PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
J Autoimmun. Author manuscript; available in PMC Dec 1, 2013.
Published in final edited form as:
PMCID: PMC3465484
NIHMSID: NIHMS383435
Animal Models used to Examine the Role of the Environment in the Development of Autoimmune Disease: Findings from an NIEHS Expert Panel Workshopa
Dori Germolec, PhD,b Dwight H. Kono, MD,c Jean C. Pfau, PhD,d* and K. Michael Pollard, PhDe
bNational Toxicology Program, NIEHS, 530 Davis Drive, Morrisville, NC 27560
cDepartment of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037
dDepartment of Biological Sciences, Idaho State University, 921 S. 8th Ave, Pocatello ID 83209
eDepartment of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037
*Corresponding author: Jean C. Pfau, Ph.D. Department of Biological Sciences, Idaho State University, 921 South 8th Ave, Pocatello, ID 83209. Tel: 208 282 3914, pfaujean/at/isu.edu
Autoimmunity is thought to result from a combination of genetics, environmental triggers, and stochastic events. Environmental factors, such as chemicals, drugs or infectious agents, have been implicated in the expression of autoimmune disease, yet human studies are extremely limited in their ability to test isolated exposures to demonstrate causation or to assess pathogenic mechanisms. In this review we examine the research literature on the ability of chemical, physical and biological agents to induce and/or exacerbate autoimmunity in a variety of animal models. There is no single animal model capable of mimicking the features of human autoimmune disease, particularly as related to environmental exposures. An objective, therefore, was to assess the types of information that can be gleaned from the use of animal models, and how well that information can be used to translate back to human health. Our review notes the importance of genetic background to the types and severity of the autoimmune response following exposure to environmental factors, and emphasizes literature where animal model studies have led to increased confidence about environmental factors that affect expression of autoimmunity. A high level of confidence was reached if there were multiple studies from different laboratories confirming the same findings. Examples include mercury, pristane, and infection with Streptococcus or Coxsackie B virus. A second level of consensus identified those exposures likely to influence autoimmunity but requiring further confirmation. To fit into this category, there needed to be significant supporting data, perhaps by multiple studies from a single laboratory, or repetition of some but not all findings in multiple laboratories. Examples include silica, gold, TCE, TCDD, UV radiation, and Theiler’s murine encephalomyelitis virus. With the caveat that researchers must keep in mind the limitations and appropriate applications of the various approaches, animal models are shown to be extremely valuable tools for studying the induction or exacerbation of autoimmunity by environmental conditions and exposures.
Keywords: autoimmunity, animal model, environmental factors, chemicals, biological
Environmental factors have been reported to be associated with autoimmunity in humans. However a direct link is difficult to establish because of the inherent limitations of epidemiological studies to draw causal conclusions. A link between environmental exposure and autoimmune disease is made more difficult because human populations are rarely exposed to a single agent, there can be a significant delay between exposure and disease onset, and it is often not possible to identify all the agents to which individuals may have been exposed. Medications are exceptions because exposed populations can be identified and affected individuals can cease use of the suspected agent in order to determine if consumption is the cause of disease [1, 2]. Nevertheless, induction of autoimmune disease as a result of medications has established that contact with exogenous agents can result in autoimmunity. Animal models have played a significant role in investigations into the mechanisms of drug-induced autoimmunity [35]. Thus animal models have proven to be useful surrogates for identification of exogenous factors that affect autoimmune disease in humans.
Investigation of autoimmune disease has resulted in the development of several animal model approaches. Idiopathic disease mechanisms can be examined in inbred murine strains that spontaneously develop organ specific (e.g. diabetes [6]) or systemic (e.g. lupus [7]) autoimmunity. Autoimmunity can also be induced in animals by immunization with specific (auto)antigen (e.g. EAE [8]), or genetic manipulation [9, 10]. Examination of the role of environmental factors in autoimmunity most often involves exposure of healthy inbred mice to determine if the agent can elicit disease in a non-autoimmune-prone population. However, such research is hindered by the complexity of disease susceptibility loci that may or may not be present in these mice. Thus studies have examined exposure in autoimmune-prone strains as examples of genetically sensitive populations. In this later case, exposure may exacerbate or accelerate disease expression. A list of common rodent models for studying environmental effects on autoimmunity are listed in Table 1.
Table 1
Table 1
Common Rodent Models
In 2010 the National Institutes of Environmental Health Sciences (NIEHS) convened a workshop to examine the role of the environment in the development of autoimmune disease. The authors of this report were charged with drawing conclusions regarding published data on animal models. This review is a condensed description of those deliberations and examines the roles that non-therapeutic chemical, physical and biological agents play in the induction and/or exacerbation/acceleration of autoimmunity in a variety of animal models. The more detailed and wider ranging white paper prepared following the NIEHS workshop is available from the corresponding author.
We did not examine drugs in this report because, although there is clear evidence that they can elicit autoimmune disease [11], they are most often taken under medical supervision and exposure is closely monitored and can be terminated at any time. This is often not the case with non-therapeutic chemical, physical and biological agents that humans may be exposed to during their lifetime.
Our review of the literature identified individual chemical, physical or biological factors that have been shown to either induce autoimmunity in non-autoimmune-prone strains, or exacerbate disease in inducible or spontaneous autoimmune models. Exposures for which multiple independent studies have found the same or similar results to provide confidence that the factor in question influences expression of autoimmunity are listed in Table 2. Those environmental factors where significant effects have been reported but multiple independent studies are lacking have been classified as appearing likely to affect autoimmunity but require further confirmation (Table 3). The tabulated studies should not be considered to encompass all published studies on animal exposure to any particular agent. Finally we identify several broad themes that should be pursued in future investigations to identify exogenous agents that affect expression of autoimmune disease in animals.
Table 2
Table 2
Environmental Factors that we are confident induce or exacerbate autoimmunity.
Table 3
Table 3
Chemical Factors that we believe are likely to induce or exacerbate autoimmunity but require confirmation.
2.1 Metals: Mercury, Gold, and Silver
Mercury has been implicated as an environmental trigger in the induction of autoimmunity in humans [4]. The extensive literature on mercury-induced autoimmunity in experimental animals has been recently reviewed [4, 12]. The response of non-autoimmune rats to mercury is strain specific, clearly implicated geneenvironment interactions. Implantation of dental amalgams into molars of BN rats results in a polyclonal B cell activation, elevated IgE and kidney deposition of IgG while Lewis rats are unaffected [13]. Mice also exhibit strain specific responses to mercury [12]. Susceptible strains given HgCl2 develop a polyclonal B cell activation with autoantibodies and tissue immune complex deposits [14, 15]. Exposure to mercury vapor increased serum immunoglobulins, autoantibodies and mesangial IgG deposits [16]. Dental amalgam resulted in hypergammaglobulinemia, autoantibodies and tissue immune deposits [17]. Murine mercury-induced autoimmunity is not transient as found in the rat but may last for many months [18].
