• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of bmcmedicineBioMed Centralsearchsubmit a manuscriptregisterthis articleBMC Medicine
BMC Med. 2013; 11: 100.
Published online Apr 4, 2013. doi:  10.1186/1741-7015-11-100
PMCID: PMC3616845

Requirements for innate immune pathways in environmentally induced autoimmunity

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.

Keywords: Autoimmunity, Environment, Innate immunity, Lupus, mercury, Pristane, Silica, Type I interferon

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-Faslpr 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-Faslpr mice reduces disease severity [28]. Deficiency of macrophage migration inhibitory factor reduces macrophage recruitment and glomerulonephritis in MRL-Faslpr mice [29]. Cultured in the presence of serum, macrophages from MRL-Faslpr 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-Faslpr[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-Faslpr, 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-Faslpr 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-Faslpr, BXSB [46] and MRL-Faslpr (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-Faslpr 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
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 ...

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.

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.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

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.

Pre-publication history

The pre-publication history for this paper can be accessed here:

http://www.biomedcentral.com/1741-7015/11/100/prepub

References

  • Ronald PC, Beutler B. Plant and animal sensors of conserved microbial signatures. Science. 2010;11(6007):1061–1064. [PubMed]
  • Iwasaki A, Medzhitov R. Regulation of adaptive immunity by the innate immune system. Science. 2010;11(5963):291–295. [PMC free article] [PubMed]
  • Mills KH. TLR-dependent T cell activation in autoimmunity. Nat Rev Immunol. 2011;11(12):807–822. [PubMed]
  • Theofilopoulos AN, Kono DH, Beutler B, Baccala R. Intracellular nucleic acid sensors and autoimmunity. J Interferon Cytokine Res. 2011;11(12):867–886. [PMC free article] [PubMed]
  • 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;11(3):146–156. [PubMed]
  • Pollard KM, Hultman P, Kono DH. Toxicology of autoimmune diseases. Chem Res Toxicol. 2010;11(3):455–466. [PMC free article] [PubMed]
  • Pollard KM, Hultman P, Kono DH. Immunology and genetics of induced systemic autoimmunity. Autoimmun Rev. 2005;11(5):282–288. [PubMed]
  • 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;11(4):323–331. [PMC free article] [PubMed]
  • 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;11(8):448–456. [PubMed]
  • Newton K, Dixit VM. Signaling in innate immunity and inflammation. Cold Spring Harb Perspect Biol. 2012;11(3):pii:a006049. [PMC free article] [PubMed]
  • Hahn BH. Targeted therapies in systemic lupus erythematosus: successes, failures and future. Ann Rheum Dis. 2011;11(Suppl 1):i64–i66. [PubMed]
  • Kono DH, Theofilopoulos AN. Genetics of SLE in mice. Springer Semin Immunopathol. 2006;11(2):83–96. [PubMed]
  • Shlomchik MJ, Craft JE, Mamula MJ. From T to B and back again: positive feedback in systemic autoimmune disease. Nat Rev Immunol. 2001;11(2):147–153. [PubMed]
  • Goodnow CC, Sprent J, Fazekas-de-St-Groth B, Vinuesa CG. Cellular and genetic mechanisms of self tolerance and autoimmunity. Nature. 2005;11(7042):590–597. [PubMed]
  • 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;11(5):543–551. [PubMed]
  • Diana J, Gahzarian L, Simoni Y, Lehuen A. Innate immunity in type 1 diabetes. Discov Med. 2011;11(61):513–520. [PubMed]
  • Obermoser G, Pascual V. The interferon-alpha signature of systemic lupus erythematosus. Lupus. 2010;11(9):1012–1019. [PMC free article] [PubMed]
  • 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;11(12):F59–63. [PMC free article] [PubMed]
  • 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;11(11):2029–2036. [PubMed]
  • Crow MK. Type I interferon in organ-targeted autoimmune and inflammatory diseases. Arthritis Res Ther. 2010;11(Suppl 1):S5. [PMC free article] [PubMed]
  • Theofilopoulos AN, Baccala R, Beutler B, Kono DH. TYPE I Interferons (alpha/beta) in immunity and autoimmunity. Annu Rev Immunol. 2005;11:307–335. [PubMed]
