Toxicology of Autoimmune Diseases

Abstract

Susceptibility to most autoimmune diseases is dependent on polygenic inheritance, environmental factors, and poorly defined stochastic events. One of the significant challenges facing autoimmune disease research is in identifying the specific events that trigger loss of tolerance and autoimmunity. Although many intrinsic factors, including age, sex, and genetics, contribute to autoimmunity, extrinsic factors such as drugs, chemicals, microbes, or other environmental factors can also act as important initiators. This review explores how certain extrinsic factors, namely, drugs and chemicals, can promote the development of autoimmunity, focusing on a few better characterized agents that, in most instances, have been shown to produce autoimmune manifestations in human populations. Mechanisms of autoimmune disease induction are discussed in terms of research obtained using specific animal models. Although a number of different pathways have been delineated for drug/chemical-induced autoimmunity, some similarities do exist, and a working model is proposed.

Full text

Toxicology of Autoimmune Diseases
K. Michael Pollard†, Per Hultman§, and Dwight H. Kono‡
† Depart of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North
Torrey Pines Road, La Jolla, California, 92037 USA
‡ Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, California, 92037 USA
§ Molecular and Immunological Pathology, Department of Clinical and Experimental Medicine,
Linköping University, SE-581 85 Linköping, Sweden
Abstract
Susceptibility to most autoimmune diseases is dependent on polygenic inheritance, environmental
factors, and poorly defined stochastic events. One of the significant challenges facing autoimmune
disease research is in identifying the specific events that trigger loss of tolerance and
autoimmunity. Although many intrinsic factors, including age, sex, and genetics, contribute to
autoimmunity, extrinsic factors such as drugs, chemicals, microbes, or other environmental factors
can also act as important initiators. This review explores how certain extrinsic factors, namely
drugs and chemicals, can promote the development of autoimmunity, focusing on a few better
characterized agents that, in most instances, have been shown to produce autoimmune
manifestations in human populations. Mechanisms of autoimmune disease induction are discussed
in terms of research obtained using specific animal models. Although a number of different
pathways have been delineated for drug/chemical-induced autoimmunity some similarities do exist
and a working model is proposed.
1. Introduction
Autoimmunity is the reaction of cells (lymphocytes) or products (antibodies) of the immune
system with constituents of the body’s own tissues leading to demonstrable pathology.
Autoimmunity can produce a variety of clinical conditions depending upon the target of the
attack, with common features including expansion of self-reactive T and B cells, production
of autoantibodies and tissue damage. The most baffling and challenging aspect of
autoimmunity is identifying the events that contribute to the initiation of the response. While
many intrinsic factors including age, sex, and genetics contribute to autoimmunity, it is
believed that extrinsic factors such as drugs, chemicals, microbes, and/or the environment
can trigger the initiation of an autoimmune response. In this review we will discuss the
contribution of extrinsic factors, to autoimmunity, the diseases produced and what has been
learned from animal models which use drugs and chemicals to initiate autoimmunity.
2. Types of Autoimmunity
2.1 Systemic Autoimmunity
Systemic autoimmune diseases are a heterogeneous group of diseases in which pathology is
evident in a number of organ systems within the body. Systemic autoimmune diseases
Correspondence to: K. Michael Pollard.
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include connective tissue diseases such as systemic lupus erythematosus (SLE),
scleroderma, Sjögren’s syndrome, inflammatory myopathies, and overlap syndromes such as
mixed connective tissue disease (MCTD) and undifferentiated (unclassified) connective
tissue diseases. Individual diseases often exhibit significant heterogeneity in clinical
features, genetics and autoantibodies. In most systemic autoimmune diseases the
autoantibody responses can be directed against a number of autoantigens, and the resulting
profile of autoantibody specificities may be disease specific [1]. Although of diagnostic
importance the contribution of autoantibodies to the initiation, exacerbation or progression
of disease remains uncertain but it has been argued that the differences in autoantibody
profiles that are associated with systemic autoimmune diseases suggest that they may
constitute molecular signatures of the disease process [2].
2.2 Organ Specific Autoimmunity
Organ-specific autoimmune diseases affect specific tissues in which the target auto-antigen
is found. Commonly targeted tissues or cells include the thyroid (thyroiditis), the β cells of
the islets of Langerhans (diabetes), gastric parietal cells (gastritis), liver (autoimmune
hepatitis) and steroid-producing cells in the adrenal and ovary (Addison’s disease) [3].
Susceptibility to these diseases are influenced in large part by genetics, particularly MHC-
related genes [4], but they may also be influenced by environmental agents [3]. A number of
toxicants have been identified that induce organ-specific autoimmune disease.
3. Toxicants that Induce Autoimmunity
A number of chemicals and drugs have been reported to be associated with features of
autoimmunity in human populations (Table 1). In the majority of instances a direct link
between exposure and disease manifestations is extremely difficult to establish because of
the inherent limitations of epidemiological studies to draw causal conclusions. Additionally
human populations are rarely exposed to a single agent over time, there can be a significant
delay between exposure and onset of disease, and it is often not possible to identify all the
toxicants to which a population may have been exposed. The notable exception to this,
however, is exposure to medications because in this situation there is a captive population
and the affected individuals can cease use of the suspected agent in order to determine if
drug consumption is the cause [5,6]. Indeed induction of autoimmunity following drug
exposure has been responsible for acceptance of the possibility that repeated contact with
chemicals and toxicants can elicit autoimmunity. In the following sections we will expand
upon the roles that drugs, toxicants, and chemicals play in the induction of autoimmunity.
Due to space limitations we will focus on a small number of agents, most of which have
been shown to produce features of autoimmunity in human populations (Table 1). Where
possible, mechanisms of induction are discussed using specific animal models.
