ArticlePDF AvailableLiterature Review


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.
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
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.
NIH Public Access
Author Manuscript
Chem Res Toxicol. Author manuscript; available in PMC 2011 April 13.
Published in final edited form as:
Chem Res Toxicol
. 2010 March 15; 23(3): 455–466. doi:10.1021/tx9003787.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
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
Pollard et al. Page 2
Chem Res Toxicol. Author manuscript; available in PMC 2011 April 13.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
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
Pollard et al. Page 3
Chem Res Toxicol. Author manuscript; available in PMC 2011 April 13.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
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
Pollard et al. Page 4
Chem Res Toxicol. Author manuscript; available in PMC 2011 April 13.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
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
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-
Pollard et al. Page 5
Chem Res Toxicol. Author manuscript; available in PMC 2011 April 13.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
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
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
Pollard et al. Page 6
Chem Res Toxicol. Author manuscript; available in PMC 2011 April 13.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
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
Pollard et al. Page 7
Chem Res Toxicol. Author manuscript; available in PMC 2011 April 13.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
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
Pollard et al. Page 8
Chem Res Toxicol. Author manuscript; available in PMC 2011 April 13.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
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-
Pollard et al. Page 9
Chem Res Toxicol. Author manuscript; available in PMC 2011 April 13.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
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
Pollard et al. Page 10
Chem Res Toxicol. Author manuscript; available in PMC 2011 April 13.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
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
Pollard et al. Page 11
Chem Res Toxicol. Author manuscript; available in PMC 2011 April 13.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
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.
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.
1. Tan EM, Chan EK, Sullivan KF, Rubin RL. Antinuclear antibodies (ANAs): diagnostically specific
immune markers and clues toward the understanding of systemic autoimmunity. Clin Immunol
Immunopathol. 1988; 47:121–41. [PubMed: 3280190]
2. Tan EM. Antinuclear antibodies: diagnostic markers for autoimmune diseases and probes for cell
biology. Adv Immunol. 1989; 44:93–151. [PubMed: 2646863]
3. Lam-Tse WK, Lernmark A, Drexhage HA. Animal models of endocrine/organ-specific autoimmune
diseases: do they really help us to understand human autoimmunity? Springer Semin
Immunopathol. 2002; 24:297–321. [PubMed: 12503056]
4. Badenhoop K, Boehm BO. Genetic susceptibility and immunological synapse in type 1 diabetes and
thyroid autoimmune disease. Exp Clin Endocrinol Diabetes. 2004; 112:407–15. [PubMed:
Pollard et al. Page 12
Chem Res Toxicol. Author manuscript; available in PMC 2011 April 13.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
5. Dedeoglu F. Drug-induced autoimmunity. Curr Opin Rheumatol. 2009
6. Vedove CD, Del Giglio M, Schena D, Girolomoni G. Drug-induced lupus erythematosus. Arch
Dermatol Res. 2009; 301:99–105. [PubMed: 18797892]
7. Rubin RL. Drug-induced lupus. Toxicology. 2005; 209:135–47. [PubMed: 15767026]
8. Totoritis MC, Rubin RL. Drug-induced lupus. Genetic, clinical, and laboratory features. Postgrad
Med. 1985; 78:149–52. 155–61. [PubMed: 3875843]
9. Rubin RL, Teodorescu M, Beutner EH, Plunkett RW. Complement-fixing properties of antinuclear
antibodies distinguish drug-induced lupus from systemic lupus erythematosus. Lupus. 2004;
13:249–56. [PubMed: 15176661]
10. Cornacchia E, Golbus J, Maybaum J, Strahler J, Hanash S, Richardson B. Hydralazine and
procainamide inhibit T cell DNA methylation and induce autoreactivity. J Immunol. 1988;
140:2197–200. [PubMed: 3258330]
11. Yung RL, Quddus J, Chrisp CE, Johnson KJ, Richardson BC. Mechanism of drug-induced lupus. I.
Cloned Th2 cells modified with DNA methylation inhibitors in vitro cause autoimmunity in vivo.
J Immunol. 1995; 154:3025–35. [PubMed: 7533191]
12. Richardson BC. Epigenetics and autoimmunity. Overview. Autoimmunity. 2008; 41:243–4.
[PubMed: 18432404]
13. Lu Q, Wu A, Richardson BC. Demethylation of the same promoter sequence increases CD70
expression in lupus T cells and T cells treated with lupus-inducing drugs. J Immunol. 2005;
174:6212–9. [PubMed: 15879118]
14. Ballestar E, Esteller M, Richardson BC. The epigenetic face of systemic lupus erythematosus. J
Immunol. 2006; 176:7143–7. [PubMed: 16751355]
15. Rubin RL, Bell SA, Burlingame RW. Autoantibodies associated with lupus induced by diverse
drugs target a similar epitope in the (H2A-H2B)-DNA complex. J Clin Invest. 1992; 90:165–73.
[PubMed: 1378852]
16. Rubin RL, Kretz-Rommel A. Initiation of autoimmunity by a reactive metabolite of a lupus-
inducing drug in the thymus. Environ Health Perspect. 1999; 107(Suppl 5):803–6. [PubMed:
17. Kretz-Rommel A, Rubin RL. Persistence of autoreactive T cell drive is required to elicit anti-
chromatin antibodies in a murine model of drug-induced lupus. J Immunol. 1999; 162:813–20.
[PubMed: 9916703]
18. Kretz-Rommel A, Rubin RL. Disruption of positive selection of thymocytes causes autoimmunity.
Nat Med. 2000; 6:298–305. [PubMed: 10700232]
19. Rubin RL, Kretz-Rommel A. A nondeletional mechanism for central T-cell tolerance. Crit Rev
Immunol. 2001; 21:29–40. [PubMed: 11642611]
20. Parks CG, Conrad K, Cooper GS. Occupational exposure to crystalline silica and autoimmune
disease. Environ Health Perspect. 1999; 107(Suppl 5):793–802. [PubMed: 10970168]
21. Otsuki T, Maeda M, Murakami S, Hayashi H, Miura Y, Kusaka M, Nakano T, Fukuoka K,
Kishimoto T, Hyodoh F, Ueki A, Nishimura Y. Immunological effects of silica and asbestos. Cell
Mol Immunol. 2007; 4:261–8. [PubMed: 17764616]
22. Hamilton JA. Nondisposable materials, chronic inflammation, and adjuvant action. J Leukoc Biol.
2003; 73:702–12. [PubMed: 12773502]
23. Hamilton RF Jr, Thakur SA, Holian A. Silica binding and toxicity in alveolar macrophages. Free
Radic Biol Med. 2008; 44:1246–58. [PubMed: 18226603]
24. Thakur SA, Beamer CA, Migliaccio CT, Holian A. Critical role of MARCO in crystalline silica-
induced pulmonary inflammation. Toxicol Sci. 2009; 108:462–71. [PubMed: 19151164]
25. Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, Fitzgerald KA, Latz E.
Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal
destabilization. Nat Immunol. 2008; 9:847–56. [PubMed: 18604214]
26. Ting JP, Willingham SB, Bergstralh DT. NLRs at the intersection of cell death and immunity. Nat
Rev Immunol. 2008; 8:372–9. [PubMed: 18362948]
27. Willingham SB, Ting JP. NLRs and the dangers of pollution and aging. Nat Immunol. 2008;
9:831–3. [PubMed: 18645588]
Pollard et al. Page 13
Chem Res Toxicol. Author manuscript; available in PMC 2011 April 13.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
28. Dostert C, Petrilli V, Van Bruggen R, Steele C, Mossman BT, Tschopp J. Innate immune
activation through Nalp3 inflammasome sensing of asbestos and silica. Science. 2008; 320:674–7.
[PubMed: 18403674]
29. Rimal B, Greenberg AK, Rom WN. Basic pathogenetic mechanisms in silicosis: current
understanding. Curr Opin Pulm Med. 2005; 11:169–73. [PubMed: 15699791]
30. Davis GS, Leslie KO, Hemenway DR. Silicosis in mice: effects of dose, time, and genetic strain. J
Environ Pathol Toxicol Oncol. 1998; 17:81–97. [PubMed: 9546745]
31. Granum B, Gaarder PI, Groeng E, Leikvold R, Namork E, Lovik M. Fine particles of widely
different composition have an adjuvant effect on the production of allergen-specific antibodies.
