"IMMUNOLOGY
AND GLOBAL BEHAVIOUR
By Professor Madeleine Bastide
Emeritus Professor
Laboratory of Immunology
and Parasitology
Faculty of Pharmacy,
University of Montpellier I
2 - DYSFUNCTION OF THE IMMUNE SYSTEM
3 - THE IMMUNE SYSTEM IN THE INDIVIDUAL'S GLOBAL AWARENESS
4 - COMMUNICATION LEVELS OF THE LIVING:
5 - NEW INTERPRETATION OF THE PATHOLOGIES OF THE IMMUNE
SYSTEM
AND THEIR THERAPY
6 - REFERENCES
The immune
system always fascinates with its complexity and originality. Indeed, its distribution
throughout the organism by the lymphatic system and the lymph nodes, its
presence materialised by various organs with apparently different functions
(bone marrow, thymus, spleen, liver, etc…), and especially its role, connected
first of all to the phenomena of cell communication, make it an ideal subject
to illustrate the concept of global awareness. This system has been called the
“the mobile brain”, which implies a function way beyond the classical
mechanistic concept and suggests a role with an “informational” capacity.
After
quickly recalling the adaptation and the working of the immune system, we are
going to analyse its dysfunction resulting in various pathologies, comparing
the vision of this system within the classical mechanistic concept with the one
achieved in another thought structure. If we depart from the vision of
molecule-receptor interactions towards another model integrating the immune
system into the individual’s global awareness, into the significant
interpretation of its relation with the outside world, we notice that
pathologies (and their therapies) allow a new interpretation.
Several
unconventional therapies, far removed from the mechanistic allopathic therapy,
seem especially well adjusted to correcting the dysfunctions of the immune
system.
I – FUNCTION OF THE IMMUNE SYSTEM
The
distinction between “the self” and the “different from the self” is the basic
principle of the immune response. The difference
from the self (commonly designated
Figure 1: Immune defence
by the term “non
self”, which implies its identification…) can be identified by the organism
which triggers the elimination systems of what is different: it is the antibody reaction (figure 1).
The self is represented by molecules of a glycoproteinic
nature depicted on the membrane of all the cells of the system and designated
by “Major Histocompatibility Complex” or MHC. Indeed, the diversity of these
molecules from an individual to another is such that they are able to
characterise the individual: they represent the self and take part in the
rejection of a transplant based upon the difference of MHC between the donor
and the receiver.
Figure
2: Structure of the MHC
molecule
(class I or II) presenting
a
pleated rigid part b and two helices a
between
which the peptide is inserted
These molecules belong to the super-family of
immunoglobulins. The homologies appearing between the structures of the
molecules of this important family imply that they derive from an ancestral
structure (going back to about 500 million years) which, throughout evolution,
has remained a basic genetic and molecular unit. In this molecular family we
find recognition molecules of the immune system (i.e. the antigen receptor of
the T lymphocyte or TCR, the antigen receptor of the B lymphocyte or
immunoglobulin), at the top of the hierarchy of adaptation to diversity, then
MHC molecules which play the role of “marker” of the self and “presenting”
peptide molecule to the T lymphocyte receptor. Indeed, we know now that the MHC
has a peculiar structure accommodating a pocket inside which peptides
originating from the antigen extraneous to the system will settle (figure 2).
The union MHC + extraneous peptide is placed at the surface of the antigen
presenting cell, ready to be recognised by the T lymphocytes using the antigen
receptor TCR (Figure 3). It was demonstrated by crystallographic analysis
(Bjorkman, 1987) that this pocket is always filled : either by peptides of the
self unable to trigger a T lymphocyte response or by peptides different from
the self (antigen), able to trigger the T lymphocyte activation (Figure 3). In
this immunoglobulin family, we also find many molecules such as cell adhesion
molecules, immunoglobulin receptors, but also neurone adhesion molecules,
confirming the original relation between the nervous system and the immune
system in evolution.