3.1. Systemic Autoimmunity
3.1.1. Drug-induced autoimmunity—The chemicals most often associated with
development of autoimmunity in humans are medications. Although the manifestations of
drug-induced autoimmunity can vary widely, they are most similar to those associated with
systemic lupus erythematosus (SLE) [5,7]. Drugs can be considered to either exacerbate pre-
existing disease or initiate disease in otherwise previously healthy individuals, with
discontinuation of the drug leading to disease abatement in the latter. Other differences in
the two types of responses exist [8], including a preponderance of females of child bearing
age and greater incidence of autoantibodies to anti-double-stranded DNA in idiopathic
lupus, and most notably the relative lack of severe disease features such as major organ
involvement (renal and neurologic) in primary “drug-induced” lupus [6]. The latter may be
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related to a significantly greater presence of complement-fixing antibodies in idiopathic
lupus than in patients with drug-induced lupus [9].
A large list of drugs have been shown to induce SLE-like disease [7] and this list continues
to grow as new therapeutics are introduced. Recently, biologics such as TNFα antagonists
are now identified as inducing more severe forms of autoimmunity [5,6]. Of the implicated
drugs only a few, such as procainamide and hydralazine, are considered to be of high risk.
Furthermore the immune responses elicited by drugs differ from hypersensitivity responses
as neither cellular nor humoral anti-drug responses contribute to the development of
autoimmunity [7]. The mechanism by which these two drugs induce an essentially identical
autoimmune response has not been completely resolved, but two tentative modes of action
have been hypothesized.
The first hypothesis is based on the finding that 4-day pre-culture of cloned T cells with
either procainamide or hydralazine resulted in autoreactive T cells that proliferated to
autologous antigen presenting cells (APC) alone without antigen [10]. Moreover, adoptive
transfer of procainamide pre-treated T cell lines into naïve mice produced autoantibodies
and glomerulonephritis [11]. The mechanism driving this response appears to reside, at least
in part, in the ability of both procainamide and hydralazine to inhibit DNA methylation. In
experimental studies, reduced DNA methylation of alu elements 5′ to the CD11a promoter
was argued to lead to an increase in CD11a transcripts and increased expression of the
integrin adhesive receptor LFA-1 (CD11a/CD18) [12]. It was postulated that increased
LFA-1 stabilizes low affinity interaction between the T cell receptor (TCR) and self class II
MHC complexes, leading to autoimmune responses [12], although this is clearly not the sole
mechanism leading to autoimmunity. Other studies have found that over expression of
CD70, a T cell costimulatory molecule encoded by the TNFSF7 gene, on CD4+ lupus T cells
as well as procainamide and hydralazine treated T cells is due to demethylation of a genetic
element that suppresses CD70 expression when methylated [13]. These findings suggest that
epigenetic modifications following exposure to drugs and chemicals may contribute to the
induction of autoimmunity [14].
Another explanation for procainamide-induced autoimmunity has sought to link two
common characteristics of drug-induced autoimmunity, namely that different drugs result in
clinically similar diseases [7] and that many drugs elicit autoantibodies primarily targeting
components of chromatin, specifically the (H2A-H2B)-DNA subnucleosome [15]. In the
case of procainamide, the reactive metabolite procainamide-hydroxylamine (PAHA) has
been shown to disrupt central immune tolerance [16]. Intrathymic injection of PAHA into
young mice produces an anti-chromatin response with reactivity against the (H2A-H2B)-
DNA subnucleosome. Adoptive transfer of anti-chromatin-reactive T cells from these mice
to naïve mice stimulates B cells to produce the same autoantibody response [17]. Studies
with thymus reaggregate cultures show that transgenic T cells specific for a cytochrome c
peptide are better able to respond to low affinity analogues if PAHA is present during their
development [18]. This mechanism argues that self tolerance (reactivity!!!) is acquired by T
cells during positive selection in the thymus due to prevention of the establishment of
anergy. It is believed that these cells have a reduced activation threshold as a consequence of
exposure to PAHA during their development and that this results in mature autoreactive T
cells seeding the peripheral immune system [19]. Although provocative these primarily in
vitro observations have yet to demonstrate how drug consumption results in metabolites of
procainamide subverting the induction of anergy during positive selection in the thymus.
3.1.2. Silica and Asbestos Induced Autoimmunity—Silica, an oxide of silicon, is the
most abundant mineral in the earth’s crust. The association of silica and development of
systemic autoimmune diseases such as SLE and scleroderma, stems from exposure during
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occupations such as mining, construction, and glass and pottery production [20]. Studies
have argued that silica has an adjuvant effect [21] mediated in part by activation of alveolar
phagocytes following inhalation of silica particles [22,23]. Scavenger receptors, such as
MARCO (macrophage receptor with collagenous structure), on alveolar macrophages have
been found responsible for the clearance of crystalline silica and the absence of MARCO
leads to exacerbations in innate pulmonary immune responses in the presence of silica [24].
Recent studies argue that phagocytosis of asbestos and silica crystals leads to activation of
the NLRP3 (NOD-like receptor family, pryin domain containing 3) inflammasome
presumably via lysosomal permeabilization [25–28]. The resulting cycle of inflammation is
associated with activation of cell signaling pathways, phosphorylation and activation of
transcription factor NFκB, increased expression of proinflammatoty cytokines especially
IL-1β, generation of reactive oxygen and nitrogen species, and cell death by apoptosis
[23,29]. Mouse strains vary in their response to aerosol inhalation of silica [30], including an
increase in ovalbumin-specific antibodies following the resulting amplification of the
inflammatory response [31].
In autoimmune-prone mice, such as the New Zealand mixed (NZM) strains, silica exposure
leads to increased inflammatory infiltrates, fibrotic lesions, collagen deposition, and reduced
survival [32]. Although IgG levels are reduced, autoantibodies are increased in silica
exposed NZM mice [32]. Following silica exposure numbers of B1a B cells and CD4+ T
cells are increased in secondary lymphoid organs and the ratio of CD4+CD25+ T regulatory
cells to T cells is decreased, providing possible reasons for the increased autoreactivity [33].
