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International Journal of Cancer Research, 2005; 1(2): 81-86.
ISSN: 1811-9727
ISSN: 1811-9735
© 2005 Asian Network of Scientific Information
Autoimmunity as Evolutionary by
Product of Adoptive Immunity and Source of Anti-tumor Immunity Failure
Ivan Bubanovic
Department of Obstetrics and Gynaecology – “Medica Centre” – Nis, Serbia
Download .pdf version of the article
Abstract
One of the biggest threats to survival is infection, so that the immune system
is under permanent and strong evolutionary pressure to be highly responsive. By
tracing the evolution of the invertebrate immune system, it can be seen that it
largely followed the “classical” model based on bi-directional “predator-prey”
relationships. Similarly, the evolutionary emergence of MHC system and the
mechanisms of immune recognition in vertebrates came as a direct result of a
microbe-exerted selection pressure. The new possibilities gave rise to new
conveniences and brought about certain risks in the new forms, like
auto-immunity, alloimmunity and reproductive efficacy. To that effect, the
evolutionary emergence of the MHC has enabled a more effective defense from
intracellular parasites, such as viruses. However, the whole complex of
processing/presenting/recognizing of antigens could be closely related to the
auto-immunity as a by-product of the evolution of MHC system and adoptive
immunity. On the other hand, tumor development is frequently accompanied by the
immune response against “self” and altered antigens expressed by tumor cells,
because these antigens are the most prevalent molecules recognized by the immune
system. The activation of the auto-immune process in parallel with an effective
anti-tumor response could mean the failure of protective control mechanisms of
the immune reaction that may be responsible for the prevention of auto-immune
diseases. At the same time, the activation of suppressor/modulatory mechanisms
possibly accompanied by the activation of anti-tumor auto-immune-like immune
response could be a factor of anti-tumor immunity failure in all vertebrates.
Keywords: Auto-immunity, vertebrate, mammals, tumor, evolution
Evolution of the Vertebrate Immune System
Some evolutionary processes can be studied directly, while the evolution of
the immune system and immunity cannot. The evolution of immunity is a
macro-evolutionary process, which can be studied by examining the patterns in
biological populations or species of related organisms and inferring process
from pattern. One of the possible ways to carry out a detailed investigation
into the issue of the evolution of the immune system is virtually by comparing
the characteristics of the immune system across species and classes. In
addition, the determination of the genes and molecules conserved throughout
evolution is helpful in identifying the mechanisms of the immune system
evolution, while variable genes as well as the emergence of new genes along
evolution enable the identification of various evolutionary pressures, their
duration and strength. This provides a better understanding of how the immune
system works under physiological and pathological conditions. This approach,
however, is not an easy one since only few percent of the total number of
species that have inhabited the planet to date are available for research.
Notwithstanding this limiting factor, previous studies have produced sufficient
findings for the construction of a hypothetical model of the evolution of the
immune system in vertebrates, and also cleared the pathway towards reaching
further relevant presumptions and conclusions.
The evolution of the immune system is a direct consequence of microbes-exerted
selection pressure on multicellular organisms. The vertebrate immune system was
to some extent inherited from invertebrates, whereas a part of it has advanced
considerably in the course of its own evolution. Although certain
vertebrate-specific properties such as immune recognition and immune memory have
also been identified in invertebrates in rudimentary forms, it is particularly
those qualities like progressive development of humoral and cellular adoptive
immunity, Major Histocompatibility Complex (MHC), variable class I and class II
genes, precise mechanisms of immune recognition and long-term immune memory that
reflect the fundamental evolutionary advancement of the vertebrate immune
system.
The presumption that auto-immunity could have represented evolutionary new forms
of strong selection pressure closely associated with the evolution of the
mammalian immune system correlates with the unique control mechanisms of immune
response verified in this vertebrate. In short, the evolution of the mammalian
immune system has possibly undergone the pressures of at least four quite
diverse factors: microbes, auto-immunity, alloimmunity/reproductive efficacy and
tumors. However, there is opinion that auto-immunity and tumors cannot be
sources of strong selection pressures, as most of these generally occur after
leaving offspring. On the contrary, alloimmunity/reproductive efficacy might
have been the source of a very strong selection pressure that greatly influenced
the evolution of the mammalian immune system.
