The Role of T Helper (TH)17 Cells as a Double-Edged Sword in the Interplay of Infection and Autoimmunity with a Focus on Xenobiotic-Induced Immunomodulation

Extensive research in recent years suggests that exposure to xenobiotic stimuli plays a critical role in autoimmunity induction and severity and that the resulting response would be exacerbated in individuals with an infection-aroused immune system. In this context, heavy metals constitute a prominent category of xenobiotic substances, known to alter divergent immune cell responses in accidentally and occupationally exposed individuals, thereby increasing the susceptibility to autoimmunity and cancer, especially when accompanied by inflammation-triggered persistent sensitization. This perception is learned from experimental models of infection and epidemiologic studies and clearly underscores the interplay of exposure to such immunomodulatory elements with pre- or postexposure infectious events. Further, the TH17 cell subset, known to be associated with a growing list of autoimmune manifestations, may be the “superstar” at the interface of xenobiotic exposure and autoimmunity. In this review, the most recently established links to this nomination are short-listed to create a framework to better understand new insights into TH17's contributions to autoimmunity.


Introduction
Long-term exposure to xenobiotic substances induces hyperactivity of the immune system, thereby increasing the incidence of autoimmune diseases (AD), especially in infectionaroused systems. Circumstances dating back to earlier exposure, as in case of heavy-metal industry workers or current exposure as in individuals harboring amalgam teeth filling, favor incidence of inflammatory processes and most likely AD [1][2][3][4]. Exposure to infectious agents leads to the induction of various cellular pathways essential to the microbe's infectivity, survival, and virulence, thus making it difficult for the microbe to go undetected by the host's immune system [5]. Upon pathogen recognition, production of a proinflammatory response, primarily by macrophages, NK and NKT cells, is the subsequent event in the early phase of the infection [5,6]. Further, the coordination between innate and adaptive immune defense systems ensures a successful eradication of pathogens, and such developed cytokine milieu determines the induction of a specific T-cell-mediated response that is critical for an effective and complete pathogen clearance. However, whether the induction of a strong host inflammation constitutes an adaptive advantage to the host or pathogen remains debated. Indeed, many disorders, including AD [7] and cancer [8], are associated with and maintained by chronic inflammation; for review, see [9,10]. The association of cancer incidence with exposure to heavy metals, such as cadmium [11], or following attainment of chronic inflammation, as in case of colitis-associated cancer, has been widely anticipated.
Research on T H 17 cells has suggested a crucial role in autoimmunity. Despite developing autoimmune signs in the absence of detectable IL-17 levels, as in case of choriomeningitis-virus-induced model of type 1 diabetes [12], a key role of T H 17 cells and their related molecules was underscored in many previously assigned "T H 1-mediated" AD including rheumatoid arthritis (RA), psoriasis, systemic lupus erythematosus (SLE), and multiple sclerosis (MS), as well as, the experimental autoimmune encephalomyelitis-EAE [7,9,[13][14][15]. Variations in disease susceptibility or outcome may be a result of co-exposure to one or multiple xenobiotic substances or infectious pathogens, so that a xenobiotic-induced polarized immune response triggers the development of AD in genetically predisposed individuals [1,2,4,[16][17][18][19]. The IL-17 response, while constituting a protective arm defending the body against various infections, also functions as a double-edged sword constituting a risk factor that mediates the development and/or induction of AD, mostly manifested following pathogenic and xenobioticinduced chronic inflammation; it then acts as a double-edged sword, constituting a risk factor that mediates the development and/or induction of AD, mostly manifested following pathogenic and xenobiotic-induced chronic inflammation. In the next sections, we revisit our view on the T H 17 cells' role in autoimmunity [9] and provide a brief description of the double-sided role of T H 17 cells and their related molecules IL-17, IL-21, and IL-22 and their participation at the initiation/induction of autoimmunity as a consequence of xenobiotic exposure.

