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Opinion
Flushing out the phlogiston ......?
Keywords: Animal; Apoptosis; Cell
Communication; Complement; Evolution; Gap Junctions; Homeostasis; Human;
Hypothesis; Immunologic Surveillance; Immunity, Natural; Models, Biological;
Models, Immunological; Necrosis; Phagocytes; Self Tolerance
Abstract
Huge advances have been made in unravelling the detailed
interactions of immune cells and their products. Nevertheless, there is still
fierce debate and difference of opinion about the grand plan - the logical
structure - of the 'immune system'. The reason may be that an 'immune system' (a
foreign organism seeking system) is just as illusory and non-existent as
phlogiston. In a series of articles, I have progressively moved to the
conclusion that the system is not an 'immune' but a 'morphostatic' (tissue
homeostatic) system. This article tidies up the concept and explores further
ramifications of the principle.
Quotations
‘Nothing in biology makes sense except in the light of
evolution’ – T. Dobzhansky, 1977
"Immunology is an invention of the devil, who is making it
up as he goes along because he's not too clear about this stuff either.". . . .
. "Besides, immunology is what we North Americans call a Rube Goldberg system,
referring to old cartoons about how to turn on the light, for example: you trip
over a footstool, thus startling the cat, who bumps into the kitchen door, which
swings shut, knocking over a chair that hits the light switch . . . you get the
idea. There has to be an easier way." – Janice H Tanne, 1990
Introduction
In metazoans, the first 'immune' cell to evolve was the phagocyte. This cell
clears away the 'mess' that accumulates within each colony of cells that
constitutes an animal (the zygote derived colony). It also encourages the
regeneration of lost tissues. It is a general assumption that vertebrates have
evolved an immune system that is 'designed' to identify and eliminate foreign
organisms.
Whilst invading, foreign organisms are undoubtedly a major threat to
morphostasis we need to remember three things. First, the tissue debris that
accumulates from degenerating cells is an essential resource for pathogenic
organisms. A prime strategy for the morphostatic system is to operate a
"scorched earth" policy (an impeccably clean extracellular environment) to deny
foreign organisms a suitable substrate for growth and reproduction. Second,
pathogenic organisms need to create extra- or intra-cellular debris to satisfy
this need for a substrate. A substantial part of a pathogenic organism's genome
is dedicated to this role and this probably leads to its reduced survivability
in a saprophyte's preferred environment. Third, dedicated, intracellular,
pathogenic organisms need to get themselves invited in and it seems likely that
the provocative display of so called PAMPs (pathogen associated molecular
patterns) might be their chosen (Trojan horse) strategy.
So, it may be possible to restructure our perception of immune cell function
so that it now champions 'the clearance of tissue mess' as the real raison
d'ętre - the grand plan - of the system. By this view, foreign organisms are
only noticed because they appear to the system as mess or they provoke a tissue
mess that triggers clearance. If this perspective is valid then it would no
longer be justified to regard, as heresy, the counterintuitive assertion that
"there is no such thing as an immune system". It might even show us some
shortcuts to establish what each element of the system has evolved to do. The
provocative title of this article implies that we may be witnessing a
conceptual-Jack-in-the-Box that will trigger an unfolding revolution in our
understanding of immune function.
This article condenses and extends concepts from previous papers (Cunliffe,
1995, 1997, 1998, 1999) into a synopsis so new references are kept to a minimum.
It is dominantly theoretical so readers must decide, for themselves, which
conjectures are valid and which are flawed.
The evolution of morphostasis
- Let us look at the sequence of 'shells' that eventually form the mammalian
'immune system' (Cunliffe, 1995, 1997). All the shells remain fully functional
and continue to fulfil their original purposes. None are abandoned. They are
layered around each other like the layers of a Russian doll. They are also
used in the same sequence - the inner layers first. Each layer will either
manage or fail to resolve the problem. Failure to resolve the problem will
promote the response to move out to the next shell. These form a barrage of
defence lines to counter mess. When a defence line fails, the system
retrenches to the next line of defence.