Gold salts have been used to treat rheumatoid arthritis (RA), but this can lead to complications including nephropathy [19]. Therefore, animal models have been used to test the ability of gold to induce autoimmunity. The response to gold is strain-specific with BN rats developing polyclonal B cell activation, autoantibodies, increased IgE, immune complex nephritis and vasculitis, while Lewis rats show less immune activation and pathology [20, 21]. As with mercury, the humoral responses in rats are transient, peaking within the first few weeks [20, 22, 23]. Immunological responses induced by gold in mice are also strain-specific, with differences in serum immunoglobulin levels and ANA responses, and humoral responses in mice persist throughout the exposure period [24, 25].
Autoantibodies are induced in mice via exposure to silver nitrate in drinking water, subcutaneous injection, or intraperitoneal implantation of silver alloy [4]. The MHC class II restricted autoantibody response targets the nucleolar protein fibrillarin [26]. Non-MHC genes influence the response rate and titer [27]. ANA have also been reported in outbred strains exposed to silver [28] suggesting that genetically heterogeneous backgrounds are susceptible to silver-induced autoantibodies. Silver exposed mice express a limited set of autoantibodies, without immune-complex deposits [27]. Thus silver results in less aggressive features of autoimmunity than mercury [4].
2.2. Mineral oil
Constituents of mineral oil and related substances are potent proinflammatory agents and adjuvants [29]. Thus, exploration of its potential to induce autoimmune response in animal models was prudent. Intradermal injection of Freund’s incomplete adjuvant and its constituents, mineral oil and Aracel A, induces an acute T cell-dependent spontaneous inflammatory arthritis in DA rats resembling adjuvant arthritis [30, 31]. Subcutaneous injection of a component of mineral oil, 2,6,10,14-tetramethylpentadecane (TMPD or pristane) in rats leads to a chronic inflammatory arthritis, with signs similar to human RA, in certain strains [32]. Among the strains, DA is the most and E3 the least susceptible; therefore clues to susceptibility genes are provided by animal models [32].
Inflammatory arthritis is induced in BALB/c mice with i.p. injections of TMPD. Serological findings consistent with rheumatoid arthritis included rheumatoid factor and anti-collagen antibodies [33]. Similar to the rat, susceptibility in mice differed among the strains examined, with the DBA/1 being highly susceptible and developing chronic erosive arthritis 4–8 months after exposure [33, 34]. Interestingly, TMPD-treated mice also exhibit many of the clinical features of human SLE including female predominance, the expression of interferon induced genes (“interferon-signature”), anti-RNP and anti-Sm antibodies, arthritis, and glomerulonephritis [29]. Susceptibility is strain dependent, as TMPD can induce autoantibody production in most immunocompetent strains with substantial variability in the time of onset, frequency, and severity [35]. TMPD also enhances the susceptibility of spontaneous lupus-prone strains except those that are Fas-deficient [3537] suggesting that the pathogenic mechanisms of induction involve apoptosis. This example demonstrates the ability of genetic manipulation of animal models to explore mechanisms involved.
2.3 Rapeseed Oil
Exposure in 1981 to an adulterated rapeseed oil manufactured for industrial use but denatured with 2% aniline, refined and sold as cooking oil, resulted in a disease termed toxic oil syndrome (TOS) [38]. Animal models helped to establish a component involved and confirm its ability to induce a similar disease in mice. Oleic acid anilide (OAA) exposure in B10.S and C57BL/6 mice resulted in a chronic polyclonal B cell activation together with autoantibodies [39, 40] while A/J mice have an acute and lethal wasting disease [39].
2.4 L-tryptophan
The eosinophilia-myalgia syndrome (EMS) associated with L-tryptophan ingestion was first recognized in the United States in 1989. EMS is characterized by eosinophilia, myalgia, joint pain, pruritus, edema, and sclerodermoid cutaneous manifestations [41]. Initial epidemiological studies implicated L-tryptophan from a single manufacturer, but other risk factors include increased dose of L- tryptophan, increased age and use of Ltryptophan as a sleeping aid [42]. High dietary tryptophan in rats amplified some of the pathological features of eosinophilia myalgia [43]. Exposure of Lewis rats resulted in inflammation of the fascia and perimysial spaces plus increased thickness of the fascia and the perimysial septae but no evidence of eosinophilia [44]. Ltryptophan and 1,1′-ethylidenebis (L-tryptophan) (EBT), a dimer of L-tryptophan found in greater concentration in case-associated L- tryptophan, failed to reproduce the inflammation of the fascia and perimysial spaces but did result in increased fascial thickness [45]. A study in C57BL/6 mice, using daily i.p. injections of L-tryptophan and/or EBT found inflammation of the fascia, fascial thickening and fibrosis but no eosinophilia [46]. Guinea pigs orally supplemented with non-case associated L-tryptophan for 14 days had decreased blood eosinophils and increased eosinophils in bronchiolar lavage but no skin changes [47]. In this case, animal models confirmed the pathogenic potential of L-tryptophan, while the variable responses suggest a complex, multi-genic susceptibility.
2.5 Iodine
The thyroid gland is frustratingly susceptible to autoimmune pathology, and yet the reasons and mechanisms behind this are not clear. Animal model studies also paint a complex picture, but are beginning to suggest mechanistic possibilities. Numerous studies have demonstrated that high dietary intake of iodine leads to increased incidence of thyroid autoimmunity in genetically predisposed NOD.H2h4 mice [4852]. These studies have shown an increase in thyroiditis (characterized by lymphocytic infiltration) and antibodies to thyroglobulin, an iodoglycoprotein synthesized in the thyroid. Studies have indicated the presence of antithyroglobulin antibodies in mice with excess iodine may be due to increased iodination of thyroglobulin, and are able to separate disease phenotypes that are inflammatory or truly autoimmune [49, 51]. Evidence of exacerbated disease has also been observed in thyroiditis-prone BB rats follow excess dietary iodine [53]. BB/W rats injected with normal iodine content thyroglobulin showed an increased incidence of thyroiditis as opposed the rats injected with low iodine content thyroglobulin [54].
2.6 Infections
Animal models have been used to demonstrate that both genetics and infections are important in the co-morbidity of autoimmune disease and have been critical in the identification of the mechanisms and linkage with autoimmune pathology. Multiple infectious agents have been associated with autoimmune disorders that target the same tissues (i.e. streptococcus, Coxsackie B virus and Trypanosoma cruzi with myocarditis; Epstein-Barr virus (EBV) and mycoplasma with rheumatoid arthritis), and individual infectious agents have been associated with multiple autoimmune diseases (i.e. Hepatitis C virus with antiphospholipid syndrome, autoimmune hepatitis and vasculitis). The examples provided below are not all-inclusive, but rather highlight the pathogenic organisms that have been used to model some of the most common autoimmune diseases.