T H 17 Cells and Their Associated Molecules Link Infection to Autoimmunity
T cells differentiate and expand into distinct lineages including T H 1, T H 2, iT Reg , and T H 17 cells [9], whereas iT Reg cells differentiate under subimmunogenic antigen presentation both during chronic inflammation and under normal homeostatic conditions of the gut and function to control severe chronic allergic inflammation and as a barrier to the eradication of tumors [20,21]. T H 17 cells derive from CD161 + precursors in umbilical cord blood and newborn thymus [22] and likely constitute the most prominent T cell subset at the crossroads of infection and autoimmunity. The contributions of T H 17 cells have prompted and were the results of intensive scientific research, which is reflected by a growing list of publications in this field (Figure 1), and have in turn led to identification of T H 17 cells' markers, as well as, their differentiation and commitment program [23]. Figure 2 demonstrates the major T cell subsets, their interaction with T H 17 cells and the main contributions of the latter. Recently, several groups delivered compelling evidence of the effects of T H 17-associated cytokines, namely IL-17, IL-21, IL-22, and IL-23, on inflammatory responses elicited by extracellular, as well as, facultative and obligate intracellular pathogens including bacteria and fungi. Exemplified contributions of IL-17 response to some infectious diseases are summarized in Table 1.  tissues was attributed to their RorC-dependent expression of the oxidase IL4I1, which impairs CD3 signaling and hence constrains IL-2 production and cell proliferation [24]. As we recently reviewed, the recruitment of T H 17 cells to inflammatory tissues accompanies the expression of the chemokine receptor CCR6, in addition to CCR4, IL-23R (involved in the survival/maturation program of T H 17 cells) [9], and CD161 [22]. T H 17 cells are considered as potent inflammation inducers that, in addition to production of IL-17, differentially produce IL-6, IL-2, IL-8, IL-9, TNF-, IL-17F, IL-21, IL-22, IL-26, IFN-, and the chemokine CCL20 and induce activation and recruitment of other cells including neutrophils that are pivotal in inflammation and AD [9,25]. Through their cytokine/chemokine production, T H 17 cells act on a broad range of cell types initiating the expression of antibodies, metalloproteinases, prostaglandin E2 (PGE 2 ), and antimicrobial peptides and inducing cyclooxygenase 2 activity [9,26], constituting, thereby, a link between innate and adaptive immune responses. In addition to its role as an arm of adaptive immunity, the current perception categorizes IL-17 also as an innate cytokine, produced mainly by NK cells [27] as well as by T cells [28][29][30][31], CD8 + T cells, and mast cells [9,32]. Indeed, detecting functional T H 17 cells and production of protective IL-17 during the early phase of the immune response [33][34][35]   even precedes the differentiation of T H 1 cells [33], together with the later contribution of T H 17 [36], highlight the crucial importance of IL-17 and other T H 17-related cytokines in the early, as well as, the late phase of infection. The upregulation of TLR1 and TLR2 and dectin 1 by IL-17-producing T cells [37] supports this belief. Moreover, studies on nucleotide oligomerization domain knockout mice (Nod1 −/− and Nod2 −/− ) demonstrated that this "early" T H 17 response was Nod1-and Nod2-dependent, and hence they have been given the name innate (i)T H 17 cells [35]. Therefore, the new look of IL-17-producing cells comprises their contribution in building the first line of host defense, besides mediating and shaping adaptive responses required for ultimate clearance.

T 17 Cells-Associated Molecules and Their
Based on a wealth of experimental data, the contribution of T H 17 cells to infection is manifold. As in the case of oral infection, the importance of IL-17 in protection against infection seems to be crucial to attain a mucosal barrier in the intestine as in case of Salmonella [30,38], in mediating protection against oral brucellosis [39], promoting granulopoiesis through induction of granulocyte colonystimulating factor G-CSF [40], and neutrophil influx through inducing neutrophil chemotactic CXCL8 (IL-8), macrophage chemotactic protein (MCP)-1, and macrophage inflammatory proteins-(MIP-) 1 and MIP-2 [9,40,41]. Additionally, we and others found that IL-17 activates phagocytosis and neutrophil cytotoxic activity [42]. Therefore, IL-17R −/− mice  [128] Clinical and Developmental Immunology 5  [135] (5) Nematode infection