  • Bar-On L, Jung S. Defining dendritic cells by conditional and constitutive cell ablation. Immunol Rev. 2010;11(1):76–89. [PubMed]
  • Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K. Development of monocytes, macrophages, and dendritic cells. Science. 2010;11(5966):656–661. [PMC free article] [PubMed]
  • Gilliet M, Cao W, Liu YJ. Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases. Nat Rev Immunol. 2008;11(8):594–606. [PubMed]
  • 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;11(6):967–978. [PMC free article] [PubMed]
  • 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;11(8):2940–2945. [PMC free article] [PubMed]
  • Li Y, Lee PY, Reeves WH. Monocyte and macrophage abnormalities in systemic lupus erythematosus. Arch Immunol Ther Exp (Warsz) 2010;11(5):355–364. [PMC free article] [PubMed]
  • 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;11(7):4744–4754. [PubMed]
  • 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;11(8):5687–5696. [PubMed]
  • 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;11(5):291–308. [PMC free article] [PubMed]
  • 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;11(2):902–915. [PMC free article] [PubMed]
  • 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;11(8):4738–4749. [PMC free article] [PubMed]
  • Elkon KB, Santer DM. Complement, interferon and lupus. Curr Opin Immunol. 2012;11(6):665–670. [PubMed]
  • Braun D, Geraldes P, Demengeot J. Type I interferon controls the onset and severity of autoimmune manifestations in lpr mice. J Autoimmun. 2003;11(1):15–25. [PubMed]
  • 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;11(7):555–567. [PubMed]
  • 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;11(7):3012–3017. [PMC free article] [PubMed]
  • 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;11(5):2499–2506. [PubMed]
  • 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;11(1):219–229. [PMC free article] [PubMed]
  • 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;11(4):1096–1101. [PMC free article] [PubMed]
  • 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;11(7):1948–1960. [PMC free article] [PubMed]
  • 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;11(6):777–788. [PMC free article] [PubMed]
  • 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;11(9):6021–6029. [PMC free article] [PubMed]
  • Hron JD, Peng SL. Type I IFN protects against murine lupus. J Immunol. 2004;11(3):2134–2142. [PubMed]
  • 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;11(12):5976–5984. [PMC free article] [PubMed]
  • 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;11(7034):772–777. [PubMed]
  • 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;11(29):12061–12066. [PMC free article] [PubMed]
  • Marshak-Rothstein A. Toll-like receptors in systemic autoimmune disease. Nat Rev Immunol. 2006;11(11):823–835. [PubMed]
  • Wu X, Peng SL. Toll-like receptor 9 signaling protects against murine lupus. Arthritis Rheum. 2006;11(1):336–342. [PubMed]
  • Santiago-Raber ML, Baudino L, Izui S. Emerging roles of TLR7 and TLR9 in murine SLE. J Autoimmun. 2009;11(3–4):231–238. [PubMed]
  • 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;11(2):321–331. [PMC free article] [PubMed]
  • 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;11(5):1618–1628. [PubMed]
  • 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;11(4):339–348. [PubMed]
  • 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;11(4):1840–1848. [PubMed]
  • 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;11(3):417–428. [PubMed]
  • 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;11(2):156–164. [PubMed]
  • Sasai M, Linehan MM, Iwasaki A. Bifurcation of Toll-like receptor 9 signaling by adaptor protein 3. Science. 2010;11(5998):1530–1534. [PMC free article] [PubMed]
  • 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. [PubMed]
  • Kawai T, Akira S. Signaling to NF-kappaB by Toll-like receptors. Trends Mol Med. 2007;11(11):460–469. [PubMed]
  • 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;11(3):296–305. [PMC free article] [PubMed]
  • Kiberd BA. Interleukin-6 receptor blockage ameliorates murine lupus nephritis. J Am Soc Nephrol. 1993;11(1):58–61. [PubMed]