Toxicol Lett. 2001; 118:171–81. [PubMed: 11137324]
32. Brown JM, Archer AJ, Pfau JC, Holian A. Silica accelerated systemic autoimmune disease in
lupus-prone New Zealand mixed mice. Clin Exp Immunol. 2003; 131:415–21. [PubMed:
33. Brown JM, Pfau JC, Holian A. Immunoglobulin and lymphocyte responses following silica
exposure in New Zealand mixed mice. Inhal Toxicol. 2004; 16:133–9. [PubMed: 15204774]
34. Pfau JC, Brown JM, Holian A. Silica-exposed mice generate autoantibodies to apoptotic cells.
Toxicology. 2004; 195:167–76. [PubMed: 14751672]
35. Rogers NJ, Lees MJ, Gabriel L, Maniati E, Rose SJ, Potter PK, Morley BJ. A defect in Marco
expression contributes to systemic lupus erythematosus development via failure to clear apoptotic
cells. J Immunol. 2009; 182:1982–90. [PubMed: 19201851]
36. Pfau JC, Sentissi JJ, Weller G, Putnam EA. Assessment of autoimmune responses associated with
asbestos exposure in Libby, Montana, USA. Environ Health Perspect. 2005; 113:25–30. [PubMed:
37. Noonan CW, Pfau JC, Larson TC, Spence MR. Nested case-control study of autoimmune disease
in an asbestos-exposed population. Environ Health Perspect. 2006; 114:1243–7. [PubMed:
38. Pfau JC, Sentissi JJ, Li S, Calderon-Garciduenas L, Brown JM, Blake DJ. Asbestos-induced
autoimmunity in C57BL/6 mice. J Immunotoxicol. 2008; 5:129–37. [PubMed: 18569382]
39. Kettaneh A, Al Moufti O, Tiev KP, Chayet C, Toledano C, Fabre B, Fardet L, Cabane J.
Occupational exposure to solvents and gender-related risk of systemic sclerosis: a metaanalysis of
case-control studies. J Rheumatol. 2007; 34:97–103. [PubMed: 17117485]
40. Posada de la Paz M, Philen RM, Borda AI. Toxic oil syndrome: the perspective after 20 years.
Epidemiol Rev. 2001; 23:231–47. [PubMed: 12192735]
41. Patterson R, Germolec D. Review article toxic oil syndrome: review of immune aspects of the
disease. J Immunotoxicol. 2005; 2:51–8. [PubMed: 18958659]
42. Bell SA, Hobbs MV, Rubin RL. Isotype-restricted hyperimmunity in a murine model of the toxic
oil syndrome. J Immunol. 1992; 148:3369–76. [PubMed: 1588038]
43. Berking C, Hobbs MV, Chatelain R, Meurer M, Bell SA. Strain-dependent cytokine profile and
susceptibility to oleic acid anilide in a murine model of the toxic oil syndrome. Toxicol Appl
Pharmacol. 1998; 148:222–8. [PubMed: 9473529]
44. Cai P, Khan MF, Kaphalia BS, Ansari GA. Immunotoxic Response of Oleic Acid Anilide and its
Hydrolysis Products in Female MRL (+/+) Mice. J Immunotoxicol. 2005; 2:231–6. [PubMed:
45. Hard GC. A search for an animal model of the Spanish toxic oil syndrome. Food Chem Toxicol.
2002; 40:1551–67. [PubMed: 12176082]
46. Hultman P, Bell LJ, Enestrom S, Pollard KM. Murine susceptibility to mercury. I. Autoantibody
profiles and systemic immune deposits in inbred, congenic, and intra-H-2 recombinant strains.
Clin Immunol Immunopathol. 1992; 65:98–109. [PubMed: 1395135]
47. Hultman P, Johansson U, Turley SJ, Lindh U, Enestrom S, Pollard KM. Adverse immunological
effects and autoimmunity induced by dental amalgam and alloy in mice. Faseb J. 1994; 8:1183–
90. [PubMed: 7958626]
48. Havarinasab S, Johansson U, Pollard KM, Hultman P. Gold causes genetically determined
autoimmune and immunostimulatory responses in mice. Clin Exp Immunol. 2007; 150:179–88.
[PubMed: 17680821]
Pollard et al. Page 14
Chem Res Toxicol. Author manuscript; available in PMC 2011 April 13.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
49. Johansson U, Hansson-Georgiadis H, Hultman P. Murine silver-induced autoimmunity: silver
shares induction of antinucleolar antibodies with mercury, but causes less activation of the
immune system. Int Arch Allergy Immunol. 1997; 113:432–43. [PubMed: 9250589]
50. Baserga SJ, Yang XD, Steitz JA. An intact Box C sequence in the U3 snRNA is required for
binding of fibrillarin, the protein common to the major family of nucleolar snRNPs. Embo J. 1991;
10:2645–51. [PubMed: 1714385]
51. Yang JM, Hildebrandt B, Luderschmidt C, Pollard KM. Human scleroderma sera contain
autoantibodies to protein components specific to the U3 small nucleolar RNP complex. Arthritis
Rheum. 2003; 48:210–7. [PubMed: 12528121]
52. Van Eenennaam H, Vogelzangs JH, Bisschops L, Te Boome LC, Seelig HP, Renz M, De Rooij DJ,
Brouwer R, Pluk H, Pruijn GJ, Van Venrooij WJ, Van Den Hoogen FH. Autoantibodies against
small nucleolar ribonucleoprotein complexes and their clinical associations. Clin Exp Immunol.
2002; 130:532–40. [PubMed: 12452846]
53. Lynes MA, Fontenot AP, Lawrence DA, Rosenspire AJ, Pollard KM. Gene expression influences
on metal immunomodulation. Toxicol Appl Pharmacol. 2005
54. Silva IA, Nyland JF, Gorman A, Perisse A, Ventura AM, Santos EC, Souza JM, Burek CL, Rose
NR, Silbergeld EK. Mercury exposure, malaria, and serum antinuclear/antinucleolar antibodies in
Amazon populations in Brazil: a cross-sectional study. Environ Health. 2004; 3:11. [PubMed:
55. Cooper GS, Parks CG, Treadwell EL, St Clair EW, Gilkeson GS, Dooley MA. Occupational risk
factors for the development of systemic lupus erythematosus. J Rheumatol. 2004; 31:1928–33.
[PubMed: 15468355]
56. Abreu Velez AM, Warfvinge G, Herrera WL, Abreu Velez CE, Montoya MF, Hardy DM, Bollag
WB, Hashimoto K. Detection of mercury and other undetermined materials in skin biopsies of
endemic pemphigus foliaceus. Am J Dermatopathol. 2003; 25:384–91. [PubMed: 14501287]
57. Van Vleet TR, Schnellmann RG. Toxic nephropathy: environmental chemicals. Semin Nephrol.
2003; 23:500–8. [PubMed: 13680539]
58. Bates MN, Fawcett J, Garrett N, Cutress T, Kjellstrom T. Health effects of dental amalgam
exposure: a retrospective cohort study. Int J Epidemiol. 2004; 33:894–902. [PubMed: 15155698]
59. Nylander M, Friberg L, Lind B. Mercury concentrations in the human brain and kidneys in relation
to exposure from dental amalgam fillings. Swed Dent J. 1987; 11:179–87. [PubMed: 3481133]
60. Schiraldi M, Monestier M. How can a chemical element elicit complex immunopathology?
Lessons from mercury-induced autoimmunity. Trends Immunol. 2009; 30:502–9. [PubMed:
61. Vas J, Monestier M. Immunology of mercury. Ann N Y Acad Sci. 2008; 1143:240–67. [PubMed:
62. Pollard KM, Lee DK, Casiano CA, Bluthner M, Johnston MM, Tan EM. The autoimmunity-
inducing xenobiotic mercury interacts with the autoantigen fibrillarin and modifies its molecular
and antigenic properties. J Immunol. 1997; 158:3521–8. [PubMed: 9120314]
63. Hultman P, Nielsen JB. The effect of toxicokinetics on murine mercury-induced autoimmunity.
Environ Res. 1998; 77:141–8. [PubMed: 9600807]
64. Warfvinge K, Hansson H, Hultman P. Systemic autoimmunity due to mercury vapor exposure in
genetically susceptible mice: dose-response studies. Toxicol Appl Pharmacol. 1995; 132:299–309.
[PubMed: 7785057]
65. Hultman P, Lindh U, Horsted-Bindslev P. Activation of the immune system and systemic immune-
complex deposits in Brown Norway rats with dental amalgam restorations. J Dent Res. 1998;
77:1415–25. [PubMed: 9649170]
66. Pollard KM, Hultman P. Effects of mercury on the immune system. Met Ions Biol Syst. 1997;
34:421–40. [PubMed: 9046578]
67. Hultman P, Bell LJ, Enestrom S, Pollard KM. Murine susceptibility to mercury. II. autoantibody
profiles and renal immune deposits in hybrid, backcross, and H-2d congenic mice. Clin Immunol
Immunopathol. 1993; 68:9–20. [PubMed: 8513597]
Pollard et al. Page 15
Chem Res Toxicol. Author manuscript; available in PMC 2011 April 13.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
68. Hultman P, Turley SJ, Enestrom S, Lindh U, Pollard KM. Murine genotype influences the
specificity, magnitude and persistence of murine mercury-induced autoimmunity. J Autoimmun.