2.6.1. Bacterial Infections
Many features of the myocardial and vascular lesions observed in rabbits that received multiple cutaneous injections of group A streptococci [55] closely approximate the pathology observed in fatal cases of rheumatic fever [56]. While the Streptococcus organism has only rarely been isolated from affected tissues in humans, the bacterial antigens can induce myocarditis when injected into multiple strains of mice [57]. Monoclonal antibodies that recognize Streptococcal N-acetyl-glucosamine have been shown to deposit in the extracellular matrix of the myocardium in DBA/2 mice [58]. These antibodies generate T-cell dependent antibody responses that cross-react with cardiac myosin and the matrix protein laminin, resulting in inflammatory lesions in the muscle and valve endothelium [59]. Immunization with antibodies to streptococcal M protein also results in cardiomyopathy and valvular lesions in Lewis rats [6062].
Immunization of susceptible rodents with heat shock proteins (HSP) from several mycobacterium strains can lead to pathology similar to rheumatoid arthritis in humans. When housed in a strictly controlled pathogenfree (SPF) environment, these mice failed to develop chronic arthritis, suggesting that infection may be a trigger for the induction of disease [63].
2.6.2. Viral Infections
Multiple sclerosis (MS) is characterized by inflammatory demyelinization throughout the nervous system. Animal models of virally-induced demyelinating diseases have similar pathology to MS. Infection with Theiler’s murine encephalomyelitis virus (TMEV) is used as a model of experimental autoimmune encephalomyelitis (EAE) [64, 65]. An initial virus-specific T cell response targets these virally infected cells leading to a transient meningio-encephalo-myelitis that resolves in mouse strains that are not genetically susceptible [66]. In SJL and other susceptible strains, this inflammatory response leads to macrophage-mediated demyelinization due to the release of pro-inflammatory cytokines and reactive oxygen species [67].
A number of viruses have been implicated in human myocarditis. Coxsackievirus B (CVB) is considered the dominant etiological agent, and infectious virus and viral RNA have been isolated from biopsy and autopsy specimens from patients with the disease [68, 69]. Resistant mouse strains eliminate the virus after an initial acute phase and do not develop autoimmune myocarditis [69, 70]. In susceptible mouse strains there is early injury to cardiomyocytes with an acute inflammatory response [71]. During the subacute phase of the infection, autoantibodies that target the myocardial proteins such as myosin, tropomysin and actin develop, and correlate with disease severity and progression to cardiomyopathy and heart failure [68]. Mice with a cardiac-specific deletion of the Coxsackievirus–adenovirus receptor, which facilitates viral entry into cells, do not develop myocarditis [72], providing strong causative evidence.
Type 1 Diabetes (T1D) results from the destruction of pancreatic β cells by autoreactive T lymphocytes and/or inflammatory cytokines. Many viruses have been reported to be associated with T1D in humans, including CVB, rubella virus, mumps virus, cytomegalovirus, Epstein-Barr virus and rotavirus [73]. There is a strong genetic component to T1D and the most commonly used animal models for the disease, the Non-obese diabetic (NOD) mouse and the Bio-Breeding (BB) rat, develop spontaneous disease. However disease incidence and severity can be affected by the microbial environment in which the animals are housed, or by exposure to microbial stimuli and viral infection. The most compelling evidence for the role of viruses in T1D comes from studies with the encephalomyocarditis (EMC) virus in mice and the Kilham rat virus (KRV) in BB rats [74]. There is sequence homology between a Coxsackie B4 viral protein and human glutamate decarboxylase (GAD; [75]), and it has been suggested that CVB may act as a molecular mimic of the GAD and stimulate the production of anti-GAD autoantibodies.
2.6.3. Parasitic Infections
Chagas’ disease cardiomyopathy is a consequence of infection with Trypanosoma cruzi, and is a major cause of cardiovascular related death in Latin America. In the century that has passed since the description of the disease, there has been (and still remains) considerable debate with regard to whether the pathogenesis of the disease is the result of parasite persistence or the development of auto-reactivity [76, 77]. Proponents of an autoimmune etiology for the disease suggest cross-reactivity between antibodies directed at the organism and myocardial or cardiac connective tissue and autoreactive cellular immunity as potential mechanisms [78]. Several animal species including dogs, monkeys, rabbits, guinea pigs, rats and mice have been used to model the disease, and there is evidence to suggest that the genotype of both the host and parasite are important in the outcome of the disease [79]. Murine models of T. cruzi infection are frequently used to study potential autoimmunity in Chagas disease. To investigate cardiac autoimmunity in the acute phase of infection, A/J mice have been infected with the Brazil strain of T. cruzi for periods ranging from 7–30 days [80]. Twenty-one days post-infection these animals demonstrated severe myocarditis, accompanied by IgG autoantibodies and delayed type hypersensitivity responses against cardiac myosin. Similarly infected C57Bl/6 mice, previously reported to be resistant to CVB-induced cardiac autoimmunity [81], generated lower levels of myosin-specific IgG and did not develop myocarditis [80].
3.1. Silica
Autoimmune prone NZM2410 mice exposed to crystalline silica (SiO2) had increased serum autoantibodies, proteinuria and reduced survival [82, 83]. Thus, silica can exacerbate autoimmunity in a lupus model, but there is limited data regarding induction in non-autoimmune strains, with only one study demonstrating the ability of silica to induce autoimmune responses in animal models that do not normally exhibit an autoimmune phenotype. Sodium silicate (NaSiO4) exposure in Brown Norway rats resulted in increased serum autoantibodies [84]. Therefore, silica has been shown to affect the expression of autoimmunity, in terms of production of autoantibodies in both mice and rats, and other disease manifestations in mice. Now that exposure to crystalline silica has been confirmed as having a strong association with autoimmune disease in humans (Reviewed in paper by Miller, et al, in this issue), subsequent studies of silica exposure in animal models should focus on mechanisms of lost tolerance and pathogenesis, including genetic susceptibility loci. This type of data can be used to inform human studies, illustrating just one example of translational application of animal models.
3.2. Metals
Mercury exposure exacerbates the expression of systemic autoimmunity in NZBWF1, MRL-Fas+/+ and BXSB mice [8587]. Mercuric chloride exacerbated the severity and onset of arthritis in a collagen-induced model [88]. In contrast HgCl2 produced a significant reduction in insulitis and delayed diabetes in nonobese diabetic (NOD) mice; however, these mice still developed a polyclonal B cell response and deposits of IgG in the kidney [89]. Similarly, tight skinned mice (C57BL/6 Tsk1/+), an animal model of scleroderma, showed no progression of skin fibrosis but developed a polyclonal B cell response and renal IgG deposits [90]. Thus, mercury appears to not only induce autoimmunity in non-autoimmune animals (discussed above), but also to exacerbate or ameliorate various autoimmune disease models.