Autoantibodies from silica-exposed NZM mice bind preferentially to apoptotic
macrophages, suggesting that silica-induced apoptosis may exacerbate autoimmune
responses by exposing autoantigens [34]. Interestingly a defect in the expression of the
aforementioned MARCO, that is responsible for the clearance of crystalline silica [24],
results in exacerbation of autoimmunity in lupus-prone mice [35]. These findings suggest
that modulation of scavenger receptor function by silica can contribute to the severity of
systemic autoimmunity.
Asbestos is another naturally occurring silicate mineral, composed of long, thin fibrous
crystals. Several epidemiological studies have linked exposure to asbestos to autoimmune
disease [21]. In Libby, Montana exposure to asbestos-contaminated vermiculite has resulted
in significant health problems including reports of an increased prevalence of systemic
autoimmune disease [36]. Examination of serum samples from residents of Libby showed
positive correlations between autoantibody titers and both lung disease severity and the
extent of exposure [36]. A case-control study among the current and former residents of
Libby who had worked at the vermiculite mine revealed increased self reporting of
autoimmune diseases including systemic lupus erythematosus, scleroderma, and rheumatoid
arthritis (odds ratio of 2.14, 95% CI, 0.90–5.10) [37]. Induction of autoimmunity following
exposure to the Libby amphibole is also supported by studies showing that exposure of non-
autoimmune C57BL/6 mice leads to autoantibodies and immune complex deposits in the
kidneys [38]. It is very likely that induction of autoimmunity in mice by asbestos occurs via
similar mechanisms to that being uncovered for silica.
3.1.3. Toxic Oil Syndrome—Xenobiotic-induced scleroderma, or pseudoscleroderma,
has been associated with occupational exposures, especially occupational exposure to
solvents [39]. In the early 1980s in Spain ingestion of adulterated cooking oil lead to an
outbreak of pseudoscleroderma [40]. The causative agent was identified as rapeseed oil,
originally destined for industrial use but refined to remove the anilide denaturant and then
sold as cooking oil for human consumption. Thousands of people were ultimately affected
with more than 1,000 deaths being ascribed to what is called Toxic Oil Syndrome (TOS)
[40]. The clinical and histopathological features of TOS resemble both eosinophilia myalgia
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syndrome (EMS), believed to be caused by impure L-tryptophan, and idiopathic diffuse
fasciitis with eosinophilia (DFE) [41]. Cases of eosinophilic fasciitis have been described to
occur simultaneously with the appearance of EMS associated with L-tryptophan ingestion.
A murine model of TOS developed by continuous exposure of mice to oleic acid anilide
revealed strain specific responses. B10.S (H-2s) mice exhibit the more chronic autoimmune
form of disease with hypergammaglobulinemia, splenomegaly and polyclonal B cell
responses associated with elevation of IL-1β and IL-6. Autoantibodies include
predominantly IgM antibodies to histone, denatured DNA, as well as rheumatoid factor [42].
C57BL/6 (H-2b) mice also develop a polyclonal B cell response but without other disease
manifestations [43], while A/J (H-2a) mice develop an acute wasting disease more typical of
the acute lethal response of humans to the anilide. Cytokine profiles of C57BL/6 mice
showed a more Th2-like response whereas the A/J mice had elevated IL- 1α, IL-10, and
IFN-γ [43]. Finally, exposure of the mildly autoimmune-prone MRL-+/+ mice to anilide
resulted in increased serum immunoglobulins and autoantibodies [44]. While these studies
have proven useful the current models do not display the full gamut of disease found in the
exposed human population. For example, no model exhibits the vasculitis, eosinophilia, and
elevated IgE levels of the acute phase [45]. This suggests that species specific genetic and/or
environmental factors are critical for the host response.
3.1.4. Metal Induced Autoimmunity—Mercury [46], silver [47] and gold [48] all
produce autoimmunity in mice but the pathological consequences differ, with silver and gold
exposure resulting in a less severe response that typically includes the production of anti-
nuclear antibodies but lacks glomerular deposits of immunoglobulin and complement
[48,49]. The most characteristic aspect of autoimmunity induced by these three metals is an
MHC-restricted autoantibody response against fibrillarin, a nucleolar protein component of
the box C/D small nucleolar ribonucleoprotein (snoRNP) complexes [50]. Such anti-
fibrillarin autoantibodies also occur in a subset of scleroderma patients [51] and in SLE [52].
The features of murine mercury-induced autoimmunity (mHgIA), including
lymphadenopathy, hypergammaglogulinemia, humoral autoimmunity, and immune-complex
deposits, are consistent with the systemic autoimmunity of SLE [53].
Human exposure to mercury has been implicated as an environmental trigger in the
induction of autoimmunity [54–56], although a non-autoimmune-mediated nephropathy is
the more common outcome [57]. Few large scale epidemiological studies have addressed the
association between mercury exposure and immune dysfunction including autoimmunity. A
study of the New Zealand Defense Forces (20,000 individuals, 84% male) found little
relationship between adverse health effects and numbers of mercury containing dental
amalgam [58]. Whether this study reflects the effects of mercury exposure is debatable as
exposure from dental amalgam correlates better with amalgam surfaces than the number of
fillings [59]. In addition, this study used broad disease categories from the International
Statistical Classification of Diseases and Related Health Problems (ICD-9 codes) and due to
the small numbers of patients with individual diseases did not examine individual
autoimmune disorders such as SLE. The role of mercury in human autoimmune disease will
not be clarified until the level of exposure in large populations of patients has been
examined.