1996; 9:139–49. [PubMed: 8738957]
69. Hultman P, Enestrom S, Pollard KM, Tan EM. Anti-fibrillarin autoantibodies in mercury-treated
mice. Clin Exp Immunol. 1989; 78:470–7. [PubMed: 2612058]
70. Yang JM, Baserga SJ, Turley SJ, Pollard KM. Fibrillarin and other snoRNP proteins are targets of
autoantibodies in xenobiotic-induced autoimmunity. Clin Immunol. 2001; 101:38–50. [PubMed:
71. Arnett FC, Reveille JD, Goldstein R, Pollard KM, Leaird K, Smith EA, Leroy EC, Fritzler MJ.
Autoantibodies to fibrillarin in systemic sclerosis (scleroderma). An immunogenetic, serologic,
and clinical analysis. Arthritis Rheum. 1996; 39:1151–60. [PubMed: 8670324]
72. Takeuchi K, Turley SJ, Tan EM, Pollard KM. Analysis of the autoantibody response to fibrillarin
in human disease and murine models of autoimmunity. J Immunol. 1995; 154:961–71. [PubMed:
73. Pollard KM, Pearson DL, Bluthner M, Tan EM. Proteolytic cleavage of a self-antigen following
xenobiotic-induced cell death produces a fragment with novel immunogenic properties. J
Immunol. 2000; 165:2263–70. [PubMed: 10925315]
74. Johansson U, Sander B, Hultman P. Effects of the murine genotype on T cell activation and
cytokine production in murine mercury-induced autoimmunity. J Autoimmun. 1997; 10:347–55.
[PubMed: 9237798]
75. Pollard KM, Pearson DL, Hultman P, Deane TN, Lindh U, Kono DH. Xenobiotic acceleration of
idiopathic systemic autoimmunity in lupus- prone bxsb mice. Environ Health Perspect. 2001;
109:27–33. [PubMed: 11171521]
76. Pollard KM, Arnush M, Hultman P, Kono DH. Costimulation requirements of induced murine
systemic autoimmune disease. J Immunol. 2004; 173:5880–7. [PubMed: 15494542]
77. Hultman P, Johansson U, Dagnaes-Hansen F. Murine mercury-induced autoimmunity: the role of
T-helper cells. J Autoimmun. 1995; 8:809–23. [PubMed: 8824708]
78. van Vliet E, Uhrberg M, Stein C, Gleichmann E. MHC control of IL-4-dependent enhancement of
B cell Ia expression and Ig class switching in mice treated with mercuric chloride. Int Arch
Allergy Immunol. 1993; 101:392–401. [PubMed: 8102566]
79. Reardon CL, Lucas DO. Heavy-metal mitogenesis: thymocyte activation by Zn++ requires 2-
mercaptoethanol and lipopolysaccharide as cofactors. Immunobiology. 1987; 174:233–43.
[PubMed: 3496267]
80. Reardon CL, Lucas DO. Heavy-metal mitogenesis: Zn++ and Hg++ induce cellular cytotoxicity
and interferon production in murine T lymphocytes. Immunobiology. 1987; 175:455–69.
[PubMed: 2448223]
81. Pollard KM, Landberg GP. The in vitro proliferation of murine lymphocytes to mercuric chloride
is restricted to mature T cells and is interleukin 1 dependent. Int Immunopharmacol. 2001; 1:581–
93. [PubMed: 11367541]
82. Jiang Y, Moller G. In vitro effects of HgCl2 on murine lymphocytes. I. Preferable activation of
CD4+ T cells in a responder strain. J Immunol. 1995; 154:3138–46. [PubMed: 7897203]
83. Hu H, Moller G, Abedi-Valugerdi M. Major histocompatibility complex class II antigens are
required for both cytokine production and proliferation induced by mercuric chloride in vitro. J
Autoimmun. 1997; 10:441–6. [PubMed: 9376071]
84. Layland LE, Wulferink M, Dierkes S, Gleichmann E. Drug-induced autoantibody formation in
mice: triggering by primed CD4+CD25- T cells, prevention by primed CD4+CD25+ T cells. Eur J
Immunol. 2004; 34:36–46. [PubMed: 14971028]
85. Whitekus MJ, Santini RP, Rosenspire AJ, McCabe MJ Jr. Protection against CD95-mediated
apoptosis by inorganic mercury in Jurkat T cells. J Immunol. 1999; 162:7162–70. [PubMed:
86. McCabe MJ Jr, Whitekus MJ, Hyun J, Eckles KG, McCollum G, Rosenspire AJ. Inorganic
mercury attenuates CD95-mediated apoptosis by interfering with formation of the death inducing
signaling complex. Toxicol Appl Pharmacol. 2003; 190:146–56. [PubMed: 12878044]
Pollard et al. Page 16
Chem Res Toxicol. Author manuscript; available in PMC 2011 April 13.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
87. McCabe MJ Jr, Eckles KG, Langdon M, Clarkson TW, Whitekus MJ, Rosenspire AJ. Attenuation
of CD95-induced apoptosis by inorganic mercury: caspase-3 is not a direct target of low levels of
Hg2+ Toxicol Lett. 2005; 155:161–70. [PubMed: 15585371]
88. Ziemba SE, McCabe MJ Jr, Rosenspire AJ. Inorganic mercury dissociates preassembled Fas/CD95
receptor oligomers in T lymphocytes. Toxicol Appl Pharmacol. 2005; 206:334–42. [PubMed:
89. Ziemba SE, Menard SL, McCabe MJ Jr, Rosenspire AJ. T-cell receptor signaling is mediated by
transient Lck activity, which is inhibited by inorganic mercury. Faseb J. 2009; 23:1663–71.
[PubMed: 19168706]
90. Mattingly RR, Felczak A, Chen CC, McCabe MJ Jr, Rosenspire AJ. Low concentrations of
inorganic mercury inhibit Ras activation during T cell receptor-mediated signal transduction.
Toxicol Appl Pharmacol. 2001; 176:162–8. [PubMed: 11714248]
91. Ziemba SE, Mattingly RR, McCabe MJ Jr, Rosenspire AJ. Inorganic mercury inhibits the
activation of LAT in T-cell receptor-mediated signal transduction. Toxicol Sci. 2006; 89:145–53.
[PubMed: 16251484]
92. Kono DH, Park MS, Szydlik A, Haraldsson KM, Kuan JD, Pearson DL, Hultman P, Pollard KM.
Resistance to xenobiotic-induced autoimmunity maps to chromosome 1. J Immunol. 2001;
167:2396–403. [PubMed: 11490030]
93. Vyse TJ, Kotzin BL. Genetic susceptibility to systemic lupus erythematosus. Annu Rev Immunol.
1998; 16:261–92. [PubMed: 9597131]
94. Tsao BP, Wallace DJ. Genetics of systemic lupus erythematosus. Curr Opin Rheumatol. 1997;
9:377–9. [PubMed: 9309191]
95. Moser KL, Gray-McGuire C, Kelly J, Asundi N, Yu H, Bruner GR, Mange M, Hogue R, Neas BR,
Harley JB. Confirmation of genetic linkage between human systemic lupus erythematosus and
chromosome 1q41. Arthritis Rheum. 1999; 42:1902–7. [PubMed: 10513806]
96. Johanneson B, Lima G, von Salome J, Alarcon-Segovia D, Alarcon-Riquelme ME. A major
susceptibility locus for systemic lupus erythemathosus maps to chromosome 1q31. Am J Hum
Genet. 2002; 71:1060–71. [PubMed: 12373647]
97. Pollard KM, Hultman P, Kono DH. Immunology and genetics of induced systemic autoimmunity.
Autoimmun Rev. 2005; 4:282–8. [PubMed: 15990075]
98. Pollard, KM.; Hultman, P.; Arnush, M.; Hildebrandt, B.; Kono, DH. Immunology and genetics of
xenobiotic-induced autoimmunity. In: Conrad, K.; Bachmann, MP.; Chan, EK.; Fritzler, MJ.;
Humbel, RL.; Sack, U.; Shoenfeld, Y., editors. From animal models to human genetics: research in
the induction and pathogenicity of autoantibodies. Vol. 4. Pabst: Lengerich; 2004. p. 130-144.
99. Kono DH, Balomenos D, Pearson DL, Park MS, Hildebrandt B, Hultman P, Pollard KM. The
prototypic Th2 autoimmunity induced by mercury is dependent on IFN- gamma and not Th1/Th2
imbalance. J Immunol. 1998; 161:234–40. [PubMed: 9647229]
100. Cauvi DM, Cauvi G, Pollard KM. Reduced expression of decay-accelerating factor 1 on CD4+ T
cells in murine systemic autoimmune disease. Arthritis Rheum. 2007; 56:1934–44. [PubMed:
101. Heeger PS, Lalli PN, Lin F, Valujskikh A, Liu J, Muqim N, Xu Y, Medof ME. Decay-
accelerating factor modulates induction of T cell immunity. J Exp Med. 2005; 201:1523–30.
[PubMed: 15883171]
102. Liu J, Miwa T, Hilliard B, Chen Y, Lambris JD, Wells AD, Song WC. The complement
inhibitory protein DAF (CD55) suppresses T cell immunity in vivo. J Exp Med. 2005; 201:567–
77. [PubMed: 15710649]
103. Miwa T, Maldonado MA, Zhou L, Yamada K, Gilkeson GS, Eisenberg RA, Song WC. Decay-
Accelerating Factor Ameliorates Systemic Autoimmune Disease in MRL/lpr Mice via Both
Complement-Dependent and -Independent Mechanisms. Am J Pathol. 2007; 170:1258–66.
[PubMed: 17392165]
104. Haggqvist B, Hultman P. Murine metal-induced systemic autoimmunity: baseline and stimulated
cytokine mRNA expression in genetically susceptible and resistant strains. Clin Exp Immunol.