The triggering of the immune response is connected to this
sole recognition of the difference of the self. As soon as this recognition
occurs, outpourings of biochemical occurrences take place inside the T
lymphocyte, resulting in its activation by derepression of growth factor genes
(interleukin 2 or 4). The fixation of interleukin 2 on its receptor depicted by
the T lymphocyte (for instance T CD4 – TH1 lymphocyte), within an autocrine
process, is going to trigger the synthesis of other cytokines able to provoke
the action of cytotoxic T lymphocytes CD8 which are going to destroy the cells
carrying the antigen through a phenomenon of cytotoxicity (cell response). The
TCD8, still designated by the name of cytotoxic lymphocytes or CTL’s, will be
helped in their elimination of unwanted cells (target) by a cytokine, the tumor
necrosis factor (TNF), and by the joint action of two other cell types, the
Natural Killer cells and the "fully activated macrophages". These
latter are going to produce nitrogen monoxide (NO) which they release and,
scattered over the target, kills it. If the orientation of the response goes
the way of the secretion of antibodies (immunoglobulins specific of the antigen
detected by the B lymphocyte for a “shape” recognition), the activated
TCD4-TH2’s release the cytokines activating the B lymphocytes, which, under the
action of various cytokines, are going to evolve towards a plasmocyte-type
structure and secrete profusely the immunoglobulin with antibody function which
had enabled their selection by the antigen.
Figure 3: The
recognition system
of the peptide inside
the MHC by the T lymphocyte.
The receptor of the T
lymphocyte antigen
recognises the
peptide and the MHC simultaneously
The special
features of these two types of responses are the specificity (with regard to the inductive antigen) and the set-up
of a cell-type memory by maintaining
the specific clone.
The immune
system ensures continuously the survival of organisms in an environment where
aggressors are multiple and diverse. Its regulation has a special importance
since the balance is worked out between an activity enabling the defence with
regard to extraneous elements while preserving the integrity of the self. For
this reason, there are regulations at all levels, producing a subtle balance
between the various cells, the cytokines (for instance interferon gamma and
interleukin 4 regulate each other), soluble receptors, regulating antibodies
(anti-idiotypic), hormones (the major negative regulator is cortisol),
neuropeptides and neuromediators (negative regulators of lymphocyte activation
such as vaso-intestinal peptide or VIP, calcitonin gene-related peptide or
CGRP, etc…).
II – DYSFUNCTION OF THE IMMUNE SYSTEM
When, for
various reasons, the balance of the immune system is disturbed (stress, viral
pathologies, immunosuppressor treatments, etc…) various pathologies appear and
show themselves in different ways according to the subject’s genetic proneness,
his environment, the nature of the immunological fracture, etc…
Pathologies
may be classified into three major groups, if we omit congenital deficits
originating from a genetic anomaly and the problem of grafts and transplants.
The latter represent a totally artificial situation of dysfunction of the
immune system created by a therapeutic act, the replacement of an organ by
another organ of another individual, of the same species or not.
The first
group includes pathologies due to an
inadequacy of efficiency of the immune system in the rejection of the
extraneous aggressor (possibly resulting in death). This phenomenon can be
slight or affect the whole system : the most suggestive case is the one of
viral infections affecting TCD4’s, like the action of HIV in AIDS. In this kind
of pathologies, one tries either to stimulate the immune system
(immunomodulators), or to eliminate pathogenic agents (anti-viral, antibiotics,
anti-parasitic), or to eliminate the cause (ex: anti-retrovirus in AIDS
associated with a protection therapy against the previously mentioned
pathogenic agents).
The second
group includes pathologies due to a
“hypersensitivity” of the immune system, the most widespread of which (30%
of the population) is immediate hypersensitivity or allergy. This
hypersensitivity results theoretically from an overproduction of
immunoglobulins E which, fixing in profusion on the blood’s basophil
granulocytes or the tissue’s mastocytes are going to provoke the degranulation
of these cells every time that specific antigens combine with the antibody
site. The result of the degranulation is the production of various inflammatory
substances released from membrane phospholipids, the formation of
pro-inflammatory cytokines, of various chemotactic substances, all this
maintaining the pathology. There are two types of therapies : either with the
purpose of preventing or neutralising the degranulation effects, or by
injecting small doses of the allergen in question to provoke a “desensitisation”.