3.3. TCDD
Dioxins are waste contaminants of industrial processes that persist in the environment and bioaccumulate [91]. Among the dioxins, the most potent is the halogenated aromatic hydrocarbon, 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD). Epidemiological studies have implicated TCDD with a variety of generally modest immunological alterations, including immunodeficiency, but have not documented an association with autoimmune disease [9196]. However, TCDD can induce autoimmunity if exposure occurs during fetal development or the early neonatal period. A single exposure of TCDD during mid gestation was shown to slightly enhance anti-DNA antibodies and/or glomerular immune complex deposits in non-autoimmune C57BL/6 or lupus-predisposed SNF1 mice [97, 98]. Neonatal exposure of NFS/sld mice to TCDD induced a Sjögren’s syndrome-like disease along with increased anti-SS-A/Ro and anti-SS-B/La autoantibodies [99]. The extensive literature on TCDD exposure in animal models thus begins to explore the possibility of adult exacerbation of disease via pre-natal exposure.
3.4. Organochlorine pesticides
Several banned organochlorine pesticides have been shown to promote the development of autoimmunity in the lupus-prone NZBWF1 strain [100, 101]. These include o, p′-dichlorodiphenyltrichloroethane (DDT), methoxychlor, and chlordecone. Exposure to these compounds accelerated mortality in ovariectomized females, and for chlordecone, exacerbated autoantibody production, glomerular immune complex deposition, and proteinuria [101]. Chlordecone also accelerated disease in ovary-intact female NZBWF1, but did not induce lupus-like disease in the non-autoimmune BALB/c strain [100], suggesting that the mechanism of action only exacerbates an already existing autoimmune disease.
3.5. Trichloroethylene (TCE)
Trichloroethylene (TCE) is an industrial solvent used in metal cleaning and degreasing and has been found to contaminate ground water. Studies on the induction and/or exacerbation of autoimmunity in humans and experimental animals by TCE and derivatives has been recently reviewed [102]. Using adult autoimmune prone MRL-Fas+/+ mice studies have demonstrated an accelerated autoimmune response including increased autoantibodies, T cell activation and inflammatory cytokines [103106] following TCE exposure via different routes and a wide range of doses. Various metabolites of TCE, including dichloroacetyl chloride [104], trichloroacetaldehyde hydrate [107, 108] and trichloroacetic acid [107] produced similar results in MRL-Fas+/+ mice as TCE. Interestingly, MRL-Fas+/+ mice exposed to TCE from conception to adulthood had evidence of accelerated autoimmunity [109] as did those exposed from gestation day 1 to 6 weeks of age [110]. Therefore, as with TCDD, animal models provide data that suggest that early exposures may be very important in subsequent development of disease, and emphasize developmental effects of exposures on the young immune system.
3.6. UV radiation
Photosensitivity contributes to human autoimmune diseases, including cutaneous lupus erythematosus (CLE) [111]. Acute or chronic doses of UV radiation (UVA and UVB) increased mortality in male lupus-prone BXSB mice but not other lupus-prone strains including MRL-Faslpr and NZBWF1 strains [112]. The increased mortality was associated with autoantibodies and glomerulonephritis and was a direct result of UVB (320–290nm) radiation.
Menke et al [113] found that UVB exposure increased skin lesions and levels of colony stimulating factor-1 (CSF-1) in MRL-Faslpr mice but not in CFS-1 deficient MRL-Faslpr mice (MRL-Faslpr/csf1−/−) or BALB/c mice. In the MRL-Faslpr or MRL-Faslpr/csf1−/− mice reconstituted with CSF-1, UVB was able to trigger an increase of macrophages in the skin and an increase in keratinocyte apoptosis, which led to an increase in CLE. Both CLE and nephritis in MRL-Faslpr mice requires the presence of CSF-1, and UVB accelerates onset of these lupus phenotypes by enhancing the production of CSF-1 and apoptotic keratinocytes. Dermal fibroblasts from lupusprone strains (MRL-Faslpr and NZBWF1) upon exposure to UVB produce more proinflammatory cytokines (IL-1β, IL-6 and TNFα) than C57BL/6 or BALB/c mice, which may relate to the increase in cell damage and enhanced autoimmunity [114].
3.7. Gluten
Celiac disease (CD) is the result of lost tolerance to grain gluten, mediated by activated CD4+ T cells specific for peptides of gliadins presented on MHC Class II. Certain animals are particularly susceptible to gluten intolerance, including Irish Setters [115] and BALB/c mice [116]. In addition, strains susceptible to other endocrine-immune diseases, such as BB rats and NOD mice, also appear susceptible to CD, and in fact a diet containing gluten increases the incidence of diabetes in NOD mice in addition to small intestinal enteropathy [117]. A relatively new model is the gluten-sensitive HLA-DQ8 transgenic mouse. Loss of gluten tolerance appears to occur in the presence of gluten peptides bound to HLA-DQ2 or DQ8. This mouse strain is therefore susceptible to CD [118]. Animal models are thus providing new evidence of gene susceptibility that may translate to our understanding of human susceptibility to this disease.
Two levels of consensus were identified. A high level of confidence was reached if there were multiple studies from different laboratories confirming the same findings. Any studies with data contrary to the majority were only excluded if there was evidence that the study and/or its interpretation were faulty. A second level of consensus identified those exposures considered likely to influence autoimmunity but requiring further confirmation. To fit into this category there needed to be significant supporting data, perhaps by multiple studies from a single laboratory, or repetition of some but not all findings in multiple laboratories.
4.1. Based on existing evidence, we are confident of the following, with supporting studies listed in Table 2
  • Forms of inorganic mercury induce systemic autoimmune disease in rats (transient) and mice, and exacerbates systemic autoimmune disease in lupus-prone mice.
  • Several mineral oil components and certain other hydrocarbons can induced an acute inflammatory arthritis in some rat strains.
  • The mineral oil component 2,6,10,14-tetramethylpentadecane (TMPD or pristane) can induce chronic lupus like disease and inflammatory arthritis in several strains of mice.
  • For a limited number of pathogens, there is a clear association between infection and the development of specific autoimmune diseases.
  • Excess iodine increases the incidence of autoimmune thyroiditis in genetically predisposed animal models.
4.2. Based on existing evidence, we consider the following likely but requiring conformation (Supporting studies listed in Table 3)
  • Gold causes (transient) nephropathy in rats. Gold and silver cause autoimmune responses, not autoimmune disease, in mice; but the ability of silver and gold to exacerbate spontaneous autoimmune disease requires study.
  • Silica exacerbates autoimmune disease but more studies are needed using more species/strains and a wider range of doses and exposure routes.
  • Trichloroethylene (TCE) exacerbates systemic autoimmunity although responses are often limited and transient. More studies are needed with additional species/strains to examine induction of autoimmune liver disease and in developmental studies.
