A semiotic perspective on the immune self the case of molecular mimicry

Tamara Stojanovi
Dept. of Semiotics, Tartu University
Tiigi 78, 50410 Tartu, Estonia
10.12.2010.

Abstract
The immune system is a rather complex phenomenon, which is researched by many disciplines: medicine,
biology, chemistry and so on. Our aim is to show in this paper that it is also a semiotic phenomenon. In fact, the
mechanisms which are found at the very core of the immune system are the mechanisms of self/non self distinction,
i.e. immunologicial tolerance. However, the very notions of self and nonself are abstract notions and it is the task
of biosemiotics to explain how are they related to the very physical notions of cell, lymphocyte, antigen and so on.
We present here a theory of endosemiotics developed by Thure von Uexkull, Werner Geigges and Jorg Herrmann
and in the framework of that theory we explain the mechanism of molecular mimicry as a pathogenic mechanism
that induces autoimmune responses.

Introduction
The major task of the immune system is to protect the organism from microbes viruses,
bacteria or fungi. When those microbes penetrate the skin end enter the organism, many different
cells, some of them specialized for the microbe involved, initiate a process of their destruction.
Once they finish, they store into memory a part of the microbe they fought so they could be
more efficient in the case the same microbe infects the body again. The description we gave here
is overly simplified, but even as such it can be used o point out the basic features of the immune
system1: self/nonself distinction, specificity to microbes and capacity to memorize past
infections2 (Abbas; Lichtman, 2004:6)The focus of our paper is the first of those characteristics
the self/nonself distinction, since it is the very basis of an immunological phenomenon called
autoimmunity. Autoimmunity is, briefly, an immunological response directed towards the cells
and organs of the organism itself and it is the cause of many autoimmune diseases: autoimmune
cardiomyopathy, Lupus erythematosus, Diabetes mellitus type 1, Rheumatoid arthritis among
others. There are many explanations concerning the causes of those diseases: genetic (e.g. the

1
2

We will be discussing here mainly the human immune system.

We mean first of all the adaptive immune system.

MHC gene), hormonal3, central and peripheral tolerance disorders, and environmental causes,
such as smoking, drug exposure, diet, chemical exposure, and sunlight. (Rose; Mackay, 2006:2729). More fascinating are, however, the very mechanisms that lead to an autoimmune response,
i.e. the mechanisms that compromise the self/nonself distinction. One of those mechanisms is
called molecular mimicry, and it indicates a particular situation during an infection when the
microbe in question, a nonself antigen, impersonates a cell of the self and thus induces the
autoagression of an autoreactive lymphocyte.
The aim of the paper is to describe the immune system (more specifically the
self/nonself distinction) and the mechanism of molecular mimicry as semiotic phenomena. To
this end we will situate those phenomena in the context of endosemiotics.
The immunological self
The immune system and immune tolerance
When talking about the human immune system we can distinguish between innate
immunity and adapted (specific or acquired) immunity. The former is a kind first defense against
microbes and it is non-specific, rapid, lacks immunologic memory and is of short duration. The
latter is specific, slower in development, has immunological memory and is long lasting. The two
systems are very much connected, and what is more important they are both able to distinguish
the self from the non/self (Abbas; Lichtman, 2004:1-5). In this paper we will be mainly
talking about the central cells of the adaptive immunity T cells and B cells. Both types of cells
are characterized by very specific antigen receptors. Thanks to genetic recombination in the early
stage of immunoglobulins (B cell receptors) and T cell receptor production, T cells and B cells
are capable of distinguishing millions of different proteins, ranging from viruses to mammals,
and each T and B cell is specialized for one protein. (Abbas; Lichtman, 2004:22-23) However,
this also means that those lymphocytes, ones produced, can recognize both self and nonself
antigens. Therefore, a process of maturation is needed, during which the lymphocytes undergo
various processes of selection. T cells maturate in the thymus while B cells maturate in the bone
marrow. They both go through the process of negative selection4, which means, that if they react
3

There is evidence that some autoimmune diseases are more frequent among women than men so it might be
possible that hormones are related to the origin of the disease. (Rose; Mackay, 2006:27-29)
4
It is not the only mechanism that takes place in those organs. First, in fact, there is the process of positive selection
after which survive only the cells capable of recognizing MHC (major histiocompatibility complex) molecules.

