulation by Yates et al. clearly shows how the influence of bistable switch
controls T
H
1 or T
H
2 polarization (Yates et al. 2004), making the induction of a state
change from naïve to polarized T-cell insensitive to the absolute level of initial input
signals provided they are above a switch threshold.
Positive feedback bistability is therefore important for a robust immune
response allowing both the amplification of variable input signals as will occur
through differences in receptor affinities and signaling intensities in inter-individual
variation. Positive feedback bistability should also allow a layer of functional
redundancy in combinatorial signaling cascades where the absence of one
component of a signal can be compensated for by increasing other components to
achieve the desired switch threshold. In both cases a robust and consistent output is
conferred from variable level inputs. The system breaks down and disease occurs
when a switch threshold is not reached. How to investigate relative inputs and switch
thresholds represents a considerable challenge, but it is possible that experiments and
models of viral interaction with DCs may prove particularly informative.
affect the functioning of the system unless
.