2001; 126:157–64. [PubMed: 11678913]
Pollard et al. Page 17
Chem Res Toxicol. Author manuscript; available in PMC 2011 April 13.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
105. Chin YE, Kitagawa M, Kuida K, Flavell RA, Fu XY. Activation of the STAT signaling pathway
can cause expression of caspase 1 and apoptosis. Mol Cell Biol. 1997; 17:5328–37. [PubMed:
106. Suk K, Chang I, Kim YH, Kim S, Kim JY, Kim H, Lee MS. Interferon gamma (IFNgamma ) and
tumor necrosis factor alpha synergism in ME-180 cervical cancer cell apoptosis and necrosis.
IFNgamma inhibits cytoprotective NF-kappa B through STAT1/IRF-1 pathways. J Biol Chem.
2001; 276:13153–9. [PubMed: 11278357]
107. Pollard KM, Pearson DL, Hultman P, Hildebrandt B, Kono DH. Lupus-prone mice as models to
study xenobiotic-induced acceleration of systemic autoimmunity. Environ Health Perspect. 1999;
107(Suppl 5):729–35. [PubMed: 10502538]
108. Burek CL, Rose NR. Autoimmune thyroiditis and ROS. Autoimmun Rev. 2008; 7:530–7.
[PubMed: 18625441]
109. Bournaud C, Orgiazzi JJ. Iodine excess and thyroid autoimmunity. J Endocrinol Invest. 2003;
26:49–56. [PubMed: 12762641]
110. Tomer Y, Huber A. The etiology of autoimmune thyroid disease: a story of genes and
environment. J Autoimmun. 2009; 32:231–9. [PubMed: 19307103]
111. Vladutiu AO. Experimental autoimmune thyroiditis in mice chronically treated from birth with
anti-IgM antibodies. Cell Immunol. 1989; 121:49–59. [PubMed: 2785867]
112. Stafford EA, Rose NR. Newer insights into the pathogenesis of experimental autoimmune
thyroiditis. Int Rev Immunol. 2000; 19:501–33. [PubMed: 11129113]
113. Vladutiu AO, Rose NR. Autoimmune murine thyroiditis relation to histocompatibility (H-2) type.
Science. 1971; 174:1137–9. [PubMed: 5133731]
114. Tang H, Sharp GC, Peterson KP, Braley-Mullen H. IFN-gamma-deficient mice develop severe
granulomatous experimental autoimmune thyroiditis with eosinophil infiltration in thyroids. J
Immunol. 1998; 160:5105–12. [PubMed: 9590262]
115. Alimi E, Huang S, Brazillet MP, Charreire J. Experimental autoimmune thyroiditis (EAT) in mice
lacking the IFN-gamma receptor gene. Eur J Immunol. 1998; 28:201–8. [PubMed: 9485200]
116. Jin Z, Mori K, Fujimori K, Hoshikawa S, Tani J, Satoh J, Ito S, Satomi S, Yoshida K.
Experimental autoimmune thyroiditis in nonobese diabetic mice lacking interferon regulatory
factor-1. Clin Immunol. 2004; 113:187–92. [PubMed: 15451476]
117. Vladutiu AO, Sulkowski E. Inhibition of murine autoimmune thyroiditis by interferon.
Biomedicine. 1980; 33:173–4. [PubMed: 6163486]
118. Rasooly L, Burek CL, Rose NR. Iodine-induced autoimmune thyroiditis in NOD-H-2h4 mice.
Clin Immunol Immunopathol. 1996; 81:287–92. [PubMed: 8938107]
119. Hutchings PR, Verma S, Phillips JM, Harach SZ, Howlett S, Cooke A. Both CD4(+) T cells and
CD8(+) T cells are required for iodine accelerated thyroiditis in NOD mice. Cell Immunol. 1999;
192:113–21. [PubMed: 10087179]
120. Braley-Mullen H, Yu S. Early requirement for B cells for development of spontaneous
autoimmune thyroiditis in NOD.H-2h4 mice. J Immunol. 2000; 165:7262–9. [PubMed:
121. Yu S, Sharp GC, Braley-Mullen H. Dual roles for IFN-gamma, but not for IL-4, in spontaneous
autoimmune thyroiditis in NOD.H-2h4 mice. J Immunol. 2002; 169:3999–4007. [PubMed:
122. Nagayama Y, Horie I, Saitoh O, Nakahara M, Abiru N. CD4+CD25+ naturally occurring
regulatory T cells and not lymphopenia play a role in the pathogenesis of iodide-induced
autoimmune thyroiditis in NOD-H2h4 mice. J Autoimmun. 2007; 29:195–202. [PubMed:
123. Fang Y, Yu S, Braley-Mullen H. Contrasting roles of IFN-gamma in murine models of
autoimmune thyroid diseases. Thyroid. 2007; 17:989–94. [PubMed: 17910526]
124. Obermayer-Straub P, Strassburg CP, Manns MP. Autoimmune hepatitis. J Hepatol. 2000;
32:181–97. [PubMed: 10728804]
125. Rieger R, Gershwin ME. The X and why of xenobiotics in primary biliary cirrhosis. J
Autoimmun. 2007; 28:76–84. [PubMed: 17360156]
Pollard et al. Page 18
Chem Res Toxicol. Author manuscript; available in PMC 2011 April 13.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
126. Leung PS, Park O, Tsuneyama K, Kurth MJ, Lam KS, Ansari AA, Coppel RL, Gershwin ME.
Induction of primary biliary cirrhosis in guinea pigs following chemical xenobiotic
immunization. J Immunol. 2007; 179:2651–7. [PubMed: 17675529]
127. Wakabayashi K, Yoshida K, Leung PS, Moritoki Y, Yang GX, Tsuneyama K, Lian ZX, Hibi T,
Ansari AA, Wicker LS, Ridgway WM, Coppel RL, Mackay IR, Gershwin ME. Induction of
autoimmune cholangitis in non-obese diabetic (NOD).1101 mice following a chemical
xenobiotic immunization. Clin Exp Immunol. 2009; 155:577–86. [PubMed: 19094117]
128. Wakabayashi K, Lian ZX, Leung PS, Moritoki Y, Tsuneyama K, Kurth MJ, Lam KS, Yoshida K,
Yang GX, Hibi T, Ansari AA, Ridgway WM, Coppel RL, Mackay IR, Gershwin ME. Loss of
tolerance in C57BL/6 mice to the autoantigen E2 subunit of pyruvate dehydrogenase by a
xenobiotic with ensuing biliary ductular disease. Hepatology. 2008; 48:531–40. [PubMed:
129. Selmi C, Gershwin ME. The role of environmental factors in primary biliary cirrhosis. Trends
Immunol. 2009; 30:415–20. [PubMed: 19643668]
130. Oertelt S, Ridgway WM, Ansari AA, Coppel RL, Gershwin ME. Murine models of primary
biliary cirrhosis: Comparisons and contrasts. Hepatol Res. 2007; 37(Suppl 3):S365–9. [PubMed:
131. Reeves WH, Lee PY, Weinstein JS, Satoh M, Lu L. Induction of autoimmunity by pristane and
other naturally occurring hydrocarbons. Trends Immunol. 2009; 30:455–64. [PubMed:
132. Cruickshank B, Thomas MJ. Mineral oil (follicular) lipidosis: II. Histologic studies of spleen,
liver, lymph nodes, and bone marrow. Hum Pathol. 1984; 15:731–7. [PubMed: 6204920]
133. Satoh M, Kuroda Y, Yoshida H, Behney KM, Mizutani A, Akaogi J, Nacionales DC, Lorenson
TD, Rosenbauer RJ, Reeves WH. Induction of lupus autoantibodies by adjuvants. J Autoimmun.
2003; 21:1–9. [PubMed: 12892730]
134. Yoshida H, Satoh M, Behney KM, Lee CG, Richards HB, Shaheen VM, Yang JQ, Singh RR,
Reeves WH. Effect of an exogenous trigger on the pathogenesis of lupus in (NZB x NZW)F1
mice. Arthritis Rheum. 2002; 46:2235–44. [PubMed: 12209530]
135. Richards HB, Satoh M, Shaw M, Libert C, Poli V, Reeves WH. Interleukin 6 dependence of anti-
DNA antibody production: evidence for two pathways of autoantibody formation in pristane-
induced lupus. J Exp Med. 1998; 188:985–90. [PubMed: 9730900]
136. Nacionales DC, Kelly-Scumpia KM, Lee PY, Weinstein JS, Lyons R, Sobel E, Satoh M, Reeves
WH. Deficiency of the type I interferon receptor protects mice from experimental lupus. Arthritis
Rheum. 2007; 56:3770–83. [PubMed: 17968932]
137. Baechler EC, Gregersen PK, Behrens TW. The emerging role of interferon in human systemic
lupus erythematosus. Curr Opin Immunol. 2004; 16:801–7. [PubMed: 15511676]
138. Satoh M, Weintraub JP, Yoshida H, Shaheen VM, Richards HB, Shaw M, Reeves WH. Fas and
Fas ligand mutations inhibit autoantibody production in pristane-induced lupus. J Immunol.
