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Requirements for innate immune pathways in environmentally induced autoimmunity

BMC Medicine volume 11, Article number: 100 (2013) Cite this article

Abstract

There is substantial evidence that environmental triggers in combination with genetic and stochastic factors play an important role in spontaneous autoimmune disease. Although the specific environmental agents and how they promote autoimmunity remain largely unknown, in part because of diverse etiologies, environmentally induced autoimmune models can provide insights into potential mechanisms. Studies of idiopathic and environmentally induced systemic autoimmunity show that they are mediated by common adaptive immune response genes. By contrast, although the innate immune system is indispensable for autoimmunity, there are clear differences in the molecular and cellular innate components that mediate specific systemic autoimmune diseases, suggesting distinct autoimmune-promoting pathways. Some of these differences may be related to the bifurcation of toll-like receptor signaling that distinguishes interferon regulatory factor 7-mediated type I interferon production from nuclear factor-κB-driven proinflammatory cytokine expression. Accordingly, idiopathic and pristane-induced systemic autoimmunity require both type I interferon and proinflammatory cytokines whereas the less aggressive mercury-induced autoimmunity, although dependent on nucleic acid-binding toll-like receptors, does not require type I interferon but needs proinflammatory cytokines. Scavenger receptors and the inflammasome may contribute to silica-induced autoimmunity. Greater understanding of the innate mechanisms responsible for idiopathic and environmentally induced autoimmunity should yield new information into the processes that instigate and drive systemic autoimmunity.

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Review

Immunity requires contributions from both the innate and adaptive arms of the immune system. The innate component, found in all classes of plant and animal life, is hard-wired to recognize and respond rapidly to pathogens, but does not confer long-lasting or protective immunity [1]. In mammals, it is essential for the activation of the evolutionarily younger adaptive immune response [2], which, unlike the innate system, can be modified to generate highly specific antibodies and T cells capable of targeting virtually all foreign antigens. Adaptive immunity also mediates immunological memory, which facilitates faster, more effective responses to previously encountered antigens. Under normal circumstances, the immune system protects against infectious organisms, requiring it to distinguish foreign agents, including viruses, bacteria, fungi and parasites, from the host's healthy tissues. Failure to distinguish foreign from host, however, can result in the development of autoimmune diseases, including organ-specific disease with restricted tissue involvement, such as multiple sclerosis and type I diabetes, or more systemic involvement such as systemic lupus erythematosus (SLE). For most idiopathic autoimmune diseases, components of both the innate and adaptive immune responses are needed [3–5]. To varying extents, environmental factors also contribute to the development of autoimmunity. However, although idiopathic and environmentally induced systemic autoimmunity share common requirements [6, 7], it is becoming clear that differences exist [8]. In this review we compare and contrast the innate immune system requirements for idiopathic systemic autoimmunity with systemic autoimmunity induced by exposure to mercury and pristane. We also discuss the innate immune components in silica-induced inflammatory responses that may contribute to silica-induced autoimmunity.

Innate immunity

The innate immune response provides an immediate response to infection and injury and is mainly mediated by circulating factors and non-lymphocytic cell types that include macrophages, dendritic cells (DCs), neutrophils and other less common leukocytes. Surveillance mechanisms involve secreted, cell surface and intracellular pattern recognition receptors, such as toll-like receptors (TLRs), NOD-like receptors and RIG-I-like receptors [4, 9]. Pattern recognition receptors respond not only to pathogen-associated molecular patterns, including bacterial and viral nucleic acids, lipoproteins and carbohydrates, but also to host-derived damage-associated molecular patterns such as ATP, high-mobility group box 1 and self-DNA. The recognition by pattern recognition receptors of these pathogen-associated molecular patterns and/or damage-associated molecular patterns results in cell signaling and activation of transcription factors such as NF-κB and IFN regulatory factors (IRFs) [10]. The resulting gene expression includes cytokines and chemokines, leading to inflammatory cell recruitment and activation, and expression of co-stimulatory molecules crucial for the induction of adaptive immunity [2].

Innate immunity in idiopathic systemic autoimmunity

Systemic autoimmunity is thought to result from a mix of genetics, environmental factors and stochastic events [6]. Given the multitude of susceptibility genes, symptoms and immunological abnormalities, it is clear that numerous pathogenic pathways contribute to systemic autoimmune disease [5, 11, 12]. A major thrust of systemic autoimmunity research has centered on elucidation of abnormalities in the adaptive immune response [13, 14]. However more recent research has identified the innate immune response as a major player in the initiation and expansion of systemic autoimmune pathology [4, 5, 9, 15, 16].

The current paradigm for the disease process of idiopathic systemic lupus-like autoimmunity argues for a central role of type I IFN [15, 17, 18]. This is based on the early observation of increased expression of IFN-α inducible genes (or IFN signature) in the peripheral blood cells of patients with SLE [17]. The type I IFN signature is found in 60% to 70% of patients with SLE, dermatomyositis, polymyositis or systemic sclerosis [19] but less frequently in patients with rheumatoid arthritis or multiple sclerosis [20]. The central role of type I IFN in SLE places special focus on the role of cells of the innate immune system, especially DCs [9, 15, 21]. DCs can be divided into three categories, conventional, plasmacytoid (pDC) and monocyte-derived [22]. DCs act as antigen presenting cells, are migratory and can control T cell responses [23]. Upon stimulation, pDCs produce large amounts of type I IFN in humans and mice and they are considered the main source of type I IFN in systemic autoimmunity [24]. Deletion of DCs, including pDCs, in lupus-prone MRL-Fas lpr mice reduces disease severity including lymphocyte expansion, anti-chromatin autoantibodies and glomerulonephritis [25]. Most significantly, lupus-predisposed mice lacking pDCs due to the absence of IRF8 or showing pDC-specific defects in type I IFN production due to mutation of peptide/histidine transporter solute carrier family 15, member 4 do not develop autoimmunity [26]. These recent findings implicate pDCs and their ability to produce type I IFN as major contributors to the pathogenesis of lupus.

The important role that monocytes and macrophages play in phagocytosis, cytokine production and antigen presentation has also identified them as influential players in the innate immune response in systemic autoimmunity [27]. Deficiency of colony-stimulating factor-1, the principal growth factor for macrophages, in MRL-Fas lpr mice reduces disease severity [28]. Deficiency of macrophage migration inhibitory factor reduces macrophage recruitment and glomerulonephritis in MRL-Fas lpr mice [29]. Cultured in the presence of serum, macrophages from MRL-Fas lpr mice have dysregulated gene expression compared with non-lupus-prone mice [30]. The presence of the complement component C1q also enhances immune-complex-mediated gene expression in monocytes of patients with SLE [31]. C1q preferentially promotes binding of immune complexes to monocytes rather than pDCs and thus indirectly reduces type I IFN production by pDCs [32]. The ability of C1q to suppress type I IFN may be an additional reason that C1q deficiency enhances susceptibility to SLE [33].

Type I IFN plays a significant role in the onset and severity of idiopathic autoimmunity. Induction of type I IFN by TLR3 and melanoma differentiation-associated protein-5 agonist, polyinosinic:polycytidylic acid (poly(I:C)), exacerbates idiopathic systemic autoimmunity, particularly nephritis, in C57BL/6-Fas lpr[34], NZW hybrid [35] and NZB/NZWF1 [36] mice. Moreover sustained production of type I IFN by injection of adenovirus-expressing IFN-α also exacerbates disease, including glomerulonephritis in idiopathic lupus models [37–40]. By contrast, deficiency of type I IFN receptor (IFNAR) reduces disease severity in most autoimmune models [41, 42] except MRL-Fas lpr, where absence of IFNAR leads to more severe disease [43] and antibody blocking of the IFNAR has minimal beneficial effect [44]. The mechanism whereby IFNAR deficiency exacerbates disease in MRL-Fas lpr mice is unknown, however, deletion of DCs (including pDCs) in this model while still allowing T and B cell activation, hypergammaglobulinemia and anti-nucleolar autoantibodies (ANoA) does substantially reduce disease severity [25], suggesting that DCs are required for promoting autoimmune disease by mechanisms beyond the production of type I IFN.

Type I IFN expression relies on activation of TLRs and signaling via IRF7 [4, 45]. Numerous studies have determined that endosomal TLRs, particularly TLR7 and TLR9, influence idiopathic systemic autoimmunity [46–49]. However, specific endosomal TLRs make different contributions to disease severity. Loss of TLR3 does not impact disease [50] although TLR3 stimulation of myeloid differentiation factor 88 (MyD88)-deficient mice, which lack TLR7 and TLR9 signaling, partially recovers disease [51]. Absence of TLR7 partially ameliorates disease [52–54] whereas deficiency of TLR9 exacerbates autoimmunity in a TLR7-dependent manner [52, 53]. The 'triple D' mutation in Unc-93 homolog B1 (Unc93b1), an integral component of endoplasmic reticulum, involved in the trafficking of TLR3, TLR7 and TLR9 [55, 56], abolishes endosomal TLR signaling [55] and suppresses disease in lupus-prone C57BL/6-Fas lpr, BXSB [46] and MRL-Fas lpr (Koh YT et al, J. Immunol. In press).