It is said that the allergic patient “sees danger when there
is none” or that he is “hypersensitive” to certain antigens.
The third
group includes the auto-immune
pathologies in which one observes an immune response directed against
certain molecules belonging to the organism (auto-antigens) causing lesions
self-maintained by the permanent presence of the auto-antigen inside the
organism. The true cause of auto-immune diseases is unknown. However, one
suspects viral or bacterial infections as inductors of tolerance rupture to
certain auto-antigens. They could be distorted by the elimination of germs at
tissue level by the immune response itself (hepatitis and anti-liver response,
juvenile diabetes and anti- pancreas b cell response, etc…). There are also
“cross reactions” resulting from a relationship of structure between the
aggressor’s antigens and auto-antigens (Streptococcus A and heart antigens,
etc…). The “genetic proneness” connected to the MHC structure, certain alleles
of which enable a better presenting of auto-antigens exist (the best example is
the relation HLA B27 and the relative risk of spondylarthritis, etc…). Then,
there is the unknown, the exceptional circumstances, “stress” and its relation
to the immune system through the hormonal ACTH-cortisol pathway or through the
pineal gland and melatonin, etc…
It seems to
us that we can group together:
(i) circumstantial auto-immune diseases (cross reactions,
infections, etc…) the appearance of which truly results from an error of recognition
of the immune system which is abused and which functions with a “mechanical”
error.
(ii) “personality” auto-immune diseases, deeper, in which we
can find certain rheumatoid arthritis, multiple sclerosis, lupus erythematosus
and all connectivities, organ diseases such as thyroiditis (Hashimoto, Basedow)
etc… about which we know that they are often triggered after a violent stress,
or an immune unbalance, and the etiology of which is unknown. It seems to us
that, in this case, there is a grave error of interpretation between the self
and what is different and to be rejected, the process of central tolerance of
the self being disturbed : it is more a question of an “immunological” and/or
physiological and/or general loss of personality than a mechanical cause. This
interpretation corresponds to therapeutic approaches obtained with certain
unconventional therapies which treat the patient much more than the illness :
indeed, the allopathic approach is, in this case, restricted to palliatives,
immunosuppressors and anti-inflammatory medication, with the function of
“limiting the damage” without eliminating the cause.
III – THE IMMUNE SYSTEM IN THE INDIVIDUAL’S GLOBAL AWARENESS
The term
“global awareness” may not be translated by a sum of interactions the way they
are described in the classical notion of immune response. Its definition calls
for no anatomic reality and no localisation. Global awareness is a dynamic
property which is intrinsic to the living and may not be reduced to its
biological components. It is situated above an interdependence of all systems
leading to a modification or adaptation of the body as a whole. The organism
calls for any usable regulation process and mixes both physical phenomena and
psychic modification. Global awareness implies a general management of the
problems which are then going to be subject to regulations adapted to each
aggression. It translates the interactions within the internal world and with
the outside world, which are the characteristics of the living. It is certain
that the immune system is one of the tools enabling the organism to withstand
certain aggressions. It is certainly a very accomplished physiological
component which has been ensuring the perenniality of species amongst hostile
situations and aggressions of all sorts, the most important one being microbial
parasitism, i.e. the invasion by all viral, unicellular or multi-cellular
organisms developing to the detriment of a living organism. The living is not a
juxtaposition of mechanical systems based upon the dogma of "all
molecular”: the organism has the characteristics of the living, its creative
ability, its adaptability, its capacity of integration into the environment and
its temporality.
It would
seem that the result obtained by the functioning of the immune systems makes up
an individual’s “global” function. But, for this, the conceptual tools enabling
this approach are lacking, for nothing has been proposed to ensure the
communication between soma and psyche, presenting themselves, however, as an
integral part of global awareness.