- In the beginning, heat shock proteins identify - then attempt to repair -
protein trash; ubiquitins escort terminally malformed proteins off the
premises; endosomes chop them up into short peptides.
- Elective suicide (a forerunner of apoptosis) evolves as a mechanism to
limit the spread of rampant disease through a colony. A similar strategy is
even used in colonial bacteria.
- Cell adhesion molecules (CAMs), surface associated molecules and
intercellular junctions evolve. These give cells a sense of
'belonging-to-the-colony' and enable them to dock with one other. This is a
discrimination of self from non-self. It remains the fundamental root of
'self'-'non-self' discrimination in mammals.
- Homeotic genes allow cells to adopt alternative (cellular) body plans.
When gap junctions evolved (about 700my ago), they (somehow) enabled
alternative, homeotic body plans to expand their sphere of influence to cover
blocks of cells interconnected by bridges of cytoplasm - so enlarging the body
plan. It also enabled the simultaneous use of several body plans within the
zygote derived colony.
- A primitive metazoan will require the following of its component cells:
when the well being of a cell is compromised it will be expected to detach
itself from the colony and it may be extruded from its immediate grouping. It
may re-attach provided it fixes the damage. If not, it will be expected to do
the decent thing, sanitise its contents (by trashing them) and then invite its
own gentle absorption by surrounding cells. Lost cells will be replaced
through cell replication. Individual cells are expected to monitor and
maintain their own health. If they cannot identify that they are
malfunctioning, and so go on to spill their cytoplasms, then they can expect
no mercy from the surrounding colonial (self) cells. Such sick cells are
potentially dangerous. They will be aggressively attacked by dedicated
phagocytes and cleared away together with their spilled contents.
- What has changed in mammals? Nothing - not, at least, as far as the grand
plan is concerned; but the system has since been elaborated to enhance the
intracellular destruction of suspect cells. It does so by encouraging
particular cells - those that sport a caricature resembling cells that spilled
their contents on a previous occasion - to adopt a lowered threshold to
apoptosis.
- Phagocytes pay little attention to cells that are in junctional
communication with each other. These cells are stable and healthy. Phagocytes
concentrate their attention on the suspicious group that have detached
themselves or that were never attached in the first place (interlopers). They
use a docking system to attach their uropod to an underlying block of
communicating cells. They (probably) check, with their lamellipods, that
adjacent cells are in (pulsatile?) ionic continuity. This docking by the
uropod has low specificity. It is able to attach to allogeneic and even
xenogeneic cells. Dedicated pathogens may find ways of fooling this
surveillance.
- Natural killer-(NK)-like cells evolve as an extension of this
low-specificity recognition. Using CAMs already evolved to enhance 'neural'
interconnections (probably IgSFs, N-CAM-like), they learn to enhance
recognition of detached cells so that this becomes more specific to the
individual. By hanging representative peptides off the cell surface, in
association with an N-CAM-like molecule (Mhc class I like), local
accumulations of these cells can sense when there is a significant deviation
away from a healthy-self, Mhc+peptide signature. The pleomorphism of this
identity system and its germline receptor mechanism (possibly enhanced by RNA
splicing) can gradually expand from two to numerous different specificities.
Possession of selfness ensures that a cell will not be attacked; its absence
or loss ensures that it will. This system is adept at recognising the internal
cell turmoil stirred up by successful Trojan-horse invaders. Should any
detached cells still go on to lysis, the next stage will be invoked. Note that
Tc cell activity is a functional inversion of this NK-like activity.
- Tc-like cells can now evolve. Detached cells that die by apoptosis have
proven that they are able to deal with whatever caused their malfunction.