All TLR signaling pathways lead to activation of the transcription factor NF-κB and production of proinflammatory cytokines (for example, IL-1, IL-6, TNFα) [4, 57, 58]. Accordingly, modulation of certain individual proinflammatory cytokines can have significant effects on the expression of idiopathic autoimmunity. For example, treatment with anti-IL-6 or anti-IL-6 receptor antibody results in reduced severity of kidney damage in lupus-prone mice [59, 60] whereas recombinant IL-6 exacerbates glomerulonephritis [61]. Complete deficiency of IL-6 in MRL-Fas lpr mice reduces clinical, immunological and histological indices of lupus and improves survival [62]. IL-1, which consists of α and β forms [63], is elevated in idiopathic lupus models [64, 65]. Treatment with recombinant IL-1 receptor [66] reduces the severity of systemic autoimmunity as does IL-1 receptor antagonist [67], although the latter appears not to be effective against established disease [68]. The contributions of the separate α and β forms of IL-1 remain to be determined. The role of another proinflammatory cytokine, TNFα, in systemic autoimmunity is less clear. Treatment with TNFα increases survival in lupus-prone mice [69, 70] and loss of Tnf[71] or Tnf receptors [72] accelerates disease. By contrast, treatment with anti-TNF receptor increases survival [73].

hese studies show that innate immune responses contribute significantly to disease severity in idiopathic systemic autoimmunity. Principal contributions, identified to date, come from pDCs and TLR- or IRF7-mediated type I IFN production. However it is clear that proinflammatory cytokines, especially IL-6, expressed by TLR or NF-κB signaling also play a significant role. In addition early components of the complement cascade are protective.

Innate immunity in environmentally induced systemic autoimmunity

That systemic autoimmunity can be elicited by exogenous factors, especially medications, is well established in both humans and animal models [6, 74, 75]. These can trigger disease in individuals with or without susceptibility to idiopathic autoimmunity or can lead to enhancement of existing autoimmune disease. However, these observations come with two clear caveats. First, there are no accepted criteria for diagnosis or classification of environmentally associated autoimmunity in humans, nor are there criteria that distinguish environmentally associated autoimmunity from types of idiopathic autoimmune diseases [76]. Second, although studies of animal models have provided critical understanding of many facets of human systemic autoimmunity [12], they are limited by incomplete representation of the full spectrum of human disease [77]. Nonetheless, common mechanisms of adaptive immunity exist for both induced and idiopathic disease in human and animals including loss of tolerance, T and B cell activation and autoantibody production [6, 78]. However, the role that innate immunity plays is only beginning to be examined. Exposure to environmental agents such as mercury [79–81], crystalline silica [82, 83] and pristane [84] are known to result in a lupus-like systemic autoimmunity in animal models. Although the mechanisms of induction are poorly understood, published as well as our preliminary studies suggest that specific environmental triggers induce or modulate systemic autoimmunity through distinct components of the innate immune system.

Pristane

Pristane, also known as 2,6,10,14-tetramethylpentadecane (or TMPD), is a component of mineral oil that induces chronic inflammation and plasmacytomas in mice [85]. In humans, mineral oil or petroleum waste has been associated with rheumatoid arthritis and possibly lupus [84]. In susceptible strains of mice, pristane injection causes a lupus-like disease characterized by a wide spectrum of primarily antinuclear autoantibodies (ANA) and immune complex-mediated glomerulonephritis [84]. Severity of disease including IgG autoantibodies and glomerulonephritis are reduced in the absence of IFN-γ [86], IL-6 [87] and IL-12p35 [88]. Pristane-induced autoimmunity may also fall under a common syndrome called ASIA (autoimmune syndrome induced by adjuvants) [89].

Similar to SLE, pristane-induced autoimmunity is associated with increased expression of type I IFN-inducible genes in peripheral blood cells (IFN signature) [90, 91]. The most severe aspects of disease are dependent on type I IFN; type I IFN receptor-deficient (Ifnar −/−) mice exposed to pristane exhibit markedly reduced lupus-specific autoantibodies, proteinuria and glomerular hypercellularity [92]. Type I IFN expression, autoantibody production and glomerulonephritis in pristane-treated mice are primarily mediated via a TLR7- and MyD88-dependent pathway [93, 94]. In addition, deficiencies in TLR4 and TLR9 also impact disease severity [95]. Interestingly, TLR deficiency differentially affects lupus-specific autoantibody production, with absence of TLR7 or TLR9 reducing anti-ribonucleoprotein responses but not anti-DNA [94, 95] whereas lack of TLR4 reduced production of both anti-ribonucleoprotein and anti-DNA autoantibodies [95]. Pristane-treated Ifnar −/− mice also have reduced expression and activation of TLR7 and TLR9 in B cells [96], suggesting a positive feedback mechanism in which type I IFN augments TLR-mediated B cell responses. In contrast to spontaneous lupus, type I IFN production in pristane-induced autoimmunity is not dependent on DCs, but is produced by immature Ly6Chigh inflammatory monocytes [97]; increases in Ly6Chigh monocyte numbers correlates with greater amounts of lupus-specific autoantibodies [97]. Type I IFN is also required for the chemokine expression necessary for recruitment of inflammatory monocytes [98], which likely results in a positive feedback signal and further acceleration of IFN production. This expansion of monocytes by type I IFN appears to be relatively specific because the lack of the inflammatory cytokines TNF-α, IL-6, IL-1 [98] and IFN-γ, which are required for disease [84], have no effect on Ly6Chigh monocyte recruitment.

The chronic inflammatory response to pristane also includes neutrophil infiltration, which in contrast to monocytes requires IL-1, specifically IL-1α, and is mediated by MyD88 and IL-1 receptor-associated kinase, but not IRF7 [99]. IL-1β, caspase 1 and the inflammasome components NOD-like receptor family, pyrin domain containing 3 (NLRP3) and apoptosis-associated speck-like protein containing a CARD (ASC) (which are required for caspase 1 activation [100]) are not required for neutrophil recruitment in pristane-induced chronic inflammation [99]. Although IL-1alpha; has not been directly linked to the autoimmunity elicited by pristane, it does induce expression of IL-6 [101], which is required for pristane-induced hypergammaglobulinemia and the production of anti-DNA and anti-chromatin [87].

The protein product of IRF5, a lupus susceptibility gene [102], acts as a transcription factor to mediate TLR induction of proinflammatory cytokines IL-6, IL-12, TNFα and, to some extent, IFN-α, independent of NF-κB [103–105]. Notably, Irf5 deficiency reduced pristane-induced disease severity including the expansion of Ly6Chigh monocytes, type I IFN signature, autoantibodies and renal disease [106–109]. This was confirmed in pure Irf5-deficient mice lacking a spontaneous Dock2 mutation found in some Irf5 knockout lines that alters pDC and B cell development and type I IFN production [108–110].

These studies suggest that disease expression and severity in the pristane model are tightly linked to nucleic acid-sensing TLR and MyD88 signaling leading to type I IFN production analogous to idiopathic lupus. Unlike idiopathic lupus, however, type I IFN production is produced by immature monocytes rather than pDCs. By contrast, although a feature of this model is chronic inflammation, inflammasome components and IL-1β appear to play little if any role.

Mercury

Exposure to mercury in humans has been associated with autoimmune manifestations in small surveys, but more definitive large-scale epidemiological studies are lacking [111]. Studies of South American gold miners documented that mercury exposure was associated with higher levels of proinflammatory cytokines (IFN-γ, TNF-α, IL-1β) and autoantibodies [80, 112]. In other studies, mercury exposure from skincare products was associated with membranous nephropathy [79, 113]. Thus, although only limited human populations at potential risk for mercury-induced autoimmunity have been studied in detail [75, 113], the severity of systemic disease that was induced by mercury exposure appears mild compared to that of idiopathic SLE.

Possible mechanisms for mercury-induced systemic autoimmunity have come largely from studies of susceptible mice and rats that, when exposed to mercury, develop lymphocyte activation, ANA and deposits of immune complexes in blood vessels and glomeruli [77]. The adaptive immune responses required for murine mercury-induced autoimmunity (mHgIA) share common requirements with idiopathic lupus including certain cytokines [114, 115], co-stimulation factors [116, 117] and transcription factors [8, 118]. However, whereas type I IFN signaling pathways predominate in idiopathic and pristane-induced autoimmune disease, our recent studies indicate that mHgIA is independent of type I IFN. Accordingly, Ifnar1-deficient C57BL/6, NZB and BXSB mice all have similar autoimmune responses to mercury exposure as wild-type mice (Kono and Pollard, unpublished observations), in contrast to the known type I IFN-dependence of spontaneous autoimmunity in both NZB and BXSB strains [41, 44]. This lack of dependence on type I IFN is further supported by the observation that mercury-induced hypergammaglobulinemia and autoantibodies in Inept mice, which are deficient in IRF7 and consequently do not produce IFN-α after TLR7 or TLR9 stimulation [119], are not reduced compared to the wild-type (Kono and Pollard, unpublished observations).

Similar to idiopathic [47, 53] and pristane-induced autoimmunity [93–95], severity of mHgIA is impacted by TLR activation because the TLR4 ligand lipopolysaccharide exacerbates disease [120]. Although the specific TLRs required for mHgIA remain to be examined, mercury-exposed autoimmune-prone BXSB mice with the triple D mutation in Unc93b1 (required for endosomal TLR3, TLR7 and TLR9 signaling [121]) do not develop ANA or increased serum IgG unlike wild-type BXSB (Kono and Pollard, unpublished observations). Thus, although endosomal TLRs contribute to mHgIA, type I IFN is not required in both autoimmune-prone and healthy genetic backgrounds. It is possible that mercury exposure can replace type I IFN by activating the IFNAR pathway or related genes downstream of IFNAR activation. Alternatively, mHgIA may not be mediated by type I IFN. Related to this, our preliminary studies show that mercury exposure suppresses IFN-α induction mediated by poly(I:C) (TLR3 agonist) while proinflammatory cytokine (for example, IL-6) production is unaffected (Kono and Pollard, unpublished observations). This supports the latter possibility that mHgIA is not mediated by type I IFN and may also explain why mHgIA is a relatively mild disease compared to idiopathic lupus [19, 80]. It remains to be determined, however, if mHgIA can be exacerbated by exogenous type I IFN. The lack of dependence on type I IFN but requirement for endosomal TLRs is similar to spontaneous lupus in the MRL background [43, 53].