I – Body signifiers as a mediation between
soma and psyche
The only
possible mediation between soma and psyche is suggested by A. Lagache (Lagache
1988, 1997a, 1997b). We owe her the suggestion of a new paradigm, the one of
body signifiers (figure 4) putting analogical communication into play, enabling
non-symbolic communications at body level. “The
body and the mind are not objects, neither are they closed “boxes” on their
substance, but living information networks, organised according to regular and
intelligible laws”.
The information is going to use mimetic presentation to
designate its object. Everything happens in the form of a purely sensitive
communication the support of which may be implied. The only example of support
we could give is the one provided by homeopathic dilutions ; we know that they
are sensitive to electromagnetic radiations (Hadji & coll., 1992) or that
their power is transferred by adapted devices (Endler & coll., 1994, 1995,
1997). Why not suggest as a hypothesis that this body information be
transmitted by very low intensity and very low frequency electromagnetic
radiations emitted in a very stable manner by succussed aqueous solvents.
Water, which represents 90% of our body, is succussed continuously by heart
contraction at about 90 beats a minute. It was recognised that, in a
non-traditional manner, water plays the role of a ligant of macromolecules,
which confers it a mediation function of molecular contacts (Douzou, 1994).
This mediation function could also be situated at the information level by
endogenous electromagnetic emission which would thus carry the information of
the substances belonging to the organism. This could be the case of certain
cytokines such as the “Colony Stimulating Factors” (CSF’s), for instance
interleukin 3 released at very low concentrations in the microenvironment of
immunocompetent cells in the course of cell interactions during the immune
response. These CSF’s can have a long-distance effect on the hematopoietic strain
cells of the bone marrow (endocrine effect). This phenomenon cannot be
explained by a serous rate comparable to that of hormones, because of the very
low initial concentration after local release and the dilution effect of the
circulating blood. A hypothesis would be the communication to the hematopoietic
strain cells of the marrow by the “informant” nature of these cytokines further
to their blood succussness. The information received by the body play the role
of “biological or body signifiers”, able to provoke physiological modifications
after treatment of the information by the organisms. This communication follows
very specific rules different from exchanges of objects (Bastide & Lagache,
1992, 1995, 1999).
Figure 4: the
paradigm of body signifiers,
a mediation between
mechanistic and symbolic paradigms.
2 – The Immunological Self in the paradigm
of Body Signifiers
We can now
introduce a new dimension in the concept of the Immunological Self, which, let
us recall, plays a fundamental role in the identification of what the organism
must reject (see § I). The Self and the global awareness of a system are
completely connected : indeed, global awareness rests upon the notion of
“self”, this “global” entity which defines a living structure, with a
complexity which is going to increase with its place within the scale of
evolution. Of course, we are concerned with the human system, the most perfect
in evolution, therefore the most complex, with its three levels representing
the paradigms indicated previously : the molecular level with its complexity
and its systems of cybernetic type retro-control ; the level of biological
information, with a carrier we can suggest as being of the electromagnetic
type, and the psychic level in its entirety. From the internal standpoint, the
organism communicates continuously, with exchanges at all levels, from the
psyche to the molecular (somatisation, allergies, etc...), building its body
representations in response to biological information (symptoms, etc...) (Bastide
& Lagache, 1999).
The system
also communicates permanently with the outside world. The organism which
receives an information or a stimulus on a given level and which can respond to
it on the same level adapts without any risk of pathology. But when the
response is partial or moved back to a lower level, the organism finds itself
in a situation of hyper compensation response : it is obliged to deal at a
lower level with an event which would require a more general regulation. The
symptom of a pathology is going to appear as being an inadequate expression
with the tendency towards fixation, preventing the system from having a
dialogue with the world. The symptom becomes the representation of the
pathology which cannot be treated naturally : the system “displays” its
pathology, each subject with the special nature of its interpretation
(individualisation).
Figure 5: the self is
a complex
structure of
different levels of information.
It is the synthetic possibility
of moving between the
various levels.
It can have exchange
functions
with the outside
word, at all levels.