Trichinella spiralis Pathogenic
Correlation of T H 17 response with increase of smooth muscle contraction probably causing gut dysfunction; association of IL-17/IL-23 axis induction with increased mortality in mice coinfected with malaria and nematode [136] revealed increased systemic dissemination of S. typhimurium from the gut [29]. The same strategy seems to be attained to combat extracellular pathogens such as Klebsiella pneumoniae [12] and fungal infections (e.g., Candida sp.), mainly due to defective IL-17 immunity [43,44], mediated by eliciting production of autoantibodies (AAs) against IL-17, IL-17F, and IL-22 that contribute to chronic mucocutaneous candidiasis [45,46]. A third arm of T H 17 cells is built through IL-22, which is also produced by other cell types including NK22 and lymphoid tissue inducer cells [47], as well as by skin homing T H 22 cells [48,49]. Besides its accepted role against infection, it induces tissue repair offering protection against injury [49]. Although both IL-22 and IL-17 or IL-17F synergize to stimulate expression of human beta-defensin-(HBD-) 2, S100 calcium binding protein A9 (S100A9) and enhanced the expression of S100A7 and S100A8 [9], IL-22, rather than IL-17, seems to contribute more to the epidermal and mucosal immunity [47,49]. It synergizes with TNFto induce secretion of initial complement factors C1r and C1s, antimicrobial peptides S100A7 and HBD-2, and antimicrobial chemokines CXCL-9/-10/-11 in primary human keratinocytes [50]. In a three-dimensional skin infection model, stimulation of keratinocytes with T H 22 supernatants or by adding IL-22 plus TNF-effectively inhibited C. albicans growth and maintained epithelial survival, and the combinatorial stimulation of keratinocytes with IL-22 plus TNF-most effectively conserved the integrity of the epidermal barrier as compared with IFN-, IL-17, IL-22, or TNFalone [50]. IL-22 also functions to induce an acute phase systemic response that extends beyond IL-22R-expressing cells and revealed diverse significant impact on coagulation and cellular constituents of blood, in addition to induction of thymic atrophy, body weight loss, and renal proximal tubule metabolic activity and biochemical changes in the liver, including induction of fibrinogen, CXCL1, and serum amyloid A [51]. Besides its contribution to protection against bacterial infection [50,52], IL-22 plays an important role in protection against viral infection, for example, hepatitis B virus [53]. On the other side, IL-22 is implicated in the induction of IBD [54] and AD such as experimental autoimmune myocarditis [9] and psoriatic disease through the induction of keratinocyte proliferation and cytokine and chemokine release [7]. This reflects the dark side of the T H 17 story; that is, a promoted T H 17 response may reflect a current or predict incidence of AD.

T 1-T 17 Cells Interaction during Infection.
Although a protective role against intracellular bacteria such as Listeria monocytogenes [55] or S. typhimurium (N. Y. A. Hemdan and A. M. Abu El-Saad, unpublished data) may be attributed to T H 17 response, this may be rather compensatory to a defective IL-12/IFN-axis as previously demonstrated by N. N. Orgun et al. [56], or a complementary function to indirectly induce type 1 response mediated by APCs endowing thereby a protection against infection, as in case of the obligate intracellular bacteria Chlamydia muridarum [57]. In case of infection with S. typhimurium and C. muridarum, neutralizing IL-17 significantly reduced pathogen-specific T H 1 but promoted higher T H 2 responses. DCs isolated from IL-17-neutralized mice demonstrated lower expression of CD40, MHC II, and IL-12 production, but higher level of IL-10 compared with control mice [57]. Furthermore, neutralizing IL-17 in case of S. typhimurium significantly reduced phagocytosis as well as T H 1 cytokine production (N. Y. A. Hemdan and A. M. Abu El-Saad, unpublished data). Moreover, delivery of an IL-17R antagonist that resulted in a 50% reduction in the neutrophilic infiltration in lungs following Chlamydia infection reversed the susceptible phenotype of C3H/HeN mice [58], indicating a key role of IL-17 in induction of neutrophil infiltration. The compromised IL-17 response in HIS (Job's syndrome) patients that contributed to higher susceptibility to Staphylococcus aureus infection [59] is evidenced by a recent finding that coinfection with influenza A abrogated host defense, which was rescued by overexpression of IL-23 and markedly improved bacterial clearance [52]. Influenza A was found to inhibit T H 17 differentiation and substantially decreased IL-17, IL-22, and IL-23 production after S. aureus infection. Interestingly, IL-17-mediated cross-protection against secondary L. monocytogenes infection has been demonstrated following immunization with Mycoplasma pulmonis [60].
In addition to the function of T H 17 cells as a substitute for a defective T H 1 response, synergism between T H 17 and T H 1 cells is proposed following infection or postvaccination challenge with Mycobacterium sp., based on the observation that IL-17 −/− mice revealed a reduced IFN-production by CD4 + T cells and impaired granuloma formation and expression of chemokines CXCL9, CXCL10, and CXCL11 [61]. Also, an enhanced T H 1 memory response in the lungs of vaccinated mice infected with M. tuberculosis was dependent upon IL-23/IL-17 axis [61]. In a model of TCR −/− mouse [62], where adoptive transfer of either T H 1 or T H 17 cells restored bacterial burdens and innate immune cell infiltrates to wild-type animals level, T H 17 transferred cells revealed plasticity within the CNS compartment with an ultimate T H 1-like cytokine profile, and this might be the reason for restoration of a strong innate immune response against infection with pyogenic bacteria; for review on various forms of T H 17 cell plasticity, refer to Hemdan [10]. Furthermore, the importance of T H 17 cells in combating HIV-associated bacterial infections has been recently elucidated [63].

