Autoimmunity Reviews 9 (2010) 785792

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Autoimmunity Reviews
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t r ev

Review

Interleukin-17-producing T helper cells in autoimmunity

Nasr YA. Hemdan a,b,, Gerd Birkenmeier c, Gunnar Wichmann b, Ahmed M. Abu El-Saad a, Thorsten Krieger d, Karsten Conrad e, Ulrich Sack f
a

Department of Zoology, Faculty of Science, University of Alexandria, Egypt ENT-Research Lab, Department of Otolaryngology, Head and Neck Surgery, Faculty of Medicine, University of Leipzig, Germany Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Germany d Asculabor Hamburg, Germany e Institute of Immunology, Faculty of Medicine, University of Dresden, Germany f Institute of Clinical Immunology, Faculty of Medicine, University of Leipzig, Germany
b c

a r t i c l e

i n f o

a b s t r a c t
With all the incredible progress in scientic research over the past two decades, the trigger of the majority of autoimmune disorders remains largely elusive. Research on the biology of T helper type 17 (TH17) cells over the last decade not only claried previous observations of immune regulations and disease manifestations, but also provided considerable information on the signaling pathways mediating the effects of this lineage and its seemingly dual role in ghting the invading pathogens on one hand, and in frightening the host by inducing chronic inammation and autoimmunity on the other hand. In this context, recent reports have implicated TH17 cells in mediating host defense as well as a growing list of autoimmune diseases in genetically-susceptible individuals. Herein, we summarize the current knowledge on TH17 in autoimmunity with emphasis on its differentiation factors and some mechanisms involved in initiating pathological events of autoimmunity. 2010 Elsevier B.V. All rights reserved.

Article history: Received 2 July 2010 Accepted 15 July 2010 Available online 18 July 2010 Keywords: Autoimmune diseases Cytokines IL-17 Interleukin 17 Regulatory T cells T helper 17 (TH17) cells

Contents 1. 2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . Key factors in the differentiation program of TH17 cells. . . . 2.1. Interleukin-6 . . . . . . . . . . . . . . . . . . . . 2.2. Transforming growth factor- . . . . . . . . . . . . 2.3. Interleukin-21. . . . . . . . . . . . . . . . . . . . 2.4. Interleukin-23. . . . . . . . . . . . . . . . . . . . 2.5. Interleukin-1 and tumor necrosis factor- . . . . . . 2.6. Signal transducer and activator of transcription 3 . . . 3. Differential regulation of TH17 cytokines and some underlying 4. Concluding remarks . . . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . of autoimmunity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 785 786 786 787 787 788 788 788 788 789 790 790 . 790

1. Introduction Although, the last years have witnessed an extensive research in the eld of autoimmunity that included both experimental as well as
Corresponding author. ENT-Research Lab, Department of Otolaryngology, Head and Neck Surgery, Faculty of Medicine, University of Leipzig, Germany. Tel.: + 49 17620781360; fax: + 49 3419721709. E-mail address: nhemdan@yahoo.de (N.Y.A. Hemdan). 1568-9972/$ see front matter 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2010.07.003

epidemiological cohort studies, most of the autoimmunity triggers remain largely hidden and many questions persist. One most important question concerns the contribution of various TH cell subsets. The TH1/ TH2 paradigm [1] was attained that upon activation, CD4+ T cells differentiate into TH1 cells (indispensable for resolution of intracellular pathogens) or TH2 cells (targeting intracellular pathogens and inducing B cell differentiation into antibody-producing cells) in presence of IL-12/ IFN- or IL-4, respectively. Both subsets attain their maturation through self-promoting and reciprocal regulatory mechanisms mediated by