The possible effects of such heterogeneous and complex evolutionary pressures
are the evolutionary development of the mammalian immune system into one of the
most complex, most organized and multilevel controlled system in the world of
living beings.
Notwithstanding the possibility that auto-immunity might be the by-product of
the evolution of adoptive immunity, this phenomenon could have been one of the
factors significantly influencing the course of the evolution of vertebrate
immune system and development of the mechanisms for the control of immune
reaction. The evolutionary modelling of the vertebrate immune system under the
influence of microbes and auto-immunity, did not probably result in the
weakening of the killer mechanisms efficacy and MHC genes variability, but could
have been followed by the introduction and co-evolution of evolutionary new
mechanisms for the control of immune reaction, that could have restrained the
potentially “self”-destructive power of the adoptive immunity.
1. The evolution of the vertebrate immune system from cartilagofish to mammals
is characterized by several processes featuring clearly perceivable evolutionary
trends (1):
2. The grouping and clustering of MHC genes;
3. Associating of TAP/LMP genes with a less variable class of MHC genes (class I
in fishes and class II in mammals);
4. The emergence of auto-immunity like a form of selection pressure;
5. The sophisticated mechanisms of “self”-tolerance mechanisms;
6. The sophisticated mechanisms of immune reaction control mediated by cells of
innate immune system;
7. The increasing of the number of the immune cell subtypes involved in the
control of immune reaction (Th1, Th2, APCs, DCs);
8. The regulation of immunoreactivity mediated by sex hormones;
9. The increasing of the number of cytokines;
10. The regulation of immunoreactivity mediated by a complex cytokine network;
These phenomena could be associated with a better and more precise control of the immune reaction. However, it is very difficult to answer the question how big the contribution of the selection pressure of auto-immunity on the evolutionary development of the vertebrate immune system is. Judging from the pathogenesis of auto-immune diseases which are clearly associated with the basic features of the adoptive immunity like MHC, and also from the high incidence of auto-immune diseases in mammals, this phenomenon could be a significant factor of the selection pressure and evolutionary modelling, and permanent re-modelling, of the vertebrate immune system and their control mechanisms.
Auto-immunity in Vertebrates
There is a large body of data that many auto-immune diseases are a
characteristic of vertebrates and that they are associated with MHC molecules.
In fact, there is no firm evidence that would suggest the existence of
auto-immune phenomena in invertebrates (2,3). The presumably MHC molecules of
aberrant target cells, TCR and APCs need to interact abnormally before
auto-immune disease can fully develop. In this abnormal interaction, additional
aberrancies in other regulatory systems may play a role in a further
exacerbation of the “self”-directed immune response, such as defects in the
hormone and cytokine synthesis and secretion. The various aberrancies are partly
genetically determined by a variety of separate genes, particularly MHC and
related genes like TAP/LMP, but they may also be environmentally induced by
viruses, chemicals, drugs or injuries (4).
In evolutionary new condition of strong (adoptive) immunity, the survival
advantage imposed by an extremely reactive immune system is jeopardized if that
system turns against the host and causes “self” destruction. Thus, evolutionary
pressures selecting for a hyperactive immune system must be combined with
similar pressures optimizing “self”-tolerance. Accordingly, the mechanisms which
evolved in response to the auto-immunity-imposed evolutionary pressure or, more
precisely, co-evolved with the phenomenon of auto-immunity, are related to
various forms of immune tolerance, strong and multileveled control
immunomodulatory and suppressive mediated by sex hormones, IL-10, TGF-b, Th2
cells, apoptosis and/or anergy of “self”-reactive clones, blood-barrier
sequestration of “self” molecules, cells, tissues and organs (5,6).