Endosomal TLR signaling leads to cell activation and to type I IFN production via IRF7 and the induction of proinflammatory cytokines IL-6, pro-IL-1β and TNF-α via the NF-κB pathway [4, 122–124]. Dependence on endosomal TLRs but not Irf7 or Ifnar suggests that mHgIA may be primarily mediated by NF-κB signaling [4]. IL-1 signaling also activates NF-κB [101] and we have shown that cell bound IL-1α is required for mercury-induced T cell proliferation in vitro[125], suggesting that cell signaling via the IL-1 receptor may also be important for mHgIA. We have, however, shown that neither NLRP3 nor caspase 1 deficiency impacts expression of mHgIA [8], suggesting that IL-1β is not required. In other experiments, we also examined the effects of IL-6, which is induced by NF-κB [101], on mHgIA and found B10.S-Il6 −/− mice exposed to HgCl2 had reduced serum IgG autoantibodies and kidney deposits of IgG compared to wild-type mice [126]. Although the pathways have yet to be defined, taken together, these studies point to the endosomal TLRs, the proinflammatory cytokines IL-1α and IL-6 but not type I IFN as the major innate factors that drive autoimmunity following exposure to mercury. Furthermore, NF-κB-associated pathways, but not IRF7 were implicated.

Silica

Silica exposure is common in mining, sandblasting, rock drilling, granite cutting, construction work, bricklaying and cement work. In 2007, the US Occupational Safety and Health Administration estimated that almost two million individuals in the USA are occupationally exposed to respirable crystalline silica [127] and exposure continues to be a national and worldwide problem [128]. Inhalation of crystalline silica can cause silicosis, which is characterized by chronic inflammation and scarring in the upper lobes of the lungs [128]. Additionally, epidemiologic data have repeatedly associated silica exposure with systemic autoimmunity [111] including SLE, rheumatoid arthritis and systemic sclerosis [83, 111, 129–131]. Notably, silica dust exposure is associated with high titers of ANA [132] and both the presence of autoantibodies and clinical symptoms are positively correlated with intensity (that is, concentration and frequency) of exposure [133, 134]. Further support has come from animal models in which lupus in susceptible mice is exacerbated by exposure to silica [135, 136] and ANAs develop in non-autoimmune mice and rats exposed to silica products [137, 138]. The mechanisms mediating silica-induced autoimmunity are not yet defined. Nevertheless, one possibility is that the chronic inflammatory milieu present in silicosis might induce or exacerbate autoimmunity through the production of proinflammatory cytokines and release of self-antigens [139–141].

Silica-induced inflammation is mainly caused by the toxic effects of silica on alveolar macrophages, resulting in the release of proinflammatory chemokines and cytokines including TNF and IL-1 [128, 142], and the influx of neutrophils, macrophages, DCs and lymphocytes [143–145]. Silica-induced pulmonary inflammation is dependent on IFN-γ [146] but not Th2 cytokines such as IL-4 and IL-13 [147], or IL-12 [148], requirements similar to those of mHgIA [8, 114]. Innate immunity mediates this process as silica-induced inflammation and fibrosis can occur in the absence of T, B, NKT or NK cells [143]. Notably, although acute lung inflammation requires IL-17 [149], chronic inflammation is dependent on type 1 IFN and IRF7 [150]. NALP3 (NACHT, LRR and PYD domains-containing protein 3) inflammasome components, caspase-1 and IL-1β, are also required for silicosis [142, 151–153] and our preliminary findings indicate that caspase-1 is required for autoantibody induction (Kono and Pollard, unpublished observations). Although the role of individual TLRs has not been examined, silica has been shown to suppress TLR-mediated activation of DCs [144], but its effect on TLR stimulation of alveolar macrophages, the primary cell-type responsible for inflammasome-mediated lung inflammation [142], is not known. Death of alveolar macrophages by silica might further promote inflammation and autoimmunity by impairing the clearance of silica and apoptotic cells, and by generating apoptotic material. In support of this, deficiency of either scavenger receptors macrophage receptor with a collagenous structure (MARCO) or CD204, expressed mainly on macrophages, was shown to impair silica clearance and exacerbate silica-induced lung inflammation [154, 155]. Additionally, MARCO-deficient mice are defective in clearing apoptotic cells [156] and both MARCO and CD204 have been argued to promote tolerance to apoptotic cell material [157]. These observations suggest that scavenger receptor-mediated uptake of silica and subsequent macrophage cell death may adversely affect clearance of dead and dying cells, which, in turn, could impact self-tolerance [158, 159] and promote autoimmunity.

Studies with silica-induced lung inflammation, while only indirectly implying mechanisms of silica-induced autoimmunity, suggest that, like idiopathic lupus and pristane-induced autoimmunity, innate mechanisms involving IRF7 and type I IFN might play pivotal roles. Silica-induced killing of scavenger receptor-bearing macrophages, inflammasome activation and IL-1β are also likely to make significant contributions. The requirement for the inflammasome pathway is clearly different from the innate immune responses required for the development of pristane-induced autoimmunity [84, 99] and mHgIA [8].

Innate immune mechanisms contributing to environmentally induced autoimmunity

As is clear from the studies discussed above, innate immunity plays an essential role in both idiopathic and environmentally induced lupus-like autoimmunity, with the requirement for endosomal TLRs and/or Unc93b1 providing a unifying mechanism for idiopathic and pristane- and mercury-induced disease [4]. Signaling by these TLRs leads to cell activation and the production of proinflammatory cytokines via NF-κB and type I IFNs by IRF7 activation [4]. By contrast, as presented above, different innate pathways have been implicated in the development of pristane-, mercury- and silica-induced autoimmune diseases that mediate the induction of inflammation, cell death, the adaptive response and autoimmunity, supporting our contention that environmental factors can induce or enhance lupus-like autoimmunity through several different innate mechanisms. How the different innate responses are elicited and how they consequently promote autoimmunity remains to be determined. However, a few possible explanations can be postulated.

Recent studies suggest that adaptor protein complex 3 (AP-3), which is involved in the sorting of transmembrane proteins to lysosomes and lysosome-related organelles (LRO), may bifurcate these signaling pathways because AP-3 is required for TLR7 and TLR9 induction of type I IFN but not proinflammatory cytokines [56]. AP-3 mediates trafficking of TLRs and UNC93B1 to the lysosome-associated membrane protein 2+ (LAMP2+) late endosomes and LROs but not to vesicle-associated membrane protein 3+ (VAMP3+) early endosomes [4, 56]. Thus UNC93B1-mediated endosomal TLR trafficking moves to early endosomes in an AP-3 independent manner, leading to NF-κB-regulated proinflammatory cytokine production (NF-κB endosome), and then in an AP-3 dependent step to late endosomes/LRO and IRF7-mediated type I IFN production (IRF7 endosome) [4]. The importance of endosomal location in DC responses has been shown by studies using different classes of CpG oligonucleotide ligands to stimulate TLR9 signaling [160–162]. In addition, viperin, a component of endoplasmic reticulum-derived lipid storage granules or lipid bodies, is required for endosomal TLR-mediated type I IFN by pDCs but does not contribute to proinflammatory cytokine production in pDCs or type I IFN production by other cell types [163]. Viperin may thus be central to the role of pDCs and type I IFN production in systemic autoimmunity.

The bifurcation of TLR trafficking and signaling regulated by AP-3 may explain the dependence of mHgIA on Unc93b1 and proinflammatory cytokines like IL-6 as well as its type I IFN independence. Mercury is known to accumulate in lysosomes [164, 165] and may thus impact AP-3 controlled TLR trafficking to the IRF7 endosome, leading to reduced type I IFN production. Silica can also affect lysosomal function, particularly in macrophages [166, 167], suggesting that silica-induced autoimmunity may also be influenced by effects on lysosome function. We can find no evidence that pristane affects lysosome function, however given the type I IFN-dependence of pristane-induced autoimmunity [92], we expect pristane not to hamper TLR trafficking and/or signaling.

In Figure 1 we outline our view of the mechanisms of innate immunity in environmentally induced autoimmunity with emphasis on the contribution of bifurcation of TLR signaling to mHgIA. We propose that the toxic response to mercury [168], pristane [169] or silica [170] leads to the availability of nucleic acid/protein self-antigens. These are then brought into the endolysosomal machinery of antigen presenting cells such as DCs, macrophages and/or B cells where they complex with TLRs and traffic to early endosomes (NF-κB endosome), leading to NF-κB-regulated proinflammatory cytokine production. IRF7-mediated type I IFN production via late endosomes/LRO (IRF7 endosome) has little role in mHgIA as suggested by the failure of Ifnar and Irf7 deficiency to suppress mHgIA. The important role of the mercury-induced NF-κB-mediated inflammatory response is likely aided by IL-1α from dead and dying cells. IL-1α is also important for mercury-induced T cell proliferation [125] and may contribute to enhanced CD4+ T cell expansion and differentiation [171]. In addition, IL-1α synergizes with IFN-γ to regulate IFN-γ induced gene expression in an NF-κB-dependent manner [172], thus linking the innate and adaptive responses in mHgIA. Interestingly, IL-1α, released from dying cells, can initiate sterile inflammation involving neutrophils [173], supporting its role in granulocyte recruitment in pristane-induced chronic inflammation [99]. We would argue that, unlike pristane, mHgIA may not require NF-κB independent proinflammatory cytokine production mediated by IRF5, particularly as IRF5 requires TNF receptor-associated factor 6 (TRAF6) [103], which is a component of the signaling complex of lipid bodies [4].