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intrinsic signals, reviewed in Refs. [24]. Activation of signal transducer and activator of transcription (STAT)1 by IFN- induces T-bet expression, which, in turn, upregulates IL-12 receptor 2-subunit (IL-12R2). IL-12, acting through STAT4, prolongs TH1 survival and IFN- expression. Commitment of TH2 is established through activation of STAT6 by IL-4 and subsequently induction of the transcription factor GATA3 that, in turn, upregulates IL-4 expression. Indeed, this TH1/TH2 paradigm seems paradoxical due to the fact that anti-IFN- antibody (Ab)-treated, IFN-/ or IFN-R/ mice develop collagen-induced arthritis (CIA) or experimental autoimmune encephalomyelitis (EAE), a model of human multiple sclerosis [5], previously known as TH1-associated diseases. Recent progress has been made in our understanding of T cell differentiation following the rst detection of IL-17 as a transcript from a rodent T cell hybridoma by Rouvier and colleagues [6] originally named cytotoxic T lymphocyte associated antigen (CTLA)-8, and the later discovery of human IL-17 [7] and IL-17 receptor (IL-17R) [8], which together with IL-22R are ubiquitously expressed in various tissues [9]. Following identifying other related effecter cytokines, the TH1/TH2 paradigm has been expanded to include TH17 cells, distinct from both TH1 and TH2 cells, and since then a new era has begun. This included implication of TH17 in induction and/or aggravation of autoimmunity in experimental models and in genetically-predisposed individuals (Table 1), that may assign TH17 cell lineage as a hallmark for autoimmunity. IL-17 is a pronociceptive cytokine [10], and together with IL-17F both are key factors for activation and recruitment of neutrophils, which are of pivotal roles in inammatory and autoimmune diseases including rheumatoid arthritis (RA) [10,11], amongst others. Both IL-17 and IL-22 are mainly produced by TH17 cells and promote production of antimicrobial peptides [12,13] constituting thereby a link between innate and adaptive responses [14,15]. Other sources of IL-17 include NK
Table 1 Protective and detrimental effecter molecules of TH17 cells in autoimmune diseases. Disease Multiple sclerosis (MS) and EAE Role of TH17 cells Observation(s)/conclusion

cells, which may be the major innate source of IL-17 [16], T cells [15,17,18] and CD8+ T cells [19]. IL-17/ mice reveal a reduced IFN- production by CD4+ T cells, impaired granuloma formation and expression of the chemokines CXCL9, CXCL10 and CXCL11 [20,21], which all signal via CXCR3 mainly expressed on TH1 cells [22], involved in wound healing [23], in autoimmune diseases [24,25] and allograft rejection [26]. Therefore, treatments, such as Natura-alpha, both prevented and treated CIA mediated by inhibiting IL-17 production and anti-type II collagen IgG development, amongst other pathogenic factors [27]. IL-22, a member of the IL-10 cytokine family, is also produced by NK cells (NK22), and lymphoid tissue inducer cells following IL-23 stimulation [2830], and is also produced by a distinct lineage, TH22 cells [31,32]. IL-22 is linked to induction of tissue repair and protection against experimental autoimmune myocarditis [33], IBD [34] and liver injury [35,36]. 2. Key factors in the differentiation program of TH17 cells Studies of TH17 dened important factors essential for establishing a sustained TH17 cell lineage. These, presumably similar in both mice and human, include differentiation factors TGF-, IL-6 and IL-21, the stabilization factor IL-23, and the transcription factors STAT3, and the retinoic acid-related orphan nuclear receptor (ROR)t and ROR. 2.1. Interleukin-6 IL-6 is a pleiotropic and proinammatory cytokine secreted by macrophages, DCs, epithelial and T cells, and exerts manifold effects in T cell differentiation. This includes induction of pathogenic TH1 response [37]. The same cytokine, however, activates transcription mediated by the nuclear factor (NF)-AT leading to production of IL-4

Reference [19,106,107] [108] [85] [41,42] [109,110] [111] [112] [113] [114] [39] [115] [12] [116] [117,118] [119] [10] [120,121] [122] [123] [124] [125,126]