2000; 165:1036–43. [PubMed: 10878381]
139. Andrews BS, Eisenberg RA, Theofilopoulos AN, Izui S, Wilson CB, McConahey PJ, Murphy
ED, Roths JB, Dixon FJ. Spontaneous murine lupus-like syndromes. Clinical and
immunopathological manifestations in several strains. J Exp Med. 1978; 148:1198–215.
[PubMed: 309911]
140. Hron JD, Peng SL. Type I IFN protects against murine lupus. J Immunol. 2004; 173:2134–42.
[PubMed: 15265950]
141. Young AL, Giesy JP, Jones PD, Newton M. Environmental fate and bioavailability of Agent
Orange and its associated dioxin during the Vietnam War. Environ Sci Pollut Res Int. 2004;
11:359–70. [PubMed: 15603524]
142. Jennings AM, Wild G, Ward JD, Ward AM. Immunological abnormalities 17 years after
accidental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Br J Ind Med. 1988; 45:701–4.
[PubMed: 3264183]
143. Kim HA, Kim EM, Park YC, Yu JY, Hong SK, Jeon SH, Park KL, Hur SJ, Heo Y.
Immunotoxicological effects of Agent Orange exposure to the Vietnam War Korean veterans.
Ind Health. 2003; 41:158–66. [PubMed: 12916745]
Pollard et al. Page 19
Chem Res Toxicol. Author manuscript; available in PMC 2011 April 13.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
144. Tonn T, Esser C, Schneider EM, Steinmann-Steiner-Haldenstatt W, Gleichmann E. Persistence of
decreased T-helper cell function in industrial workers 20 years after exposure to 2,3,7,8-
tetrachlorodibenzo-p-dioxin. Environ Health Perspect. 1996; 104:422–6. [PubMed: 8732953]
145. Baccarelli A, Mocarelli P, Patterson DG Jr, Bonzini M, Pesatori AC, Caporaso N, Landi MT.
Immunologic effects of dioxin: new results from Seveso and comparison with other studies.
Environ Health Perspect. 2002; 110:1169–73. [PubMed: 12460794]
146. Signorini S, Gerthoux PM, Dassi C, Cazzaniga M, Brambilla P, Vincoli N, Mocarelli P.
Environmental exposure to dioxin: the Seveso experience. Andrologia. 2000; 32:263–70.
[PubMed: 11021518]
147. Wolfe WH, Michalek JE, Miner JC, Rahe A, Silva J, Thomas WF, Grubbs WD, Lustik MB,
Karrison TG, Roegner RH, et al. Health status of Air Force veterans occupationally exposed to
herbicides in Vietnam. I. Physical health. Jama. 1990; 264:1824–31. [PubMed: 2402041]
148. Funatake CJ, Marshall NB, Steppan LB, Mourich DV, Kerkvliet NI. Cutting edge: activation of
the aryl hydrocarbon receptor by 2,3,7,8-tetrachlorodibenzo-p-dioxin generates a population of
CD4+ CD25+ cells with characteristics of regulatory T cells. J Immunol. 2005; 175:4184–8.
[PubMed: 16177056]
149. Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF, Bettelli E, Caccamo M, Oukka M,
Weiner HL. Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor.
Nature. 2008; 453:65–71. [PubMed: 18362915]
150. Esser C, Rannug A, Stockinger B. The aryl hydrocarbon receptor in immunity. Trends in
Immunology. In Press, Corrected Proof.
151. Ishimaru N, Takagi A, Kohashi M, Yamada A, Arakaki R, Kanno J, Hayashi Y. Neonatal
exposure to low-dose 2,3,7,8-tetrachlorodibenzo-p-dioxin causes autoimmunity due to the
disruption of T cell tolerance. J Immunol. 2009; 182:6576–86. [PubMed: 19414813]
152. Mathis D, Benoist C. Aire. Annu Rev Immunol. 2009; 27:287–312. [PubMed: 19302042]
153. Cai P, Konig R, Boor PJ, Kondraganti S, Kaphalia BS, Khan MF, Ansari GA. Chronic exposure
to trichloroethene causes early onset of SLE-like disease in female MRL +/+ mice. Toxicol Appl
Pharmacol. 2008; 228:68–75. [PubMed: 18234256]
154. Blossom SJ, Doss JC, Gilbert KM. Chronic exposure to a trichloroethylene metabolite in
autoimmune-prone MRL+/+ mice promotes immune modulation and alopecia. Toxicol Sci.
2007; 95:401–11. [PubMed: 17077186]
155. Gilbert KM, Pumford NR, Blossom SJ. Environmental Contaminant Trichloroethylene Promotes
Autoimmune Disease and Inhibits T-cell Apoptosis in MRL(+/+) Mice. J Immunotoxicol. 2006;
3:263–7. [PubMed: 18958707]
156. Blossom SJ, Doss JC. Trichloroethylene Alters Central and Peripheral Immune Function in
Autoimmune-Prone MRL(+/+) Mice Following Continuous Developmental and Early Life
Exposure. J Immunotoxicol. 2007; 4:129–41. [PubMed: 18958721]
157. Cooper GS, Makris SL, Nietert PJ, Jinot J. Evidence of autoimmune-related effects of
trichloroethylene exposure from studies in mice and humans. Environ Health Perspect. 2009;
117:696–702. [PubMed: 19479009]
158. Parks CG, Cooper GS. Occupational exposures and risk of systemic lupus erythematosus.
Autoimmunity. 2005; 38:497–506. [PubMed: 16373255]
159. Michielsen CC, van Loveren H, Vos JG. The role of the immune system in hexachlorobenzene-
induced toxicity. Environ Health Perspect. 1999; 107(Suppl 5):783–92. [PubMed: 10502545]
160. Cripps DJ, Peters HA, Gocmen A, Dogramici I. Porphyria turcica due to hexachlorobenzene: a 20
to 30 year follow-up study on 204 patients. Br J Dermatol. 1984; 111:413–22. [PubMed:
161. Daniel V, Huber W, Bauer K, Suesal C, Conradt C, Opelz G. Associations of blood levels of
PCB, HCHS, and HCB with numbers of lymphocyte subpopulations, in vitro lymphocyte
response, plasma cytokine levels, and immunoglobulin autoantibodies. Environ Health Perspect.
2001; 109:173–8. [PubMed: 11266329]
162. Ezendam J, Vos JG, Pieters R. Research articles mechanisms of hexachlorobenzene-induced
adverse immune effects in brown norway rats. J Immunotoxicol. 2005; 1:167–75. [PubMed:
Pollard et al. Page 20
Chem Res Toxicol. Author manuscript; available in PMC 2011 April 13.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
163. Yurino H, Ishikawa S, Sato T, Akadegawa K, Ito T, Ueha S, Inadera H, Matsushima K.
Endocrine disruptors (environmental estrogens) enhance autoantibody production by B1 cells.
Toxicol Sci. 2004; 81:139–47. [PubMed: 15166399]
164. Sobel ES, Gianini J, Butfiloski EJ, Croker BP, Schiffenbauer J, Roberts SM. Acceleration of
autoimmunity by organochlorine pesticides in (NZB x NZW)F1 mice. Environ Health Perspect.
2005; 113:323–8. [PubMed: 15743722]
165. Leffel EK, Wolf C, Poklis A, White KL Jr. Drinking water exposure to cadmium, an
environmental contaminant, results in the exacerbation of autoimmune disease in the murine
model. Toxicology. 2003; 188:233–50. [PubMed: 12767694]
166. Hudson CA, Cao L, Kasten-Jolly J, Kirkwood JN, Lawrence DA. Susceptibility of lupus-prone
NZM mouse strains to lead exacerbation of systemic lupus erythematosus symptoms. J Toxicol
Environ Health A. 2003; 66:895–918. [PubMed: 12825236]
167. Pumford NR, Halmes NC. Protein targets of xenobiotic reactive intermediates. Annu Rev
Pharmacol Toxicol. 1997; 37:91–117. [PubMed: 9131248]
168. Kono DH, Haraldsson MK, Lawson BR, Pollard KM, Koh YT, Du X, Arnold CN, Baccala R,
Silverman GJ, Beutler BA, Theofilopoulos AN. Endosomal TLR signaling is required for anti-
nucleic acid and rheumatoid factor autoantibodies in lupus. Proc Natl Acad Sci U S A. 2009;
106:12061–6. [PubMed: 19574451]
Pollard et al. Page 21
Chem Res Toxicol. Author manuscript; available in PMC 2011 April 13.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
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
Chem Res Toxicol. Author manuscript; available in PMC 2011 April 13.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Pollard et al. Page 23
Table 1
Substances associated with autoimmunity in humans and the animal models used to examine disease
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
- 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.
Chem Res Toxicol. Author manuscript; available in PMC 2011 April 13.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Pollard et al. Page 24
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.
dGraft versus host disease
eexperimental autoimmune encephalomyelitis
Chem Res Toxicol. Author manuscript; available in PMC 2011 April 13.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Pollard et al. Page 25
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
Chem Res Toxicol. Author manuscript; available in PMC 2011 April 13.
... When an individual's immune system starts to evoke a robust response against its own healthy cells and tissues, the condition is known as autoimmunity. The commonly targeted cells, tissues, and organs by xenobiotics to manifest autoimmunity include thyroid (thyroiditis), gastric parietal cells (gastritis), liver (autoimmune hepatitis and cholangitis), the β cells of the islets of Langerhans (diabetes), and steroid-producing cells in the adrenal and ovary (Addison's disease), among others [17,18]. Many intrinsic and extrinsic factors contribute to the susceptibility to autoimmune diseases. ...