too strongly with self-antigens in the thymus and bone marrow, they get eliminated. This is a
mechanism of the

central immunological tolerance. Once mature, T and B cells go into

peripheral organs and are there subject to the mechanisms of peripheral tolerance. Peripheral
tolerance is important because there are self-antigens which are not present in the thymus and it
also works as a back-up system, when central tolerance is incomplete. The mechanisms
involved in this process are: cell anergy (functional inactivation the cell is alive, but cannot
perform its role in the immune response), deletion and immune suppression. The last mechanism
is restricted to T cells and it is carried out by another type of T cells called regulatory T cells 5.
Central and peripheral tolerance, thus, do not destroy all the potentially dangerous lymphocytes.
A number of them, capable of recognizing self-antigens, remains present in the body and are
called autoreactive lymphocytes. (Abbas; Lichtman, 2004:161-172)
So, we have seen that the human body produces a great variety of lymphocytes, some of
them harmful, and that their activity is regulated by the mechanisms of immune tolerance. In
other words, those mechanisms are the very basis of the self/nonself distinction. Therefore, if
in any case those mechanisms would be compromised, the autoreactive cells could initiate an
autoimmune response. This is exactly what happens in the case of molecular mimicry.
Molecular mimicry
Mimicry is a phenomenon very common in the animal world. According to Timo Maran,
mimicry is first a situation of communication and as such it includes an unpredictable element
of interpretation. (Maran, 2007:225) More generally speaking, a situation of mimicry includes a
mimic, a model and a signal receiver. (Maran, 2007:226) The signal receiver in our case is a
particular autoreactive lymphocyte, the model is the self-protein that the lymphocyte is supposed
to recognize and the mimic is the foreign antigen whose epitope 6 is either identical or similar to
the self-protein in question7. Clearly, it is here an issue of erroneous recognition. In fact, the
Those molecules are crucial for T cells, because their receptors cannot recognize antigens unless it is bound with an
MHC molecule. (Abdul; Lichtman, 2004:164-170)
5
It is still not clear how this kind of T cells develops nor what the mechanisms of suppression specifically consist
of. (Abdul; Lichtman, 2004:164-173)
6
The epitope or antigenic determinant is the part of the antigen subject to recognition.
7
Molecular mimicry has been demonstrated to occur in several different forms including complete identity at the
protein level, homology at the protein level, similarity at the level of amino acid sequences and structural similarity.
(Shoenfeld et al. 2007:13)

nonself antigen and the self antigen, though possibly different on the biological level, are
identical on the semiotical level they function as signs for activation to the T cell (Kull in
Maran, 2007:233).
Both autoreactive T cells and B cells can be included in the process of molecular
mimicry. Here, we present a case of the activation of a T cell.

From Cellular and immunological

biology (p.437)

The antigen presentation cell (APC) is the cell which presents the antigen in combination
to the MHC molecule to the T cell. Under normal circumstances, if the antigen in question is a
self-antigen the APC does not stimulate the T cell. On the other hand, in case of a foreign
antigen, that is exactly what happens the APC stimulates the autoreactive T cell, which
interacts first with the foreign antigen and then with the similar or identical self antigen. This is
known as cross-reaction. (Abbas; Lichtman, 2004:175)Similarly, T cells in charge of
costimulating B cells can stimulate self-ractive B cells which will also cross-react with self
antigens. (Rose; Mackay, 2006:175)
The mechanism of molecular mimicry is fascinating because, at first sight, the idea that
two proteins, one deriving from a microbe, and other from the host organism can be so similar
seems statistically very improbable. However, it is the very statistics that show that crossreactivity of lymphocytes during infections is not that rare. (Oldstone, 2005: 4) An example of
this cross-reaction is when antistreptococcal antibodies first fight a streptococcal infection and
the cross-react with myocardial proteins causing myocarditis. (Abbas et al, 2007:437)
As we have shown, molecular mimicry, as animal mimicry, is a semiotic phenomenon
since it is a part of intercellular communication which involves the process of recognition. In
addition, it is a mechanism that compromises the self/nonself distinction. But what is exactly

this self? Biologically, we could say, perhaps, that all cells that constitute an organism are self
while the foreign ones are nonself. However, this is how things look like from the perspective of
the observer. We are interested in how this distinction is conceived from the inside, from the
perspective of the cells. Therefore, we are turning to the models of endosemiotics.