Pathogenic Elevated IL-17 response in blood and CSF cells of MS patients during clinical exacerbations Inhibition of chemokine expression in brain by anti-IL-17 antibody treatment Reduction of incidence in IL-1RI/ mice correlates with failure to induce autoantigen-specic TH17 cells Resistance of IL-6/ and anti-IL-6 Ab-treated mice due to compromised TH17 response Reduction of severity and recruitment of TH17 cells to inammatory tissues on deletion of CCR6 or of IL-17 Induction of TH17 response promotes EAE Psoriasis-like dermatitis Pathogenic Dependence of disease development on an intact IL-23/IL-17 axis Psoriasis Pathogenic Presence of TH17 in psoriasis skin lesions. Correlation of IL-17 and IL-22 mRNA levels with disease activity Anti-IL-12/23 p40 Ab is effective in the treatment of psoriasis Presence of TH17 in psoriasis skin and contribute to IL-6-mediated resistance to Treg suppression Increase of IL-17F CD4+ T cells in psoriatic skin lesions IL-22- and IL-17-mediated induction of human -defensin 2, S100A9, S100A7 and S100A8 in psoriatic skin Rheumatoid arthritis and Ag-induced Pathogenic IL-1, TNF-, IL-17, and IL-10 mRNA levels in synovial membrane, pronounced with shorter disease Arthritis duration, correlate with joint damage Induction of TH17 response in arthritis patients (IL-17, TNF- and GM-CSF). IL-17-dependent enhancement of K/BxN serum-transferred; enrichment of IL-17-producing KRN T cells in inamed joints by arthritogenic AAs Inhibition of hypernociception in TNFR/ mice, by pre-treament with anti-IL-17, anti TNF-, or anti IL-1R Disease attenuation and reduction of systemic IL-6 and synovial IL-1- and RANKL-positive cells on absence of IL-17 Induction of inammation by IFN- and IL-17 in proteoglycan-induced arthritis Autoimmune diabetes Pathogenic Reduction of peri-islet T-cell inltrates and GAD65 AA levels by anti-IL-17 and IL-25 Anti-neutrophil cytoplasm antibody Pathogenic Induction of serum IL-17, IL-23 and autoantigen-specic IL-17-, but not IFN--producing cells during (ANCA)-associated vasculitis disease convalescence Sjogren's syndrome Pathogenic Domination of IL-17-positive cells in the inammatory lesions, and abundant expression of TGF-, IL-6 and IL-23; Induction of TH17-associated mRNA transcripts in cornea and conjunctiva following disruption of IL-2 signalling in CD25/ mice results in age-dependent SS-like autoimmune lacrimal-keratoconjunctivitis Allergen-induced airway and contact Pathogenic Detection of inltrating neutrophils and cells expressing IL-17, IL-22, CCR6, and IL-22R in inamed skin of Hypersensitivity nickel-challenged allergic individuals. TH17 and TH1 cells in memory PB cells Airway neutrophilia following allergic sensitization mediated by natural and primed TH17 cells Induction of IL-17 levels in asthmatics, that correlates with severity. Reduction of contact, delayed-type, and airway hypersensitivity responses, and T-dependent Ab production in IL-17/ mice Autoimmune thyroid diseases Pathogenic Induction of TH17 response in patients (high IL-17 and IL-22, IL-23 and IL-23R) Thrombocytopenia Pathogenic Elevation of IL-21 plasma levels and IL-21+, IL-17+ and IFN-+ T cells in patients

[127] [50,128] [129] [130] [131]

