A Possible Link Between Autoimmunity and Cancer

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A Possible Link Between
Autoimmunity and Cancer
Erika Cristaldi, Giulia Malaguarnera,
Alessandra Rando and Mariano Malaguarnera
University of Catania
Italy
1. Introduction
The most important cause of mortality after cardiovascular diseases is due to cancer, that
affects both young and elderly people. The increasing incidence of tumour discovery is a
consequence of improving diagnosis techniques and sensitization acts, thus facilitating a
precocious identification and consequently an immediate therapeutic approach
(Malaguarnera et al., 2010).
Autoimmune diseases represent one of the main growing health problem worldwide with
wide variations in incidence and severity (Silink, 2002). Autoimmune diseases arise from an
overactive immune response of the body against substances and tissues normally present in
the body and they are due to the breakdown of immune tolerance to specific self-antigens.
Cancers and autoimmunity are often coincident—more coincident than is generally
appreciated; thereby it has been raised more interest the relationship and the possible
temporal consequence between autoimmune disease and cancer onset. Particularly, since a
high level of autoimmunity is unhealthy, a low level of autoimmunity may actually be
beneficial, thereby autoimmune reactions may be considered as a defence processes played
by the host against tumour, or it may be possible that the anti-tumour immune response
may result in elicitation of auto-antibodies against various auto-antigens, including self
antigens expressed in tumour cells.
Some autoimmune diseases, such as Sjögren's syndrome, rheumatoid arthritis and systemic
lupus erythematosus have been associated with the development of lymphoproliferative
malignancies (Kiss et al., 2010), and a pleyade of autoantibodies have been found in patients
with solid tumours (Bei et al., 2009). In addition, patients with dermatomyositis have a
greater risk of developing solid-organ malignancies than the general population. In these
patients, cancer can precede, parallel or follow myositis diagnosis (Zampieri et al., 2010).
The mechanism behind disease etiology remains unknown for most autoimmune diseases.
This situation is distinct from cancer where our understanding of how genetic mutations
lead to disease, is increasing. These advancements in cancer biology may have provided a
very important piece to the autoimmunity puzzle. However, the relationship between
cancer and autoimmunity is not well known. Despite minimal supporting evidence, the
standard model for explaining this coincidence is that autoimmunity leads to cancer due to
the rapid cell division associated with the regeneration of damaged tissues at the site of

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inflammation (Coussens & Werb, 2002). The relationship between autoimmunity and cancer
was investigated, focusing on implication of immune system, apoptosis and new
therapeutic agents for autoimmune diseases.
2. Break tolerance mechanisms in autoimmune diseases
The clinical signs and symptoms of different autoimmune diseases overlap, and individual
patients often present with syndromes that combine features of more than one disease.
Different autoimmune diseases share some genetic predisposing factors, including human
leukocyte antigen (HLA) alleles (SLEGEN et al., 2008) or the T-cell regulatory gene CTLA-4
(Ueda et al., 2003). Our current knowledge suggests that multiple mutation might be needed
before a self-reactive clone bypasses sequential tolerance-checkpoints and gives rise to an
autoimmune disease (Baechler et al., 2003). The development of autoantibodies reflects a
loss of B- and T- cell tolerance, which might result from a combination of genetic
predisposition, persistent inflammatory responses, abnormal handling of apoptotic material
and immune complexes, abnormal presentation of self-antigens and other events. As a high
level of autoimmunity is unhealthy, a low level of autoimmunity may actually be beneficial.
First, low-level autoimmunity might aid in the recognition of neoplastic cells by CD8+ T
cells, and thus reducing the incidence of cancer. Second, autoimmunity may have an
important role, allowing a rapid immune response in the early stages of an infection when
the availability of foreign antigens limits the response (i.e., when there are few pathogens
present).
Diseases such as rheumatoid arthritis and tireotoxicosis are associated with the loss of
immunological tolerance, which is the ability of an individual to ignore self, while reacting
to non-self. This breakage leads to the immune system mounting an effective and specific
immune response against self determinants. The exact genesis of immunological tolerance is
still unclear, but several theories have been proposed to explain its origin. Two hypotheses
have gained widespread attention among immunologists:

Clonal Deletion theory, proposed by Burnet (1988), according to which self-reactive
lymphoid cells are destroyed during their development. The extent to which the
thymus can mediate tolerance to tissue-specific proteins and how organ specific
tolerance is mediated remains an open question. While some tissue-specific proteins
might reach the thymus through the circulation, this mechanism may be unnecessary
due to expression within the thymus of the autoimmune regulator protein AIRE, which
acts as a promiscuous ubiquitin ligase with the potential function of controlling
transcription of a broad array of tissue-specific target genes in thymic epithelial cells
(Nagamine et al., 1997).

Clonal Anergy theory, proposed by Nossal et al. (1982), in which self-reactive T- or B-
cells become inactivated in the normal individual and cannot amplify the immune
response. This process is based upon the requirement of two signals for T-cell
activation. The first is provided by the recognition of MHC-complexes and the second is
due to the interaction between CD28 on T cells and B7 on activated antigen presenting
cell (APC), that are induced by pro-inflammatory factors, such as bacterial products,
pro-inflammatory cytokines, and other signals.
Previously, conditions such as cancer could not stimulate immune responses due to lack of co-
stimulatory signals. However, this notion was based on cancers at late or advanced stages of
disease, when tumour-induced immunosuppression may be at its highest degree (e.g. through

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production of the regulatory cytokines, transforming growth factor (TGF)-β and IL-10); in fact
there is a considerable potential for newly transformed cells to evoke danger signals through
the engagement of pro-inflammatory signaling pathways (Eisenlohr & Rothstein, 2006).
3. Autoimmune diseases and cancer - pathogenetic aspects
Positive associations have been reported between certain lymphomas and inflammation,
autoimmune disease and infectious agents (Rosenquist, 2008).
Normally, tolerance checkpoints silence self-reactive T and B cells by preventing
uncontrolled stimulation through self-antigens exposure. Several observations suggest that
lymphocyte clones having bypassed tolerance mechanisms may be involved both in
autoimmunity and malignancy (Goodnow, 2007). There are epidemiological observations of
autoimmunity and lymphoma occurring simultaneously in diseases like systemic lupus
erythematosus, rheumatoid arthritis and Sjögren's syndrome regardless of the use of
immunosuppressive therapy (Bernatsky et al., 2007).
Infectious agents causing lymphomas can be classified according to several mechanisms.
First, some viruses can directly transform lymphocytes as for Burkitt’s lymphomas that may
occur following infection with HIV; as well as T-cell lymphomas may occur following
chronic antigen challenge with wheat in celiac disease (Cellier et al., 2000). Second, some
infections increase lymphoma risk through chronic immune stimulation (Engels, 2007),
which is also present in autoimmune diseases. Since uncontrolled stimulation of antigen
receptors and lymphocyte proliferation triggered by chronic infection (e.g. Helicobacter
pylori) may result in mucosa-associated lymphoid- tissue B-cell lymphomas (Suarez et
al.,2006), it may be supposed that chronic stimulation of autoreactive cells paired with
somatic hypermutation and recombinase activator gene (RAG) activity directed at non-
antigen receptor loci may underlie lymphoma in systemic lupus erythematosus, rheumatoid
arthritis and Sjögren's syndrome (Schuetz et al., 2010).
Treatments for autoimmune and chronic inflammatory disorders could also affect the risk of
lymphoproliferative malignancies. Another reason for the association could be shared
environmental risk factors (Landgren et al., 2006), and in some autoimmune diseases genetic
mutations are discovered, leading to lymphoproliferation (Turbyville & Rao, 2010). Somatic
mutations in lymphocytes may additionally contribute to the pathogenesis of autoimmunity
and lymphoid malignancies as observed in patients with autoimmune lymphoproliferative
syndrome carrying a mutated FAS gene in a single hematopoietic stem cell that contributes
to a small fraction of blood cells. These patients may present with autoimmune symptoms
and lymphoma formation just like patients with inherited FAS mutations (Holzelova et al.,
2004).
4. The role of adaptive immunity
4.1 Treg cells
Regulatory T (Treg) cells are currently considered as key players in the mechanisms of
peripheral immune tolerance. They are classified in natural and inducible CD4+CD25+
FOXP3+ Treg cells. The transcription regulator FOXP3 (Forkhead box P3) appears to be
required for the development, maintenance, and suppressor function of Treg cells (Hori et
al., 2003), and the loss of FOXP3 in Treg cells - or its reduced expression - leads to the
acquisition of effector T-cell properties including the production of non-Treg cell specific