ClassI+peptide epitopes hung off the cell's surface allows the respective Tc-cell
receptor to get a snapshot of the turmoil that is going on in the cytoplasm of
that sick cell. Cells that sport a caricature, similar to cells that
previously died by apoptosis, can be safely left to get on with it by
themselves; but cells resembling those that spilled their cytoplasmic contents
last time round have proven that they cannot. On any new encounter, they need
to be recognised and encouraged into an early apoptosis.
- A key point to grasp is that it matters not one jot whether the
Mhc+peptide signature is formed dominantly from peptides derived from self or
from some foreign intracellular nasty. A precursor Tc cell that is able to
recognise this combinatorial epitope will classify the encounter according to
an association with tidy (apoptotic) or messy (leaky) death. A previous
encounter in a generally messy environment will encourage an aggressive
response in the future. Paratopes interacting with Mhc+self-peptide are
relatively resistant to an easy promotion into aggression. The staggeringly
enormous volume of successful apoptosis that occurs naturally in the body mops
up precursor T-cells, capable of responding to the presented epitopes, into
tolerance. There is also a tendency for younger, precursor Tc cells to be hard
to enrol into aggression. Tc cells are designed to kill self-cells. This is
their cardinal role. That is why it is so easy to produce adjuvant arthritis
and other experimental autoimmune disorders (note that over-exuberant Th1
aggression is a dominant accompaniment of most of these disorders). They are
precipitated when there is a great deal of membrane damage, cytoplasmic
spillage and a prolonged stimulation of the aggressive T-cell system but there
is an absence (or paucity) of clearly strange antigen to focus attention onto
the disordered cells that provoked the mess. By rapidly focusing aggressive
attention on the cells that are rupturing (say eg, due to a viral infection)
then the whole process can be brought to a rapid resolution as this selective
aggression will be directed preferentially towards some unusual epitope
characteristic of the infected cells. Since there will be only a few precursor
Tc cells available that are specific to the local tissue (most having been
mopped up following previous apoptosis) and they are, anyway, young and
resistant to recruitment into aggression, the differential expansion of
aggressive Tc cell clones will strongly favour strange over self epitopes.
Note that macrophages that die catastrophically, rather than in a controlled
shutdown (apoptosis), should also stimulate Tc cells.
- Cells that die suddenly in trauma (e.g. heart attacks, burns) have not
been preparing for apoptosis. Cells that die of viral infections or other
intracellular nasties have probably moved somewhere along the path towards it.
This means that cells that die by trauma do not spill much Il-1 whereas
infected cells do. Spilt Il-1 is a strong contender to be one of the danger
signals (eicosanoids, which are released after membrane perturbations, are
another). (Note that apoptotic bodies that rupture before they are cleared
should be a potent trigger of T-cell aggression.) Nevertheless, Dressler's
syndrome is the occasional autoimmune sequel to a heart attack - so trauma
does increase the risk of autoimmunity. Similarly, in burns and major trauma,
autoimmune activity is easy to demonstrate. Indeed, it is the probable
precipitant of the phagocytic anergy that appears before multiple organ
failure sets in. Any system that allows auto-rejection of normal cells must
sport a failsafe cut off device to inhibit the piecemeal destruction of self
(Regan and Barbul, 1989).
- Th1 cells evolve as an elaboration of the Tc cell system. Now, the
cellular and cytoplasmic debris of leaking cells can be digested by APCs and
then processed so that representative peptides can be presented on the APC's
surface. Apoptosis of these APCs (which have successfully cleared the debris
and have detached from the tissues to migrate to and apoptose in the local
lymph nodes) will favour tolerance to ClassII+peptide epitopes. But, when
these APCs fail to contain the problem, they will start to rupture (together
with tissue cells) and create a messy environment that favours Th1 aggression.
On any future encounter with a similarly caricatured APC (not of the pathogen
nor of its native antigen), the inflammatory response can be quickly ramped up
- bringing in copious aggressive phagocytes and NK cells. This is designed to
give inflammation a memory. The newly immigrant phagocytes still have to sort
healthy-self-cells from the rest but they are now stirred up into a frenzy of
eagerness to get on with this job.