Interaction of T 17 Cells with Commensal Bacteria.
Of a crucial importance is the recent clue linking the induction of T H 17 response with gut commensal bacteria. Colonization of the small intestine of mice with a single commensal microbe, segmented filamentous bacterium (SFB), was sufficient to induce IL-17-and IL-22-producing T H 17 cell responses in the lamina propria, and this was correlated with enhanced expression of inflammation-and antimicrobial-associated genes and increased resistance to the intestinal pathogens Citrobacter and Salmonella [35,64]. Induction of T H 17 cells mediated autoimmune arthritis in K/BxN mice [65], whereas when the same mice were held under germ-free conditions, autoimmune arthritis was strongly attenuated and mice revealed reductions in serum AAs titers, splenic AAs-secreting cells, germinal centers, and splenic T H 17 cells as well as the lack of T H 17 cells in the small intestinal lamina propria [65]. These findings suggest the role of T H 17 cells not only in defending the gastrointestinal tract against pathogens, but also in mediating AD (Table 1). How does the immune system monitor the resident intestinal microbes and coordinate between host defense and tolerance and how do dysregulated host-microbe interactions lead to intestinal inflammation were recently discussed [66]. The increased production of IL-17 and IL-23 by PBMCs derived from patients of primary Sjogren's syndrome upon TLR2, TLR4, and TLR6 stimulation [67] highlights the link between TLR ligation and autoimmune induction in such disease settings, where the participation of T H 17 cytokines in their pathogenesis is evident [68,69].  [70,71]. Although a protective role of IL-17 against bone loss has been described [72], induction of osteoclastogenesis by T H 17 cells has been suggested in various inflammatory models [73]. Proinflammatory cytokines correlated with osteoclastogenic or antiosteoclastogenic manifestations in human OP and OA, for example, negative correlations of hip bone mineral density (BMD) with TNF-in OA and with RANKL/RANK in OP [70]. In a mouse model of type II diabetes, whereas osteocalcin and osteoprotegerin (osteoblast-specific bone forming markers) were decreased, osteoclast-driven bone resorption markers such as IL-6 and RANK were elevated and coincided with enhanced RANKL and IL-17 expression by CD4 + cells; IL-17 induction was directly promoted upon leptin treatment [74]. The authors proposed that leptin and IL-6 stimulate IL-17 production and, thereby, induce RANKL-mediated osteoclastogenesis. A direct link of IL-17 to osteoclast induction was proved in cultures of PBMCs drained from patients with Crohn's disease [71]. Altogether, IL-17 may be a valuable target for controlling bone diseases, at least those accompanying chronic inflammations as in Crohn's disease or inflammatory arthritis.