... The extrinsic factors include environmental, toxic chemicals, drugs, and microbes, whereas the intrinsic factors may include genetic makeup, age, and sex, among others. Although it is challenging to link exposure to xenobiotics to autoimmune diseases since the amplitude of autoreactivity differs, and the manifestation can take a very long time, attempts are being made by using various experimental models to decipher the mechanisms and contribution of immune components [17][18][19]. It can become further challenging as the same agent can induce a range of autoimmune disorders, whereas exposure to a variety of agents can produce a similar clinical feature [18]. ...
... Although it is challenging to link exposure to xenobiotics to autoimmune diseases since the amplitude of autoreactivity differs, and the manifestation can take a very long time, attempts are being made by using various experimental models to decipher the mechanisms and contribution of immune components [17][18][19]. It can become further challenging as the same agent can induce a range of autoimmune disorders, whereas exposure to a variety of agents can produce a similar clinical feature [18]. Drosophila can be an excellent choice for studying xenobiotics-associated immune responses to expand the repertoire of animal models on disposal. ...
Full-text available
Altered immune responses associated with human disease conditions, such as inflammatory and infectious diseases, cancers, and autoimmune diseases, are among the primary causes of morbidity across the world. A wealth of studies has demonstrated the efficiency of nanoparticles (NPs)-based immunotherapy strategies in different laboratory model systems. Nanoscale dimensions (<100 nm) enable NPs to have increased surface area to volume ratio, surface charge, and reactivity. Physicochemical properties along with the shapes, sizes, and elasticity influence the immunomodulatory response induced by NPs. In recent years, NPs-based immunotherapy strategies have attained significant focus in the context of cancers and autoimmune diseases. This rapidly growing field of nanomedicine has already introduced ~50 nanotherapeutics in clinical practices. Parallel to wide industrial applications of NPs, studies have raised concerns about their potential threat to the environment and human health. In past decades, a wealth of in vivo and in vitro studies has demonstrated the immunotoxicity potential of various NPs. Given that the number of engineered/designed NPs in biomedical applications is continuing to increase, it is pertinent to establish the toxicity profile for their safe and intelligent use in biomedical applications. The review is intended to summarize the NPs-induced immunomodulation pertaining to toxicity and therapeutic development in human health.
... Autoimmunity is an immune response against self-antigens leading to demonstrable pathology (Pollard et al. 2010). Epidemiological studies indicated that autoimmune diseases (ADs) are the 10th most common cause of mortality in developing countries (Nielsen and Hultman. ...
... Extrinsic factors such as drugs, chemicals, microbes, and environmental constituents including silica, mercury, cadmium, gold, and L canavanine can trigger the initiation of an autoimmune response (Hess. 2002;Pollard et al. 2010). The mechanism by which these substances induce autoimmunity can be grouped into three general categories: inhibiting deletion of newly generated autoreactive cells permitting their release to the circulation, modification of gene expression in the immune cells allowing lymphocytes to react to signals normally not enough to initiate a response or allowing the antigen-presenting cells to abnormally trigger a response and activate autoreactive cells, and alteration of self-antigen such that they are recognized by the immune system as foreign (Rao and Richardson. ...
Full-text available
Autoimmune disease is a complex chronic disease that triggers immune activation against autoantigens resulting in tissue damage. Epidemiological data showed that autoimmune diseases are increasing worldwide over the last decades owing to increased environmental pollution. This study investigates the therapeutic effect of myrrh as a natural medicine compared to prednisolone in the treatment of immune-mediated glomerulonephritis induced by silicate. The autoimmune disease model in rats was induced by injecting 5 mg crystalline sodium silicate suspension subcutaneously once weekly for 20 weeks, and then the rats were treated either with myrrh extract or prednisolone or with both for 6 weeks. Liver and kidney function tests, histopathology, and immunohistochemistry of TNF-α expression in kidney tissue were performed. The creatinine significantly elevated in silica-treated group and decreased in other treated groups. Histopathology of the kidney revealed improvement of glomerular and tubular basement thickness in all treated groups, but the inflammatory cell count slightly decreased in the group treated with myrrh than the other treated groups which showed a marked decrease. TNF-α expression was significantly decreased in all treated groups. Interestingly, the myrrh did not produce hepatic lesions and improve the side effect of prednisolone in the liver when taken in combination. Therefore, myrrh extract possessed anti-inflammatory properties and counteracted the side effect of prednisolone on the liver. Myrrh extract can serve as a conjunctive therapy with prednisolone to treat autoimmune diseases.
... The role of these two factors may differ among individuals, but these factors modulate the immune system and produce autoantibodies via autoreactive T and B cells that lead to AD progression (2,4). One of the important factors known to be involved in ADs is exposure to environmental contaminants (4)(5)(6). Our previous studies have shown that trichloroethene [trichloroethylene (TCE)], an environmental toxicant, and its metabolites induce an autoimmune response in experimental animals (5,(7)(8)(9)(10), and oxidative stress plays an important role in TCE-mediated autoimmunity (5,(9)(10)(11). ...
Full-text available
Trichloroethene (TCE), an occupational and ubiquitous environmental contaminant, is associated with the induction of autoimmune diseases (ADs). Although oxidative stress plays a major role in TCE-mediated autoimmunity, the underlying molecular mechanisms still need to be delineated. Altered non-coding RNAs, including the expression of microRNAs (miRNAs), can influence target genes, especially related to apoptosis and inflammation, and contribute to ADs. Therefore, the objective of this study was to delineate the contribution of miRNAs in TCE-mediated inflammatory and autoimmune response. To achieve this, we treated female MRL+/+ mice with TCE (10 mmol/kg in corn oil, i.p., every fourth day) with/without antioxidant sulforaphane (SFN; 8 mg/kg in corn oil, i.p., every other day) for 6 weeks. With the use of miRNA microarray, 293 miRNAs were analyzed, which included 35 miRNAs that were relevant to inflammation and ADs. Among those 35 miRNAs, 8 were modulated by TCE and/or TCE+SFN exposure. TCE treatment led to increased expression of 3 miRNAs and also decreased expression of 3 miRNAs. Interestingly, among the 35 differentially expressed miRNAs, antioxidant SFN modulated the expression of 6 miRNAs. Based on the microarray findings, we subsequently focused on two miRNAs (miRNA-21 and miRNA-690), which are known to be involved in inflammation and autoimmune response. The increases in miRNA-21 and miR-690 (observed using miRNA microarray) were further validated by RT-PCR, and the TCE-mediated increases in miR-21 and miR-690 were ameliorated by SFN treatment. Modulating miR-21 and miR-690 by respective inhibitors or mimics suppressed the expression of NF-κB (p65) and IL-12 in RAW 264.7 cells. Our findings suggest a contributory role of miR-21 and miR-690 in TCE-mediated and its metabolite dichloroacetyl chloride (DCAC)-mediated inflammation and autoimmune response and support that antioxidant SFN could be a potential therapeutic candidate for inflammatory responses and ADs.
... 12 A number of other agents-such as solvents, vinyl chloride, mercury, dioxins, pesticides, plastic-related components, and air pollution-have been associated with autoimmunity. 6,[13][14][15] In addition to 'well-defined' autoimmune disorders, exposure has been linked to features that suggest autoimmunity-such as Raynaud's phenomenon or the presence of autoantibodies, immune complexes, or excess production of immunoglobulinbut without the full clinical features of an autoimmune disease. Moreover, suffering from one autoimmune disorder increases the risk of developing additional autoimmune diseases (polyautoimmunity). ...
Full-text available
Immune-mediated, noncommunicable diseases—such as autoimmune and inflammatory diseases—are chronic disorders, in which the interaction between environmental exposures and the immune system plays an important role. The prevalence and societal costs of these diseases are rising in the European Union. The EXIMIOUS consortium—gathering experts in immunology, toxicology, occupational health, clinical medicine, exposure science, epidemiology, bioinformatics, and sensor development—will study eleven European study populations, covering the entire lifespan, including prenatal life. Innovative ways of characterizing and quantifying the exposome will be combined with high-dimensional immunophenotyping and -profiling platforms to map the immune effects (immunome) induced by the exposome. We will use two main approaches that “meet in the middle”—one starting from the exposome, the other starting from health effects. Novel bioinformatics tools, based on systems immunology and machine learning, will be used to integrate and analyze these large datasets to identify immune fingerprints that reflect a person’s lifetime exposome or that are early predictors of disease. This will allow researchers, policymakers, and clinicians to grasp the impact of the exposome on the immune system at the level of individuals and populations.
... Hg is a potent de novo inducer of a systemic autoimmune disease in rodents with certain MHC (H-2) class II genotypes Nielsen, 1997, 2001;Fournié et al., 2002;Vas and Monestier, 2008;Schiraldi and Monestier, 2009;Pollard et al., 2010). While these rodent models continue to be very useful for elucidating immunological mechanisms in systemic autoimmunity, dose-response studies applied to humans show it to be likely that de novo induction of autoimmunity by these agents will require exposure levels occurring only in specific hazardous workplaces, or during accidental exposure or voluntary ingestion. ...