- Since extensive tissue destruction is undesirable, phagocytes must be
inhibited when the Th1 cell amplification process becomes too fierce.
Phagocyte activity is consequently inhibited (as, eg in a boil) and this
increases the amount of debris left to be cleaned up; the IgM antibody system
arose to act as a debris mop. B-cells (cells that evolve from the macrophage
line) have an immunoglulin receptor that internalises only targeted debris and
processes this into peptide+ClassII epitopes. Then, when a suitable CD4 T-cell
receptor encounters this epitope, it triggers the respective B-cell to
differentiate into a plasma cell that then secretes free antibodies (but note
that some IgM production is independent of T-cell help). This then tags the
debris and enhances its clearance. So, progression to Th2 activity is most
likely to occur when cell-mediated auto-rejection is inhibited in the
interests of inhibiting piecemeal self-destruction. But this inhibits the
clean disposal of mess. The release of IgM is an attempt to compensate for
this. All the other immunoglobulins have evolved as shells that envelop IgM
(e.g. IgG, IgA, IgE).
- Thymic tolerance is probably designed to enhance the tolerance of
lymphocytes (perhaps macrophages and epithelial cells too) so that it
pre-emptively inhibits their auto-rejection. These cells are expected to
migrate to lymph nodes - areas where mess-making agents are likely to be
concentrated. This is probably why the thymus turned up in the pharyngeal arch
- close to the place where copious seawater (with many mess making
contaminants) is passed across the large and convoluted surfaces of the gills.
In this view, both thymic and peripheral tolerance are seen as the consequence
of the tidy disposal of apoptotic cells and are essentially the same process.
Synopsis
So, the whole process works through differential rates of cell death.
Irremediably dysfunctional cells are expected to do the decent thing and die
early by trashing their cytoplasms. In the process, they sanitise their
contents. The fact that infection is a frequent cause of intracellular
dysfunction is of no interest to the system. Cells don't think 'I am - or you
are - infected'. They realise 'I am - or you are - irrecoverably sick'. The
corollary is that there is a differential nurturing of healthy-self-cells that
are in junctional communication with their neighbours. The adaptive 'immune
system' simply remembers some caricature of those cells (or their debris) that
failed to do the decent thing last time and it then watches out for similarly
caricatured cells (and their debris) the next time round.
The progression of morphostasis
This leads to some thoughts on how the morphostatic response begins at the
innermost shell and progressively enrols successive shells until morphostasis is
achieved. The heat shock protein system may achieve morphostasis on its own,
fixing the problem with minimal disruption. When the volume of malformed protein
is too great the next stage is induced (eg, the dumping of representative
peptides on the cell surface in association with Mhc molecules). Intracellular
surveillance watches for cell dysfunction and triggers apoptosis where
appropriate. Where the mess is dominantly genetic, a healthy p53 gene is
required in order to trigger apoptosis. Resident phagocytes (dendritic cells)
try to remove the debris of cells or organisms that start making a mess
(including p53 mutated cells) - and they are mostly successful. But this can
fail. So, at this point, the agent that precipitated the crisis has overcome all
the defence lines thus far. Now there is an increased flow of lymph bringing in
phagocytes from the blood. These will ingest the mess then proceed to apoptosis.