Figure 1
figure 1

Innate immune mechanisms contributing to environmentally induced autoimmunity. The toxic response to environmental agents results in self nucleic acid/protein complexes that may become ligands for endosomal TLRs via scavenger receptors, particularly in macrophages. UNC93B1-mediated trafficking of endosomal TLRs leads first to VAMP3+ early endosomes, where signaling results in NF-κB activation and proinflammatory cytokine production. TLRs, again in concert with Unc93b1, also traffic to LAMP2+ LROs where IRF7 is activated to stimulate type I IFN expression. Lipid bodies, which contain components of the TLR signaling complex, may contribute to type I IFN particularly in pDCs. Activation of IRF5 in complex with TRAF6 can lead to proinflammatory cytokine production. NF-κB-mediated proinflammatory cytokine production may be augmented by release of constitutively expressed IL-1α from dead and dying cells. IL-1α may also contribute to adaptive immunity via differentiation and expansion of CD4+ T cells and enhanced expression of IFN-γ-stimulated genes such as IRF1. The large box signifies signaling events in innate immune responses that may occur in one or more cell types. Steps required for mHgIA are shown in rectangles with a thick black line while those not required are shown by ovals with a broken line. Steps required for pristane-induced autoimmunity include those leading to type I IFN and proinflammatory cytokine production and may also include pathways involving IL-1α, particularly IL-1α-driven NF-κB activation. AP-3, adaptor protein complex 3; Hg, mercury; IFN, interferon; IFNAR, type I IFN receptor; IL, interleukin; IRF, interferon regulatory factors; LAMP2, lysosome-associated membrane protein 2; LRO, lysosome-related organelle; NF, nuclear factor; Si, silica; Th1, T helper type 1; TLR, Toll-like receptor; TNF, tumor necrosis factor; TRAF6, TNF receptor associated factor 6; UNC93B1, Unc-93 homolog B1; VAMP3, vesicle-associated membrane protein 3.

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Conclusions

Innate immunity plays an essential role in both idiopathic and environmentally induced autoimmunity, however there are clear differences in the required molecular and cellular components that mediate disease development. In idiopathic autoimmunity, both type I IFN and proinflammatory cytokines are needed for disease with pDCs being the primary cells involved in type I IFN production. By contrast, in pristane-induced autoimmunity, TLR/MyD88 signaling, leading to type I IFN and proinflammatory cytokines, does not require DCs, but rather immature monocytes. Mercury-induced autoimmunity, although showing clear evidence of TLR involvement does not require type I IFN, but rather shows significant dependence on proinflammatory cytokines such as IL-1α and IL-6. Additional pathways may apply to silica-induced autoimmunity as scavenger receptors and the inflammasome are central to silica-induced inflammatory responses. It can be speculated that some of these differences may be related to the bifurcation of TLR signaling that distinguishes IRF7-mediated type I IFN production and NF-κB-driven proinflammatory cytokine expression. These findings from several environmentally induced models suggest that environmental triggers can induce autoimmunity through diverse innate pathways. A greater understanding of the specific innate processes that initiate or exacerbate disease will be key to understanding the role of environmental factors in autoimmunity.

Funding

This work was funded by the National Institutes of Health grants ES014847 and ES020388 to KMP and AR053731 and AR060181 to DHK.

Abbreviations

AP-3:

Adaptor protein complex 3

DC:

Dendritic cells

IFN:

Interferon

IFNAR:

Type I IFN receptor

Hg:

Mercury

Ig:

Immunoglobulin

IL:

Interleukin

IRF:

Interferon regulatory factors

LAMP2:

Lysosome-associated membrane protein 2

LRO:

Lysosome-related organelles

MARCO:

Macrophage receptor with a collagenous structure

mHgIA:

Murine mercury-induced autoimmunity

MyD88:

Myeloid differentiation factor 88

NF:

Nuclear factor

NK:

Natural killer

pDC:

Plasmacytoid dendritic cell

Si:

Silica

SLE:

Systemic lupus erythematosus

TLR:

Toll-like receptor

TNF:

Tumor necrosis factor

TRAF6:

TNF receptor associated factor 6

Unc93b1:

Unc-93 homolog B1

VAMP3:

Vesicle-associated membrane protein 3.

References

  1. Ronald PC, Beutler B: Plant and animal sensors of conserved microbial signatures. Science. 2010, 330 (6007): 1061-1064.

    CAS  PubMed  Google Scholar 

  2. Iwasaki A, Medzhitov R: Regulation of adaptive immunity by the innate immune system. Science. 2010, 327 (5963): 291-295.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Mills KH: TLR-dependent T cell activation in autoimmunity. Nat Rev Immunol. 2011, 11 (12): 807-822.

    CAS  PubMed  Google Scholar 

  4. Theofilopoulos AN, Kono DH, Beutler B, Baccala R: Intracellular nucleic acid sensors and autoimmunity. J Interferon Cytokine Res. 2011, 31 (12): 867-886.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Theofilopoulos AN, Gonzalez-Quintial R, Lawson BR, Koh YT, Stern ME, Kono DH, Beutler B, Baccala R: Sensors of the innate immune system: their link to rheumatic diseases. Nat Rev Rheumatol. 2010, 6 (3): 146-156.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Pollard KM, Hultman P, Kono DH: Toxicology of autoimmune diseases. Chem Res Toxicol. 2010, 23 (3): 455-466.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Pollard KM, Hultman P, Kono DH: Immunology and genetics of induced systemic autoimmunity. Autoimmun Rev. 2005, 4 (5): 282-288.

    CAS  PubMed  Google Scholar 

  8. Pollard KM, Hultman P, Toomey CB, Cauvi DM, Hoffman HM, Hamel JC, Kono DH: Definition of IFN-gamma-related pathways critical for chemically-induced systemic autoimmunity. J Autoimmun. 2012, 39 (4): 323-331.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Baccala R, Gonzalez-Quintial R, Lawson BR, Stern ME, Kono DH, Beutler B, Theofilopoulos AN: Sensors of the innate immune system: their mode of action. Nat Rev Rheumatol. 2009, 5 (8): 448-456.

    CAS  PubMed  Google Scholar 

  10. Newton K, Dixit VM: Signaling in innate immunity and inflammation. Cold Spring Harb Perspect Biol. 2012, 4 (3): pii:a006049.

    Google Scholar 

  11. Hahn BH: Targeted therapies in systemic lupus erythematosus: successes, failures and future. Ann Rheum Dis. 2011, 70 (Suppl 1): i64-i66.

    CAS  PubMed  Google Scholar 

  12. Kono DH, Theofilopoulos AN: Genetics of SLE in mice. Springer Semin Immunopathol. 2006, 28 (2): 83-96.

    PubMed  Google Scholar 

  13. Shlomchik MJ, Craft JE, Mamula MJ: From T to B and back again: positive feedback in systemic autoimmune disease. Nat Rev Immunol. 2001, 1 (2): 147-153.

    CAS  PubMed  Google Scholar 

  14. Goodnow CC, Sprent J, Fazekas-de-St-Groth B, Vinuesa CG: Cellular and genetic mechanisms of self tolerance and autoimmunity. Nature. 2005, 435 (7042): 590-597.

    CAS  PubMed  Google Scholar 

  15. Baccala R, Hoebe K, Kono DH, Beutler B, Theofilopoulos AN: TLR-dependent and TLR-independent pathways of type I interferon induction in systemic autoimmunity. Nat Med. 2007, 13 (5): 543-551.

    CAS  PubMed  Google Scholar 

  16. Diana J, Gahzarian L, Simoni Y, Lehuen A: Innate immunity in type 1 diabetes. Discov Med. 2011, 11 (61): 513-520.

    PubMed  Google Scholar 

  17. Obermoser G, Pascual V: The interferon-alpha signature of systemic lupus erythematosus. Lupus. 2010, 19 (9): 1012-1019.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Ronnblom L, Alm GV: A pivotal role for the natural interferon alpha-producing cells (plasmacytoid dendritic cells) in the pathogenesis of lupus. J Exp Med. 2001, 194 (12): F59-63.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Higgs BW, Liu Z, White B, Zhu W, White WI, Morehouse C, Brohawn P, Kiener PA, Richman L, Fiorentino D, Greenberg SA, Jallal B, Yao Y: Patients with systemic lupus erythematosus, myositis, rheumatoid arthritis and scleroderma share activation of a common type I interferon pathway. Ann Rheum Dis. 2011, 70 (11): 2029-2036.

    CAS  PubMed  Google Scholar 

  20. Crow MK: Type I interferon in organ-targeted autoimmune and inflammatory diseases. Arthritis Res Ther. 2010, 12 (Suppl 1): S5.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Theofilopoulos AN, Baccala R, Beutler B, Kono DH: TYPE I Interferons (alpha/beta) in immunity and autoimmunity. Annu Rev Immunol. 2005, 23: 307-335.

    CAS  PubMed  Google Scholar 

  22. Bar-On L, Jung S: Defining dendritic cells by conditional and constitutive cell ablation. Immunol Rev. 2010, 234 (1): 76-89.

    CAS  PubMed  Google Scholar 

  23. Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K: Development of monocytes, macrophages, and dendritic cells. Science. 2010, 327 (5966): 656-661.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Gilliet M, Cao W, Liu YJ: Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases. Nat Rev Immunol. 2008, 8 (8): 594-606.

    CAS  PubMed  Google Scholar 

  25. Teichmann LL, Ols ML, Kashgarian M, Reizis B, Kaplan DH, Shlomchik MJ: Dendritic cells in lupus are not required for activation of T and B cells but promote their expansion, resulting in tissue damage. Immunity. 2010, 33 (6): 967-978.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Baccala R, Gonzalez-Quintial R, Blasius AL, Rimann I, Ozato K, Kono DH, Beutler B, Theofilopoulos AN: Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus. Proc Natl Acad Sci U S A. 2013, 110 (8): 2940-2945.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Li Y, Lee PY, Reeves WH: Monocyte and macrophage abnormalities in systemic lupus erythematosus. Arch Immunol Ther Exp (Warsz). 2010, 58 (5): 355-364.

    CAS  Google Scholar 

  28. Lenda DM, Stanley ER, Kelley VR: Negative role of colony-stimulating factor-1 in macrophage, T cell, and B cell mediated autoimmune disease in MRL-Fas(lpr) mice. J Immunol. 2004, 173 (7): 4744-4754.