T 17 Cells in the Bone
Overall, in addition to expecting counterprotective impacts of T H 17-associated cytokines, the induction of T H 17 response seems to be an intrinsic feature originally evolved to fight bacterial, viral, and fungal infections. However, what drives such an immune arm to react against the body's own elements, that is, the loss of tolerance, remains elusive. Upon infection, it seems to be a failure to eliminate the invader, whereby an inflammation-potent cell response is amplified, whose army calls for other inflammation competent cells that might have lost the ability to recognize the body's own MHC molecules and therefore attack the self and/or induce production of AAs. Such a modified response attained through a persistent infection constitutes an additional load against the 7 system's strategy of pathogen clearance and the culmination of the immune response to its steady state thereafter. In other words, boosting such a potent inflammatory cell type as T H 17 through an initial inflammation, for example, through inflammatory cytokine-mediated induction of NF-B, see next, should normally be accompanied by induction of a regulation program; otherwise autoimmunity occurs. On the basis of current understanding, we propose that the T H 17-driven autoimmune response is manifold, attaining its incidence through (i) activating T H 1 responses and the later conversion of T H 17 themselves into T H 1-like cells or double T H 1/T H 17 cytokine producers having the inflammatory potency of both subsets; (ii) activating B cells and their production of AAs, especially through IL-21-dominated responses; (iii) inducing inflammatory cells like macrophages and neutrophils and their recruitment through induction of chemokines, facilitating thereby tissue destruction and release of intrinsic cellular factors, which, in turn, leads to local or systemic induction of the autoimmune traits; and (iv) promoting cytotoxicity of NK and CD8 + cells and the conversion of the latter cells into IL-17 producers that further magnify the whole response. On the basis of current knowledge, introducing the T H 17 efficacy as a potent inflammatory lineage, targeting IL-23/T H 17 axis, may be a promising approach that paves the way for additive and alternative treatment of chronic inflammation and AD [75].

T H 17 Cells Are Key Players in Heavy-Metal-Elicited Autoimmunity
Whereas some heavy metals (e.g., copper, selenium, iron, and zinc) are essential to maintain our metabolism, the majority of heavy metals are non-essential, for example, arsenic (As 3+ , As 4+ ), cadmium (Cd 2+ ), chromium (Cr 3+ , Cr 4+ ), mercury (Hg 2+ ), and lead (Pb 2+ ), and are ranked among the most highly toxic substances. Great evidence exists that various heavy metals elicit immunomodulation increasing thereby the incidence of human AD and cancer [3,18,76]. It has been recently found that patients with autoimmune thyroiditis (AT) and other AD, including MS, psoriasis, SLE, and atopic eczema, showed increased lymphocyte reactivity to inorganic Hg 2+ , Ni 3+ , and other metals and that replacement of amalgam in Hg 2+ -allergic subjects resulted in improvement of health in about 70% of AT patients [3]. Furthermore, recent data implied that exposure of mice to low micromolar concentrations of Cd 2+ and Hg 2+ induces a robust T H 17 response, that was also inferred by mild but significant increase of IL-17 profile in serum of individuals occupationally exposed to the same metals, as well as a robust ex vivo T H 17 response (N. Y. A. Hemdan et al., unpublished data).