Both the immunology of mercury and the mHgIA model have been recently reviewed in
great detail [60,61] and so the following discussion is limited to those aspects we believe
most relevant to induction and expression of autoimmunity. In animal models mHgIA can
be induced by subcutaneous injection [62] or oral ingestion of HgCl2 [63], inhalation of
mercury vapor [64], and dental [65] or peritoneal [47] implantation of mercury containing
dental amalgam [47]. Depending on the strain disease can range from apparent non-
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responsiveness to full-blown immune cell activation, lymphadenopathy, elevated
immunoglobulin levels, autoantibodies and immune complex glomerulonephritis
[46,60,66,67]. The resulting autoantibody responses are primarily against chromatin, and the
small nucleolar ribonucleoprotein (snoRNP) component fibrillarin [47,68,69], but can
include antibodies to other components of snoRNP complexes [70], as well as to other
nuclear and cytoplasmic antigens. Spontaneous human and mercury-induced murine anti-
fibrillarin antibodies are both under MHC control [46,67,71] and share recognition of a
conserved conformational antigenic determinant [72]. Autoantibodies in scleroderma also
recognize other protein components of snoRNP complexes, particularly those of the U3
snoRNP [51] suggesting that RNA/protein complexes may be the source of immunogenic
material for the anti-snoRNP response in both mercury-induced and idiopathic responses
[51,70]. The mechanism of autoantibody recognition of fibrillarin in spontaneous human
autoimmunity or mercury-induced autoimmunity does not involve a mercury-fibrillarin
complex [62]. Of potential significance, mercury-induced cell death results in the proteolysis
of fibrillarin to a 19kDa fragment which has been shown to elicit an autoantibody response
similar to that produced following mercury exposure [73], whereas immunization with
native fibrillarin does not elicit an autoantibody response. Thus, proteolysis associated with
mercury-induced cell death results in the generation of novel protein fragments that may be
sources of cryptic self-antigenic determinants to which B and T lymphocytes have not been
tolerized.
mHgIA is associated with increases in the activation and proliferation of CD4+ T cells and is
dependent on co-stimulatory molecules CD28 and CD40L [74–77]. Thus, mercury does not
simply activate T cells directly, but, consistent with the observed increased expression of
MHC class II on APCs in mHgIA [78], appears to enhance APC and T cell activity. The
mechanism for how mercury induces T cell proliferation in vivo, however, remains
incompletely understood [66,79,80], although the time course of the response mimics an
antigen-specific response and proliferation of T cell subsets show strain specific differences
[81,82]. In vitro proliferation studies have also documented the requirement for T cells,
adherent cells [79–83], and IL-1 [81]. T cells also contribute to the suppression of mHgIA as
demonstrated by the reduction in disease cause by CD4+CD25+ T regulatory cells [84].
Possible molecular mechanisms responsible for mercury-induced lymphocyte activation and
proliferation have been further examined in in vitro studies. Low doses of inorganic mercury
perturb CD95 (Fas) mediated apoptotic cell death enhancing survival of Jurkat cells (human
T cell line) [85]. This effect appears to be due to disruption of both the death inducing
signaling complex (DISC) [86] and death receptor mediated caspase-3 activation [87]. The
failure of active DISC formation appears due to the ability of low concentrations of mercury
to dissociate preassembled Fas receptor complexes required for DISC formation [88]. Thus
mercury exposure would enable T cells, including self reactive T cells, to survive Fas-Fas
ligand mediated cell death. However the exacerbation of mHgIA in the absence of
functional Fas, as seen in B10.S-Faslpr mice (Pollard and Kono, unpublished), argues that
inhibition of Fas-mediated cell signaling is not the only mechanism that can lead to mHgIA.
Another proposed mechanism is the attenuation of T cell receptor (TCR) signaling by
mercury which may allow self reactive cells to escape elimination during T cell selection
[89]. Experiments with Jurkat cells shows that inorganic mercury inhibits the ability of the
TCR to activate Ras and ERK MAP kinase [90] that is associated with negative selection of
T cells. The failure of Ras activation appears due to lack of phosphorylation of the upstream
component LAT (Linker for Activation of T cells) and the lack of activation of the LAT
reactive tyrosine kinase ZAP-70 [91]. The failure of ZAP-70 activation (phosphorylation) is
due to the ability of mercury to inhibit phosphorylation of lymphocyte-specific protein
tyrosine kinase (Lck) thus impeding early steps in TCR signal transduction [89]. Although
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these effects highlight the ability of mercury to impact pathways of T cell survival and
selection, it must be noted that adult thymectomy does not impact development of mHgIA
suggesting that T cell tolerance is broken in the periphery and not during T cell selection in
the thymus (Rubin and Pollard, unpublished).
Examination of the spectrum of disease induced by mercury has identified several mouse
strains that are resistant to mHgIA [46]. This resistance resides in non-MHC genes because
strains with the same MHC can be either sensitive or resistant. Genome-wide scans using F2
intercrosses of the mHgIA resistant DBA/2 (H-2d) strain with the autoimmune-prone NZB
(H-2d) and the mHgIA prone SJL (H-2s) identified a single major quantitative trait locus
(QTL) on the distal end of chromosome 1, designated Hmr1, as responsible for resistance to
development of glomerular immune-complex deposits [92]. This region of chromosome 1 in
the mouse overlaps lupus susceptibility loci identified in several other murine studies [93].
The syntenic region of human chromosome 1 lies between 1q31 and 1q42 and is known to
carry human lupus susceptibility loci [94–96].
The most significant information on the mechanisms involved in mHgIA have come from
animal studies which have shown that individual genes can influence the initiation and
development of mHgIA in a variety of ways [61,97,98]. The absence of some genes (e.g.
IL-4) appears to have little effect on disease expression, while others influence specific
facets of the mHgIA phenotype. Absence of other genes results in suppression of disease
(e.g. IFN-γ, CD28, CD40 ligand), while others exacerbate disease (e.g. Daf1). These studies
have revealed that mHgIA and idiopathic lupus share a number of effector genes in common
including IFN-γ [99], CD28 and CD40 ligand [76], and Daf1 [100], and IgH6 which results
in a loss of B cells [97].
Of recent interest, decay accelerating factor 1 (Daf1), has been shown to enhance T cell
responses following immunization [101,102] suggesting that Daf1 acts as a negative
modulator of T cell immunity. This is supported by studies showing that Daf1 deficiency
exacerbates systemic [103] and organ specific [102] autoimmunity. A characteristic of the
hyper-T cell responses in Daf1 deficient mice is elevated IFN-γ secretion [101,102]. The
dependence of mHgIA on the presence of IFN-γ [99], coupled with the association of
reduced Daf1 on activated T cells in mHgIA [100] and the elevated Daf1 levels in mHgIA-
resistant DBA/2 [100] argues that Daf1 is a potentially important regulator of chemical-
induced autoimmunity. Daf1 lies at the proximal end of the Hmr1 locus and shows greater
expression in mHgIA-resistant DBA/2 mice than the autoimmune-prone NZB [100].