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by nave Th0 cells and their differentiation into effecter TH2 cells [38]. The latter authors found that IL-6 inhibits TH1 differentiation via upregulating expression of the transcription factor suppressor of cytokine signaling (SOCS)-1 that interferes with IFN- signaling and the development of TH1 cells. This may constitute a negative feedback loop to culminate TH1 induction, and moreover can support a more tolerant state. Furthermore, IL-6 signaling through STAT3 enables T cells to escape from Treg suppression [39]. Applying neutralizing anti-IL-6 Ab, which completely abolished differentiation of TH17, highlights the importance of IL-6 in the direct induction of TH17 [40], and inhibits TH17-mediated development of EAE [41]. Treg cells can be substituted by TGF-1, which, together with IL-6, subverts TH1 and TH2 differentiation for the generation of TH17 cells [40], a process that is amplied by IL-1 and TNF-. All of these ndings endorse earlier studies, pre-dating the discovery of TH17 cells, which implicate IL-6 in development of EAE [42], SLE [43] or Aginduced arthritis [44] probably due to defective TH17 repertoires. Taken together, and because of the perception that IL-6 release is a key cytokine of the acute phase response during infection [45], may be similar to other downstream proinammatory cytokines, a subversion of Treg cells into IL-17-producers is most likely to occur. Recent results driven from investigations on IL-6R/ mice reveal that the local control of IL-6 trans-signaling regulates the effector characteristics of T cell inltrates and promotes the maintenance of TH17 cells [46]. Another interesting recent study using Lyn/ mice, which develop Ab-mediated autoimmune disease resembling SLE, demonstrated that Lyn/ leukocytes, notably B cells, overproduce IL-6 and thereby facilitate hyperactivation of B and T cells, enhance myelopoiesis, splenomegaly and ultimately the generation of pathogenic autoreactive antibodies (AA) [47]. Moreover, deleting IL-6 on a Lyn/ background does not alter B cell development, plasma cell accumulation, or DC hypermaturation, but hyperactivation of B and T cells, extramedullary hematopoiesis, expansion of the myeloid lineage and autoimmune disease are all ameliorated [47]. The authors elegantly formulated that although Lyn/ B cells may be autoreactive, it is the IL-6-dependent inammatory environment they engender that dictates their disease-causing potential. However, a possible interference with IL-17 response has not been directly issued. We propose that a possible IL-17-mediated mechanism might orchestrate such an autoimmune disorder. Altogether, it may then not be surprising that several groups have demonstrated the feasibility of IL-6-targeting therapies of some autoimmune diseases such as RA [48], or of Graft-versus-host disease mediated by TH17 cells [49]. A novel set of memory-like natural TH17 (termed nTH17), however, can develop in the absence of the IL-6/STAT3 signaling and express substantial amounts of IL-17, and IFN- but not IL-17F, under the control of RORt, and play a crucial role in induction of neutrophilia [50]. 2.2. Transforming growth factor-

cooperates with IL-4 to support a distinct population of IL-9-producing TH9 T cells [52]. Whereas, local administration of neutralizing anti-TGF- Ab in target sites of chronic inammation ameliorated the disease through limiting TH17 cell differentiation, similar interventions at mucosal sites exacerbated disease in experimental models of colitis [53], implying distinct functions of TH17 cells as well as their protective role in mucosal immunity, see below. In a model of EAE, the adoptive transfer of induced Treg cells suppresses EAE when administrated before induction or during ongoing disease due to the direct inhibition of cell proliferation [54]. Because the inhibitory effects are inuenced by Foxp3 [55], suppressing IL-2, IL-4 and IFN- transcription through interactions with NF-B and NF-AT [56], it is then the balance between TGF- and Foxp3 that determines the outcome of the TregTH17 balance in favor of one subset at the expense of the other, an assumption that accords well with the association of impaired Treg cell activities with autoimmune disorders including SLE [57]. Indeed, the reciprocal interrelationship between Treg and TH17 cells has been proved in several models, however, both lineages were increased in psoriasis patients both in the peripheral circulation and skin tissue lesions and were positively correlated with disease severity [58]. In the absence of TGF- signaling, mice did not develop EAE due to the absence of TH17 cells [59]. Furthermore, TGF-1/ mice developed lethal immunopathology in multiple organs, which was associated with differentiated TH1 and TH2 cells. In a transfer model, TGF-1 produced by Foxp3+ Treg cells was required to inhibit differentiation of TH1 cells as well as IBD [59], implying that Treg cells might be the source of TGF- in this model. This nding is consistent with the induced differentiation of TH17 on the adaptive transfer of Treg cells, although it prevented the disease when administered early in the course by suppressing expansion of T cells [54]. TGF-1 is for sustained expression of IL-17F and IL-17 [60] and is also necessary for IL-17-competent T thymocytes, an innate source of IL-17 that retained in thymus particularly during the postnatal life [61]. Incubating CD4+ T cells from DO11.10/RAG2/ mice with C5aR/ spleen-derived DC results in increased production of TGF-, the de novo differentiation of Treg cells and induced high levels of IL-6 and IL-23 but minor amounts of IL-12 lead to differentiation of TH17 cells [62]. This implies an important role of C5aR in DC directing the differentiation of T cells [62]. Induction of TH17 cells is achieved through inhibition of MEK-ERK signaling that otherwise promotes production of IL-2 and activation STAT5 [63], and thereby Treg cells. A recent identied group of CCR6+ Treg cells in human PB and lymphoid tissue is generated in the periphery, coexpresses FOXP3 and RORt, and produces IL-17 upon activation [64]. Furthermore, CD4+ FOXP3+ CCR6 Treg cells differentiate into IL-17 producers upon TCR stimulation in the presence of IL-1, IL-2, IL-21, IL-23, and human serum (probably a source of TFG-).

