DISCUSSION FORUM
doi: 10.1111/j.1365-3083.2008.02159.x
..................................................................................................................................................................
Beginning of the End of (Understanding) the Immune
Response
Z. Dembic
Abstract
Department of Oral Biology, University of Oslo,
Oslo, Norway
Received 13 June 2008; Accepted in revised
form 3 July 2008
Correspondence to: Dr Z. Dembic, Department
of Oral Biology, University of Oslo, PB 1052
Blindern, N 0316 Oslo, Norway.
E-mail: zlatko.dembic@odont.uio.no
The algorithm about the workings of the immune system should incorporate
in its basic form the ability to explain several basic features: the ability to
reject pathogens, to respond differently to invasions by class switching, to
retain memory of rejecting past infections, the regulatory T-cell formation and
the acquisition of a life-long antigen tolerance in adults. The Danger and the
two self–non-self theories – Pathogenicity (Janeway) and the Associated Antigen Recognition (Langman and Cohn) – cannot explain satisfactorily one or
more of these issues. By failing to find appropriate solutions to help their corresponding basic algorithms to be operative, these theories negate, instead of
finding explanations (no matter how complicated) for interpretations of certain
results, one of them being the existence of a regulatory cell as a physiological
component of the immune system. On the other hand, the integrity model can
incorporate regulatory T cells in a basic algorithm of the workings of the
immune system, explaining it as a downregulation of the immune response
provided advantageous commensalism prevails over disadvantages of parasitism.
According to the Danger (Matzinger) [1, 2] and Integrity
(Dembic) [3–6] models, the immune system (at least
comprising dendritic cells, macrophages, granulocytes,
NK, B lymphocytes, plasma and T cells) distinguishes
damaged from healthy tissue, and uses this information
as an alarm that allows the activation of naive T or B
cells via antigenic peptides or antigens respectively. In
the Pathogenicity hypothesis (Janeway) [7–9], the
immune system gets activated by discriminating between
self and non-self provided and alarm is sounded via recognition of pathogen-specific molecular patterns by the
innate immunity. The latter hypothesis, however, ignores
signals emanating from any damaged tissue. Similarly,
the control of the immune response is supposedly intrinsic (i.e. tissues do not control the extent of the immune
response, as it is the case according to the Danger [2] and
Integrity hypotheses [5, 6]). The extent and cessation of
the response as well as the memory formation remains
solely under the control of the initial interactions of cells
enabling peptide ⁄ MHC–T-cell receptor and antigen–Bcell receptor interactions (as opposed to tissue control of
the immune response in the Danger and Integrity models). In another self–non-self recognition hypothesis – the
Associated Antigen Recognition by Langman and Cohn
[10, 11], and as discussed by Cohn [12] and in this issue
(Cohn, discussion forum), the self–non-self discrimination
[13] is at the core of the B- and T-lymphocyte activation,
which effectively neglects, as a principle, the pathogen
recognition via molecular pattern receptors, as well as the
alarm from the damaged tissue. I believe this represents
an older view of the function of the immune system, and
is, basically, an oversimplification.
The complexity of tissue interactions and cellular signalling in our body is extensive, especially in the immunological and neurological systems, but luckily – finite,
because it is determined by the number of functionally
active genes. A computer model of the immune system
should, besides the simplest basic working algorithm,
allow an implementation of such complex interactions. It
seems that an oversimplified algorithm (such as presented
in this issue by Cohn) can put restrictions on the workings of the immune system, such as the impossibility of
the ‘regulatory T-cell’ formation, acquisition of a lifelong antigen tolerance later in life and effector cell-type
switching. I see a problem with this, because out of these
three only the last one can be allowed by the additional
arguments to the basic algorithm. So, one out of three
that can be explained (with a complication) is bad. In
fact, the first two issues are denied to be real, because
their existence would falsify the theory! How can we then
explain the observations to the contrary? Why do the
regulatory cells seem unreal and why do liver transplants
2008 The Author
Journal compilation 2008 Blackwell Publishing Ltd. Scandinavian Journal of Immunology 68, 381–382
381
382 A Response to Cohn, 2008
Z. Dembic
..................................................................................................................................................................
that can stay as ‘self’ throughout the lifetime of patients
pose like some fantastic achievements? Are those reports
really bad interpretations of our results and experimentations, or are we just too proud to admit that we were
wrong in accepting the self–non-self theory in the first
place, or for that matter any theory that forbids such
explanations?