Induction of mHgIA leads to a reduction of Daf1 expression on activated/memory CD4+ T
cells in mHgIA-sensitive B10.S mice [100]. Mercury exposed DBA/2 mice, which show no
change in Daf1 expression following exposure to mercury, fail to accumulate activated/
memory CD4+ T cells. Reduction of Daf1 expression in mHgIA was found to require CD4+
T cell co-stimulation as mercury exposure of CD28 deficient mice did not result in an
increase of CD44high Daf1low CD4+ T cells [100]. Mercury treatment of C57BL/6 Daf1
deficient mice results in increased levels of serum immunoglobulins, autoantibodies and
increased expression of inflammatory cytokines including IFN-γ (Toomey and Pollard,
unpublished). Thus Daf1 plays an important role in modulating adaptive immune responses,
although the mechanism of action remains unclear.
IFN-γ is required for mHgIA with even mice heterogeneous for the gene deletion showing
dramatically reduced disease [99]. Identification of increased IFN-γ expression in lymphoid
organs in mHgIA has proven difficult to demonstrate however [98,99], although a small
increase has been noted in the most susceptible mouse strain A.SW [104]. Cytokine
expression appears greatest at the site of exposure [98] with significant increases of IFN-γ
being observed in a number of cell types (Cauvi and Pollard, unpublished). IL-1β is also
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significantly elevated as is NLRP3 (Toomey and Pollard, unpublished) suggesting that
activation of the inflammasome [25] is an early event in mHgIA. Interestingly absence of
IFN-γ reduces both IL-1β and NALP3 (Toomey and Pollard, unpublished) hinting that the
ability of IFN-γ to activate the STAT signaling pathway leading to caspase-1 expression and
cell death [105,106] may contribute to the role of the inflammasome in mHgIA.
Mercury exposure of lupus-prone mice (NZBWF1, BXSB, MRL-+/+) leads to acceleration
of the underlying autoimmune predisposition [107]. Studies in female BXSB mice show that
this acceleration is dose dependent and has features of spontaneous disease [75].
Furthermore, tissue mercury levels of mice exposed to lower doses (0.4 μg HgCl2/injection)
fell within the range found in non-occupationally exposed humans [59]; yet these mice have
accelerated anti-chromatin antibodies and proteinuria. This suggests that environmentally
relevant tissue levels of mercury may be associated with exacerbations of autoimmunity in
genetically susceptible hosts [75].
3.2. Organ-Specific Autoimmunity
3.2.1. Thyroiditis—Autoimmune thyroiditis, also known as chronic lymphocytic or
Hashimoto’s thyroiditis, is characterized by autoantibodies to thyroid-specific antigens such
as thyroglobulin and thyroperoxidase that lead to inflammation and eventual impairment of
the thyroid gland [108]. Excess iodine ingestion has been identified as a contributing factor
in the induction and exacerbation of autoimmune thyroiditis [109,110]. Experimental
autoimmune thyroiditis (EAT) is induced in mice by immunization with mouse
thyroglobulin and adjuvant [111]. The disease is characterized by infiltration of the thyroid
by T cells, B cells and macrophages [112], and is influenced by differences in MHC
genotype [113]. EAT does not require IFN-γ [114], its receptor [115] or interferon
regulatory factor 1 (IRF-1) [116], which is one of the earliest genes expressed in response to
IFN-γ. These observations support earlier studies showing that administration of IFN-γ
suppresses EAT [117]. This lack of dependence on IFN-γ contrasts with findings in the
NOD.H2h4 mouse, a cross between the non-obese diabetic (NOD) mouse and the B10.A
(4R) mouse, which develops spontaneous autoimmune thyroiditis (SAT), but not
automimmune insulin dependent diabetes mellitus (IDDM) [118]. Ingestion of excess iodine
accelerates the development of thyroid lesions and IgG2a, IgG2b and IgM anti-
thyroglobulin antibodies in these mice [118]. SAT requires both CD4+ and CD8+ T cells
[119], B cells [120], and IFN-γ [121]. Depletion of CD25+ T regulatory cells in these mice
exacerbates thyroiditis, anti-thyroglobulin antibodies and mRNA levels of both IL-4 and
IFN-γ [122]. The contrasting role of IFN-γ in these two models of autoimmune thyroiditis
remains unexplained but may be influenced by various factors including the amount of IFN-
γ produced, site of expression, its presence at various stages of the inflammatory response
[123], or the likelihood that EAT, like similarly adjuvant-induced experimental autoimmune
encephalomyelitis (EAE) may be also dependent on IL-17 and T cells. It is also possible that
the difference in dependence for IFN-γ reflects requirement for this cytokine for antibody
production to weakly antigenic self molecules but not for immunization in the presence of
adjuvant [99].
3.2.2 Autoimmune liver disease—Various chemicals and drugs have been implicated
in autoimmune liver diseases including tienilic acid, dihydralazine, and halothane in
autoimmune hepatitis [124]. Moreover, primary biliary cirrhosis (PBC) which is
characterized by anti-mitochondrial antibodies (AMA) is also argued to be associated with
environmental factors [125]. AMA recognize the inner lipoyl domain of the E2 subunits of
2-oxo-acid dehydrogenase complexes, in particular the E2 component of the pyruvate
dehydrogenase complex (PDC-E2) [125]. Synthetic chemical mimics representing a
xenobiotically modified lipoyl hapten led to identification of structures that are recognized
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by AMA with affinities higher than the parent lipoylated-PDC-E2 [125], and such
xenobiotically modified antigens can be used to induce PBC in animals. Immunization of
rabbits with one of these compounds, 6-bromohexanoate, conjugated to bovine serum
albumin (BSA) elicit AMA but no liver pathology, while in contrast, guinea pigs immunized
with the same synthetic mimic resulted in both AMA and autoimmune cholangitis [126]. A
further study reported two new xenobiotic-induced PBC murine models based on
immunization with 2-octynoic acid. NOD.1101 mice developed high titer AMA and liver
pathology, including portal infiltrates enriched in CD8+ T cells and liver granulomas [127]
while C57BL/6 mice manifested AMA, autoimmune cholangitis, increased liver lymphoid
cell numbers, an increase in CD8+ liver infiltrating cells, and elevation of serum TNFα and
IFN-γ [128]. However, both models of liver injury failed to progress to cirrhosis [129].