  • 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;11(5):927–937. [PMC free article] [PubMed]
  • 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;11(1):60–70. [PubMed]
  • Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol. 2009;11:519–550. [PubMed]
  • 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;11(1):118–124. [PubMed]
  • 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;11(7):495–503. [PubMed]
  • 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;11(Spec No):C117–120. [PubMed]
  • 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;11(1):18–20. 24. [PubMed]
  • 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;11(2):131–137. [PubMed]
  • Jacob CO, McDevitt HO. Tumour necrosis factor-alpha in murine autoimmune 'lupus' nephritis. Nature. 1988;11(6154):356–358. [PubMed]
  • 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;11(3):421–434. [PubMed]
  • 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;11(7):2038–2047. [PubMed]
  • 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;11(4):2532–2541. [PMC free article] [PubMed]
  • 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;11(10):3399–3408. [PMC free article] [PubMed]
  • Rubin RL. Drug-induced lupus. Toxicology. 2005;11(2):135–147. [PubMed]
  • Pollard KM. Gender differences in autoimmunity associated with exposure to environmental factors. J Autoimmun. 2012;11(2–3):J177–186. [PMC free article] [PubMed]
  • 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;11(4):253–258. [PMC free article] [PubMed]
  • 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;11(4):285–293. [PMC free article] [PubMed]
  • Gualtierotti R, Biggioggero M, Penatti AE, Meroni PL. Updating on the pathogenesis of systemic lupus erythematosus. Autoimmun Rev. 2010;11(1):3–7. [PubMed]
  • 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;11(3):439–444. [PMC free article] [PubMed]
  • 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;11(4):345–354. [PMC free article] [PubMed]
  • 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;11(4):316–318. [PubMed]
  • Parks CG, Cooper GS. Occupational exposures and risk of systemic lupus erythematosus. Autoimmunity. 2005;11(7):497–506. [PubMed]
  • 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;11(7):1840–1850. [PubMed]
  • Reeves WH, Lee PY, Weinstein JS, Satoh M, Lu L. Induction of autoimmunity by pristane and other naturally occurring hydrocarbons. Trends Immunol. 2009;11(9):455–464. [PMC free article] [PubMed]
  • Anderson PN, Potter M. Induction of plasma cell tumours in BALB-c mice with 2,6,10,14-tetramethylpentadecane (pristane) Nature. 1969;11(5197):994–995. [PubMed]
  • 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;11(6):2173–2180. [PubMed]
  • 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;11(5):985–990. [PMC free article] [PubMed]
  • 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;11(3):897–905. [PubMed]
  • Shoenfeld Y, Agmon-Levin N. 'ASIA' - autoimmune/inflammatory syndrome induced by adjuvants. J Autoimmun. 2011;11(1):4–8. [PubMed]
  • 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;11(5):2610–2615. [PMC free article] [PubMed]
  • 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;11(4):1227–1240. [PMC free article] [PubMed]
  • 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;11(11):3770–3783. [PMC free article] [PubMed]
  • 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;11(13):2995–3006. [PMC free article] [PubMed]
  • 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;11(4):1107–1115. [PubMed]
  • 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;11(4):291–298. [PubMed]
  • 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. [PMC free article] [PubMed]
  • 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;11(7):5101–5108. [PMC free article] [PubMed]
  • 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;11(5):2023–2033. [PMC free article] [PubMed]
  • 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;11(3):1747–1754. [PMC free article] [PubMed]
  • Bryant C, Fitzgerald KA. Molecular mechanisms involved in inflammasome activation. Trends Cell Biol. 2009;11(9):455–464. [PubMed]
  • Weber A, Wasiliew P, Kracht M. Interleukin-1 (IL-1) pathway. Sci Signal. 2010;11(105):cm1. [PubMed]