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cytokines (Wan & Flavell, 2007). Treg cells are engaged in the control of immune self-
tolerance, allograft rejection, allergy, and are also important for inhibiting the effector
functions during infection and tumours development. In addition, the removal or a
functional defect of Treg cells from normal rodents leads to the development of various
autoimmune diseases (Weiner, 2001), because these cells actively suppress the activation
and expansion of autoreactive immune cells.
Sometimes the studies investigating the role of Treg cells in SLE, have given controversial
results (Khun et al., 2009). Most studies have found a reduced or normal frequency of Treg
cells in SLE (La Cava, 2008), although other studies may have shown increased number. It
has been observed a decreased number of Treg cells, during active disease flares (Miyara et
al., 2005) and active SLE pediatric patients, thereby showing a poor suppressive capacity
and an inverse correlation between Treg cells and disease activity as well as autoantibody
levels (Lee et al., 2006). However,
immunosuppressive agents has been found to promote an increase in the number of Treg
cells, particularly of peripheral Treg cells. Also, increased mRNA levels of CD25, FOXP3,
and GITR have been found in B-cell depleted patients treated with rituximab at the time of B
cell repopulation (Cepika et al., 2007).
In the collagen-induced arthritis model of systemic joint inflammation, the adoptive transfer
of Treg cells protects from disease, whereas a depletion of Treg cells accelerates it (Morgan
et al., 2005). Furthermore, in patients with early rheumatoid arthritis (RA), a reduced
number of peripheral Treg cells is observed (Lawson et al., 2006), although the synovial
fluid can often contain increased numbers of Treg cells (Cao et al., 2003).
Furthermore, increased frequency of Foxp3+ Treg cells has been documented in tumour
tissues and peripheral blood of patients with several types of cancer consistent with a role in
tumour escape from immunological control. And also, not only the quantitative aspect of
Treg cells, but also their functions are different between tumour patients and healthy
control. Treg cells are considered inhibitors
CD4+CD25+Foxp3+ regulatory T cells have been considered as a candidate for cancer
immunotherapy for over a decade. Attempts to block or eliminate Treg cells have been
made by the use of chemotherapy; these strategies, aimed at block Treg cells induction and
migration, may be clinically useful, as suggested by experimental evidences in tumour
models (Langier et al., 2010).
Data concerning the role of CD4+CD25+ regulatory T cells in human cancer derived from a
work, which showed that the presence of such Treg cells in advanced ovarian cancer
correlated with reduced survival (Curiel et al., 2004). In addition, TGF-β is a cytokine
produced by Treg and Type 1 T regulatory cells, that is involved in the suppression of T cell
proliferation and function (M.L. Chen et al., 2005). The experimental results supplied by
other researchs indicate that TGF-β, secreted by ovarian carcinoma cells, owns vital function
in the process of converting peripheral CD4+CD25– T cells into CD4+CD25+ regulatory T
cells, likely providing a possible immunotherapeutic target for ovarian cancer (Zheng et al.,
2004).
One of the new therapeutic approach to cancer is based on the adoptive transfer of tumour-
specific cytotoxic T cells and anti-CD25 antibodies. A combination of Treg cell-depletion,
using anti-CD25 monoclonal antibodies, and cytotoxic T lymphocytes administration is a
possible approach for treatment of cancers which enable further exploration in the clinical
setting (Ohmura et al., 2008), though these future approaches suggest a possible
development of autoimmune diseases, due to decreased Treg cells occurrence.
treatment with corticosteroids and/or
of anti-tumour immunity and