2.3. Interleukin-21 The transforming growth factor (TGF)-, together with IL-10, was mostly assigned as an anti-inammatory cytokine, produced mostly by CD4+ CD25+ Treg cells, which attained a distinct immunosuppressive property on various arms of immune response and maintain selftolerance [51]. This view does not, however, t into the recent perception that TGF- is indispensable for the differentiation of murine and human TH17 cells. Because of its key role in the differentiation program of TH17 cells and in the differentiation of Treg cells in the periphery, TGF- is at the crossroads of both T cell subsets, which are mutually exclusive. Both lineages are descendants of a common Foxp3+ RORt+ precursor that develops on convergence of IL-2 and TGF- signaling, as reviewed in Ref. [4]. Subsequent TGF- or IL-6 signaling upregulates one lineage and inhibits the other via activating Foxp3 or RORt, respectively. A recent nding that also challenges the old view of TGF- is that under certain conditions, it IL-12 is an IL-2 cytokine family member produced by activated T and NKT cells but not by APC [65], with an autocrine activity that regulates its own production through potently suppressing Foxp3 expression, enhancing TH17 proliferation and expression of RORc [66,67]. In the absence of Treg cells, IL-6/ mice developed a TH17mediated EAE, probably induced by IL-21, as IL-21R/ T cells are compromised in TH17 [68]. The contribution of IL-21, in the absence of IL-6, seems to suppress TGF--induction of Foxp3, and together with TGF- to induce TH17. The combination of both cytokines promotes the differentiation of human nave CD4+ T cells into TH17 cells expressing RORc2 [69] and RORt [70,71]. A recent report indicates that IL-21 expression correlates with the appearance of TH17 cells in synovial uid and peripheral blood in RA patients [67], indicating that targeting IL-21 may be tractable to dampen autoimmune induction

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[72] that results in downregulation of IL17 production [73], B cell activity and production of Abs. [74]. 2.4. Interleukin-23 Similar to IL-12 for TH1 and IL-4 for TH2 [75,76], IL-23, an IL-12 cytokine family member that shares with IL-12 a common subunit, p40, is a key factor for sustained commitment of TH17 cells. Therefore, following their initial induction via TGF- signaling, TH17 cells upregulate IL-23R to confer their responsiveness to IL-23 [7779]. In a model of CIA [80], IL-12p35/ mice developed more IL-17-producing T cells, accompanied by elevated mRNA expression of TNF-, IL-1 and IL-6 in affected tissues of diseased than in wild-type mice. In the absence of TGF-, however, both of IL-23 and IL-12 suppress IL-17 and enhance IFN- production in a STAT4- and T-bet-dependent manner [81]. This implies that IL-23 alone cannot initiate TH17 differentiation. Giving the crucial importance of IL-23, it is then not surprising that p19/ mice, decient in functional IL-23, are resistant to EAE [82]. Interestingly, McGreachy et al. [83] found that stimulation of myelinreactive T cells with TGF- plus IL-6 completely abrogated their pathogenic function despite upregulation of IL-17 production. These cells failed to induce CNS inammation and produced IL-10 and thereby acted as regulatory-cells. Stimulation with IL-23, however, promoted expression of IL-17 and proinammatory chemokines but not IL-10, and therefore the authors concluded that TGF- and IL-6 drive the initial commitment of TH17 cells but simultaneously restrain their pathogenic potential, implying that IL-23 is indispensable for full acquisition of effecter TH17 cells. 2.5. Interleukin-1 and tumor necrosis factor- Both of IL-1 and TNF- are important factors of pathogenesis in various diseases, e.g. MS [84]. The importance of IL-1 in induction of TH17 response is evident from IL-1/IL-1R/ mice studies. For example, upon immunization with myelin peptide, the incidence of EAE is signicantly lower in IL-1RI/ compared with wild-type mice, and this correlates with a failure to induce autoantigen-specic TH17 cells [85]. Similarly, IL-1 induces the differentiation of human TH17 cells, most of them also produced IFN- [86], and the combination of IL-1 and IL-6 boosts IL-17 production but not IFN-. Furthermore, Lee and colleagues found that IL-1 induces IL-17 production from human CD4+ T cells and this can be blocked by IL-1R antagonist [87]. That IL-7, IL-15 and TGF- upregulate IL-1R type I in nave umbilical cord-driven CD4+ T cells that lack this receptor indicates that this takes place in the periphery. Because of the nding that IL-1RI+ memory CD4+ T cells increase gene expression of IL-17, RORc and IRF4 even before TCR triggering, the authors suggest that the effect of IL-1 is programmed in these cells via IL-1RI. 2.6. Signal transducer and activator of transcription 3 The role of STAT3 in the commitment of TH17 cells is presented in a recent excellent review [4,88]. IL-6 upregulates IL-23R on the differentiated TH17 cells, and together with IL-23 or IL-21 promotes TH17 differentiation via activation of STAT3 [88]. Mice with targeteddeletion of STAT3 in CD4+ T cells do not develop experimental autoimmune uveoretinitis (EAU) or EAE [89], revealing a defective TH17 response and exaggerated increases in Foxp3-, IL-10-, IL-4-, and IFN--expressing T cells. Mice with EAU reveal a high percentage of IL-17-expressing T cells in their peripheral lymphoid organs, characterized also by secretion of IFN-, and hence propose the involvement of TH17 and IL-17-expressing TH1 cells. In presence of TGF-, STAT3 induces ROR and RORt [88,90,91], and hence is indispensable for the susceptibility to EAE [90]. Therefore, differentiation of TH17 was greatly impaired in STAT3 decient T cells, marked