  • There is some indication that TCDD can promote autoimmunity when exposure occurs during fetal or early neonatal development.
  • Organochlorine pesticides have been reported to enhance lupus-like disease in a predisposed mouse strain.
  • UV radiation exacerbates lupus in genetically prone mice.
4.3. We believe the following broad themes should be pursued in future investigations
Based upon the literature review and discussion points raised during the NIEHS Expert Panel Workshop to Examine the Role of the Environment in the Development of Autoimmune Disease a number of broad themes were identified to be worthy of further study and/or consideration by investigators.
  • Responses of animals to environmental exposure should not be the only driving force for human studies. Studies should be “shaped by what is observed in humans, not by what is possible in mice” [119].
  • A single mouse strain is clearly unable to encompass the heterogeneity of the human population. Thus studies should not be restricted to the identification and/or use of a “gold standard” animal model. Rather models should be investigated that best reflect human genetic heterogeneity, and/or ask specific mechanistic questions that a particular model is able to address.
  • When using spontaneous disease models it is important to consider whether environmental exposures directly impacts idiopathic autoimmunity, or reflects environmental factor-specific autoimmunity.
  • More studies on the effects of environmental factor exposure on expression of autoimmunity during different stages of life (gestational to adulthood) are needed.
4.4. General Conclusions
Our survey of the literature clearly shows that an autoimmune response following exposure to environmental factors is dependent upon genetic background of the host and can vary widely among species and strains. Our review also revealed that most animal models only recapitulate some features of human disease but that this provides useful information given the genetic heterogeneity of individual human autoimmune diseases. It is also clear that to establish the validity of any animal model of environmentally induced human autoimmunity there should be well defined markers of disease expression and pathology that are easily accessible in biological samples of both humans and the animals under investigation. We also believe that it is important that a catalog of animal models, along with their characteristics, be established to help investigators identify the most appropriate strains and/or species for their studies. The strength of animal models lies not only in the genetic homogeneity of inbred stains but also the ability to control experimental conditions.
Research Highlights
  • Responses following environmental exposures in animals depend on genetic background.
  • Animal models have enough features of human disease to provide useful information.
  • Strengths of animal models: genetic homogeneity and control of experimental design.
  • Animal models provide strong data linking certain exposures to autoimmune disease.
  • Other exposures likely impact autoimmunity, but require confirmation.
Acknowledgments
This review is a condensed version of a white paper prepared following the National Institute of Environmental Health Sciences (NIEHS) Expert Panel Workshop to Examine the Role of the Environment in the Development of Autoimmune Disease held in Durham, North Carolina, USA on September 7–8, 2010. The more detailed and wider ranging workshop white paper, including agents that suppress autoimmunity, is available from the corresponding author. The Authors gratefully acknowledge the contributions of the following individuals in compiling the literature review: Ryan Marcum (Idaho State University), Sarah Briwa (Siena College), Sang-Hyun Kim PhD (NIEHS), David A. Lawrence PhD (Wadsworth Center), and Michael McCabe Jr., PhD (Robson Forensic, Inc). Support was provided by the NIEHS, and the American Autoimmune Related Diseases Association, East Detroit, Michigan, USA.
Footnotes
aAuthors are listed alphabetically
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1. Dedeoglu F. Drug-induced autoimmunity. Curr Opin Rheumatol. 2009;21:547–51. [PubMed]
2. Vedove CD, Del Giglio M, Schena D, Girolomoni G. Drug-induced lupus erythematosus. Arch Dermatol Res. 2009;301:99–105. [PubMed]
3. Rubin RL, Kretz-Rommel A. A nondeletional mechanism for central T-cell tolerance. Crit Rev Immunol. 2001;21:29–40. [PubMed]
4. Pollard KM, Hultman P, Kono DH. Toxicology of autoimmune diseases. Chem Res Toxicol. 2010;23:455– 66. [PMC free article] [PubMed]
5. Richardson B. DNA methylation and autoimmune disease. Clin Immunol. 2003;109:72–9. [PubMed]
6. Roep BO, Atkinson M, von Herrath M. Satisfaction (not) guaranteed: re-evaluating the use of animal models of type 1 diabetes. Nat Rev Immunol. 2004;4:989–97. [PubMed]
7. Kono DH, Theofilopoulos AN. Genetics of SLE in mice. Springer Semin Immunopathol. 2006;28:83–96. [PubMed]
8. Andersson A, Karlsson J. Genetics of experimental autoimmune encephalomyelitis in the mouse. Arch Immunol Ther Exp (Warsz) 2004;52:316–25. [PubMed]
9. Cohen PL, Caricchio R, Abraham V, Camenisch TD, Jennette JC, Roubey RA, Earp HS, Matsushima G, Reap EA. Delayed apoptotic cell clearance and lupus-like autoimmunity in mice lacking the c-mer membrane tyrosine kinase. J Exp Med. 2002;196:135–40. [PMC free article] [PubMed]
10. Seery JP. IFN-gamma transgenic mice: clues to the pathogenesis of systemic lupus erythematosus? Arthritis Res. 2000;2:437–440. [PMC free article] [PubMed]
11. Rubin RL. Drug-induced lupus. Toxicology. 2005;209:135–47. [PubMed]
12. Vas J, Monestier M. Immunology of mercury. Ann N Y Acad Sci. 2008;1143:240–67. [PubMed]
13. Hultman P, Lindh U, Horsted-Bindslev P. Activation of the immune system and systemic immunecomplex deposits in Brown Norway rats with dental amalgam restorations. J Dent Res. 1998;77:1415–25. [PubMed]
14. Abedi-Valugerdi M, Hansson M, Moller G. Genetic control of resistance to mercury-induced immune/autoimmune activation. Scand J Immunol. 2001;54:190–7. [PubMed]