  • Hu W, Ren H. A meta-analysis of the association of IRF5 polymorphism with systemic lupus erythematosus. Int J Immunogenet. 2011;11(5):411–417. [PubMed]
  • 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;11(7030):243–249. [PubMed]
  • 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;11(10):6003–6012. [PMC free article] [PubMed]
  • 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;11(9):3402–3407. [PMC free article] [PubMed]
  • 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;11(8):4113–4121. [PMC free article] [PubMed]
  • 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;11(22):10154–10159. [PMC free article] [PubMed]
  • 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;11(6):1477–1487. [PMC free article] [PubMed]
  • 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;11(7):3741–3750. [PMC free article] [PubMed]
  • 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;11(15):E898–904. [PMC free article] [PubMed]
  • 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;11(4):253–258.
  • 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;11(1):11. [PMC free article] [PubMed]
  • 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;11(5):1721. author reply 1721–1722. [PubMed]
  • 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;11(1):234–240. [PubMed]
  • Balomenos D, Rumold R, Theofilopoulos AN. Interferon-gamma is required for lupus-like disease and lymphoaccumulation in MRL-lpr mice. J Clin Invest. 1998;11(2):364–371. [PMC free article] [PubMed]
  • Pollard KM, Arnush M, Hultman P, Kono DH. Costimulation requirements of induced murine systemic autoimmune disease. J Immunol. 2004;11(9):5880–5887. [PubMed]
  • 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;11(6):3153–3159. [PubMed]
  • Reilly CM, Olgun S, Goodwin D, Gogal RM Jr, Santo A, Romesburg JW, Ahmed SA, Gilkeson GS. Interferon regulatory factor-1 gene deletion decreases glomerulonephritis in MRL/lpr mice. Eur J Immunol. 2006;11(5):1296–1308. [PubMed]
  • 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;11(46):19973–19978. [PMC free article] [PubMed]
  • 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;11(2):238–247. [PMC free article] [PubMed]
  • Kim YM, Brinkmann MM, Paquet ME, Ploegh HL. UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes. Nature. 2008;11(7184):234–238. [PubMed]
  • 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;11(8):2186–2196. [PMC free article] [PubMed]
  • 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;11(2):703–710. [PMC free article] [PubMed]
  • 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;11:767. [PMC free article] [PubMed]
  • 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;11(3):581–593. [PubMed]
  • 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;11(3):567–576. [PMC free article] [PubMed]
  • Thomas CR, Kelley TR. A brief review of silicosis in the United States. Environ Health Insights. 2010;11:21–26. [PMC free article] [PubMed]
  • Leung CC, Yu IT, Chen W. Silicosis. Lancet. 2012;11(9830):2008–2018. [PubMed]
  • 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;11(11):2172–2180. [PMC free article] [PubMed]
  • 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;11(11):3648–3654. [PubMed]
  • 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;11(4):255–262. [PubMed]
  • 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;11(1):1–3. [PubMed]
  • Conrad K, Mehlhorn J. Diagnostic and prognostic relevance of autoantibodies in uranium miners. Int Arch Allergy Immunol. 2000;11(1):77–91. [PubMed]
  • 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;11(1):62–69. [PubMed]
  • Brown JM, Pfau JC, Holian A. Immunoglobulin and lymphocyte responses following silica exposure in New Zealand mixed mice. Inhal Toxicol. 2004;11(3):133–139. [PubMed]
  • Brown JM, Archer AJ, Pfau JC, Holian A. Silica accelerated systemic autoimmune disease in lupus-prone New Zealand mixed mice. Clin Exp Immunol. 2003;11(3):415–421. [PMC free article] [PubMed]
  • Pfau JC, Sentissi JJ, Li S, Calderon-Garciduenas L, Brown JM, Blake DJ. Asbestos-induced autoimmunity in C57BL/6 mice. J Immunotoxicol. 2008;11(2):129–137. [PubMed]
  • 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;11(5):413–417. [PubMed]
  • 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;11(4):268–278. [PubMed]