Genetic manipulation has also produced several murine strains that exhibit features of PBC
[130]. They include the dnTGFβRII mice which express a dominant negative form of the
TGFβ receptor under control of the CD4 promoter resulting in the production of AMA and
lymphocytic infiltration in the liver with periportal inflammation. The IL-2Rα knockout,
which does not express CD25 and thus lacks T regulatory cells, also develops AMA and
portal inflammation, but also biliary ductular damage. Yet another model is the congenic
NOD.c3c4 mouse, which has genetic material from B6 and B10 mice introduced into the
NOD mouse, a well-characterized spontaneous model of autoimmune type 1 diabetes. The
NOD.c3c4 develops biliary lymphocytic infiltrates, autoantibodies, and progressive, often
fatal, biliary obstruction. Whether toxicants associated with autoimmune liver diseases
exacerbate disease in these spontaneous models has yet to be reported.
3.3. Other Examples
There are a number of other agents associated with perturbation of the human immune
system and autoimmunity, a few of which have been tested for their ability to induce
autoimmune disease in animals. The adjuvant properties of certain hydrocarbons can
precipitate inflammatory or autoimmune disease in humans and animals and this topic has
been recently reviewed in detail [131]. Tetramethylpentadecane (TMPD) is a common
constituent of mineral oil and is found in a number of processed foods made for human
consumption. Exposure can elicit “lipogranulomas” (follicular lipidosis), a chronic
inflammatory response, in a number of organs (e.g. liver, spleen, lymph nodes) [132].
Adjuvant oils, especially TMPD (commonly known as pristane) [131], elicit systemic
autoimmunity in otherwise healthy mice [133], and exacerbates autoimmunity in lupus-
prone NZBWF1 mice [134]. Induction of autoimmunity is promoted by both type I (IFN-α
and -β) and type II (IFN-γ) interferons and IL-12 [131]. Absence of IL-6 reduces anti-
chromatin and anti-DNA antibodies but not anti-RNP, anti-Sm, or anti-Su [135], suggesting
that induction of these autoantibody specificities can occur by different pathways, or differ
in their susceptibility to TMPD. Exposure of mice to TMPD results in many features of SLE
including female preponderance, arthritis, and glomerulonephritis [131]. TMPD exposed
mice also possess the “interferon signature” associated with human SLE [136]; the lupus-
interferon signature consists of the over expression of interferon-induced genes in the
peripheral blood cells of SLE patients [137]. TMPD-induced disease requires Fas, a member
of the TNF-receptor superfamily that plays a central role in the physiological regulation of
cell death, as C57BL/6 mice lacking either Fas or Fas ligand do not develop autoimmunity
[138]; this contrasts with the mHgIA model (Pollard and Kono, unpublished), procainamide-
induced lupus [17], and lupus-prone MRL-Faslpr mice [139] in which absence of Fas
exacerbates autoimmunity. Another difference between pristane-induced autoimmunity and
both mHgIA (Kono and Pollard, unpublished) and lupus-prone MRL-Faslpr mice [140] is the
reduced role that type I interferons plays in the latter two models. Another unique feature of
pristane-induced autoimmunity is the spectrum of autoantibodies produced (anti-DNA, anti-
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ribosomal P, anti-Su, anti-chromatin and anti-anti-RNP/Sm) which mimics the diversity of
autoantibody responses in SLE [131].
The halogenated aromatic hydrocarbon 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the
most potent of the dioxins and is an unintentional by-product of many industrial processes.
TCDD is also a contaminant of the herbicide Agent Orange [141]. The role of TCDD in
autoimmune responses is controversial. Seventeen years after exposure to TCDD eighteen
workers were in good health although they did have significantly greater frequency of anti-
nuclear antibodies and immune complexes in their serum, and increased numbers of Leu-7+
(CD57) natural killer cells compared to matched controls [142]. Korean veterans of the
Vietnam War, who did military service from 1964 to 1973 and were exposed to TCDD
contaminated Agent Orange, had reduced IgG levels especially IgG1 and reduced IFN-γ, but
increased IgE, IL-4 and IL-10 suggesting disturbed immune-homeostasis [143].
Lymphocytes from a group of German industrial workers showed reduced proliferative
responses in the mixed lymphocyte reaction or with IL-2 suggesting mild
immunosuppression 20 years after TCDD exposure [144]. Reduced IgG levels were also
found in individuals exposed to TCDD following an industrial accident in Seveso, Italy
[145]. Moreover, children exposed to TCDD in the same accident had initially reduced total
lymphocyte numbers and total serum complement activity that returned to normal within ten
years [146]. In contrast, examination of 995 individuals involved in aerial spraying of
herbicides in Vietnam reported similar health problems to 1299 controls [147], however the
TCDD exposure of these two groups was not quantitatively determined. These
epidemiological studies suggest that while TCDD does influence the human immune system
there is little evidence of autoimmunity.
In contrast, animal studies of TCDD have revealed novel and intriguing affects on the
immune system. The immunosuppressive effects of TCDD have been argued due to
activation of the aryl hydrocarbon receptor (Ahr) by TCDD and the generation of CD4+
CD25+ T regulatory cells [148]. Moreover Ahr activation by TCDD can induce T regulatory
cells that suppress experimental autoimmune encephalomyelitis (EAE) while another Ahr
ligand, 6-formylindolo[3,2-b]carbazole (FICZ-carbazole), interfers with T regulatory cell
development, boosting Th17 cell development and increasing the severity of EAE [149].