Perhaps, if we compare how the above-mentioned
hypotheses treat these two ‘impossibilities’, we might be
closer to an answer. The Pathogenicity and other alarm
evoking hypotheses (Danger and Integrity) allow effector
class switching in its simplest ‘algorithm’ (according to
my understanding). The Danger and Integrity hypotheses, but not the Pathogenicity, allow life-long tolerance
formation. However, only the Integrity hypothesis allows
the regulatory cell formation. Why does the Danger (and
all other) model(s) negate the suppressors? Well, it boils
down to the Integrity model algorithm that, in its simplest form, allows symbiosis or commensalisms, whereas
the Danger model treats all foreign micro-organisms as
potential dangerous matter (and the other theories, as
non-self). Consequently, if micro-organisms do damage,
they are dangerous, but if they provide beneficent properties, there is no signal in the Danger theory that can
allow protection of that benefit. The same is true for
self–non-self hypotheses. The Integrity hypothesis, on the
other hand, by allowing in the algorithm the protection
of micro-organisms that benefit a larger organism, makes
possible an explanation for the formation of regulatory
cells! The signals from damaged tissue due to invasion of
micro-organisms can be counteracted by positive signals
from a tissue. These could transmit ‘profit’ or some selective advantage for particular organism that possesses an
immune system. The immune system would be able to
translate such messages and generate a protection for such
beneficent micro-organisms. If we can accept such an
understanding, then we might rename the immune system into a guardian (gate keeper) system. And, then we
might begin to understand the last and the most recently
discovered property of the immune system – the regulatory T cell.
References
1 Matzinger P. Tolerance, danger, and the extended family. Annu Rev
Immunol 1994;12:991–1045.
2 Matzinger P. Friendly and dangerous signals: is the tissue in control? Nat Immunol 2007;8:11–3.
3 Dembic Z. Do we need integrity? Scand J Immunol
1996;44:549–50.
4 Dembic Z. Immune system protects integrity of tissues. Mol Immunol 2000;37:563–9.
5 Dembic Z. Response to Cohn: the immune system rejects the harmful, protects the useful and neglects the rest of microorganisms.
Scand J Immunol 2004;60:3–5.
6 Dembic Z. The function of toll-like receptors. In: Rich T, ed. Toll
and Toll-Like Receptors: An Immunologic Perspective. Georgetown: Landes ⁄ Eurekah.com and Kluwer Academic ⁄ Plenum Press, 2005:
18–55.
7 Janeway C Jr. Approaching the asymptote? Evolution and revolution in immunology. Cold S Harb Symp Quant Biol 1989;54:1–13.
8 Janeway C Jr, Medzhitov R. Introduction: the role of innate immunity in the adaptive immune response. Semin Immunol 1998;10:
349–50.
9 Medzhitov R, Janeway C Jr. Innate immune recognition: mechanisms and pathways. Immunol Rev 2000;173:89–97.
10 Langman RE, Cohn M. Two signal models of lymphocyte
activation? Immunol Today 1993;14:235–7.
11 Langman RE, Cohn M. Cutting edge: terra firma: a retreat from
‘‘danger’’. J Immunol 1996;157:4273–6.
12 Cohn M. Does the signal for the activation of T cells originate from
the antigen-presenting cell or the effector T-helper? Cell Immunol
2006;241:1–6.
13 Bretscher P, Cohn M. A theory of self–nonself discrimination.
Science 1970;169:1042–9.
2008 The Author
Journal compilation 2008 Blackwell Publishing Ltd. Scandinavian Journal of Immunology 68, 381–382