by impaired RORt expression and instead elevated expression of T-bet and Foxp3 [88]. Through Smad signal transduction pathway, TGF- inhibits IL-6- and IL-21-induced SOCS3 promoter activity, i.e. SOCS3 expression, and thereby enhances and prolongs STAT3 activation in nave T cells [92] (Fig. 1). In mice with impaired TGF- signaling, IL-6-induced expression of SOCS3 in T cells is higher, whereas STAT3 activation is lower compared with wild-type cells [92]. Interestingly, similar to the need of Treg cells for IRF4 to suppress TH2 [93] or for T-bet to suppress TH1 [94], Chaudhry and colleagues found that it is the same requisite transcription factor STAT3 that is also required by Treg cells to suppress TH17 response [95], ensuring, thereby, as the authors proposed, a class-specic control of immune-mediated inammation. 3. Differential regulation of TH17 cytokines and some underlying mechanisms of autoimmunity As mentioned above, TH17 cells produce IL-6, IL-10, TNF-, IFN-, IL-26 and mainly IL-17, IL-21 and IL-22. The production of these cytokines is differentially regulated. In their interesting work, Volpe et al. [96] have used a multi-parametric analysis of TH17-associated cytokines and reported that the regulation pattern of IL-22 was most closely related to IFN- and not to IL-17. Moreover, whereas IL-12 and IL-23 induce high levels of IL-22 but not IL-17, TGF-, inhibits IL22 production but promoted IL-17 [96], and more extremely, its absence induces a shift from a TH17 prole to a TH1-like prole [97]. Interestingly, So et al. [98] found that thymus (T)-CD4+ T cells express very low levels of TGF-R and IL-21R, which are essential to induce IL-17 expression. Under TH17-skewing conditions, these cells revealed a compromised induction of RORt and hence reduced IL17 expression, which could be restored via ectopic expression of RORt. Therefore, the authors delivered an excellent conclusion that the defect of IL-17 and RORt expression in these cells is cell intrinsic, a characteristic that helps control the generation of the TH17 lineage. IL-27, a member of the IL-12 cytokine family, which is build up of two non-covalently bound subunits, Epstein Barr virus-induced gene-3 and p28, and can be also secreted as a homodimeric IL-27p28 [99], is an inhibitor of TH17 cells [100]. Altogether, and recalling that Treg and TH17 cells are reciprocally regulated and that low levels of TGF- plus IL-6 or IL-21 is enough for initiation of effecter TH17 but not for production of IL-22-producing cells, unless in presence of IL23, an immune response is programmed to function in a way that: 1) following infection, pathogen-specic induction of IL-12/IFN- axis favors proliferation of TH1 response, that together with IL-27 keep TH17 in their steady-state; 2) the increase in IL-6 production inhibits TH1 and Treg cells and together with low TGF- levels promotes differentiation of TH17 cells with a regulatory function that still needs support of IL-23 to attain their full effecter potency producing IL-22, CXC chemokines, antimicrobial peptides and IL-21; 3) long-lasting apoptosis-resistant TH17 cells [101] activate B cells and their immunoglobulin production mediated by IL-21 [74]. TH17 cells may lead to the induction of latent inammatory TH17 response and hyper-activation of B cells and production of auto-reactive Abs (AA). Distinct from its proinammatory effects, IL-17 promotes autoimmune disease by enhancing formation of spontaneous germinal centers (GCs), as shown by autoimmune BXD2 mice that express more IL-17 than wild-type counterparts and show spontaneous development of GCs before they increase production of pathogenic AA [102]. IL-17R/ mice have reduced GC B cell development and humoral responses. Production of IL-17 correlates with induction of the genes Rgs13 and Rgs16, which encode regulators of G-protein signaling, and results in suppression of the B cell chemotactic response to the chemokine CXCL12. The latter chemokine is constitutively expressed by the CNS [103], its expression on the