They may do this locally or after being swept away in the lymph to the local
lymph nodes. When this shell fails to resolve the mess, NK cells are brought
into play. These are more specific about self-identity. They concentrate
dominantly on disconnected cells. Nevertheless, some mess makers still lead to
the rupture of cytoplasms. By this time the lymph flow has increased to a
torrent and both immune and detached sick cells are swept off to the local
nodes. Now the Tc cell system is brought into play. This memorises the
caricature of cells that were associated with cell rupture the last time that
they were met. Their first encounter with uncommitted T-cells is in the local
lymph nodes. The Tc cell system encourages cells - with a caricature that
resembles cells that previously presented in association with rupture - to do
the decent thing next time around. This system provides a clean clearance of the
sick cells - while it works. But, even this may be overcome - at which time we
are left with a mess of spilled cell debris. This debris is easily recognised
and eliminated (by phagocytes). The Th1 system then categorises the resulting
ClassII+debris-peptide epitope on the basis of whether or not it has previously
been encountered in an inflammatory environment. Aggression (Th1 activity) is
favoured when APCs meet the epitope in an inflammatory encounter and Tc activity
will be provoked to macrophages that rupture rather than apoptose. When a Th1
cell meets a similarly caricatured phagocyte (which must already have started to
clean up the cell debris to be able to sport this epitope on its cell membrane)
then it will bring in a whole army of activated phagocytes to carry out the job
more swiftly. But this lays the system open to phagocyte anergy. When the going
gets too intense, extensive tissue destruction must be aborted by phagocyte
anergy - and this results in a failure to contain mess by Th1 induced clearance.
This anergy leads to a sea of extracellular debris and so to the need to recruit
IgM. I am sure that a little thought would allow us to extend into the next
rounds (the other Igs) but I will stop here. I have omitted complement here for
brevity - that is covered in the other articles (Cunliffe, 1995, 1997). It is
worth noting, though, that complement is also likely to fit better into a
'mess'-'non-mess' discriminating system (see below).
Thus, for each insult, there is a sequential move from the inner to the outer
shells. Now this is rather like the evolutionary steps that formed the mammalian
morphostatic system. Remember that ontogeny tends to shadow phylogeny. So, is
the gradual aging of the 'immune system' the stochastic accumulation of all
possible responses to various mess-making insults through these shells? For some
insults, the move to the outer shells is early and for others it is late. Could
this, superimposed by the gradual genetic divergence of the zygote-derived
colony, be the source of the immune changes observed as mammals age?
The immune system is dead: long live the immune system
The term immune (freedom from burden or taxes) is now encumbered with the
presumption that the system is "designed" to find, identify and kill foreign
invaders. This pervasive conviction may be so misleading that we will have to
exorcise it - at least for a generation - until we have shed a (mis)conceptual
mill-stone. This counterintuitive view must seem strange to those who know that
it is manifestly obvious that the system is designed to kill micro-organisms.
After all, infection runs rife when the system fails.
And the earth is flat too ….! Thinking the unthinkable has often been the
vanguard to a revolution in understanding. It does not make the old views
"wrong"- it simply shows that they did not run deep enough. In particular, such
revolutions expose the underlying (false) presumptions.
A heretic idea can be justified by demonstrating that it cannot be dismissed
as invalid. While this does not necessarily prove the old view wrong, it helps
to expose the hidden assumption. Morphostasis provides an alternative view
(Cunliffe, 1998, 1999). It restructures our perspective of a "self/non-self"
discriminating system into an "order/disorder" discriminating system. The
fundamental principle of life - its raison d'ętre - may be to beat back the tide
of entropy. Thus, maintenance and extension of order may be the core function of
life. The natural gradient is towards disorder. Living systems use a selfish
survival strategy to "rob Peter of a little bit more than they are prepared to
pay Paul" to maintain form (molecules through to animals). Selfish is
misleading, for there is no persistence without survival. Only the most
pervasive, invasive and successful ordering strategies have survived from life's
origins. Little wonder, then, that the analogue, catalytic systems that first
propagated order were soon themselves ordered by a digitised copy code of tRNA.
This began to ensure the faithful propagation, replication and dispersion of
order-out-of-the-jaws-of-degeneration systems (in line with "integrity", Dembic,
2000).
