Scand. J. Immunol. 44, 549–550, 1996
REVIEW COMMENTARY
Do We Need Integrity?
Z. DEMBIC
Institute of Immunology and Rheumatology, Oslo, Norway
This paper could stimulate an interested reader of theoretical
immunology to a great extent. I believe that many would profit
from the opportunity to reconcile their own views (positively or
negatively) with those put forth in this paper. My opinion is that
the separation of theories about immune recognition in space and
time seem to be inappropriate, over reduced and too general.
From Einstein we have learned that time can only exist if there is
space (matter) and vice versa. Thus, the argument about the
differences between models and levels of sophistication (time
models being the only viable possibility) can barely be supported
by such simplification and slice analysis (of time). The models
should be dealt with in their full complexities if a unifying theory
of the immune system is to be built. The authors state that the
division of antigens into two kinds, self (S) and nonself (NS), is
biochemically impossible but immunologically possible. Thus,
our biological system has to develop a defence strategy which
needs time, and is under pressure to develop specificity. This
might simply not be true, because it is not obvious that the shift
from the biochemical to the biological level is qualitative in
discriminating antigens, and there is no need to fight the
unknown. There are other models in existence which explain
that a qualitative switch between the biochemical and biological
levels is possible only via signals.
I suggest that the basic function of the immune system is to
discriminate between signals for ‘‘integrity’’ (of a tissue, organ
or organism) on the one hand, and disruption of homeostasis, on
the other. Differences between self/nonself antigens are classified as such only by the outside viewer and not by the cell which,
I believe, needs additional signals (grouped as Signal[3]) to make
use of them. These signals are not necessarily simple markers of
S and NS, but might comprise a network of molecules and
soluble mediators. If a cell which can be activated and tolerized
binds S, it reacts and undergoes apoptosis if the integrity of the
tissue is not interrupted. The disruption of integrity provokes
Signal[2]: co-stimulation for T cells and T-cell help for B cells.
The inclusion of this third Signal[3] (like danger/Signal[0] in P.
Matzinger’s model) adds to the complexity of the mechanism,
but is in essence an initiator of Signal[2] and at the same time a
modulator of Signal[1]. Because of the duality in the third signal,
Correspondence: Dr Z. Dembic, Institute of Immunology and Rheumatology,
Fr. Qvamsgt 1, 0172 Oslo, Norway.
q 1996 Blackwell Science Ltd
Signal[2] can be indirectly associated with the nonself. In the
case of T cells, this situation can accommodate the generation of
specificities and dissociation of Signal[2] from the antigenspecific cell (more detailed explanation to follow below). For
B cells, Signal[2] comes from the antigen-specific cell (T-cell),
as in the Langman & Cohn model.
Therefore, if there is a lack of necessity for the immune system
to differentiate between self and nonself antigens when monitoring signals of inner balance, why does the specificity evolve?
Once the system has been alerted, the component of the dual
Signal[3] which can modulate Signal[1] drives the elimination of
the pathogen and requires specificity. The successful elimination
is a selective pressure under which simple and complicated
immune repertoires have developed, including those (probably
in the following order) of phagocytes, NK, gd-T, ab-T/B cells;
the differences reflecting the spatial shifts of selection as the
pathogens try to evade and win over the immune response, and to
gain access to the organism. The most successful have learned
how to mimick integrity signals, which we perceive as a loss of
pathogenicity, and tolerance. For the same reason tumours are
recognized as part of an individual. Signal[3] causes activation
and should be the oldest on the evolutionary scale; it can be
thought of as a marker for nonself and as such underlies the
indiscriminate repertoire of phagocytes. With the precedent of
NK cells, Signal[1] emerges on the evolutionary clock as a
deactivating signal because NK cells do not kill in the presence
of Signals[1] and [3], but do so if there is a lack of Signal[1]. For
example, Signal[1] is the recognition of self-MHC molecules and
Signal[3] might be IFNa. These signals are markers of S and NS
and require limited specificity, as seen in the repertoire of NK
cells. With T and B cells another activating signal is introduced:
Signal[2], a novel marker for nonself. The generation of specificities depends on the variability of Signal[2]. Since it has been
put under the control of Signal[3] its variability became conditional, and so it shifted the nonself marker to Signal[3].
Signal[3], in turn, shifted the marker to Signal[1] because it
made antigen presentation possible. Thus, Signal[3] assumed a
dual nature, as it can initiate Signal[2] and modulate Signal[1]. It
follows, therefore, that T and B cells are controlled by Signals[1]
and [2] which suffice for the generation of diversity. The
question of the nature of the third signal remains open. It may
be as complex as the signals involved in homeostasis are
expected to be. Disruption of these would generate the third
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550 Z. Dembic
signal. Disruption of Signal[1] or [2] cannot be considered as the
third signal, and the lack of them will, respectively, paralyse or
tolerise the immune system. The probability of residual anti-S
cells to cause self-damage in the ‘integrity’ model is equivalent
to that in the S-NS discrimination model because during the life
of an individual, anti-S cells are constantly pacified with one of
the signals of self-integrity, namely Signal[1].
The belief of S-NS discrimination as advocated by Langman
& Cohn is based on the importance of preformed defence, in
order to preserve ourselves. The belief in discrimination of the
signals, as suggested above, is a refinement of the same and the
model by Matzinger, but it shuffles their basic axiom: the
immune system helps to preserve the state of balanced integrity
of signals within any tissue, bodily part, or organism, and by
doing so it learns to discriminate when disturbed. In conclusion,
the reason why the immune system functions is the fundamental
need to preserve self signals and not to discriminate the nonself
from self, which is merely a consequence.
The Editors have also asked other scientists to comment further
on the Review by Langman & Cohn.
Their commentaries will appear in a future issue of the Journal
together with a Commentary by Langman & Cohn.
q 1996 Blackwell Science Ltd, Scandinavian Journal of Immunology, 44, 549–550