15. 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]
16. 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]
17. 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]
18. 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]
19. Lockie LM, Smith DM. Forty-seven years experience with gold therapy in 1,019 rheumatoid arthritis patients. Semin Arthritis Rheum. 1985;14:238–46. [PubMed]
20. Tournade H, Guery JC, Pasquier R, Nochy D, Hinglais N, Guilbert B, Druet P, Pelletier L. Experimental gold-induced autoimmunity. Nephrol Dial Transplant. 1991;6:621–30. [PubMed]
21. Qasim FJ, Thiru S, Gillespie K. Gold and D-penicillamine induce vasculitis and up-regulate mRNA for IL-4 in the Brown Norway rat: support for a role for Th2 cell activity. Clin Exp Immunol. 1997;108:438–45. [PubMed]
22. Savignac M, Badou A, Delmas C, Subra JF, De Cramer S, Paulet P, Cassar G, Druet P, Saoudi A, Pelletier L. Gold is a T cell polyclonal activator in BN and LEW rats but favors IL-4 expression only in autoimmune prone BN rats. Eur J Immunol. 2001;31:2266–76. [PubMed]
23. Tournade H, Guery JC, Pasquier R, Vial MC, Mandet C, Druet E, Dansette PM, Druet P, Pelletier L. Effect of the thiol group on experimental gold-induced autoimmunity. Arthritis Rheum. 1991;34:1594–9. [PubMed]
24. Pietsch P, Vohr HW, Degitz K, Gleichmann E. Immunological alterations inducible by mercury compounds. II. HgCl2 and gold sodium thiomalate enhance serum IgE and IgG concentrations in susceptible mouse strains. Int Arch Allergy Appl Immunol. 1989;90:47–53. [PubMed]
25. 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]
26. Hansson M, Abedi-Valugerdi M. Xenobiotic metal-induced autoimmunity: mercury and silver differentially induce antinucleolar autoantibody production in susceptible H-2s, H-2q and H-2f mice. Clin Exp Immunol. 2003;131:405–14. [PubMed]
27. Hultman P, Ganowiak K, Turley SJ, Pollard KM. Genetic susceptibility to silver-induced anti-fibrillarin autoantibodies in mice. Clin Immunol Immunopathol. 1995;77:291–7. [PubMed]
28. Abedi-Valugerdi M. Mercury and silver induce B cell activation and anti-nucleolar autoantibody production in outbred mouse stocks: are environmental factors more important than the susceptibility genes in connection with autoimmunity? Clin Exp Immunol. 2009;155:117–24. [PubMed]
29. 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. [PMC free article] [PubMed]
30. Holmdahl R, Lorentzen JC, Lu S, Olofsson P, Wester L, Holmberg J, Pettersson U. Arthritis induced in rats with nonimmunogenic adjuvants as models for rheumatoid arthritis. Immunol Rev. 2001;184:184–202. [PubMed]
31. Kleinau S, Erlandsson H, Holmdahl R, Klareskog L. Adjuvant oils induce arthritis in the DA rat. I. Characterization of the disease and evidence for an immunological involvement. J Autoimmun. 1991;4:871–80. [PubMed]
32. Olofsson P, Holmdahl R. Pristane-induced arthritis in the rat. Methods Mol Med. 2007;136:255–68. [PubMed]
33. Wooley PH, Seibold JR, Whalen JD, Chapdelaine JM. Pristane-induced arthritis. The immunologic and genetic features of an experimental murine model of autoimmune disease. Arthritis Rheum. 1989;32:1022–30. [PubMed]
34. Clynes R, Calvani N, Croker BP, Richards HB. Modulation of the immune response in pristane-induced lupus by expression of activation and inhibitory Fc receptors. Clin Exp Immunol. 2005;141:230–7. [PubMed]
35. Satoh M, Richards HB, Shaheen VM, Yoshida H, Shaw M, Naim JO, Wooley PH, Reeves WH. Widespread susceptibility among inbred mouse strains to the induction of lupus autoantibodies by pristane. Clin Exp Immunol. 2000;121:399–405. [PubMed]
36. 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. [PMC free article] [PubMed]
37. 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]
38. Pestana A, Munoz E. Anilides and the Spanish toxic oil syndrome. Nature. 1982;298:608. [PubMed]
39. 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]
40. 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]
41. Clauw DJ. Animal models of the eosinophilia-myalgia syndrome. J Rheumatol Suppl. 1996;46:93–7. discussion 92, 97–8. [PubMed]
42. Okada S, Kamb ML, Pandey JP, Philen RM, Love LA, Miller FW. Immunogenetic risk and protective factors for the development of L-tryptophan-associated eosinophilia-myalgia syndrome and associated symptoms. Arthritis Rheum. 2009;61:1305–11. [PMC free article] [PubMed]
43. Gross B, Ronen N, Honigman S, Livne E. Tryptophan toxicity--time and dose response in rats. Adv Exp Med Biol. 1999;467:507–16. [PubMed]
44. Crofford LJ, Rader JI, Dalakas MC, Hill RH, Jr, Page SW, Needham LL, Brady LS, Heyes MP, Wilder RL, Gold PW, et al. L-tryptophan implicated in human eosinophilia-myalgia syndrome causes fasciitis and perimyositis in the Lewis rat. J Clin Invest. 1990;86:1757–63. [PMC free article] [PubMed]
45. Love LA, Rader JI, Crofford LJ, Raybourne RB, Principato MA, Page SW, Trucksess MW, Smith MJ, Dugan EM, Turner ML, et al. Pathological and immunological effects of ingesting L-tryptophan and 1,1′-ethylidenebis (L-tryptophan) in Lewis rats. J Clin Invest. 1993;91:804–11. [PMC free article] [PubMed]
46. Silver RM, Ludwicka A, Hampton M, Ohba T, Bingel SA, Smith T, Harley RA, Maize J, Heyes MP. A murine model of the eosinophilia-myalgia syndrome induced by 1,1′-ethylidenebis (L-tryptophan) J Clin Invest. 1994;93:1473–80. [PMC free article] [PubMed]
47. Stahl JL, Cook EB, Pariza MA, Cook ME, Graziano FM. Effect of L-tryptophan supplementation on eosinophils and eotaxin in guinea pigs. Exp Biol Med (Maywood) 2001;226:177–84. [PubMed]
48. Teng X, Shan Z, Teng W, Fan C, Wang H, Guo R. Experimental study on the effects of chronic iodine excess on thyroid function, structure, and autoimmunity in autoimmune-prone NOD. H-2h4 mice Clin Exp Med. 2009;9:51–9. [PubMed]
49. McLachlan SM, Braley-Mullen H, Chen CR, Aliesky H, Pichurin PN, Rapoport B. Dissociation between iodide-induced thyroiditis and antibody-mediated hyperthyroidism in NOD. H-2h4 mice Endocrinology. 2005;146:294–300. [PubMed]
50. Braley-Mullen H, Sharp GC, Medling B, Tang H. Spontaneous autoimmune thyroiditis in NOD. H-2h4 mice J Autoimmun. 1999;12:157–65. [PubMed]