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Figure 1. Model of differentiation of IL-17-producing T helper cells (TH17). Differentiation of TH17 from uncommitted nave (TH0) cells showing cytokines and transcriptional factors at the nexus of various TH cell lineages is depicted. Upon stimulation with pathogens or allergens, antigen presenting cells (APC) induce differentiation of TH0 cells into distinct effecter lineages TH1, TH2, TH9, TH17 or TH22 as well as the forkhead box P3 (Foxp3)-expressing T regulatory (Treg) cells according to local cytokine milieu produced by various innate immune cells. Whereas activation of STAT1 induces expression of T-bet (the key differentiation factor of TH1 cells), STAT6 signaling up-regulates the expression of the master regulator of TH2 cell differentiation GATA3. TH1 and TH2 cells reciprocally regulate each other and negatively regulate the generation of TH17 cells through their hallmark effecter cytokines, interferon (IFN)- and interleukin (IL)-4, respectively. Differentiation of TH17 requires co-stimulatory signals of CD28 and ICOS and the absence of TH1 and TH2 cytokines (IL-12/IFN- and IL-4, respectively) and their key transcriptional factors (T-bet and GATA3). Induction of Treg and TH17 is mutually exclusive. In presence of low levels of TGF-, that signals through the Smad pathway, IL-6 (as well as other proinammatory cytokines IL-1, TNF-, IL-18 or IL-21) favor differentiation of TH17 cells. TGF- alone induces Foxp3 expression and hence Treg differentiation, also is indispensable for induction of expression of RORt (RORc in human) which is yet inactive and can be only activated in presence of proinammatory cytokines to start the full transcript machinery of TH17. TGF- maintains the cell responsiveness to IL-6 signaling that, in turn, activates STAT3. STAT3 inhibits SOCS3 and thereby induces the transcription factors RORt and ROR and subsequently IL-23R. IL-23 is crucial for survival and effecter functions of TH17 cells and production of IL-22 (TH22?).

parenchymal surface of the CNS endothelium normally functions to localize inltrating leukocytes to peri-vascular spaces, preventing CNS inltration [104]. In patients with CNS autoimmune diseases, this polarized pattern is destructed leading to inappropriate leukocyte trafcking and disease progression [104].

4. Concluding remarks Amongst CD4+ T helper cell subsets are the most prominent TH17 cells, constituting a distinct lineage of T cells bridging the innate and adaptive immunity. These TH17 cells are characterized by expression of