Thus modulation of the Ahr influences both suppression and development of autoimmunity
[150]. Neonatal exposure of NFS/sld mice to TCDD elicited a phenotype consistent with the
human autoimmune disease Sjögren’s Syndrome with increased anti-SS-A/Ro and anti-SS-
b/LA autoantibodies and elevated IL-2 and IFN-γ [151]. In this model TCDD exposure was
associated with reduced AIRE, a protein that has been found to be important for the
maintenance of self tolerance [152], suggesting that thymocyte differentiation and central
tolerance may be disrupted by TCDD [151].
Trichloroethylene (TCE) is a chlorinated hydrocarbon commonly used as an industrial
solvent. Exposure of moderately lupus-prone MRL-+/+ mice to TCE exacerbates features of
autoimmunity in adult mice [153–155] as well mice exposed from conception [156], and
recent studies have suggested that TCE-induced protein oxidation (carbonylation and
nitration) may be responsible [157]. Although these studies provide compelling evidence
that TCE is capable of exacerbating autoimmunity in mice, occupational cohorts with
exposures to TCE or other specific solvents lack well-characterized exposure histories that
would support its role as a causative agent in human autoimmunity [157,158].
Exposure to the fungicide hexachlorobenzene (HCB) is associated with a form of hepatic
porphyria called porphyria turcica, which resembles porphyria cutanea tarda, a disease
caused by altered porphyrin metabolism. Porphyria turcica is associated with bullous skin
lesions, mainly in sun-exposed skin areas, that heal with severe scars, and primarily affects
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children 6–16 years of age [159]. Other reported clinical manifestations include
hepatomegaly, enlarged thyroid, splenomegaly, hyperpigmentation, hirsutism, enlarged
lymph nodes and painless arthritic changes of the hands, with the arthritis increasing in
prevalence 3–5 years after exposure [159]. Exposure to HCB can also produce neurological,
dermatological, and orthopaedic abnormalities that may persist for decades [160]. Elevated
levels of HCB in the blood, however, correlate with reduced IFN-γ, but only weakly with
other immune abnormalities [161]. Studies in Brown Norway rats suggests that HCB may
act as an adjuvant, activating macrophages and generating pro-inflammatory cytokines and
polyclonal activation of T and B cells leading to visible clinical sign such as skin lesions and
lung eosinophilia [162].
As described above, a common approach in testing the effects of chemicals on
autoimmunity is to expose autoimmune-prone strains and determine if the chemical in
question alters the natural history of the disease. Other chemicals examined in this way
include the synthetic steroid diethylstilbesterol [163], organochlorine pesticides [164], and
the metals cadmium [165] and lead [166].
A significant problem demonstrated by a number of the agents described above, including
mercury, TMPD, TCDD, TCE and HBC, is the difficulty in determining the relevance of
exposure to human autoimmune diseases. While each of these toxicants does elicit
immunological responses, evidence for a significant role in human autoimmunity is lacking
for the most part because adequate studies are difficult and have not been done. However
many of these agents do induce autoimmunity in animal models with significant similarities
to human disease [131].
4. Mechanisms of Toxicant Induced Autoimmunity
Experimental data from animal models suggest that induction of autoimmunity by drugs and
chemicals can occur through different mechanisms. Drugs such as procainamide and
contaminants like TCDD can influence central tolerance mechanisms, solvents such as TCE
can perturb the development of the immune system in utero, and a lowered threshold of
activation for T cells appears to contribute to autoimmunity induced by mercury and
procainamide. Autoimmunity induced by silica, asbestos, and heavy metals such as mercury
are also associated with chronic inflammatory processes, cell death, suppression of
immunoregulation, and perturbation of self/non-self discrimination. It is also important to
consider that extrinsic agents may interact with self-molecules and that such interactions
may affect development of autoimmunity [167]; however in the majority of situations in
which chemicals, particularly drugs, induce autoimmunity it is clear that a chemical–self-
antigen conjugate is not the target of an autoantibody response [7,62]. Additionally, most
extrinsic agents can exacerbate autoimmunity in the presence of a lupus-prone genotype
indicating a role for genetic susceptibility in toxicant-induced autoimmunity. While it is
unlikely that toxicant-induced autoimmunity can be explained by a single mechanism, the
development of disease following exposure to individual agents can share certain aspects
with the pathogenesis of spontaneous autoimmunity (Table 2).
Induction of systemic autoimmunity by drugs and chemicals requires a source of self
antigens. However an unanswered question, especially for intracellular antigens, is how and
in what form the inciting self antigens are made available to the immune system. For some
toxicants this is very likely via mechanisms of cell death that may be reflective of the
toxicant rather than an established biological process such as classical apoptosis. For
example, in the case of mHgIA it appears that an aberrant form of cell death results in
altered proteolysis of cellular material [73], while in the case of silica it has been suggested
that engulfment of silica by alveolar macrophages leads to disruption of the normal
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internalization process of endocytosis, leading to cytokine release and cell death [23].
Whatever the process, these mechanisms most likely lead to activation of pattern recognition
receptors, such as Toll-like receptors (TLR) and Nod-like receptors (NLR) (Figure 1), that
are essential elements in the activation of the innate immune system. The resulting response
includes both inflammation following proinflammatory cytokine production via the
inflammasome and NLRP3 [25,28] and activation of the TLR system though recognition of
complexes of RNA and DNA bound to nuclear proteins. In the latter case it is the specificity
of TLRs for their cognate (nuclear) ligands that is required for the production of the anti-
nuclear autoantibodies that characterize many forms of idiopathic [168] and chemical-
induced autoimmunity (Kono and Pollard, unpublished).