51. 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]
52. Rasooly L, Burek CL, Rose NR. Iodine-induced autoimmune thyroiditis in NOD-H-2h4 mice. Clin Immunol Immunopathol. 1996;81:287–92. [PubMed]
53. Mooij P, de Wit HJ, Drexhage HA. An excess of dietary iodine accelerates the development of a thyroidassociated lymphoid tissue in autoimmune prone BB rats. Clin Immunol Immunopathol. 1993;69:189– 98. [PubMed]
54. Ebner SA, Lueprasitsakul W, Alex S, Fang SL, Appel MC, Braverman LE. Iodine content of rat thyroglobulin affects its antigenicity in inducing lymphocytic thyroiditis in the BB/Wor rat. Autoimmunity. 1992;13:209–14. [PubMed]
55. Murphy GE, Swift HF. Induction of cardiac lesions, closely resembling those of rheumatic fever, in rabbits following repeated skin infections with group A streptococci. J Exp Med. 1949;89:687–98. [PMC free article] [PubMed]
56. Murphy GE, Swift HF. The induction of rheumatic-like cardiac lesions in rabbits by repeated focal infections with group A streptococci; comparison with the cardiac lesions of serum disease. J Exp Med. 1950;91:485–98. [PMC free article] [PubMed]
57. Cunningham MW. Streptococcus-induced myocarditis in mice. Autoimmunity. 2001;34:193–7. [PubMed]
58. Liao L, Sindhwani R, Rojkind M, Factor S, Leinwand L, Diamond B. Antibody-mediated autoimmune myocarditis depends on genetically determined target organ sensitivity. J Exp Med. 1995;181:1123–31. [PMC free article] [PubMed]
59. Malkiel S, Liao L, Cunningham MW, Diamond B. T-Cell-dependent antibody response to the dominant epitope of streptococcal polysaccharide, N-acetyl-glucosamine, is cross-reactive with cardiac myosin. Infect Immun. 2000;68:5803–8. [PMC free article] [PubMed]
60. Quinn A, Kosanke S, Fischetti VA, Factor SM, Cunningham MW. Induction of autoimmune valvular heart disease by recombinant streptococcal m protein. Infect Immun. 2001;69:4072–8. [PMC free article] [PubMed]
61. Li Y, Heuser JS, Cunningham LC, Kosanke SD, Cunningham MW. Mimicry and antibody-mediated cell signaling in autoimmune myocarditis. J Immunol. 2006;177:8234–40. [PubMed]
62. Gorton D, Govan B, Olive C, Ketheesan N. B- and T-cell responses in group a streptococcus M-protein- or Peptide-induced experimental carditis. Infect Immun. 2009;77:2177–83. [PMC free article] [PubMed]
63. Yoshitomi H, Sakaguchi N, Kobayashi K, Brown GD, Tagami T, Sakihama T, Hirota K, Tanaka S, Nomura T, Miki I, et al. A role for fungal {beta}-glucans and their receptor Dectin-1 in the induction of autoimmune arthritis in genetically susceptible mice. J Exp Med. 2005;201:949–60. [PMC free article] [PubMed]
64. Pordeus V, Szyper-Kravitz M, Levy RA, Vaz NM, Shoenfeld Y. Infections and autoimmunity: a panorama. Clin Rev Allergy Immunol. 2008;34:283–99. [PubMed]
65. Mohindru M, Kang B, Kim BS. Initial capsid-specific CD4(+) T cell responses protect against Theiler’s murine encephalomyelitisvirus-induced demyelinating disease. Eur J Immunol. 2006;36:2106–15. [PubMed]
66. Denic A, Johnson AJ, Bieber AJ, Warrington AE, Rodriguez M, Pirko I. The relevance of animal models in multiple sclerosis research. Pathophysiology. 2010 [PubMed]
67. Pope JG, Karpus WJ, VanderLugt C, Miller SD. Flow cytometric and functional analyses of central nervous system-infiltrating cells in SJL/J mice with Theiler’s virus-induced demyelinating disease. Evidence for a CD4+ T cell-mediated pathology. J Immunol. 1996;156:4050–8. [PubMed]
68. Rose NR. Myocarditis: infection versus autoimmunity. J Clin Immunol. 2009;29:730–7. [PubMed]
69. Esfandiarei M, McManus BM. Molecular biology and pathogenesis of viral myocarditis. Annu Rev Pathol. 2008;3:127–55. [PubMed]
70. Wolfgram LJ, Beisel KW, Herskowitz A, Rose NR. Variations in the susceptibility to Coxsackievirus B3- induced myocarditis among different strains of mice. J Immunol. 1986;136:1846–52. [PubMed]
71. McManus BM, Chow LH, Wilson JE, Anderson DR, Gulizia JM, Gauntt CJ, Klingel KE, Beisel KW, Kandolf R. Direct myocardial injury by enterovirus: a central role in the evolution of murine myocarditis. Clin Immunol Immunopathol. 1993;68:159–69. [PubMed]
72. Shi Y, Chen C, Lisewski U, Wrackmeyer U, Radke M, Westermann D, Sauter M, Tschope C, Poller W, Klingel K, et al. Cardiac deletion of the Coxsackievirus-adenovirus receptor abolishes Coxsackievirus B3 infection and prevents myocarditis in vivo. J Am Coll Cardiol. 2009;53:1219–26. [PubMed]
73. Jun HS, Yoon JW. A new look at viruses in type 1 diabetes. Diabetes Metab Res Rev. 2003;19:8–31. [PubMed]
74. Yoon JW, Jun HS. Viruses cause type 1 diabetes in animals. Ann N Y Acad Sci. 2006;1079:138–46. [PubMed]
75. Atkinson MA, Bowman MA, Campbell L, Darrow BL, Kaufman DL, Maclaren NK. Cellular immunity to a determinant common to glutamate decarboxylase and coxsackie virus in insulin-dependent diabetes. J Clin Invest. 1994;94:2125–9. [PMC free article] [PubMed]
76. Tarleton RL, Reithinger R, Urbina JA, Kitron U, Gurtler RE. The challenges of Chagas Disease-- grim outlook or glimmer of hope. PLoS Med. 2007;4:e332. [PMC free article] [PubMed]
77. Kierszenbaum F. Where do we stand on the autoimmunity hypothesis of Chagas disease? Trends Parasitol. 2005;21:513–6. [PubMed]
78. Cunha-Neto E, Bilate AM, Hyland KV, Fonseca SG, Kalil J, Engman DM. Induction of cardiac autoimmunity in Chagas heart disease: a case for molecular mimicry. Autoimmunity. 2006;39:41–54. [PubMed]
79. Andersson J, Orn A, Sunnemark D. Chronic murine Chagas’ disease: the impact of host and parasite genotypes. Immunol Lett. 2003;86:207–12. [PubMed]
80. Leon JS, Godsel LM, Wang K, Engman DM. Cardiac myosin autoimmunity in acute Chagas’ heart disease. Infect Immun. 2001;69:5643–9. [PMC free article] [PubMed]
81. Traystman MD, Beisel KW. Genetic control of Coxsackievirus B3-induced heart-specific autoantibodies associated with chronic myocarditis. Clin Exp Immunol. 1991;86:291–8. [PubMed]
82. 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]
83. 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]