Our understanding of the effect of metals (including ions and their compounds) on the immune system continues to evolve. Observed effects include immunosuppression, immune stimulation, hypersensitivity, and autoimmunity. Many metals show a paradoxical dose-response pattern comprising stimulation of immune function at low doses and suppression at higher doses, but global immune function is often preserved due to the redundancy and the reserve capacity of the immune system, and clinically relevant effects are uncommon. Clinically relevant hypersensitivity reactions due to metals are dominated by T cell-mediated allergic contact dermatitis, particularly in response to exposure to beryllium, cobalt, chromium, gold, mercury, and nickel. Immediate (type I) hypersensitivity reactions dominated by airways symptoms occur infrequently, and then most often with platinum, but rarely with nickel or chromium. The induction of metal-induced autoimmunity, including the formation of immune-complex deposits, is well documented in humans, but the number of recognized cases is few. Studies in rodents using mercury and gold have increased our knowledge of the mechanisms of metal-induced autoimmunity. Of special importance is the unraveling of genetic factors that regulate susceptibility to mercury-induced autoimmunity, including the uptake and retention of mercury, as well as the threshold metal concentrations for eliciting autoimmunity. Recently mercury, lead, and cadmium have been shown to accelerate and/or exacerbate autoimmunity in autoimmune-prone animal models. The importance of metal exposure for inducing and/or accelerating autoimmunity in humans remains to be determined.
Cancer/Testis antigens (CTAs) are a group of antigens whose expression is restricted to male germ cells. However, the CTA gene promoters are methylated and silenced in the normal somatic cells. Since certain CTAs are immunogenic and can elicit cellular and humoral responses, we propose that there is a link between the re-expression of CTAs and autoimmune disorders. The hypothesis assumes that the demethylation of particular CTA gene promoters is triggered by any of the risk factors predisposing to autoimmunity. Hence, those CTAs genes are expressed by the help of binding of cell-specific transcription factors. Examination of the promoter sequences revealed that CTA genes, particularly X-linked ones, possess binding motifs for the cell-specific transcription factors in the cells associated with the respective autoimmune disease. If proves true, this hypothesis will provide a unified mechanism for the numerous autoimmune disorders and will open the way for developing novel therapeutic approaches targeting the CTAs. The share link:
Full-text available
Autoimmune diseases have emerged as a pandemic in our modern societies, especially after World War II. There are currently more than 80 autoimmune diseases that compromise the lives of millions of patients around the world. There is a variety of factors that are involved in the pathogenesis of autoimmune diseases that vary from environmental factors to genetic susceptibility. The GI tract is one of the most susceptible subsystems in human bodies for autoimmune organ-specific diseases. There are five autoimmune GI tract diseases that are most common. This review consists of two chapters. In part I, we shed the light on introducing the concept of autoimmunity, the description of the disease's pathogenesis and the diagnosis, the link between the gut and brain through what is known as the gut-brain axis, and the relationship of this axis in GI autoimmune diseases. In part II, we will shed light on the role of antibodies as markers for the prediction of the disease, artificial intelligence in GI autoimmune diseases, the nutritional role and implications in the five GI autoimmune diseases, and finally the treatment of those diseases.
Background The prevalence of autoimmunity in the U.S. has increased recently for undetermined reasons. Little is known about associations between autoimmunity and environmental causes. Objectives In a large representative sample of the U.S. population, we expanded our prior exploratory study of how exposures to selected xenobiotics and dioxin-like (DL) mixtures relate to antinuclear antibodies (ANA), the most common biomarker of autoimmunity. Methods We analyzed cross-sectional data on 12,058 participants aged ≥12 years from three time periods of the National Health and Nutrition Examination Survey between 1988 and 2012, of whom 14% were ANA-positive. We used lognormal regression models and censored-data methods to estimate ANA associations with xenobiotic concentrations overall and in sex, age, and race/ethnicity subgroups. Our analyses adjusted for potential confounders and appropriately handled concentrations below detection limits. Results Observed ANA associations were positive for most DL compounds and nonDL polychlorinated biphenyls (PCBs), negative for most phthalates, and mixed for other xenobiotic classes. After correcting for multiple comparisons, some associations remained statistically significant. In subgroup analyses, the most significant finding was a positive ANA association with N-acetyl-S-(2-hydroxy-3-butenyl)-L-cysteine (MHB2) in males, followed by positive associations with 2,2',3,5'-tetrachlorobiphenyl (PCB 44), 2,2',4,5'-tetrachlorobiphenyl (PCB 49), and 2,2',3,4',5',6-hexachlorobiphenyl (PCB 149) in 12-19 year-olds, with 3,4,4',5-tetrachlorobiphenyl (PCB 81), 2,2',3,3',4,4',5,5',6-nonachlorobiphenyl (PCB 206), and N-acetyl-S-(phenyl)-L-cysteine (PMA) in Mexican Americans. Negative associations were found with mono-benzyl phthalate (MBzP) in 20-49 year-olds and mono-n-butyl phthalate (MnBP) in 12-19 year-olds. In overall analyses, combining stratum-specific results across race/ethnicity strata revealed a positive ANA association with PCB 81 and a negative ANA association with N-acetyl-S-(2-hydroxyethyl)-L-cysteine (HEMA). Discussion This study identified potential associations between ANA and various xenobiotics. Further investigation to confirm these observations and elucidate effects of certain xenobiotics on immune regulation could have important mechanistic, preventive, and treatment implications for a variety of immune-mediated disorders.
Autoimmune diseases are complex conditions that are increasing in incidence worldwide. Autoimmune disorders are often associated clinical challenges in regards to clear diagnoses, comorbidities, and effective disease management and treatment strategies. Importantly, research suggests that an individual’s nutritional status and metabolic health, such as the presence of obesity or metabolic syndrome, may play a role in the risk, pathophysiology, and management of autoimmune diseases. Further, adherence to Western or Mediterranean-style dietary patterns, as well as intake of specific macronutrients (e.g., carbohydrates, protein, fatty acids), micronutrients (e.g., vitamin D, selenium, sodium) and non-nutrient dietary factors (e.g., food contaminants, gut microbiome profiles), may modulate autoimmune disease development and complications. Thus, nutritional interventions may represent an effective approach to mitigate risk and support the management of autoimmune disorders.
Full-text available
Imbalances of Th1- and Th2-type responses have been postulated to be a predisposing factor for both humoral and cellular mediated autoimmune diseases. To further define their roles in systemic autoimmunity, IL-9 and IFN-gamma gene knockout mice were studied for susceptibility to the prototypic Th2-mediated mercury-induced autoimmunity, A predominant Th2-type response following HgCl2 treatment of wild-type B10.S mice was confirmed by the findings of a significant increase in splenic IL-4 and hypergammaglobulinemia primarily of the IgG1 isotype, without an increase in IFN-gamma levels, paradoxically, IL-4-deficient mice developed the characteristic anti-nucleolar autoantibodies and tissue deposition of immune complexes, while IFN-gamma-deficient mice had very low autoantibody levels and essentially normal immunohistology. Studies to define defects in Ab responses of IFN-gamma-deficient mice, using the T-dependent Ag (4-hydroxy-3-nitrophenyl)acetyl, revealed an attenuated IgG response to low and to a lesser extent high doses of (4-hydroxy-3-nitrophenyl)acetyl-hemocyanin maintenance of affinity maturation, These results indicate that Th1/Th2 imbalance does not directly play a role in susceptibility to mercury-induced autoimmunity, and suggest that the dependence on Th1-type responses in certain autoimmune diseases is due to the requirement for IFN-gamma for Ab production to weakly antigenic self molecules.
Silicosis patients (SILs) and patients who have been exposed to asbestos develop not only respiratory diseases but also certain immunological disorders. In particular, SIL sometimes complicates autoinumme diseases such as systemic scleroderma, rheumatoid arthritis (known as Caplan syndrome), and systemic lupus erythematoses. In addition, malignant complications such as lung cancer and malignant mesothelioma often occurr in patients exposed to asbestos, and may be involved in the reduction of, tumor immunity. Although silica-induced disorders of autoimmunity have been explained as adjuvant-type effects of silica, more precise analyses are needed and should reflect the recent progress in immunomolecular findings. A brief summary of our investigations related to the immunological effects of silica/asbestos is presented. Recent advances in immunomolecular studies led to detailed analyses of the immunological effects of asbestos and silica. Both affect immuno-competent cells and these effects may be associated with the pathophysiological development of complications in silicosis and asbestos-exposed patients such as the occurrence of autoinumme disorders and malignant tumors, respectively. In addition, immunological analyses may lead to the development of new clinical tools for the modification of the pathophysiological aspects of diseases such as the regulation of autoimmunity or tumor immunity using cell-mediated therapies, various cytokines, and molecule-targeting therapies. In particular, as the incidence of asbestos-related malignancies is increasing and such malignancies have been a medical and social problem since the summer of 2005 in Japan, efforts should be focused on developing a cure for these diseases to eliminate nationwide anxiety.