The
immunological self is then merged into the biological self (Figure 5): it is
only its special nature which uses the immunological tools at its disposal in
order to survive. The notion of symptom, dear to homeopathy, since it serves as
a basis for the law of similarity,
can also appear there. “Non-apparent” illnesses to which
Charles Nicolle his Nobel prize are a striking example of this. These
infectious pathologies (toxoplasmosis, rubella, etc…), due to a well-identified
aggressor, may be treated naturally by the organism without any
symptom, thus their designation by the term “non-apparent”;
however, the serological scar is there, proving the immunological phenomenon of
defence. This means that the symptom only appears in the situation when normal
behaviour cannot be exercised (in general, during an immuno-depression, even a
slight one).
3 – The T lymphocyte receptor:
semantic means of identification of the Self
The living body does not have the capacity
of the object which is the norm of the mechanistic paradigm: it receives and
deals with information enabling it to organise its own existence. The mechanistic
interpretation of cell interactions in Immunology for instance, results in
a great difficulty in the concept of presenting the antigen to T lymphocytes:
are there any specific structures of the self which may be identified by lymphocytes,
some of which being tolerated and others rejected? The structuralist approach
is undergoing difficulties in this respect. The immune system considered as
a semantic system then comes under another logic.
If we
recall what was said in § I, antigen presenting by the competent cells (antigen
presenting cells) to T lymphocytes is always done in a pocket made up by the
terminal areas of the two chains of MHC (for class II molecules), or by the
last two domains of the MHC chain (for class I molecules). In the MHC pocket
there is a peptide able to be recognised by the receptor of a T lymphocyte. Two
situations can occur: either the peptide originates from an “extraneous”
molecule, or the peptide belongs to the self. Indeed, this pocket is never
empty and in the absence of antigenic stimulation, a peptide of the self is
going to occupy it. The lymphocyte, through its TCR receptor, is going to
identify the peptide and the MHC simultaneously (fig. 3).
Therefore, two situations are possible (fig. 6):
i) the
lymphocyte is going to identify the peptide originating from the molecules of
the self and the pair SELF/MHC + SELF/PEPTIDE will be presented to the
lymphocyte. This association does not trigger the activation of the lymphocyte
which notices no difference since in both cases it is a peptide of the same
origin, the self.
(ii) on the
contrary, when the pocket is occupied by a peptide with an extraneous origin
(SELF-MHC + FOREIGN/PEPTIDE), a difference appears which becomes significant
for the immune system; indeed, from the semantic point of view, the difference
always generates a meaning: “In fact, what we call information – the elementary
information unit – is a difference which creates a difference” (Bateson, 1980).
The very fact for the extraneous peptide to be included into the MHC molecule
which is an element of the self creates the difference. The antigen then
becomes an object able to be identified by the body: MHC makes the antigen
significant to the organism. From the time this information is identified by
the appropriate T CD4 lymphocyte clone (initiators of the immune response) which
plays the role of receptor of this information, a succession of events
connected to the synthesis of cytokines and receptors expressed on the membrane
is going to provoke the clonal expansion of responding lymphocytes which in
turn are going to induce a series of cell interactions leading to the
elimination of the antigen by activation of cytotoxic cells or through the
action of antibody molecules (Bastide & Lagache, 1992, Bastide, Lagache
& Missone, 1995).
Figure 6: Meaning of
the peptide
recognition inside
the MHC by the T lymphocyte
(the peptide is
included into the MHC molecule)
One must underline that the recognition process of the
antigen which triggers all the
specific immunological phenomena by analysis of “structures” (mechanistic
paradigm) has not yet been elucidated. Peptides, made up of a few amino acids,
(7 to 11 for class II molecules and 10 to 17 for class I molecules), always
structured in helix a, do not make up a deciding
conformational variability identifiable as a self or “non self”. One can see
that the term “non self”, classically used by immunologists, suggests an
“identification” of the antigen to be destroyed, while the term “different from
the self” only suggests the analysis of a difference. Moreover, the positive
selection of lymphocytes inside the thymus is done only by the ability of T
lymphocytes to recognise and identify the MHC, i.e. the self.