Surprisingly, auto-immunity is not a feature of a young immune system, when the
immune network functions at its prime. Instead, the risk of developing
auto-immune disease increases with age. In general, auto-immunity manifests in
hosts who have passed the apex of their reproductive years and in whom
evolutionary pressures towards prompt immune responsiveness are declining. The
ageing of the immune system should be associated with the loss of function, and
the likelihood of developing auto-immunity should progressively decrease. The
traditional paradigm interprets auto-immunity as an aberrant response of the
adaptive immune system to “self” molecule(s), consistent with the view that
auto-immunity is a result of overreacting. It has been proposed that T
lymphocytes specific for such “self” molecule(s) induce a memory response, which
is relatively resistant to natural immuno-suppressive mechanisms. Tissue
destruction has been understood as the after-effects of persistent
immunocompetent cells. This model ignores that the risk for auto-immunity is
inversely related to the functionality of the adaptive immune system throughout
a lifetime. The new evolutionary concept of auto-immunity proposes that the
accelerated immunity and failure of control mechanisms after reproductive time
might be the primary risk factor for auto-immunity.
From the evolutionary point of view, the immune system based on adoptive
immunity has been made into a more complex and advanced defence system,
developed under a strong selection pressure of microbes during the vertebrate
evolution. Such model of vigorous immunity in vertebrates produced a new form of
selection pressure, known nowadays as auto-immunity. Because the positive
selection pressure of the adoptive immunity was probably stronger than the
negative pressure of auto-immunity, the selection pressure of auto-immunity gave
rise to the emergence of the control immunomodulatory and immunosuppressive
mechanisms and to the “deferring” of the emergence of auto-immune diseases until
post-reproductive age. Recent data have provided evidence of a feed-back loop
between reproductive hormones, mainly estrogens, and the expression,
distribution and activity of cytokines. For instance, in vitro studies using
mice cell cultures showed that while androgens decreased the production of IFN-g,
IL-4 and IL-5, estrogens enhanced IFN-g production by murine lymphoid cells.
Moreover, estrogens treatment of macrophages from male mice increased IL-1
secretion. In CD4+ cell clones from auto-immune patients, both IL-10 and IFN-g
production were increased in the presence of estradiol (5,6,7).
In general, females have a more responsive immune system than males. Females
have a greater humoral response, as evidenced by higher serum Ig concentrations
than males (8) and a greater antibody response to various antigens after
immunization (9). In addition, females reject skin allograft faster and have a
reduced incidence of tumors, indicating that they also have a greater cellular
immune response (10,11). This difference in immune response is thought to be
responsible for the greater susceptibility of females to the auto-immune
diseases such as multiple sclerosis, rheumatoid arthritis, and systemic lupus
erythematosus. This gender difference has also been observed in animal models of
auto-immune disease in NZBxNZW mice (5).
A protective effect of testosterone is thought to underlie why males are less
susceptible to auto-immune disease than females. This is based on studies that
include removing testosterone from male mice via castration as well as by
treatment of female mice with testosterone. For example, the castration of male
non-obese diabetic mice resulted in an increased prevalence of diabetes (12),
and the castration of male mice increased the incidence of auto-immunity (7).
Conversely, female non-obese diabetic mice implanted with testosterone pellets
had a lower incidence of diabetes and less incidence of auto-immune disease,
respectively, compared with those implanted with placebo pellets (6). The same
studies have indicated that gender differences in susceptibility may be due to
gender differences in cytokine production upon auto-antigen-specific
stimulation. In males, compared with females, greater Th2 and less Th1 cytokine
production has been observed. The balance between cytokines produced by Th1 and
Th2 lymphocytes is considered central to the development of auto-immune disease.
Th1 lymphocytes produce IFN-g, IL-2, and TNF-a. Th2 lymphocytes secrete IL-4,
IL-5, IL-6, IL-10, and IL-13. These two cell types are mutually inhibitory, and
their development occurs under very specific conditions. If a naive T lymphocyte
is initially stimulated with antigen in the presence of IL-12, the immune
response is skewed toward Th1. However, if a naive T lymphocyte is initially
stimulated with antigen in the presence of IL-4, the immune response is skewed
toward Th2 (5,6). The same and other studies have collectively shown that immune
cells under male sex hormones produce more IL-4 and IL-10, and less IFN-g and
IL-12, supporting the conclusion that the male immune system is shifted toward
Th2 immunity (6,7). The mechanisms underlying why there is a sex hormones
difference in cytokine production remain unknown. Many possibilities exist such
as differences in the levels of male sex hormones, differences in female sex
hormones, and differences in genes located on sex chromosomes.