Ligation of Metal Ion with the Aryl Hydrocarbon Receptor.
Like other xenobiotic stimuli [77], one mechanism so far delineated is the ligation of metal ion with the aryl hydrocarbon receptor (AhR) as in the case of Cd 2+ , As 3+ , Cr 6+ [78,79], and Pb 2+ [80]. Such ligand-specific activation of the AhR was found to regulate the balance between T H 17 and T Reg cell responses [81]. Whereas AhR activation by TCDD (dioxin) induces functional T Reg cells that suppress EAE, activation by 6-formylindolo [3,2-b]carbazole induces T H 17 cells and ultimately the disease severity. AhR is expressed by T H 17 cells, T cells, and DCs [82,83] and is indispensible for IL-22 production as evidenced by AhR −/− mouse studies [82] and by downregulation of the AhR on RNA-mediated interference, as well as, by applying AhR agonists [48], where it substantially altered the balance of IL-22-versus IL-17-producing cells. In DCs, activation of AhR induces expression of IDO1 and IDO2 that mediate induction of T Reg cells [83]. Therefore, we hypothesized that exposure to heavy metals may mediate autoimmune initiation/induction through metal ligation of AhR. Recent works of other groups and our unpublished data indicate the association of IL-22 with the appearance of autoimmune signs, as inferred in the pathogenesis of psoriasis [7]. These data raise the AhR as a sequential segment linking such potent inflammatory T H 17 cells with the heavy-metal-induced autoimmune induction and reveal a mechanism for further differentiation of T H 17 into T H 22 under organ-or pathogen-specific conditions, including AhR ligation pathways. Therefore, targeting AhR may offer a possibility for differential regulation of T H 17 cytokines and thereby reduction of autoimmune susceptibility in heavy-metal occupationally exposed individuals; however, the paradoxical effect of various AhR ligands should be considered.
AhR-mediated immunomodulation by heavy metals may involve several mechanisms; one of which is the regulation of CYP1A1 expression, for example, in the case of Pb 2+ [80] that coincided with increase of heme-oxygenase-(HO-) 1 mRNA level and production of reactive oxygen species (ROS). Induction of CYP1A1 expression by AhR ligation is well documented; its downstream signal mediates cellular responses probably through modifying cytokine secretion, including IL-6 [84], IL-17, and IL-22 [37,82,85]. Induction of oxidative stress has been reported in case of Pb 2+ [86], Cd 2+ [87][88][89], and Hg 2+ exposure [90], inferred by reduced activity of antioxidant enzymes catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) and reduction of glutathione (GSH). Smoking, a major source of Cd [91], also initiates ROS production accompanied by augmented cell signaling pathways implicated in the pathogenesis of AD such as psoriasis that implicates mitogen-activated protein kinase (MAPK), NF-B and Janus kinase JAK/STAT [92], and reduced antioxidants malondialdehyde and SOD [93]. Oxidative stress comprising production of free radicals such as reactive oxygen and nitrogen species is closely related to inflammation and discussed as an underlying mechanism of inflammatory diseases, accompanying activation of the leucocytes and generation of peroxynitrite, at the early stages of induction, or appearing before the incidence of various AD such as IBD [94,95], systemic sclerosis [96], SLE [97], psoriasis [93,98], and in cardiovascular inflammation [99]. Therefore, depletion of endogenous antioxidants such as GSH, Cu, and ZnSOD was manifested in experimental models of IBD [100], accompanied, however, by induction of HO-1. The latter catalyzes CO production, and, although it is considered as a prooxidant due to iron released from HO activity [101], it may be a compensatory response to oxidative stress and chronic inflammation [102], whose protective function has been elucidated in various AD including MS [103].
The protective role of antioxidants in combating inflammation has been clarified in various models by applying exogenous antioxidants or by manipulating expression of endogenous antioxidants. Depletion of NF-E2-related factor 2 (Nrf2), for instance, markedly enhanced susceptibility of experimental IBD [104]. Moreover, by disrupting GSH metabolism through targeting GSH peroxidase (GPx) 1 and GPx2 derived development of colitis [105], or by depleting GSH though curcumin-elicited glyoxalase 1 activity inhibition that enhanced the anti-inflammatory response as well as anticarcinogenetic potency [106], it became clear how close the metabolic stress is related to cell response and cell survival, an assumption that is confirmed by many studies [107]. Unfortunately, although the role of T H 17 cells-related products such as IL-17 in the previous experimental settings has not been addressed, T H 17 together with T H 1 cells are drawn as being major players in the IBD as well as in other inflammatory concerts [108]. Therefore, the elevation of ROS levels links heavy metal exposure to induction of inflammation and cancer. Indeed, induction of T H 17 cell response by heavy metals is likely a downstream event of hydrogenperoxide-(H 2 O 2 -) mediated IL-6 induction, which is found to protect resident lung cells from ROS-induced injury [109]. Ye et al. [110] found that fumarates induced type II DCs as a result of initial GSH depletion followed by induction of HO-1, which interacts with AP-1 and NF-B sites of Il23p19 promoter and inactivates STAT1 and thereby improves T H 1and T H 17-mediated AD including MS and psoriasis.