IV – COMMUNICATION LEVELS OF THE LIVING: APPLICATION
TO THE IMMUNE SYSTEM
We were
able to list the various possibilities of communication in the living (Bastide
& Lagache, 1999). To do this, the use of the three paradigms (§ III-2) is
necessary to establish this hierarchy (figure 7). This brings us to detail the
paradigm of body signifiers while mechanistic and symbolic paradigms are known
in our philosophical culture.
1 – The paradigm of body signifiers
The
information received by the body (§III-2) plays the role of “biological
signifiers”, able to provoke physiological alterations after treatment of the
information by the organism. This communication follows very specific rules
different from exchanges of objects (no loss after exchange but a different
situation before and after the information) (Lagache, 1988, 1997a, 1997b). The
most simple examples are those which analyse experimentally the action of
endogenous substances (part of the organism itself). In the case of highly
diluted and succussed endogenous substances, therefore in an informational
form, the information provided is automatically read by the system which “knows”
its own constituents. The molecules composing the organism have a natural
meaning for this system. Thus, high succussed dilutions of bursin (a tripeptide
isolated from the Fabricius bursa of chicken) were able to “replace” the
Fabricius bursa in chickens having undergone a bursectomy to such a point that
they were able to secrete and regulate their antibodies just like normal
chicken (Youbicier-Simo & coll., 1993, 1996a, 1996b, 1997).
When, on
the contrary, we are dealing with exogenous molecules the information of which
cannot be identified naturally by the organism, a “reading frame” is necessary
for the organism to be able to deal with this information. This key can be
provided either by the law of identity, or by the law of similarity suggested
by homeopathy. Let us take the example of the
law of identity (there is object identity between what causes the pathology
and the origin of succussed dilutions): renal tubular cells treated with high
dilutions of cadmium received the cadmium “information” (solution concentrated
at 10-40M) which is going to provoke their resistance to
intoxication by this same metal (Cal & coll., 1986. Delbancut, 1994). In
this case, we are within a law of
identity: the information and the toxic stress have the same origin and the
cell was able to protect itself; the phenomenon is strictly specific as
demonstrated (Delbancut, 1994).
When we
consider the law of similarity in the
homeopathic field stricto sensu, we
notice that the correspondence between the symptoms observed in the pathogenesis
of a remedy given to a healthy subject and those presented by the patient
enables the correction of the patient’s symptoms. But what is a symptom? In the
patient, it represents an expression
of his illness; an expression is nothing but the fulfilment of the self in a
given form, under the dual aegis of adaptation and totality, according to data
and history. However, the pathological circumstances have it so that the
symptom is an expression which does not result in a resolution, an uncompleted,
blocked expression. The symptom becomes then a body representation of this
expression which results from the conjunction of external and internal
circumstances: it becomes a significant creation of the individual as a whole,
in his global awareness, representing the expression the subject gives to his
illness. One finds again the Freudian notion of the symptom as healing attempt:
the patient submits to his symptoms as if they were “imposed upon” him, but
they are always an active attempt at a solution. Therefore, one understands why
the homeopathic therapy has such power: by observing the representation of the
illness read in its entirety, the therapist can reflect upon this ill body a similar image to this representation
provided by the diluted and succussed remedy. This similar image reproduces the
symptoms observed in a healthy subject having received this remedy in the
informational form. This image plays a role of re-information about the
pathology and the body is then able to treat his symptoms himself by an effect
which could be of the cathartic type (Lagache, 1988, 1997a, 1997b; Bastide
& Lagache, 1992, 1995, 1999). Therefore, the system appears as a sort of
uncompleted and somewhat misled expression which homeopathic therapy through
similarity, gets going in the direction of the capacity for change, therefore
the health balance. Therefore,
this biological signifier paradigm takes into account the similarity, the use
of highly diluted and succussed solutions and finally the individualisation
within global awareness. It is no
longer the body reduced to the condition of object of mechanistic science, but
indeed the properties of the living, its originality and its evolution
throughout time.