Similar to previous studies, Stephanie et al. (13) found that levels of the Th2
cytokines IL-4 and IL-10 were higher and the IL-12 level was lower in
splenocytes from males compared with females. Also, splenocytes from female mice
implanted with testosterone pellets, like splenocytes from male mice, secreted
more IL-10 and less IL-12. However, the treatment with testosterone did not
cause increased IL-4 production. This clearly indicates that testosterone does
not recapitulate all the cytokine differences seen in male versus female mice,
and that the increase in IL-4 must be due to gender differences in other sex
hormones and/or genes found on sex chromosomes (13). The finding of increased
IL-10 production is equally as important as the finding of decreased IL-12
production upon testosterone treatment. Numerous studies have shown that IL-10
is essential in down regulation of cellular immune reaction. Specifically, the
treatment of auto-immune patients with IL-10 has been shown to ameliorate
disease (14,15), whereas the administration of anti-IL-10 antibodies has
exacerbated disease (15). Although the treatment of auto-immune patients with
IL-4 also ameliorated disease (16), studies of IL-4- and IL-10-deficient mice
and IL-4 as well as IL-10 transgenic mice have shown that IL-10 may play a more
critical role in the protection from auto-immunity. Indeed, IL-10-/- mice
developed more severe auto-immune disease compared with wild-type mice, and
overexpression of IL-10 rendered mice resistant to auto-immunity (17). Because
IL-10 has been shown to play a protective role and IL-12 a disease-promoting
role in auto-immunity, and because testosterone increases IL-10 and decreases
IL-12, testosterone would appear to play an important role in susceptibility to
auto-immunity and immune reaction control. Although many cells within spleen
express the testosterone receptor (TR), testosterone probably can act directly
upon CD4+ T lymphocytes to increase IL-10 expression during stimulation with
anti-CD3. The PCR analysis showed that CD4+ lymphocytes express the TR,
supporting the possibility of direct action of testosterone on these cells.
However, the TR is also expressed by CD8+ lymphocytes and macrophages. Thus, an
indirect action of testosterone mediated through these cells was also possible.
In vitro stimulation of CD4+ T lymphocytes in the presence of testosterone and
in the absence of other cells resulted in increased IL-10 production (13).
Estrogens modulate its effect by binding to estrogens receptors (EsR) present in
the immune target cells. The EsR is a nuclear transcription factor that
regulates gene expression. Some of the genes regulated by estrogens are
progesterone receptor, bcl-2 apoptosis inhibitor, FasL and other growth-related
genes responsible for estrogen’s effects on cell death and proliferation.
Different authors have shown EsR in human peripheral blood mononuclear cells,
thymocytes, spleen cells and APCs. The recent discovery of a second estrogens
receptor, EsRb, presents new possibilities for control of immune targets by
different selective estrogens receptor modulators (5,6,7,13).
A shift toward Th2 cytokine production has been demonstrated during pregnancy
and high dose estrogens therapy and is thought to be the primary mechanism by
which estrogens suppress the cellular immune response. However, a low dose
estrogens treatment is equally suppressive in the absence of a significant shift
in cytokine production. Estrogens treatment in cytokine-deficient and wild type
mice up-regulate Th2 cytokine production. Also, estrogens effectively suppress
the development of experimental auto-immunity in both, IL-4/IL-10 knockout mice
and in auto-antigen-immunized wild type mice (5,6,7,13).