The self, the nonself and molecular mimicry in endosemiosis

Jakob von Uexkll used the word Umwelt to talk about the phenomenal world of an
organism. The interactions of the organism and the elements of Umwelt are researched in the
domain of exosemiotics while the semiotic phenomena inside one organism are the research
subject of endosemiotics. In many ways von Uexkll and al. (1993) continued the work of Jakob
von Uexkll. They expanded the Umwelt theory to one single organism and his inner world8.
This inner world is constituted by counterworlds the central nervous system and the immune
system. (Uexkll, T. von et al. 1993: 284) They are called counterworlds because they reflect
and act upon the organisms Umwelt:
each sign contains the self of its receiver as a distinctive code. To put it more precisely, each

sign leads to a change of the individual, subjective self of the receiver who or which in this
manner is informed about the signied non-self and its properties. Green, hard, blue, or
warm are modes of experience in which the self nds itself changed in comparison with a
previous or different state, and which, by the same token, signify properties of something which
is not the self for example, a meadow, a stone, the sky, or the bath water. (Uexkll, T. von et
al. 1993: 308)

This definition of the self provides also a good example of the functioning of affordances
and counteraffordances. We could say: where there is warm there are tactile organs, where there
is green and blue there are visual organs etc. Von Uexkll et al. write about the mathematical
equation: affordance + counteraffordance = action. This equation has a double implication:
affordance and counteraffordance contribute to the action and, conversely, the action provides a
framework for affordances and counteraffordances to be realized. In this action-based semiosis,
the signified or the object are not to be found in nor are they generated by the organism they
8

This inner world of the organism includes several integrational levels that ar mutually related. (Uexkll, T. von et
al. 1993: 288-289)

are created in the interaction of the organism with the Umwelt. In this way, an ecological
balance is preserved neither the organism controls the environment not vice versa. (Uexkll, T.
von et al. 1993:290-291)
The model of semiosis that as presented by the authors is a tetradic model involving a
living system (it has receptors for taking physical instances as sign vehicles, and effectors for
behavior), the sign (contains the encoded sign vehicles), the interpretant (has the function of
encoding, i.e. it attributes meaning) and the denoted object (actualized in the affordancecounteraffordance interaction). (Uexkll, T. von et al. 1993:291) So, depending on the state of
the organism, the interpretant attributes meaning to a sign vehicle, and encodes that meaning into
signs that set of an effector action. Since the organism is described as a self-constructing and
self-maintaining system, a totality, which encodes meanings necessary for its construction and
survival into signs governing its behavior we can say that the attribution of meaning is in
function of the survival and maintenance of the organism. The only possible way for an observer
to identify the interpretant is to examine the behavior of the living system. In the process of
endosemiosis the last action is an indexical sign which points to the interpretant, which is
responsible for the attribution of meaning to the sign. (Uexkll, T. von et al. 1993:292)
However, it is also suggested that the interpretant functions as an encoder, which implies that
there is a code which regulates how the effects from the Umwelt are going to be encoded into
signs. Von Uexkll and al. see this code deriving from the genetic code. Their standpoint is that
the zygote interpretes the code as kind of instruction for building a tool for survival and with
the help of this tool the egg can survive and develop. The ultimate function of the tool is to test
the suitability of the organism to the ecological niche the only real object in the world of
living systems. (Emmeche and Hoffmeyer in Uexkll, T. von et al. 1993:294 ) Therefore, the
self is a translator who translates the immensely long ancestral line into the analogue code of
present sign processes in order to prompt the construction of an individual which is to serve as a
tool for testing and maintaining a niche.( Uexkll, T. von et al. 1993:295)
In the context of the immune system, we could analogously to the first definition of the
self, say that that immunogenic 9 is a mode of experience in which the self is indeed
changed, and which does, in fact, signify a property of a nonself of various microbes. The
9

Immunogenic is something that causes immune response.

authors of Endosemiosis provide also very illustrative metaphorical descriptions of the