  • 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;11(4):261–268. [PubMed]
  • 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;11(2–3):172–179. [PMC free article] [PubMed]
  • 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;11(26):9035–9040. [PMC free article] [PubMed]
  • 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;11(3):547–557. [PMC free article] [PubMed]
  • Beamer CA, Holian A. Silica suppresses Toll-like receptor ligand-induced dendritic cell activation. Faseb J. 2008;11(6):2053–2063. [PubMed]
  • 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;11(1):77–83. [PubMed]
  • Davis GS, Holmes CE, Pfeiffer LM, Hemenway DR. Lymphocytes, lymphokines, and silicosis. J Environ Pathol Toxicol Oncol. 2001;11(Suppl 1):53–65. [PubMed]
  • 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;11(1):L107–113. [PubMed]
  • Davis GS, Pfeiffer LM, Hemenway DR, Rincon M. Interleukin-12 is not essential for silicosis in mice. Part Fibre Toxicol. 2006;11:2. [PMC free article] [PubMed]
  • 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;11(11):6367–6377. [PubMed]
  • 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;11(2):682–692. [PubMed]
  • 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;11(5876):674–677. [PMC free article] [PubMed]
  • Biswas R, Bunderson-Schelvan M, Holian A. Potential role of the inflammasome-derived inflammatory cytokines in pulmonary fibrosis. Pulm Med. 2011;11:105707. [PMC free article] [PubMed]
  • 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;11(4):527–533. [PubMed]
  • Thakur SA, Beamer CA, Migliaccio CT, Holian A. Critical role of MARCO in crystalline silica-induced pulmonary inflammation. Toxicol Sci. 2009;11(2):462–471. [PMC free article] [PubMed]
  • 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;11(2):L186–195. [PubMed]
  • 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;11(4):1982–1990. [PubMed]
  • 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;11(10):2259–2265. [PMC free article] [PubMed]
  • 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;11(2–3):114–121. [PubMed]
  • Munoz LE, Gaipl US, Franz S, Sheriff A, Voll RE, Kalden JR, Herrmann M. SLE–a disease of clearance deficiency? Rheumatology (Oxford) 2005;11(9):1101–1107. [PubMed]
  • 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;11(7036):1035–1040. [PubMed]
  • 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;11(8):1999–2008. [PMC free article] [PubMed]
  • 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;11(9):4465–4474. [PubMed]
  • 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;11(3):352–363. [PubMed]
  • Christensen MM. Histochemical localization of autometallographically detectable mercury in tissues of the immune system from mice exposed to mercuric chloride. Histochem J. 1996;11(3):217–225. [PubMed]
  • 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;11(2):93–96. [PubMed]
  • Hamilton RF Jr, Thakur SA, Holian A. Silica binding and toxicity in alveolar macrophages. Free Radic Biol Med. 2008;11(7):1246–1258. [PMC free article] [PubMed]
  • Costantini LM, Gilberti RM, Knecht DA. The phagocytosis and toxicity of amorphous silica. PLoS One. 2011;11(2):e14647. [PMC free article] [PubMed]
  • 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;11(4):2263–2270. [PubMed]
  • 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;11(8):602–611. [PubMed]
  • Hamilton RF Jr, Thakur SA, Mayfair JK, Holian A. MARCO mediates silica uptake and toxicity in alveolar macrophages from C57BL/6 mice. J Biol Chem. 2006;11(45):34218–34226. [PubMed]
  • 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;11(17):7119–7124. [PMC free article] [PubMed]
  • 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;11(12):5044–5049. [PMC free article] [PubMed]
  • 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;11(9):4835–4843. [PubMed]

Articles from BMC Medicine are provided here courtesy of BioMed Central

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • EST
    EST
    Published EST sequences
  • MedGen
    MedGen
    Related information in MedGen
  • Nucleotide
    Nucleotide
    Published Nucleotide sequences
  • PubMed
    PubMed
    PubMed citations for these articles

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...