    CAS  PubMed  Google Scholar 

  29. Hoi AY, Hickey MJ, Hall P, Yamana J, O'Sullivan KM, Santos LL, James WG, Kitching AR, Morand EF: Macrophage migration inhibitory factor deficiency attenuates macrophage recruitment, glomerulonephritis, and lethality in MRL/lpr mice. J Immunol. 2006, 177 (8): 5687-5696.

    CAS  PubMed  Google Scholar 

  30. Antoni A, Patel VA, Fan H, Lee DJ, Graham LH, Rosch CL, Spiegel DS, Rauch J, Levine JS: Macrophages from lupus-prone MRL mice have a conditional signaling abnormality that leads to dysregulated expression of numerous genes. Immunogenetics. 2011, 63 (5): 291-308.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Santer DM, Wiedeman AE, Teal TH, Ghosh P, Elkon KB: Plasmacytoid dendritic cells and C1q differentially regulate inflammatory gene induction by lupus immune complexes. J Immunol. 2012, 188 (2): 902-915.

    CAS  PubMed  Google Scholar 

  32. Santer DM, Hall BE, George TC, Tangsombatvisit S, Liu CL, Arkwright PD, Elkon KB: C1q deficiency leads to the defective suppression of IFN-alpha in response to nucleoprotein containing immune complexes. J Immunol. 2010, 185 (8): 4738-4749.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Elkon KB, Santer DM: Complement, interferon and lupus. Curr Opin Immunol. 2012, 24 (6): 665-670.

    CAS  PubMed  Google Scholar 

  34. Braun D, Geraldes P, Demengeot J: Type I interferon controls the onset and severity of autoimmune manifestations in lpr mice. J Autoimmun. 2003, 20 (1): 15-25.

    CAS  PubMed  Google Scholar 

  35. Jorgensen TN, Thurman J, Izui S, Falta MT, Metzger TE, Flannery SA, Kappler J, Marrack P, Kotzin BL: Genetic susceptibility to polyI:C-induced IFNalpha/beta-dependent accelerated disease in lupus-prone mice. Genes Immun. 2006, 7 (7): 555-567.

    CAS  PubMed  Google Scholar 

  36. Triantafyllopoulou A, Franzke CW, Seshan SV, Perino G, Kalliolias GD, Ramanujam M, van Rooijen N, Davidson A, Ivashkiv LB: Proliferative lesions and metalloproteinase activity in murine lupus nephritis mediated by type I interferons and macrophages. Proc Natl Acad Sci U S A. 2010, 107 (7): 3012-3017.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Mathian A, Weinberg A, Gallegos M, Banchereau J, Koutouzov S: IFN-alpha induces early lethal lupus in preautoimmune (New Zealand Black x New Zealand White) F1 but not in BALB/c mice. J Immunol. 2005, 174 (5): 2499-2506.

    CAS  PubMed  Google Scholar 

  38. Liu Z, Bethunaickan R, Huang W, Lodhi U, Solano I, Madaio MP, Davidson A: Interferon-alpha accelerates murine systemic lupus erythematosus in a T cell-dependent manner. Arthritis Rheum. 2011, 63 (1): 219-229.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Ramanujam M, Kahn P, Huang W, Tao H, Madaio MP, Factor SM, Davidson A: Interferon-alpha treatment of female (NZW x BXSB)F(1) mice mimics some but not all features associated with the Yaa mutation. Arthritis Rheum. 2009, 60 (4): 1096-1101.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Fairhurst AM, Mathian A, Connolly JE, Wang A, Gray HF, George TA, Boudreaux CD, Zhou XJ, Li QZ, Koutouzov S, Banchereau J, Wakeland EK: Systemic IFN-alpha drives kidney nephritis in B6.Sle123 mice. Eur J Immunol. 2008, 38 (7): 1948-1960.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Santiago-Raber ML, Baccala R, Haraldsson KM, Choubey D, Stewart TA, Kono DH, Theofilopoulos AN: Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice. J Exp Med. 2003, 197 (6): 777-788.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Agrawal H, Jacob N, Carreras E, Bajana S, Putterman C, Turner S, Neas B, Mathian A, Koss MN, Stohl W, Kovats S, Jacob CO: Deficiency of type I IFN receptor in lupus-prone New Zealand mixed 2328 mice decreases dendritic cell numbers and activation and protects from disease. J Immunol. 2009, 183 (9): 6021-6029.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Hron JD, Peng SL: Type I IFN protects against murine lupus. J Immunol. 2004, 173 (3): 2134-2142.

    CAS  PubMed  Google Scholar 

  44. Baccala R, Gonzalez-Quintial R, Schreiber RD, Lawson BR, Kono DH, Theofilopoulos AN: Anti-IFN-alpha/beta receptor antibody treatment ameliorates disease in lupus-predisposed mice. J Immunol. 2012, 189 (12): 5976-5984.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Honda K, Yanai H, Negishi H, Asagiri M, Sato M, Mizutani T, Shimada N, Ohba Y, Takaoka A, Yoshida N, Taniguchi T: IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature. 2005, 434 (7034): 772-777.

    CAS  PubMed  Google Scholar 

  46. 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 (29): 12061-12066.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Marshak-Rothstein A: Toll-like receptors in systemic autoimmune disease. Nat Rev Immunol. 2006, 6 (11): 823-835.

    CAS  PubMed  Google Scholar 

  48. Wu X, Peng SL: Toll-like receptor 9 signaling protects against murine lupus. Arthritis Rheum. 2006, 54 (1): 336-342.

    CAS  PubMed  Google Scholar 

  49. Santiago-Raber ML, Baudino L, Izui S: Emerging roles of TLR7 and TLR9 in murine SLE. J Autoimmun. 2009, 33 (3–4): 231-238.

    CAS  PubMed  Google Scholar 

  50. Christensen SR, Kashgarian M, Alexopoulou L, Flavell RA, Akira S, Shlomchik MJ: Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus. J Exp Med. 2005, 202 (2): 321-331.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Sadanaga A, Nakashima H, Akahoshi M, Masutani K, Miyake K, Igawa T, Sugiyama N, Niiro H, Harada M: Protection against autoimmune nephritis in MyD88-deficient MRL/lpr mice. Arthritis Rheum. 2007, 56 (5): 1618-1628.

    CAS  PubMed  Google Scholar 

  52. Santiago-Raber ML, Dunand-Sauthier I, Wu T, Li QZ, Uematsu S, Akira S, Reith W, Mohan C, Kotzin BL, Izui S: Critical role of TLR7 in the acceleration of systemic lupus erythematosus in TLR9-deficient mice. J Autoimmun. 2010, 34 (4): 339-348.

    CAS  PubMed  Google Scholar 

  53. Nickerson KM, Christensen SR, Shupe J, Kashgarian M, Kim D, Elkon K, Shlomchik MJ: TLR9 regulates TLR7- and MyD88-dependent autoantibody production and disease in a murine model of lupus. J Immunol. 2010, 184 (4): 1840-1848.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Christensen SR, Shupe J, Nickerson K, Kashgarian M, Flavell RA, Shlomchik MJ: Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity. 2006, 25 (3): 417-428.

    CAS  PubMed  Google Scholar 

  55. Tabeta K, Hoebe K, Janssen EM, Du X, Georgel P, Crozat K, Mudd S, Mann N, Sovath S, Goode J, Shamel L, Herskovits AA, Portnoy DA, Cooke M, Tarantino LM, Wiltshire T, Steinberg BE, Grinstein S, Beutler B: The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9. Nat Immunol. 2006, 7 (2): 156-164.

    CAS  PubMed  Google Scholar 

  56. Sasai M, Linehan MM, Iwasaki A: Bifurcation of Toll-like receptor 9 signaling by adaptor protein 3. Science. 2010, 329 (5998): 1530-1534.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Kawai T, Akira S: The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010, 11 (5): 373-384.

    CAS  PubMed  Google Scholar 

  58. Kawai T, Akira S: Signaling to NF-kappaB by Toll-like receptors. Trends Mol Med. 2007, 13 (11): 460-469.

    CAS  PubMed  Google Scholar 

  59. Liang B, Gardner DB, Griswold DE, Bugelski PJ, Song XY: Anti-interleukin-6 monoclonal antibody inhibits autoimmune responses in a murine model of systemic lupus erythematosus. Immunology. 2006, 119 (3): 296-305.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Kiberd BA: Interleukin-6 receptor blockage ameliorates murine lupus nephritis. J Am Soc Nephrol. 1993, 4 (1): 58-61.

    CAS  PubMed  Google Scholar 

  61. Ryffel B, Car BD, Gunn H, Roman D, Hiestand P, Mihatsch MJ: Interleukin-6 exacerbates glomerulonephritis in (NZB x NZW)F1 mice. Am J Pathol. 1994, 144 (5): 927-937.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Cash H, Relle M, Menke J, Brochhausen C, Jones SA, Topley N, Galle PR, Schwarting A: Interleukin 6 (IL-6) deficiency delays lupus nephritis in MRL-Faslpr mice: the IL-6 pathway as a new therapeutic target in treatment of autoimmune kidney disease in systemic lupus erythematosus. J Rheumatol. 2010, 37 (1): 60-70.

    CAS  PubMed  Google Scholar 

  63. Dinarello CA: Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol. 2009, 27: 519-550.

    CAS  PubMed  Google Scholar 

  64. Boswell JM, Yui MA, Endres S, Burt DW, Kelley VE: Novel and enhanced IL-1 gene expression in autoimmune mice with lupus. J Immunol. 1988, 141 (1): 118-124.

    CAS  PubMed  Google Scholar 

  65. Prud'homme GJ, Kono DH, Theofilopoulos AN: Quantitative polymerase chain reaction analysis reveals marked overexpression of interleukin-1 beta, interleukin-1 and interferon-gamma mRNA in the lymph nodes of lupus-prone mice. Mol Immunol. 1995, 32 (7): 495-503.