immune system. Antigens are considered to have their proper names, i.e. parts of amino
sequences that are found on the surface of the antigen and lymphocytes are cells that are capable
of reading those proper names. Put differently, lymphocytes carry photographic plates of all the
possible enemies, and a photograph is developed only when the enemy is actually encountered.
(Uexkll, T. von et al. 1993: 312). Therefore, lymphocytes can recognize only what is already
known to them, which makes the non-self a variety of the self. (Uexkll, T. von et al. 1993:311312)
In the case of the proper function of the immune system, the indexical sign formed in the
last act of semiosis should point to the nonself. For instance, when an antigen encounters its
antibody (affordance and counteraffordance), the iconicity of the antibody (the photo) is
replaced by indexicality. This is the precise place where molecular mimicry introduces an error.
The self-reactive lymphocyte is activated by a microbes epitope, but this does not create an
indexical sign for nonself, on the contrary, it creates an indexical sign for the self, which
effectively misguides the further immune response and turns it into an autoimmune response. We
would like to illustrate this phenomenon using the tetradic model of semiosis as presented by von
Uexkll et al for a case of autoreactive T cell: the T cell is the living system, the epitope is the
sign vehicle which belongs to the microbe the sign. This sign denotes an object that induces
activation, and the interpretant is the activation of the T cell itself. The mistake that occurred
here is at the level of denoted object. In fact, the microbes antigen was not supposed to activate
the T cell, since it is an autoreactive cell. However, as we mentioned, because of the similarity or
identity of the microbes antigen and the self-antigen, the T cell first becomes active and then
cross-reacts with the cells possessing self-antigens.
How should this be interpreted? Perhaps we could say that in this case the self as a
translator has made a mistake one effect from the Umwelt was wrongly encoded into a sign for
activation and that way contributed not to the survival but to the destruction of the organism. We
could also speculate that the individual as a tool for testing and maintaining the niche received a
negative feedback. In this case there would implications concerning the suitability of the niche.
However molecular mimicry is a phenomenon which is still researched and there are no final
conclusions. Although experiments on animal bring plenty of evidence concerning molecular

mimicry as a pathogenic mechanism, there is still not enough evidence in the case of humans.
(Oldstone, 2005:10-11).

Finally, molecular mimicry as a pathogenic mechanism could be

interpreted simply as a stochastic event. The code used in encoding the meaning, like the
language code and every other code, simply is not perfect.

Conclusion
The immune system, although researched in medicine, biology, chemistry and other
disciplines, is an important notion also in biosemiotics. It is conceptualized as a system able to
differentiate between self and non/self. This inevitably leads us to semiotics, since self and
nonself are abstract entities which are inferred by very physical objects: cell, antigen,
lymphocyte etc. It is obvious the, that we are walking in the realm of signs.
The discipline concerned with the internal processes of an organism, and therefore also
the immune system, is called endosemiotics. One of the theories regarding endosemiosises comes
from Thure von Uexkull et al. and it is in the framework of this theory that we analyzed the
notions of self and nonself. Moreover, in the same framework, we examined the mechanism
of molecular mimicry as a mechanism that disrupts this distinction.
We came to an understanding of the self as a translator which provides a code for the
meaning attribution processes. In the case of the immune self/nonself, the nonself is
considered, because of the biological background, as a variety of the self. In the immune
response, the encounter between a foreign antigen and an antibody creates an indexical sign
pointing to the nonself. On the contrary, in the case of molecular mimicry the indexical sign
points to the self and causes autoimmunity. On a cellular level, it is a mistake in the denotation
object.
We believe that a further investigation of molecular mimicry and autoimmune responses
in general would greatly contribute to the knowledge about the immune system, and more
specifically to the conceptualization of the self and nonself. By investigating the cases where
such distinction is compromised, we could redefine the concepts of self and nonself, remodel

them and shortly, provide another map for the territory 10 which would, perhaps, shed some light
on certain issues concerning the immune system. Such task is, we believe, in the hands of
biosemiotics.

References:

Abbas, Abdul K; Lichtman Andrew H. 2004 [2001] Basic immunology: Functions and disorders
of the immune system. Philadelphia (Pa.) : Saunders Elsevier
Maran, Timo 2007. Semiotic interpretations of biological mimicry, Semiotica 167(1/4), pp. 223248.
Oldstone, M. B. A. 2005 Molecular mimicry, microbial infection, and autoimmune disease:
Evolution of the concept in Molecular mimicry:infection-inducing autoimmune disease, Berlin
Heidelberg New York: Springer, 1-19
Rose, Noel R.; Mackay Ian R 2006 The Autoimmune diseases. StLuis, San Diego, London:
Elsevier Academic Press
Shoenfeld Yehuda; Gershwin M. Eric; Meroni Pier-Luigi 2007 Autoantibodies. Burlington, San
Diego, London: Elsevier
Uexkll, Thure von; Geigges, Werner; Herrmann, Jrg 1993 Endosemiosis, in: Essential
reading in biosemiotics Vol.3 (2009) Springer Dordrecht Heidelberg London New York:
Springer, 279-323

10

The idea that the map is not the territory was first introduced by the scientist and philosopher Alfred Korzybski.