The activation of elements of the innate immune system, dendritic cells and macrophages,
by cellular material is accompanied by antigen presentation to T cells. Activation of self-
reactive T cells proceeds via breaking of self-tolerance which may be mediated by a number
of mechanisms including inhibition of Fas-mediated cell death as suggested in the case of
mercury exposure [85,88]. Defects in expression of regulators of T cell function such as
Daf1 [100] can enhance T cell responses which in turn leads to activation of autoantibody
producing B cells. The formation of immune complexes of self-antigen and autoantibodies
provides material that can be bound by antigen presenting cells such as B cells and
macrophages leading to further rounds of T cell activation and expansion. Deposition of
immune-complexes in tissues such as the kidney can lead to tissue injury which can provide
additional cellular material for the activation of innate immune cells. Although this appears
to be a vicious cycle it is easy to see how, in the absence of a lupus-prone genotype, removal
of the toxicant would result in a significant attenuation of the process.
5. Conclusion
There is ample evidence that exposure to a variety of drugs and chemicals can lead to
autoimmunity. In many situations the drug or chemical-induced disease resembles idiopathic
disease although the presence of disease is dependent upon exposure to the drug or
chemical. Animal model studies have revealed a number of possible mechanisms, some of
which are shared by different drug and chemical agents. Intriguingly exposure of
autoimmune-prone mice to many autoimmune-inducing chemicals and drugs leads to earlier
onset and exacerbation of disease arguing that exposure in the presence of a susceptible
genotype likely increases the risk of developing human autoimmunity.
Acknowledgments
This work was supported by National Institutes of Health grants ES007511 and ES014847 to KMP and ES08666,
AR053731, and AR42242 to DHK. This is manuscript number 20422 from the Scripps Research Institute.
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Figure 1. Putative mechanism of drug/chemical-induced autoimmunity
Exposure to a toxicant results in aberrant cell death making available cellular material which
activates Nod-like receptors (NLR) and Toll-like receptors (TLR). In the case of NLR
activation this leads to NLRP3-inflammasome activation and proinflammatory events
including production of proinflammatory cytokines such as IL-1β, IL-6, and IFN-γ. For
TLR-mediated response, activation of TLR by nuclear material is essential for autoantibody
responses to nuclear antigens such as chromatin and RNA/protein complexes. Activation of
self-reactive T cells proceeds via breaking of self-tolerance which may be mediated by a
number of mechanisms (see text). Reduction in the expression of regulators of T cell
activation, such as Daf1, enhances T cell responses and promotes the activation of
autoantibody producing B cells. The binding of autoantibodies to self-antigen leads to
immune-complex formation and tissue injury which in turn can release cellular material to
amplify the response. Self-antigen containing immune complexes can also be taken up by B
cells and other antigen presenting cells (e.g. dendritic cells) and amplify activation of
autoreactive T cells.
Pollard et al. Page 22
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Table 1
Substances associated with autoimmunity in humans and the animal models used to examine disease
mechanisms.
Drugs/Chemicals aHuman disease Animal model bReferences
Drugs (procainamide) Drug-induced lupus Mouse
- central tolerance 16,17,18,19
- DNA methylation 10,11,12
Silica/Asbestos Lupus, systemic sclerosis, rheumatoid
arthritis, vasculitis Mouse
- C57Bl/6 38
- lupus-prone 32,33,34
Adulterated rapseed oil Toxic Oil Syndrome Mouse
- B10.S 42,43
- lupus-prone 44
Iodine Thyroiditis Mouse
- NOD-H-2h4 119
Trichloroethylene Hypersensitivity skin disorder, Scleroderma,
Hepatitis Mouse
- lupus prone 153,154,155
- lupus prone (prenatal) 156
Metals (Hg, Au, Ag) Nephropathy, Autoantibodies Mouse
- B10.S (Hg) 46,47 (Ag)
47,49 (Au) 48
- lupus-prone 76,108
TCDD, dioxincAnti-nuclear autoantibodies, Mouse
- GVHDd149
- EAEe150
- neonatal exposure 152
Pesticides/Fungicides (Hexachlorobenzene) Chronic inflammatory response Rat 162
Mouse
- lupus prone 164
Mineral oil (Pristane, TMPDf)Chronic inflammatory response (follicular
lipidosis) Mouse
- C57BL/6, BALB/c 134,139
- lupus prone 135
aWhere multiple examples of a drug or chemical exist only those discussed in the text or cited in the accompanying publications are noted.
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bIn many studies examining the lupus-inducing potential of toxins mouse strains that are prone to develop lupus spontaneously (e.g. NZBWF1,
NZM, BXSB, MRL) are used as models of sensitive populations to determine if a specific drug or chemical exposure can affect the natural
progression of disease.
c2,3,7,8-Tetrachlorodibenzo-p-dioxin
dGraft versus host disease
eexperimental autoimmune encephalomyelitis
ftetramethylpentadecane
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Table 2
Features of autoimmunity shared by different autoimmunity-inducing drugs and chemicals.
Drugs/Chemicals Mechanism References
Silica/Asbestos Adjuvant effect 21
T regulatory cells 33
Inflammasome (NLRP3a, IL-1β)28
Exacerbates lupus-prone genotype 32
Heavy Metals (Hg, Ag, Au) T cell activation threshold 86
T regulatory cells 80
Inflammasome (NLRP3a, IL-1β)Toomey and Pollard (unpublished)
Exacerbates lupus-prone genotype 76,108
Drugs (procainamide) T cell activation threshold 12
Central tolerance 18
TCDD, dioxinbCentral tolerance 152
Aryl hydrocarbon receptor 150
T regulatory cells 150
Adjuvant oils (pristane) Adjuvant effect 134
Exacerbates lupus-prone genotype 135
Pesticides/Fungicides (Hexachlorobenzene) Adjuvant effect 162
Exacerbates lupus-prone genotype 164
Adulterated rapseed oil Exacerbates lupus-prone genotype 44
Iodine T regulatory cells 110
Trichloroethylene (TCE) Exacerbates lupus-prone genotype 153
aNOD-like receptor family, pryin domain containing 3
b2,3,7,8-Tetrachlorodibenzo-p-dioxin
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