    PubMed  Google Scholar 

  66. Schorlemmer HU, Kanzy EJ, Langner KD, Kurrle R: Immunoregulation of SLE-like disease by the IL-1 receptor: disease modifying activity on BDF1 hybrid mice and MRL autoimmune mice. Agents Actions. 1993, 39 (Spec No): C117-120.

    CAS  PubMed  Google Scholar 

  67. Sun H, Liu W, Shao J, Xu H, Xiao K, Sheng G: Study on immunoregulation by interleukin-1 receptor antagonist in NZB/W F mice. J Tongji Med Univ. 1997, 17 (1): 18-20. 24

    CAS  PubMed  Google Scholar 

  68. Kiberd BA, Stadnyk AW: Established murine lupus nephritis does not respond to exogenous interleukin-1 receptor antagonist; a role for the endogenous molecule?. Immunopharmacology. 1995, 30 (2): 131-137.

    CAS  PubMed  Google Scholar 

  69. Jacob CO, McDevitt HO: Tumour necrosis factor-alpha in murine autoimmune 'lupus' nephritis. Nature. 1988, 331 (6154): 356-358.

    CAS  PubMed  Google Scholar 

  70. Gordon C, Ranges GE, Greenspan JS, Wofsy D: Chronic therapy with recombinant tumor necrosis factor-alpha in autoimmune NZB/NZW F1 mice. Clin Immunol Immunopathol. 1989, 52 (3): 421-434.

    CAS  PubMed  Google Scholar 

  71. Kontoyiannis D, Kollias G: Accelerated autoimmunity and lupus nephritis in NZB mice with an engineered heterozygous deficiency in tumor necrosis factor. Eur J Immunol. 2000, 30 (7): 2038-2047.

    CAS  PubMed  Google Scholar 

  72. Jacob N, Yang H, Pricop L, Liu Y, Gao X, Zheng SG, Wang J, Gao HX, Putterman C, Koss MN, Stohl W, Jacob CO: Accelerated pathological and clinical nephritis in systemic lupus erythematosus-prone New Zealand Mixed 2328 mice doubly deficient in TNF receptor 1 and TNF receptor 2 via a Th17-associated pathway. J Immunol. 2009, 182 (4): 2532-2541.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Bethunaickan R, Sahu R, Liu Z, Tang YT, Huang W, Edegbe O, Tao H, Ramanujam M, Madaio MP, Davidson A: Anti-TNF treatment of IFN induced lupus nephritis reduces the renal macrophage response but does not alter glomerular immune complex formation. Arthritis Rheum. 2012, 64 (10): 3399-3408.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Rubin RL: Drug-induced lupus. Toxicology. 2005, 209 (2): 135-147.

    CAS  PubMed  Google Scholar 

  75. Pollard KM: Gender differences in autoimmunity associated with exposure to environmental factors. J Autoimmun. 2012, 38 (2–3): J177-186.

    CAS  PubMed  Google Scholar 

  76. Miller FW, Pollard KM, Parks CG, Germolec DR, Leung PS, Selmi C, Humble MC, Rose NR: Criteria for environmentally associated autoimmune diseases. J Autoimmun. 2012, 39 (4): 253-258.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Germolec D, Kono DH, Pfau JC, Pollard KM: Animal models used to examine the role of the environment in the development of autoimmune disease: findings from an NIEHS Expert Panel Workshop. J Autoimmun. 2012, 39 (4): 285-293.

    PubMed  PubMed Central  Google Scholar 

  78. Gualtierotti R, Biggioggero M, Penatti AE, Meroni PL: Updating on the pathogenesis of systemic lupus erythematosus. Autoimmun Rev. 2010, 10 (1): 3-7.

    CAS  PubMed  Google Scholar 

  79. Li SJ, Zhang SH, Chen HP, Zeng CH, Zheng CX, Li LS, Liu ZH: Mercury-induced membranous nephropathy: clinical and pathological features. Clin J Am Soc Nephrol. 2010, 5 (3): 439-444.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Gardner RM, Nyland JF, Silva IA, Ventura AM, de Souza JM, Silbergeld EK: Mercury exposure, serum antinuclear/antinucleolar antibodies, and serum cytokine levels in mining populations in Amazonian Brazil: a cross-sectional study. Environ Res. 2010, 110 (4): 345-354.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Tang HL, Chu KH, Mak YF, Lee W, Cheuk A, Yim KF, Fung KS, Chan HW, Tong KL: Minimal change disease following exposure to mercury-containing skin lightening cream. Hong Kong Med J. 2006, 12 (4): 316-318.

    CAS  PubMed  Google Scholar 

  82. Parks CG, Cooper GS: Occupational exposures and risk of systemic lupus erythematosus. Autoimmunity. 2005, 38 (7): 497-506.

    CAS  PubMed  Google Scholar 

  83. Parks CG, Cooper GS, Nylander-French LA, Sanderson WT, Dement JM, Cohen PL, Dooley MA, Treadwell EL, St Clair EW, Gilkeson GS, Hoppin JA, Savitz DA: Occupational exposure to crystalline silica and risk of systemic lupus erythematosus: a population-based, case–control study in the southeastern United States. Arthritis Rheum. 2002, 46 (7): 1840-1850.

    PubMed  Google Scholar 

  84. Reeves WH, Lee PY, Weinstein JS, Satoh M, Lu L: Induction of autoimmunity by pristane and other naturally occurring hydrocarbons. Trends Immunol. 2009, 30 (9): 455-464.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Anderson PN, Potter M: Induction of plasma cell tumours in BALB-c mice with 2,6,10,14-tetramethylpentadecane (pristane). Nature. 1969, 222 (5197): 994-995.

    CAS  PubMed  Google Scholar 

  86. Richards HB, Satoh M, Jennette JC, Croker BP, Yoshida H, Reeves WH: Interferon-gamma is required for lupus nephritis in mice treated with the hydrocarbon oil pristane. Kidney Int. 2001, 60 (6): 2173-2180.

    CAS  PubMed  Google Scholar 

  87. 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 (5): 985-990.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Calvani N, Satoh M, Croker BP, Reeves WH, Richards HB: Nephritogenic autoantibodies but absence of nephritis in Il-12p35-deficient mice with pristane-induced lupus. Kidney Int. 2003, 64 (3): 897-905.

    CAS  PubMed  Google Scholar 

  89. Shoenfeld Y, Agmon-Levin N: 'ASIA' - autoimmune/inflammatory syndrome induced by adjuvants. J Autoimmun. 2011, 36 (1): 4-8.

    CAS  PubMed  Google Scholar 

  90. Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, Shark KB, Grande WJ, Hughes KM, Kapur V, Gregersen PK, Behrens TW: Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A. 2003, 100 (5): 2610-2615.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Nacionales DC, Kelly KM, Lee PY, Zhuang H, Li Y, Weinstein JS, Sobel E, Kuroda Y, Akaogi J, Satoh M, Reeves WH: Type I interferon production by tertiary lymphoid tissue developing in response to 2,6,10,14-tetramethyl-pentadecane (pristane). Am J Pathol. 2006, 168 (4): 1227-1240.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 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 (11): 3770-3783.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Lee PY, Kumagai Y, Li Y, Takeuchi O, Yoshida H, Weinstein J, Kellner ES, Nacionales D, Barker T, Kelly-Scumpia K, van Rooijen N, Kumar H, Kawai T, Satoh M, Akira S, Reeves WH: TLR7-dependent and FcgammaR-independent production of type I interferon in experimental mouse lupus. J Exp Med. 2008, 205 (13): 2995-3006.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Savarese E, Steinberg C, Pawar RD, Reindl W, Akira S, Anders HJ, Krug A: Requirement of Toll-like receptor 7 for pristane-induced production of autoantibodies and development of murine lupus nephritis. Arthritis Rheum. 2008, 58 (4): 1107-1115.

    CAS  PubMed  Google Scholar 

  95. Summers SA, Hoi A, Steinmetz OM, O'Sullivan KM, Ooi JD, Odobasic D, Akira S, Kitching AR, Holdsworth SR: TLR9 and TLR4 are required for the development of autoimmunity and lupus nephritis in pristane nephropathy. J Autoimmun. 2010, 35 (4): 291-298.

    CAS  PubMed  Google Scholar 

  96. Thibault DL, Graham KL, Lee LY, Balboni I, Hertzog PJ, Utz PJ: Type I interferon receptor controls B-cell expression of nucleic acid-sensing Toll-like receptors and autoantibody production in a murine model of lupus. Arthritis Res Ther. 2009, 11 (4): R112.

    PubMed  PubMed Central  Google Scholar 

  97. Lee PY, Weinstein JS, Nacionales DC, Scumpia PO, Li Y, Butfiloski E, van Rooijen N, Moldawer L, Satoh M, Reeves WH: A novel type I IFN-producing cell subset in murine lupus. J Immunol. 2008, 180 (7): 5101-5108.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Lee PY, Li Y, Kumagai Y, Xu Y, Weinstein JS, Kellner ES, Nacionales DC, Butfiloski EJ, van Rooijen N, Akira S, Sobel ES, Satoh M, Reeves WH: Type I interferon modulates monocyte recruitment and maturation in chronic inflammation. Am J Pathol. 2009, 175 (5): 2023-2033.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Lee PY, Kumagai Y, Xu Y, Li Y, Barker T, Liu C, Sobel ES, Takeuchi O, Akira S, Satoh M, Reeves WH: IL-1alpha modulates neutrophil recruitment in chronic inflammation induced by hydrocarbon oil. J Immunol. 2011, 186 (3): 1747-1754.

    CAS  PubMed  Google Scholar 

  100. Bryant C, Fitzgerald KA: Molecular mechanisms involved in inflammasome activation. Trends Cell Biol. 2009, 19 (9): 455-464.