84. Al-Mogairen SM. Role of sodium silicate in induction of scleroderma-related autoantibodies in brown Norway rats through oral and subcutaneous administration. Rheumatol Int. 2011;31:611–5. [PubMed]
85. al-Balaghi S, Moller E, Moller G, Abedi-Valugerdi M. Mercury induces polyclonal B cell activation, autoantibody production and renal immune complex deposits in young (NZB x NZW)F1 hybrids. Eur J Immunol. 1996;26:1519–26. [PubMed]
86. 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. [PMC free article] [PubMed]
87. 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. [PMC free article] [PubMed]
88. Hansson M, Djerbi M, Rabbani H, Mellstedt H, Gharibdoost F, Hassan M, Depierre JW, Abedi-Valugerdi M. Exposure to mercuric chloride during the induction phase and after the onset of collagen-induced arthritis enhances immune/autoimmune responses and exacerbates the disease in DBA/1 mice. Immunology. 2005;114:428–37. [PubMed]
89. Brenden N, Rabbani H, Abedi-Valugerdi M. Analysis of mercury-induced immune activation in nonobese diabetic (NOD) mice. Clin Exp Immunol. 2001;125:202–10. [PubMed]
90. Hansson M, Abedi-Valugerdi M. Mercuric chloride induces a strong immune activation, but does not accelerate the development of dermal fibrosis in tight skin 1 mice. Scand J Immunol. 2004;59:469–77. [PubMed]
91. Schecter A, Birnbaum L, Ryan JJ, Constable JD. Dioxins: an overview. Environ Res. 2006;101:419–28. [PubMed]
92. 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]
93. 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. [PMC free article] [PubMed]
94. 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. [PMC free article] [PubMed]
95. 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]
96. 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. [PMC free article] [PubMed]
97. Holladay SD, Mustafa A, Gogal RM., Jr Prenatal TCDD in mice increases adult autoimmunity. Reprod Toxicol. 2011;31:312–8. [PMC free article] [PubMed]
98. Mustafa A, Holladay SD, Witonsky S, Sponenberg DP, Karpuzoglu E, Gogal RM., Jr A single mid-gestation exposure to TCDD yields a postnatal autoimmune signature, differing by sex, in early geriatric C57BL/6 mice. Toxicology. 2011 [PMC free article] [PubMed]
99. Ishimaru N, Takagi A, Kohashi M, Yamada A, Arakaki R, Kanno J, Hayashi Y. Neonatal exposure to lowdose 2,3,7,8-tetrachlorodibenzo-p-dioxin causes autoimmunity due to the disruption of T cell tolerance. J Immunol. 2009;182:6576–86. [PubMed]
100. Sobel ES, Wang F, Butfiloski E, Croker B, Roberts SM. Comparison of chlordecone effects on autoimmunity in (NZBxNZW) F(1) and BALB/c mice. Toxicology. 2006;218:81–9. [PubMed]
101. 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. [PMC free article] [PubMed]
102. 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. [PMC free article] [PubMed]
103. Griffin JM, Blossom SJ, Jackson SK, Gilbert KM, Pumford NR. Trichloroethylene accelerates an autoimmune response by Th1 T cell activation in MRL +/+ mice. Immunopharmacology. 2000;46:123–37. [PubMed]
104. Khan MF, Kaphalia BS, Prabhakar BS, Kanz MF, Ansari GA. Trichloroethene-induced autoimmune response in female MRL +/+ mice. Toxicol Appl Pharmacol. 1995;134:155–60. [PubMed]
105. Griffin JM, Gilbert KM, Pumford NR. Inhibition of CYP2E1 reverses CD4+ T-cell alterations in trichloroethylene-treated MRL+/+ mice. Toxicol Sci. 2000;54:384–9. [PubMed]
106. Griffin JM, Gilbert KM, Lamps LW, Pumford NR. CD4(+) T-cell activation and induction of autoimmune hepatitis following trichloroethylene treatment in MRL+/+ mice. Toxicol Sci. 2000;57:345–52. [PubMed]
107. Blossom SJ, Pumford NR, Gilbert KM. Activation and attenuation of apoptosis of CD4+ T cells following in vivo exposure to two common environmental toxicants, trichloroacetaldehyde hydrate and trichloroacetic acid. J Autoimmun. 2004;23:211–20. [PubMed]
108. Blossom SJ, Doss JC, Gilbert KM. Chronic exposure to a trichloroethylene metabolite in autoimmuneprone MRL+/+ mice promotes immune modulation and alopecia. Toxicol Sci. 2007;95:401–11. [PubMed]
109. 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]
110. Blossom SJ, Doss JC, Hennings LJ, Jernigan S, Melnyk S, James SJ. Developmental exposure to trichloroethylene promotes CD4+ T cell differentiation and hyperactivity in association with oxidative stress and neurobehavioral deficits in MRL+/+ mice. Toxicol Appl Pharmacol. 2008;231:344–53. [PubMed]
111. Werth VP. Cutaneous lupus: insights into pathogenesis and disease classification. Bull NYU Hosp Jt Dis. 2007;65:200–4. [PubMed]
112. Ansel JC, Mountz J, Steinberg AD, DeFabo E, Green I. Effects of UV radiation on autoimmune strains of mice: increased mortality and accelerated autoimmunity in BXSB male mice. J Invest Dermatol. 1985;85:181–6. [PubMed]
113. Menke J, Hsu MY, Byrne KT, Lucas JA, Rabacal WA, Croker BP, Zong XH, Stanley ER, Kelley VR. Sunlight triggers cutaneous lupus through a CSF-1-dependent mechanism in MRL-Fas(lpr) mice. J Immunol. 2008;181:7367–79. [PMC free article] [PubMed]
114. Foltyn VN, Golan TD. In vitro ultraviolet irradiation induces pro-inflammatory responses in cells from premorbid SLE mice. Lupus. 2001;10:272–83. [PubMed]
115. Garden OA, Pidduck H, Lakhani KH, Walker D, Wood JL, Batt RM. Inheritance of gluten-sensitive enteropathy in Irish Setters. Am J Vet Res. 2000;61:462–8. [PubMed]
116. Bodinier M, Leroy M, Ah-Leung S, Blanc F, Tranquet O, Denery-Papini S, Wal JM, Adel-Patient K. Sensitization and elicitation of an allergic reaction to wheat gliadins in mice. J Agric Food Chem. 2009;57:1219–25. [PubMed]
117. Maurano F, Mazzarella G, Luongo D, Stefanile R, D’Arienzo R, Rossi M, Auricchio S, Troncone R. Small intestinal enteropathy in non-obese diabetic mice fed a diet containing wheat. Diabetologia. 2005;48:931–7. [PubMed]
118. Verdu EF, Huang X, Natividad J, Lu J, Blennerhassett PA, David CS, McKay DM, Murray JA. Gliadindependent neuromuscular and epithelial secretory responses in gluten-sensitive HLA-DQ8 transgenic mice. Am J Physiol Gastrointest Liver Physiol. 2008;294:G217–25. [PubMed]
119. von Herrath M, Nepom GT. Animal models of human type 1 diabetes. Nat Immunol. 2009;10:129–32. [PubMed]