MRL/1 and BXSB male mice have a systemic lupus erythematosus (SLE)-like disease similar to but more acute than that occurring in NZB X W mice. The common elements of lymphoid hyperplasia, B-cell hyperactivity, autoantibodies, circulating immune complex (IC), complement consumption, IC glomerulonephritis with gp70 deposition, and thymic atrophy were found in all three kinds of SLE mice. On the basis of these common elements, SLE seen in these mice can be considered a single disease in the same sense that human SLE is one disease. The differences in the SLE expressed in the different mice are no greater than those found in an unselected series of humans with SLE. However, the significant quantitative and qualitative variations in abnormal immunologic expression suggest that different constellations of factors, genetic and/or pathophysiologic, may operate in the three murine strains and that each constellation is capable of leading, via its particular abnormal immunologic consequences, to the activation of common immunopathologic effector mechanisms that cause quite similar SLE-like syndromes. From an experimental point of view, the availability of several inbred murine strains of commonplace histocompatibility types that express an SLE-like syndrome makes possible innumerable manipulations which should help to elucidate the nature and cause(s) of this disorder.
Tissues obtained from 600 routine autopsies were studied. Mineral oil lipidosis was present in the spleen (76 per cent), liver (45 per cent), bone marrow (26 per cent), and lymph nodes; more than 50 per cent of the lymph nodes from the mesentery, porta hepatis, and mediastinum were affected. Mineral oil and its metabolic products produce a nonfibrogenic reaction in these tissues. The differential diagnosis of mineral oil lipidosis in lymph nodes with reaction to radiopaque oils and Whipple's disease is discussed. The presence of mineral oil in para-aortic (42 per cent) and internal iliac (15 per cent) lymph nodes could result in false-positive readings after lymphangiography.
The Air Force Health Study is a 20-year comprehensive assessment of the health of Air Force veterans of Operation Ranch Hand, the unit responsible for aerial spraying of herbicides in Vietnam. The study compares the health and noncombat mortality of Ranch Hand veterans with a comparison group of Air Force veterans primarily involved with cargo missions in Southeast Asia but who were not exposed to herbicides. This report summarizes the health of these veterans as determined at the third in a series of physical examinations. Nine hundred ninety-five Ranch Hands and 1299 comparison subjects attended the second follow-up examination in 1987. The two groups were similar in reported health problems, diagnosed skin conditions, and hepatic, cardiovascular, and immune profiles. Ranch Hands have experienced significantly more basal cell carcinomas than comparison subjects. The two groups were not different with respect to melanoma and systemic cancer. (JAMA. 1990;264:1824-1831)
Systemic treatment of susceptible mouse strains with HgCl2 is known to induce elevated serum concentrations of IgG1, IgG2A, and IgE, formation of antinuclear (ANA) and antinucleolar autoantibodies (ANolA), and immune glomerulonephritis. The development of these HgCl2-induced immunological alterations requires CD4+ T cells. The H-2S haplotype encodes susceptibility and, as far as studied, H-2d determines resistance. For a better understanding of susceptibility and resistance to HgCl2 at the level of Th and B cells, we compared the effects of HgCl2 treatment in the H-2 congenic mouse strains B10.S (H-2S) and B10.D2/n (H-2d). We show that (1) H-2S but not H-2d mice responded to HgCl2 treatment with massive activation of their B cells and switch to IgE, IgG1, and IgG2A; (2) both H-2S and H-2d mice responded to HgCl2 with IL-4-dependent increases in B cell la expression, but significantly higher levels were induced in H-2S than in H-2d mice; (3) splenic CD4+ T cells of HgCl2-treated H-2S mice showed a strong increase in IL-4 mRNA, whereas those of H-2d mice showed only a weak increase; (4) both H-2S and H-2d mice expressed enhanced splenic numbers of CD45RBlo CD4+ T cells, suggesting activation of T cells in both strains. These results indicate that the MHC, presumably by its class II loci, modulates the T cell response to the etiologic agent HgCl2, and, hence, determines which type of immune effector mechanism is activated. A possible explanation of the observed strain difference is that H-2S and H-2d mice responded to systemic treatment with HgCl2 by preferential activation of Th2 and Th1 cells, respectively.Copyright © 1993 S. Karger AG, Basel
Objective Genetic susceptibility to systemic lupus erythematosus (SLE) is undoubtedly complex and, presumably, involves multiple loci. Linkage of SLE to D1S229 at chromosome 1q41 has been previously reported in a cohort of 52 affected sibpairs. The present study sought to confirm this reported linkage in an independent cohort of 127 extended multiplex SLE pedigrees containing 107 affected sibpairs.Methods Genotype data were collected for D1S229 and 18 flanking microsatellite markers spanning chromosome 1q32–1q42. Analyses of genotype data included a model-based logarithm of odds (LOD) score approach, affected sibpair analyses, and transmission disequilibrium tests.ResultsA maximum LOD score of 1.46 was found with D1S229 in a subgroup of 78 European American pedigrees, with additional support from multiple markers clustered around D1S229. Increased allele sharing in affected siblings was most significant at D1S2616, particularly in European Americans (P = 0.0005), followed by D1S229 (P = 0.002), D1S490 (P = 0.028), and D1S1605 (P = 0.037). Although linkage in a subgroup of 40 African American pedigrees was not suggested by the analyses of any marker tested in the chromosomal region surrounding D1S229, a maximum LOD score of 3.03 was found with D1S3462, mapped 15 centimorgans distal to D1S229.Conclusion Our linkage analysis results in European Americans at D1S229 are remarkably similar to those previously reported. That at least 1 genetic effect near this locus is important for susceptibility to lupus should now be generally accepted, and efforts to identify the gene are thereby justified.
Objective. To determine the frequency, clinical associations, and any major histocompatibility complex correlations of antifibrillarin antibodies in patients with systemic sclerosis (SSc). Methods. Antifibrillarin antibodies were determined by indirect immunofluorescence, immunoblotting, and immunoprecipitation, and HLA class II alleles by DNA oligotyping, in a large cohort of SSc patients. Results. Antifibrillarin was found in 8% of 335 SSc sera and was significantly more common in blacks (16%) than whites (5%), in males (33%) than females (14%), and in patients with cardiac, renal, or gut involvement. The HLA class II haplotype DRB1*1302, DQB1*0604 was found significantly more frequently in SSc patients with antifibrillarin compared with racematched normal controls and 260 SSc patients without antifibrillarin. In addition, 1 or more of the HLA–DQB1 alleles *0604, *0301, *0602, and/or *0302 was found in all antifibrillarin-positive patients, and 62% of the antifibrillarin-positive patients had 2 of these HLA–DQB1 alleles, a highly significant difference from both race-matched normal controls and antifibrillarin-negative SSc patients. Conclusion. Antifibrillarin, although an infrequent nucleolar autoantibody, is a marker for severe SSc, especially in blacks and males, and is strongly associated with a unique HLA haplotype, as well as with combinations of certain HLA–DQB1 alleles.
Autoimmune hepatitis (AIH) is a rare disease, characterized by female predominance, hypergammaglobulinemia, autoantibodies, association with HLA DR3 and HLA DR4 and a good response to immunosuppression. Different subtypes of AIH may be distinguished, based on differences in the autoantibody patterns. AIH type 1 is characterized by anti-nuclear (ANA) and/or anti-smooth muscular (SMA) autoantibodies. AIH type 2 is characterized by liver/kidney microsomal autoantibodies (LKM). AIH type 3 may be distinguished by autoantibodies to soluble liver proteins (SLA) or the liver pancreas antigen (LP). AIH-2 affects predominantly pediatric patients and is characterized by a more severe clinical course, a higher frequency of relapse under immunosuppressive treatment and a more frequent progression to cirrhosis. In contrast, AIH types 1 and 3 show a higher age of onset and a better long-term response to immunosuppressive treatment. At present, the treatment of choice is prednisone alone or a combination with prednisone and azathioprine. Both treatment protocols show high survival rates. However, a rate of 13% of treatment failures and the failure to induce permanent remission in most patients underlines the urgent need to develop additional treatment regimens. A yet unknown genetic predisposition is believed to act as the underlying etiological factor in AIH. This genetic predisposition includes a few known risk factors such as the presence of HLA DR3 or HLA DR4, deletions of C4A alleles and female gender. Furthermore, it has to be postulated that defects in immunoregulatory genes exist. A model for such defects may be the autoimmune polyglandular syndrome type 1 (APS1), which results from the defects in a single gene, the autoimmune regulator type 1 (AIRE-1). Patients with APS1 suffer from mucocutaneous candidiasis and a number of organ-specific autoimmune diseases. Characteristic is a high variability in the number and character of the disease components in APS1, indicating that other genetic and environmental factors may strongly modulate the outcome of disease. Environmental factors may comprise chemical influences, such as nutritional compounds and drugs, or virus infections. Several drugs or chemicals were shown to induce hepatitis with autoimmune involvement, e.g. tienilic acid, dihydralazine and halothane. Adduct formation of an activated metabolite is believed to act as a trigger and to induce a specific immune response. Similarly, viruses were repeatedly shown to trigger autoimmune hepatitis. In virus infections, sequence similarities between viral and self-proteins may trigger autoimmune processes and the simultaneous presence of inflammatory cytokines during virus infection may further increase the risk of developing self-perpetuating autoimmune reactions which overshoot.