    CAS  PubMed  Google Scholar 

  101. Weber A, Wasiliew P, Kracht M: Interleukin-1 (IL-1) pathway. Sci Signal. 2010, 3 (105): cm1.

    PubMed  Google Scholar 

  102. Hu W, Ren H: A meta-analysis of the association of IRF5 polymorphism with systemic lupus erythematosus. Int J Immunogenet. 2011, 38 (5): 411-417.

    CAS  PubMed  Google Scholar 

  103. Takaoka A, Yanai H, Kondo S, Duncan G, Negishi H, Mizutani T, Kano S, Honda K, Ohba Y, Mak TW, Taniguchi T: Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature. 2005, 434 (7030): 243-249.

    CAS  PubMed  Google Scholar 

  104. Feng D, Sangster-Guity N, Stone R, Korczeniewska J, Mancl ME, Fitzgerald-Bocarsly P, Barnes BJ: Differential requirement of histone acetylase and deacetylase activities for IRF5-mediated proinflammatory cytokine expression. J Immunol. 2010, 185 (10): 6003-6012.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Yanai H, Chen HM, Inuzuka T, Kondo S, Mak TW, Takaoka A, Honda K, Taniguchi T: Role of IFN regulatory factor 5 transcription factor in antiviral immunity and tumor suppression. Proc Natl Acad Sci U S A. 2007, 104 (9): 3402-3407.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Xu Y, Lee PY, Li Y, Liu C, Zhuang H, Han S, Nacionales DC, Weinstein J, Mathews CE, Moldawer LL, Li SW, Satoh M, Yang LJ, Reeves WH: Pleiotropic IFN-dependent and -independent effects of IRF5 on the pathogenesis of experimental lupus. J Immunol. 2012, 188 (8): 4113-4121.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Savitsky DA, Yanai H, Tamura T, Taniguchi T, Honda K: Contribution of IRF5 in B cells to the development of murine SLE-like disease through its transcriptional control of the IgG2a locus. Proc Natl Acad Sci U S A. 2010, 107 (22): 10154-10159.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Feng D, Yang L, Bi X, Stone RC, Patel P, Barnes BJ: Irf5-deficient mice are protected from pristane-induced lupus via increased Th2 cytokines and altered IgG class switching. Eur J Immunol. 2012, 42 (6): 1477-1487.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Yang L, Feng D, Bi X, Stone RC, Barnes BJ: Monocytes from Irf5−/− mice have an intrinsic defect in their response to Pristane-induced lupus. J Immunol. 2012, 189 (7): 3741-3750.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Purtha WE, Swiecki M, Colonna M, Diamond MS, Bhattacharya D: Spontaneous mutation of the Dock2 gene in Irf5−/− mice complicates interpretation of type I interferon production and antibody responses. Proc Natl Acad Sci U S A. 2012, 109 (15): E898-904.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Miller FW, Alfredsson L, Costenbader KH, Kamen DL, Nelson LM, Norris JM, De Roos AJ: Epidemiology of environmental exposures and human autoimmune diseases: findings from a National Institute of Environmental Health Sciences Expert Panel Workshop. J Autoimmun. 2012, 39 (4): 253-258.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 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 (1): 11.

    PubMed  PubMed Central  Google Scholar 

  113. Pollard KM, Hultman P: Skin-lightening creams are a possible exposure risk for systemic lupus erythematosus: comment on the article by Finckh et al. Arthritis Rheum. 2007, 56 (5): 1721-author reply 1721–1722

    PubMed  Google Scholar 

  114. 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 (1): 234-240.

    CAS  PubMed  Google Scholar 

  115. Balomenos D, Rumold R, Theofilopoulos AN: Interferon-gamma is required for lupus-like disease and lymphoaccumulation in MRL-lpr mice. J Clin Invest. 1998, 101 (2): 364-371.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Pollard KM, Arnush M, Hultman P, Kono DH: Costimulation requirements of induced murine systemic autoimmune disease. J Immunol. 2004, 173 (9): 5880-5887.

    CAS  PubMed  Google Scholar 

  117. Tada Y, Nagasawa K, Ho A, Morito F, Koarada S, Ushiyama O, Suzuki N, Ohta A, Mak TW: Role of the costimulatory molecule CD28 in the development of lupus in MRL/lpr mice. J Immunol. 1999, 163 (6): 3153-3159.

    CAS  PubMed  Google Scholar 

  118. Reilly CM, Olgun S, Goodwin D, Gogal RM, Santo A, Romesburg JW, Ahmed SA, Gilkeson GS: Interferon regulatory factor-1 gene deletion decreases glomerulonephritis in MRL/lpr mice. Eur J Immunol. 2006, 36 (5): 1296-1308.

    CAS  PubMed  Google Scholar 

  119. Blasius AL, Arnold CN, Georgel P, Rutschmann S, Xia Y, Lin P, Ross C, Li XH, Smart NG, Beutler B: Slc15a4, AP-3, and Hermansky-Pudlak syndrome proteins are required for Toll-like receptor signaling in plasmacytoid dendritic cells. P Natl Acad Sci USA. 2010, 107 (46): 19973-19978.

    CAS  Google Scholar 

  120. Abedi-Valugerdi M, Nilsson C, Zargari A, Gharibdoost F, DePierre JW, Hassan M: Bacterial lipopolysaccharide both renders resistant mice susceptible to mercury-induced autoimmunity and exacerbates such autoimmunity in susceptible mice. Clin Exp Immunol. 2005, 141 (2): 238-247.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Kim YM, Brinkmann MM, Paquet ME, Ploegh HL: UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes. Nature. 2008, 452 (7184): 234-238.

    CAS  PubMed  Google Scholar 

  122. Wu T, Qin X, Kurepa Z, Kumar KR, Liu K, Kanta H, Zhou XJ, Satterthwaite AB, Davis LS, Mohan C: Shared signaling networks active in B cells isolated from genetically distinct mouse models of lupus. J Clin Invest. 2007, 117 (8): 2186-2196.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Endo T, Nishio M, Enzler T, Cottam HB, Fukuda T, James DF, Karin M, Kipps TJ: BAFF and APRIL support chronic lymphocytic leukemia B-cell survival through activation of the canonical NF-kappaB pathway. Blood. 2007, 109 (2): 703-710.

    CAS  PubMed  Google Scholar 

  124. Pone EJ, Zhang J, Mai T, White CA, Li G, Sakakura JK, Patel PJ, Al-Qahtani A, Zan H, Xu Z, Casali P: BCR-signalling synergizes with TLR-signalling for induction of AID and immunoglobulin class-switching through the non-canonical NF-kappaB pathway. Nat Commun. 2012, 3: 767.

    PubMed  PubMed Central  Google Scholar 

  125. 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 (3): 581-593.

    CAS  PubMed  Google Scholar 

  126. Havarinasab S, Pollard KM, Hultman P: Gold- and silver-induced murine autoimmunity–requirement for cytokines and CD28 in murine heavy metal-induced autoimmunity. Clin Exp Immunol. 2009, 155 (3): 567-576.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Thomas CR, Kelley TR: A brief review of silicosis in the United States. Environ Health Insights. 2010, 4: 21-26.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Leung CC, Yu IT, Chen W: Silicosis. Lancet. 2012, 379 (9830): 2008-2018.

    CAS  PubMed  Google Scholar 

  129. Cooper GS, Wither J, Bernatsky S, Claudio JO, Clarke A, Rioux JD, Fortin PR: Occupational and environmental exposures and risk of systemic lupus erythematosus: silica, sunlight, solvents. Rheumatology (Oxford). 2010, 49 (11): 2172-2180.

    CAS  Google Scholar 

  130. Finckh A, Cooper GS, Chibnik LB, Costenbader KH, Watts J, Pankey H, Fraser PA, Karlson EW: Occupational silica and solvent exposures and risk of systemic lupus erythematosus in urban women. Arthritis Rheum. 2006, 54 (11): 3648-3654.

    PubMed  Google Scholar 

  131. Makol A, Reilly MJ, Rosenman KD: Prevalence of connective tissue disease in silicosis (1985–2006) - a report from the state of Michigan surveillance system for silicosis. Am J Ind Med. 2011, 54 (4): 255-262.

    PubMed  Google Scholar 

  132. Masson C, Audran M, Pascaretti C, Chevailler A, Subra JF, Tuchais E, Kahn MF: Silica-associated systemic erythematosus lupus or mineral dust lupus?. Lupus. 1997, 6 (1): 1-3.

    CAS  PubMed  Google Scholar 

  133. Conrad K, Mehlhorn J: Diagnostic and prognostic relevance of autoantibodies in uranium miners. Int Arch Allergy Immunol. 2000, 123 (1): 77-91.

    CAS  PubMed  Google Scholar 

  134. Conrad K, Mehlhorn J, Luthke K, Dorner T, Frank KH: Systemic lupus erythematosus after heavy exposure to quartz dust in uranium mines: clinical and serological characteristics. Lupus. 1996, 5 (1): 62-69.

    CAS  PubMed  Google Scholar 

  135. Brown JM, Pfau JC, Holian A: Immunoglobulin and lymphocyte responses following silica exposure in New Zealand mixed mice. Inhal Toxicol. 2004, 16 (3): 133-139.

    CAS  PubMed  Google Scholar 

  136. 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 (3): 415-421.

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Pfau JC, Sentissi JJ, Li S, Calderon-Garciduenas L, Brown JM, Blake DJ: Asbestos-induced autoimmunity in C57BL/6 mice. J Immunotoxicol. 2008, 5 (2): 129-137.

    CAS  PubMed  Google Scholar 

  138. Al-Mogairen SM, Al-Arfaj AS, Meo SA, Adam M, Al-Hammad A, Gad El Rab MO: Induction of autoimmunity in Brown Norway rats by oral and parenteral administration of sodium silicate. Lupus. 2009, 18 (5): 413-417.