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4.2 Dendritic cells
Dendritic cells have been recognized as the most efficient antigen presenting cells that have
the capacity to initiate naïve T-cell response in vitro and in vivo. During their differentiation
and maturation pathways, DCs can efficiently capture, process and present antigens for T-
cell activation. The functional activities of DCs mainly depend on their state of activation
and differentiation: iDC are involved in the maintenance of peripheral tolerance whereas
mature DC can efficiently induce the development of effector T cells. Thereby, accumulated
iDCs, which are educated at the tumour site, act as functional inhibitors of a tumour-specific
immune response in cancer, immature pDCs are activated by Toll-like receptors, which lead
to B- and T-cell immune responses in autoimmune disease (Lang et al., 2005). The
immunological tolerance is produced by tumour-derived soluble factors (TDSFs) and
immature dendritic cells (iDCs), which inhibit DC and T-cell activation, and exclusively
inhibit the DNA–IgG immune complex, inducing pro-inflammatory responses needed for an
immune response. Immunological ignorance is produced by reduced levels of tumour
antigens. Dendritic cells not only initiate T-cell responses, but are also involved in silencing
T-cell immune response. DC can play a central role in the development of T-cell tolerance,
and its maintenance in the periphery is critical for the prevention of autoimmunity.
4.3 T helper 17 cells (Th17)
T helper 17 cells constitute a third subset of T helper cells that are important in the
development of autoimmune diseases and in the immune response against infections.
These cells are characterized as preferential producers of IL-17A, IL-17F, IL-21, IL-22 and IL-
26 in humans. The IL-17 production is required to differentiate Th17 cells, from IFN-γ
producing Th1 cells, or IL-4 producing Th2 cells. IL-17 (A and F) induces production of a
broad range of pro-inflammatory cytokines and chemokines, including IL-6, colony-
stimulating factors, chemokines (CCL2, CCL7, CXCL1, and CCL20), human β-defensin-2
and matrix metalloproteinases (MMP-3 and MMP-13), by a variety of cells (Weaver et al.,
2007). Conversely, inhibition of IL-17 signaling leads to impaired host defence against
bacterial infection (Ye et al., 2001) and resistance to autoimmune diseases (Yang et al., 2008).
IL-17 regulates host defence against infectious organisms through promoting granulopoiesis
and neutrophil trafficking (Linden et al., 2005).
Although FOXP3+ Treg cells are critical for control of autoimmunity and inflammation
(Sakaguchi, 2004), Th17 cells have been implicated in mediating inflammation and
autoimmune diseases (Weaver et al., 2007). It has been shown that the balance between Treg
and Th17 cells is a key factor which regulates T-helper cell function relating to the Th1 ⁄ Th2
shift in autoimmune disease and graft versus host disease (GVHD) (Afzali et al., 2007). In
fact, elevated levels of IL-17 have been associated with inflammatory diseases in humans,
including rheumatoid arthritis, scleritis, uveitis, asthma, systemic lupus erythematosus, and
allograft rejection (Kolls & Linden, 2004).
However, there are limited information on the balance between Treg and Th17 cells in
cancer patients and on the active role played by Th 17 in anti-tumour immunity (Kryczek et
al., 2009). The function of IL-17 in tumour immunity is a controversial subject. The effects of
IL-17 on tumour development are directly influenced by the existence of an adaptive
immune system. In the presence of lymphocytes, IL-17 promotes tumour rejection, whereas
in the absence of those, IL-17 favours tumour growth and angiogenesis (Martin-Orozco &
Chen Dong, 2009a). By using IL-17-deficient mice in a model of lung melanoma, it has been
provided direct evidence for a protective role of IL-17 in anti tumour responses (Martin-