Modification of NF-B Signaling.
A key pathway through which heavy metals, amongst other xenobiotic substances, exert impacts on the immune response occurs via modifying NF-B signaling. Several distinct NF-B activation pathways are identified, including responses to various cell stresses and stimuli such as proinflammatory cytokines TNF-and IL-1, bacterial products, genotoxic stimuli such as ionizing radiation and some chemotherapeutic drugs [88], in addition to exposure of various cell types to heavy metals such as Cd 2+ [88,111]. This may highlight NF-B activation as a trait of carcinogenicity assigned to heavy metals including Cd 2+ [112]. The increased production of cytokines, for example, IL-6 and IL-17, in murine models and in heavy-metalexposed individuals (Hemdan & Abul El-Saad, unpublished data), might ultimately lead to excessive induction of NF-Bmediated chronic inflammation [113]. This is consistent with the involvement of IL-17 in the differentiation of plasma cells mediated by NF-B-regulated TF Twist-1 [114]; we recall the correlation of higher IL-17 levels with the severity of various AD and the appearance of autoimmune signs accompanying exposure to heavy metals. Therefore, delicate intervention to regulate NF-B activation may help prevent chronic inflammation, simultaneous tissue cell damage, and reduce incidence of AD in individuals occupationally exposed to heavy metals or those with an accidental exposure history.

Disruption of Ca 2+ Homeostasis.
A third event by which heavy metals like Cd 2+ modify cell survival and function is modifying Ca 2+ displacement and ultimately adherence/tight junctions, mediated by disrupting expression and translocation of E-cadherin/ -catenin, in a way that mimics Wntsignaling [88,115], providing a clue for the carcinogenicity of heavy metals. Previous studies [116] as well as our unpublished data identified some protein kinases including ROCK-II as a target of Cd 2+ -and Hg 2+ -mediated induction of IL-17, which activates NF-B through CIKS/Act1 adaptor proteins, inducing thereby chronic inflammation and cancer.

Modification of Zinc Metabolism.
A further important element in the interplay of heavy metals such as Cd 2+ with immunomodulation is represented by its interaction with zinc. Zinc was found to inhibit cancer through regulating various oncogenic pathways including NF-B, AP-1, Notch-1, and PI3K/Akt, apoptosis, cytotoxicity, regulating tumor suppressors such as p53 and macrophage phagocytic activities and increased production of ROS and inflammatory cytokines TNF-, IL-1 , IL-8, VCAM, and MCP-1 [112]. Similarly, Zn probably inhibits STAT3 activation and thereby T H 17-mediated collagen-induced arthritis [117]. Via targeting such oncogenic pathways, Zn supplements may participate in attaining promising antitumor approaches, at least in cases where Cd 2+ is considered to have a carcinogenic potential.

Concluding Remarks
Ongoing research provides a preponderance of evidence that T H 17 cells and related molecules act as double agents both in favor of but also against the harboring individual. They elicit various antimicrobial mechanisms on one hand, but, on the other hand, when dysregulated, likely triggered by xenobiotic agents including pollutants and infectious agents, initiate/promote chronic inflammatory/autoimmune manifestations. A delineation of the underlying mechanisms that culminate into hyperactivation of T H 17 cells and the resultant production of related mediators would facilitate the development of potential therapeutic approaches to combat their deteriorating effects but simultaneously allow their benefits to act. Therefore, various research directions gave more attention in the last decade to T H 17-cells-related molecules to help attain and evaluate valuable therapeutic strategies. Manipulating T H 17 differentiation and function by targeting differentiation/promoting cytokines, transcription factors, or commensal-bacteria-elicited immune induction may be valuable for treating AD; however, the risk of increasing the vulnerability of attacking infections should remain in focus. Therefore, it may be of worth to apply prophylactic antibacterial and antifungal therapy in case of treating patients of AD with IL-17/-22/-23 inhibitors.

Take-Home Messages
(i) T H 17 cells and their related products act as double agents both to mediate various antimicrobial mechanisms and to initiate/promote chronic inflammatory/autoimmune manifestations.
(ii) Simultaneous or successive exposure to xenobiotic substances and infectious agents renders the genetically susceptible individual vulnerable to autoimmune incidence via induction of inflammatory mediators.
(iii) A compromise should be met to facilitate development of potential therapeutics aiming at targeting AD via inhibiting differentiation of T H 17 cells and/or commitment factors for the benefit of attaining the antimicrobial response intact, for example, by applying prophylactic therapy combined with IL-17/-22/-23 inhibitors.