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the transcription factors RORt and ROR, the surface markers CCR4, CCR6 and IL-23R, the production of the potent proinammatory molecules IL-17, IL-17F, IL-21, IL-22, IL-26 and G-CSF as well as the chemokine CCL20. Although intensive research approaches have been made, the mechanisms underlying the generation of these cells in vivo remain incomplete. In addition to the naturally occurring nTH17 cells, differentiation of TH17 from nave CD4+ requires co-stimulatory signals of CD28 and ICOS and the absence of TH1 and TH2 cytokines (IL-12 plus IFN- and IL-4, respectively) as well as the transcriptional factors T-bet and GATA3. At low levels of TGF-, signaling through Smad pathway, IL-6 (as well as other proinammatory cytokines IL-1, TNF-, or IL-21) favors differentiation of TH17 cells. TGF- (that induces Foxp3 expression and hence Treg cell differentiation) is indispensable for expression of RORt (RORc in human), which can be only activated in presence of proinammatory cytokines IL-6 or IL-21 to start the full transcript machinery of TH17. TGF-, maintaining the cell's responsiveness to IL-6 signaling, activates STAT3, which, in turn, inhibits SOCS3 and thereby induces RORt and ROR and subsequently IL-23R. IL-23 is required for survival and development of effecter TH17 cells capable of producing IL-22. Despite its participation at host defense, the functional behavior of TH17 comprises a detrimental role of this seemingly innocent lineage in induction of chronic inammation triggered by latent probably uncontrolled infections, resulting in fostering allergic and autoimmune diseases. Despite the corroboration that both TH17 and TH1 are critical mediators of various autoimmune diseases, clinical trials targeting both subsets revealed mixed results [105], and call for more investigations to delineate the underlying mechanisms. Take-home messages TH17 cells are potent inammatory mediators that are, due to the ubiquitous expression of their effecter cytokine receptors, with manifold contributions to a growing list of disorders including asthma, allergy, psoriasis, RA, lupus and IBD. The differentiation factors of TH17 include: (i) Cytokines: TGF- plus IL-6/IL-21; (ii) Transcription factors: STAT3, IRF4, ROR and RORt, and (iii) The survival/maturation factor IL-23. Treg and TH17 cells are reciprocally regulated via the induction of either the transcription factors Foxp3 or RORt, respectively, together with low or high levels of IL-6. Effecter TH17 cytokines include: (i) IL-17 (key factor for activation and recruitment of neutrophils); (ii) IL-21 (autologous activation of TH17 and B cells and Ig production); and (iii) IL-22 (involved in skin inammation and mucosal immunity, provokes wound healing and protects against hepatic injury). Therapeutic strategies aiming at attenuating but not abrogating IL-17 response or other associated factors may be promising to ameliorate inammatory and autoimmune diseases.

Acknowledgements Authors acknowledge Engy Mohamed (ENT-Research Lab, Department of Otolaryngology, Head and Neck Surgery, Faculty of Medicine, University of Leipzig) for reading through the manuscript. References
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The Interferon-continuum: a common ring in autoimmune diseases One of the challenges of the most recent researches is to find common pathways between autoimmune disorders. Within the mosaic of autoimmunity many dowels are shared by different diseases and at least some of these plugs may represent key targets for therapy. Interferons (IFNs) are proteins made and released by lymphocytes in response to the presence of pathogens that besides this protective functions they may participate in the development of autoimmune diseases. Type-I IFN has been associated with systemic lupus erythematosus, where plasmocytoid dendritic cells (PDCs) represent the main source of this molecule leading to the production of autoantibodies and immune complexes. The evidence that there is a spectrum IFN-mediated diseases is looming up and also systemic sclerosis (SSc) can be part of this IFN-mediated continuum. Assassi and coworkers raised such interesting hypothesis (Assassi et al. Systemic sclerosis and lupus: points in an interferon-mediated continuum. Arthritis Rheum. 2010;62:589-98). In this recently published paper SSc has demonstrated to have several similarities with SLE at the level of transcript profile of common genes. A modular analysis framework was used to achieve these results, that allowed to define that the IFN-signature is a quantitative trait that can be expressed as an IFN score. Furthermore, SSc patients could be sub-grouped on the basis the strength of this IFN signature, with patients with anti-U1 RNP or antitopoisomerase antibodies more likely to have this feature. All this evidences can be merged together with the recent results of a clinical trial of subcutaneous IFNa in early SSc, that showed a worsening of lung function and a trend towards skin deterioration, suggesting that SSc belongs to the family of IFN-mediated disease as well as SLE, with subgroups of patients showing lupus-like high IFN-inducible gene expression pattern correlating with the presence of specific autoantibodies. More targeted therapeutic interventions in SSc are now awaited.