By analogy, the immune system is like a mindless caretaker. Unless residents
are stood in rows, "holding hands", co-operating and behaving modestly he will
ask them for some form of identification. Should they start making a mess -
particularly spilling their own or other's innards or disrupting the (connective
tissue) structure of the building - then the caretaker will regard them either
as potential mess-makers or as mess in need of clearance. To make the system
favour its own kind (healthy zygote derived cells) and not some other's, cells
will also need to commit tidy suicide by wrapping up their own debris in
suitable containers marked "for tidy and quiet disposal" when they become
irremediably compromised. The illusion that non-self organisms are actively
hunted is, overwhelmingly, a consequence of the active protection of
healthy-self cells in an environment that is otherwise inclined to encourage the
degeneration of all cellular material. This leads to the nurture of order and
the repulsion of anything potentially disordering. Complement starts the process
by coating all biological surfaces with C3 products. Healthy-self cells are
protected because their activated C3 is converted to a C3 derivative that does
not attract aggressive phagocyte attention (it might even promote cell-to-cell
co-operation).
By this view, anything disordered - self or foreign - is a legitimate target
for phagocytes and the retinue of cells that evolved from them and are still
commanded by them. The innate and adaptive immune systems cease to be viewed as
fundamentally disparate entities.
Gallucci et al (1999) have recently provided compelling evidence that tidy
apoptosis leads to T-cell tolerance. This occurs in both the thymus and in the
periphery so the two mechanisms are likely to be similar. T-cell aggression
probably occurs when controlled shutdown (by apoptosis) is threatened, fails or
the volume of apoptosis exceeds the capacity of the surrounding cells and
phagocytes to clear it. Apoptotic bodies are potential "inflammatory bombs" that
will explode if their membranes burst. The recent demonstration that gap
junctions play a critical and unforseen role in immune cell activation
(Oviedo-Orta et al, 2000) adds more weight to the order/disorder perspective.
The finale
An established paradigm can accumulate a large surfeit of apparent anomalies and
yet still survive as the valid framework for a majority of minds. A new paradigm
must face every apparent anomaly as if it were solid evidence of falsification.
To approach omniscience (understanding every facet of how it works and every
extrapolation of its function) will require multiple minds and many years of
consideration. So, any new paradigm should be assessed on its broad - not its
focused - applicability as such omniscience will take years and many
protagonists to establish.
Acknowledgements
My thanks to the Wessex Medical Library who made this study
possible. Especial thanks to
Jim Trosko for reminding me of phlogiston. I
apologise to all those who have reported seminal work that I have either not
found or not quoted in this series of articles.
References
(Please note that there are many relevant references
in the first four articles; I have not repeated them here).
Cunliffe, J., 1995. Morphostasis and Immunity. [Published
erratum appears in Med. Hypotheses (1995) 44, 428] Med Hypotheses 44, 89-96.
Cunliffe, J., 1997. Morphostasis: an evolving perspective.
Med
Hypotheses 49, 449-459.
Cunliffe, J. 1998. Morphostasis: a revolution? Southampton
Health Journal 14(2), 35-38 & 55 [full text visible at
http://www.morphostasis.org.uk/Papers/MRevolut.htm ].
Cunliffe, J., 1999 From terra firma to terra plana - danger is
shaking the foundations: deconstructing the immune system.
Med. Hypotheses 52,
213-219.
Dembic, Z., 2000. Immune system protects integrity of tissues.
Mol. Immunol. 37, 563-569.
Gallucci, S., Lolkema, M., & Matzinger. P., 1999. Natural
Adjuvants: Endogenous activators of dendritic cells.
Nature Med. 5, 1249-1255
Oviedo-Orta, E., Hoy, T., Evans, W.H., 2000. Intercellular
communication in the immune system: Differential expression of connexin40 and
43, and perturbation of gap junction channel functions in peripheral blood and
tonsil human lymphocyte subpopulations.
Immunology 99, 578-590
Regan, M.C., Barbul, A., 1989. The Role of the Wound in
Posttraumatic Immune Dysfunction. In Immune consequences of trauma, shock and
sepsis: mechanisms and therapeutic approaches. Edited by Faist, E., Ninnemann,
J., Green, D.. Springer-Verlag pp1043-1049.
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