    CAS  PubMed  Google Scholar 

  139. Maeda M, Nishimura Y, Kumagai N, Hayashi H, Hatayama T, Katoh M, Miyahara N, Yamamoto S, Hirastuka J, Otsuki T: Dysregulation of the immune system caused by silica and asbestos. J Immunotoxicol. 2010, 7 (4): 268-278.

    CAS  PubMed  Google Scholar 

  140. 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 (4): 261-268.

    CAS  PubMed  Google Scholar 

  141. Blake DJ, Wetzel SA, Pfau JC: Autoantibodies from mice exposed to Libby amphibole asbestos bind SSA/Ro52-enriched apoptotic blebs of murine macrophages. Toxicology. 2008, 246 (2–3): 172-179.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Cassel SL, Eisenbarth SC, Iyer SS, Sadler JJ, Colegio OR, Tephly LA, Carter AB, Rothman PB, Flavell RA, Sutterwala FS: The Nalp3 inflammasome is essential for the development of silicosis. Proc Natl Acad Sci U S A. 2008, 105 (26): 9035-9040.

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Beamer CA, Migliaccio CT, Jessop F, Trapkus M, Yuan D, Holian A: Innate immune processes are sufficient for driving silicosis in mice. J Leukoc Biol. 2010, 88 (3): 547-557.

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Beamer CA, Holian A: Silica suppresses Toll-like receptor ligand-induced dendritic cell activation. Faseb J. 2008, 22 (6): 2053-2063.

    CAS  PubMed  Google Scholar 

  145. Lacher SE, Johnson C, Jessop F, Holian A, Migliaccio CT: Murine pulmonary inflammation model: a comparative study of anesthesia and instillation methods. Inhal Toxicol. 2010, 22 (1): 77-83.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Davis GS, Holmes CE, Pfeiffer LM, Hemenway DR: Lymphocytes, lymphokines, and silicosis. J Environ Pathol Toxicol Oncol. 2001, 20 (Suppl 1): 53-65.

    CAS  PubMed  Google Scholar 

  147. Misson P, Brombacher F, Delos M, Lison D, Huaux F: Type 2 immune response associated with silicosis is not instrumental in the development of the disease. Am J Physiol Lung Cell Mol Physiol. 2007, 292 (1): L107-113.

    CAS  PubMed  Google Scholar 

  148. Davis GS, Pfeiffer LM, Hemenway DR, Rincon M: Interleukin-12 is not essential for silicosis in mice. Part Fibre Toxicol. 2006, 3: 2.

    PubMed  PubMed Central  Google Scholar 

  149. Lo Re S, Dumoutier L, Couillin I, Van Vyve C, Yakoub Y, Uwambayinema F, Marien B, van den Brule S, Van Snick J, Uyttenhove C, Ryffel B, Renauld JC, Lison D, Huaux F: IL-17A-producing gammadelta T and Th17 lymphocytes mediate lung inflammation but not fibrosis in experimental silicosis. J Immunol. 2010, 184 (11): 6367-6377.

    CAS  PubMed  Google Scholar 

  150. Giordano G, van den Brule S, Lo Re S, Triqueneaux P, Uwambayinema F, Yakoub Y, Couillin I, Ryffel B, Michiels T, Renauld JC, Lison D, Huaux F: Type I interferon signaling contributes to chronic inflammation in a murine model of silicosis. Toxicol Sci. 2010, 116 (2): 682-692.

    CAS  PubMed  Google Scholar 

  151. 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 (5876): 674-677.

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Biswas R, Bunderson-Schelvan M, Holian A: Potential role of the inflammasome-derived inflammatory cytokines in pulmonary fibrosis. Pulm Med. 2011, 2011: 105707.

    PubMed  PubMed Central  Google Scholar 

  153. Srivastava KD, Rom WN, Jagirdar J, Yie TA, Gordon T, Tchou-Wong KM: Crucial role of interleukin-1beta and nitric oxide synthase in silica-induced inflammation and apoptosis in mice. Am J Respir Crit Care Med. 2002, 165 (4): 527-533.

    PubMed  Google Scholar 

  154. Thakur SA, Beamer CA, Migliaccio CT, Holian A: Critical role of MARCO in crystalline silica-induced pulmonary inflammation. Toxicol Sci. 2009, 108 (2): 462-471.

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Beamer CA, Holian A: Scavenger receptor class A type I/II (CD204) null mice fail to develop fibrosis following silica exposure. Am J Physiol Lung Cell Mol Physiol. 2005, 289 (2): L186-195.

    CAS  PubMed  Google Scholar 

  156. 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 (4): 1982-1990.

    CAS  PubMed  Google Scholar 

  157. Wermeling F, Chen Y, Pikkarainen T, Scheynius A, Winqvist O, Izui S, Ravetch JV, Tryggvason K, Karlsson MC: Class A scavenger receptors regulate tolerance against apoptotic cells, and autoantibodies against these receptors are predictive of systemic lupus. J Exp Med. 2007, 204 (10): 2259-2265.

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Gaipl US, Munoz LE, Grossmayer G, Lauber K, Franz S, Sarter K, Voll RE, Winkler T, Kuhn A, Kalden J, Kern P, Herrmann M: Clearance deficiency and systemic lupus erythematosus (SLE). J Autoimmun. 2007, 28 (2–3): 114-121.

    PubMed  Google Scholar 

  159. Munoz LE, Gaipl US, Franz S, Sheriff A, Voll RE, Kalden JR, Herrmann M: SLE–a disease of clearance deficiency?. Rheumatology (Oxford). 2005, 44 (9): 1101-1107.

    CAS  Google Scholar 

  160. Honda K, Ohba Y, Yanai H, Negishi H, Mizutani T, Takaoka A, Taya C, Taniguchi T: Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Nature. 2005, 434 (7036): 1035-1040.

    CAS  PubMed  Google Scholar 

  161. Guiducci C, Ott G, Chan JH, Damon E, Calacsan C, Matray T, Lee KD, Coffman RL, Barrat FJ: Properties regulating the nature of the plasmacytoid dendritic cell response to Toll-like receptor 9 activation. J Exp Med. 2006, 203 (8): 1999-2008.

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Kerkmann M, Rothenfusser S, Hornung V, Towarowski A, Wagner M, Sarris A, Giese T, Endres S, Hartmann G: Activation with CpG-A and CpG-B oligonucleotides reveals two distinct regulatory pathways of type I IFN synthesis in human plasmacytoid dendritic cells. J Immunol. 2003, 170 (9): 4465-4474.

    CAS  PubMed  Google Scholar 

  163. Saitoh T, Satoh T, Yamamoto N, Uematsu S, Takeuchi O, Kawai T, Akira S: Antiviral protein Viperin promotes Toll-like receptor 7- and Toll-like receptor 9-mediated type I interferon production in plasmacytoid dendritic cells. Immunity. 2011, 34 (3): 352-363.

    CAS  PubMed  Google Scholar 

  164. Christensen MM: Histochemical localization of autometallographically detectable mercury in tissues of the immune system from mice exposed to mercuric chloride. Histochem J. 1996, 28 (3): 217-225.

    CAS  PubMed  Google Scholar 

  165. Villegas J, Martinez R, Andres A, Crespo D: Accumulation of mercury in neurosecretory neurons of mice after long-term exposure to oral mercuric chloride. Neurosci Lett. 1999, 271 (2): 93-96.

    CAS  PubMed  Google Scholar 

  166. Hamilton RF, Thakur SA, Holian A: Silica binding and toxicity in alveolar macrophages. Free Radic Biol Med. 2008, 44 (7): 1246-1258.

    CAS  PubMed  Google Scholar 

  167. Costantini LM, Gilberti RM, Knecht DA: The phagocytosis and toxicity of amorphous silica. PLoS One. 2011, 6 (2): e14647.

    CAS  PubMed  PubMed Central  Google Scholar 

  168. 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 (4): 2263-2270.

    CAS  PubMed  Google Scholar 

  169. Herman S, Kny A, Schorn C, Pfatschbacher J, Niederreiter B, Herrmann M, Holmdahl R, Steiner G, Hoffmann MH: Cell death and cytokine production induced by autoimmunogenic hydrocarbon oils. Autoimmunity. 2012, 45 (8): 602-611.

    CAS  PubMed  Google Scholar 

  170. Hamilton RF, Thakur SA, Mayfair JK, Holian A: MARCO mediates silica uptake and toxicity in alveolar macrophages from C57BL/6 mice. J Biol Chem. 2006, 281 (45): 34218-34226.

    CAS  PubMed  Google Scholar 

  171. Ben-Sasson SZ, Hu-Li J, Quiel J, Cauchetaux S, Ratner M, Shapira I, Dinarello CA, Paul WE: IL-1 acts directly on CD4 T cells to enhance their antigen-driven expansion and differentiation. Proc Natl Acad Sci U S A. 2009, 106 (17): 7119-7124.

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Hurgin V, Novick D, Werman A, Dinarello CA, Rubinstein M: Antiviral and immunoregulatory activities of IFN-gamma depend on constitutively expressed IL-1alpha. Proc Natl Acad Sci U S A. 2007, 104 (12): 5044-5049.

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Rider P, Carmi Y, Guttman O, Braiman A, Cohen I, Voronov E, White MR, Dinarello CA, Apte RN: IL-1alpha and IL-1beta recruit different myeloid cells and promote different stages of sterile inflammation. J Immunol. 2011, 187 (9): 4835-4843.

    CAS  PubMed  Google Scholar 

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  1. Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA

    Kenneth Michael Pollard

  2. Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, 92037, USA

    Dwight H Kono

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This review is an expanded version of a presentation given at the 8th International Congress on Autoimmunity in Granada, Spain in 2012. KMP and DHK designed the review and concepts and drafted the manuscript. Both authors read and approved the final manuscript.

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Pollard, K.M., Kono, D.H. Requirements for innate immune pathways in environmentally induced autoimmunity. BMC Med 11, 100 (2013). https://0-doi-org.brum.beds.ac.uk/10.1186/1741-7015-11-100

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