Anti-tumor Immunity as Auto-immunity
Tumor development is frequently accompanied by the immune response against
“self” and altered antigens expressed by tumor cells, because these antigens on
vertebrate tumors are the most prevalent molecules recognized by the immune
system (18,19). This reflects the fact that tumor arise from the hosts’ own
tissues, and are not truly “foreign”, except in the cases when tumor cells
express the so-called fusion proteins and/or viral peptides. Thus, in some
respects, the immune recognition of tumor appears to be different from the
immune recognition of bacteria, and typically more akin to auto-immunity. In
addition, the immune reaction to virally infected cells showing no malignant
alterations, displays some characteristics of auto-immune reaction. This
inevitably activates the regulatory mechanisms which prevent a complete
destruction of tissues and organs. From these reasons, the recognition of “self”
antigens on tumor cells in most circumstances presents problems for the host
immune system. First, the immunity to tumor may not develop because all
vertebrates pass across the embryonic phase of establishing of specific immune
tolerance on “self” molecules. Second, even when the immune system can recognize
and respond to tumor antigens, immunity may not be sufficient to reject cancers,
due to the activation of the mechanisms which control auto-immunity. Finally, if
immunity to “self”-tumor antigens develops, there are potential auto-immune
sequelae, which may also result in the activation of the control suppressor/modulatory
mechanisms of the immune reaction.
Auto-antibodies specific to different “self” molecules have been found in the
sera of tumor bearers, which could be taken as an evidence for frequent joint
activity of anti-tumor immunity and auto-immunity. This emphasizes the idea that
tumor patients can mount tumor immunity which could be, in part, auto-immunity.
In contrast to patients with auto-immune diseases, in the majority, if not all,
tumor patients the immune system is unable to combat tumor growth.
Tumors seem to find ways to generate tolerance in the immune system by
activating the control mechanisms of auto-immune reaction responsible for the
tolerance against “self” molecules. These mechanisms include a down-regulation
of MHC class I molecules and cellular constituents involved in the antigen
processing and presentation pathways (20). Tumors can also induce several
different biochemical defects in physiology of T lymphocytes. In addition, the
immune response against tumors is hindered by the functional hierarchy in the
immunogenicity of T and B cell determinants, abnormalities occurring in the
communication between the cells of innate and adoptive immunity, as well as the
inadequate cytokine network (21).
In line with Burnett’s theory of clonal selection, T-cell clones specific to
dominant determinants of tumor antigens are probably deleted during embryonic
development in the process of negative selection. This could possibly continue
into an adult stage as a central (thymic) deletion of tumor-specific clones, or
even as a peripheral deletion in the course of extrathymic lymphocyte maturation
(22). Thus, most of the tumor determinants are expected to be immunologically
silent; hence effective tumor immunity cannot be induced via “self”-vaccination.
Additionally, as tumor accumulates antigens during transformation they also
gradually induce tolerance in T cells against these antigens.
Notwithstanding these and other escape mechanisms, in few cancer patients a
spontaneous regression of malignant tumors was observed (23,24). Data about
potential coupling of auto-antibodies and prolonged/sustained survival or even
spontaneous tumor regression corroborate the previous observation. Breast cancer
patients with a natural humoral response to MUC-1 and/or hsp90 exhibited a
better outcome (25,26). Similar to immunological events in some auto-immune
diseases, tumor in regression exhibited mainly a Th1 type response, as well as
non-pathogenic auto-antibodies, but thus the form of auto-immunity did not
always develop into the auto-immune disease. There is data that about the
potential coupling of tumor immunity with auto-immunity has been suggested by
the clinical observation that the patients with metastatic melanoma who develop
vitiligo have a better prognosis (27). In addition, there are observations that
support a possible protective role for the auto-immune diseases in cancer
patients. In this respect, the mortality rate of cancer patients with multiple
sclerosis was found to be significantly lower than that of cancer patients in
general (23). This could be associated with the activation of control
anti-auto-immune mechanisms which may also inhibit auto-immunity and anti-tumor
activity of the immune system.
In conclusion, the potential coupling of tumor immunity with auto-immunity has
been suggested by the clinical observation that patients with metastatic tumor
who develop auto-immune phenomena have a better prognosis and are more likely to
respond to therapy (27,28). The differences in mechanisms underlying tumor
immunity and auto-immunity could be a consequence of fundamental differences in
effector mechanisms used to kill tumor cells versus normal cells. At the same
time, the mechanisms controlling “self”-destructive immune reaction might be one
of the important factors of anti-tumor immunity failure.
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