Th17 cells in MS and experimental autoimmune encephalomyelitis.
Abstract: Multiple sclerosis (MS) is regarded as a T-cell-mediated autoimmune disease of the central nervous system (CNS).

It has been traditionally seen as a Th1-mediated autoimmune disease, a notion which has been largely supported by studies in its animal model, experimental autoimmune encephalomyelitis (EAE). However, evidence has accumulated in recent years that a newly described lineage of (autoantigen-specific) T-cells, which are characterized by the production of the inflammatory cytokine interleukin 17 (Th17) cells, might be the relevant effector cell population instead. This is supported by studies both in MS patients and in the EAE mouse model. Research in this field currently centres on the endogenous factors which are required for the priming and expansion of CNS-autoantigen-specific Th17 cells as well as on exogenous factors which trigger Th17 differentiation and activation. This review tries to provide an overview of the relevant literature and to summarize the current body of evidence on the role of Th17 cells in CNS autoimmune disease.

KEY WORDS: MULTIPLE SCLEROSIS; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; T-CELL CYTOKINES; INTERLEUKIN 17; AUTOIMMUNITY; ANTI- CYTOKINE TREATMENT; PERTUSSIS TOXIN
Article Type: Report
Subject: Encephalomyelitis (Development and progression)
Encephalomyelitis (Models)
Autoimmunity (Models)
Autoimmunity (Physiological aspects)
Multiple sclerosis (Development and progression)
Interleukins (Health aspects)
Authors: Hofstetter, H.H.
Gold, R.
Hartung, H.-P.
Pub Date: 03/01/2009
Publication: Name: The International MS Journal Publisher: PAREXEL MMS Europe Ltd. Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 PAREXEL MMS Europe Ltd. ISSN: 1352-8963
Issue: Date: March, 2009 Source Volume: 16 Source Issue: 1
Product: Product Code: 2831332 Interleukin NAICS Code: 325414 Biological Product (except Diagnostic) Manufacturing SIC Code: 2836 Biological products exc. diagnostic
Geographic: Geographic Scope: Germany Geographic Code: 4EUGE Germany
Accession Number: 217847854
Full Text: Introduction: T-cell Cytokines in Autoimmunity

Over the past two decades, an intense search for key pro- and anti-inflammatory mediators in T-cell-mediated autoimmune disorders has been conducted. (1,2) T-helper cells (CD4+ cells) play a crucial role in initiating autoimmune reactions. Since specific subsets of T-helper cells drive specific and qualitatively different adaptive immune responses, T-helper cell cytokines have been grouped in different categories which potentially cross-inhibit each other. One main classification tried to distinguish between type-1 or Th1 cytokines (e.g. IFNg, TNF-a or IL-2) and type-2 or Th2 cytokines (e.g. IL-4, IL-5, IL-9, IL-10 and IL-13). In autoimmunity, a general concept held for a long time that a Th1 response is associated with a proinflammatory, disease-enhancing reaction, whereas a Th2 response exerts a modulatory function and can under certain circumstances protect against disease. However, Th2 responses also can be involved in the pathogenesis of inflammation mediated disorders, including autoimmune disorders. (3) In autoimmune disorders and their animal models, IL-12 was considered to play a central upstream role in regulating the Th1/Th2 balance by providing the necessary signals for switching towards a Th1 response and subsequent clinical disease symptoms. (4) Experimental studies in recent years, however, have suggested by use of cytokine knockout mice that the IL-23/IL-17 axis might be the relevant cytokine axis and not the IL-12/Th1 axis: (5-8) CD4+ T-cells which are expanded via IL-23 are characterized by the production of IL-17. (9) IL-12- and IL-23-modulated T-cells differ in their characteristics in regard to autoimmune disease induction and the resulting pathology in the target organ. (10)

Th17 Cells as a New T-cell Lineage and their Involvement in Autoimmune Disease

The IL-17 cytokine family is a group of six cytokines, IL-17A to IL-17F. IL-17 (IL-17A) is the original member of this cytokine group. (11) Th17 cells specifically express IL-17F in addition to IL-17, both cytokines being closely related and having a common receptor. IL-17 is mainly secreted by activated T-cells and has an important function as an inflammatory mediator. (2,11,12) Its principal role has been seen to strengthen the adaptive component of the immune response against microbial pathogens, which is characterized by a strong reliance on cells of the innate immune system. It induces the production of other cytokines and chemokines from a variety of cell types, (13,14) and coordinates the recruitment of myeloid cells like monocytes and neutrophils to the site of an inflammation, (15) thereby furthering the local inflammatory environment. This suggested that IL-17 can have a critical role in inflammatory conditions in general. For this reason, IL-17-producing T-cells in the past years has moved into the centre of research on T-cell mediated immune disorders, in particular autoimmune disease conditions. This includes rheumatoid arthritis and its corresponding animal models, (16-19) transplant rejection, (20,21) pancreatitis, (22) inflammatory bowel disease, (23) allergic asthma, (24,25) adhesion formation, (26) systemic sclerosis, (27) Behcet's disease (28) or MS. (1,29-31) IL-17 producing T-cells represent an independent T-cell lineage. (32,33) IL-6 and TGF-b can induce differentiation of Th17 cells, whereas IL-23 does not directly induce Th17 lineage commitment, but is necessary for further differentiation and expansion of the Th17 cell population in vivo (Figure 1). (1,2,34) Regulatory T-cells and IL-17-producing T-cells are regulated in a partially reciprocal fashion, with IL-6 and TGF-b being a critical requirement for the differentiation of IL-17-producing cells. (35) However, there are also observations that in regard of human Th17 cells, TGF-b is not necessarily required. (36) IL-18 receptor alpha is required for the generation of pathogenic Th17 cells, but not IL-18 itself. (37) Moreover, Th17 cells co-express IL-22, which, however, is not directly required for pathogenicity. On a molecular level, CD4+ T-cell lineage differentiation is controlled by specific transcription factors. It has been demonstrated that Th1 differentiation is influenced by STAT1, STAT4 and T-bet and Th2 differentiation is influenced by STAT6, c-maf and GATA-3. For Th17 cells, ROR-a and ROR-g are the relevant transcription factors which lead to Th17 differentiation, but also STAT3 is involved. (38-41) In addition, significance for other factors like IRF-4 is emerging. (42)

[FIGURE 1 OMITTED]

Th17 Cells and CNS Autoimmunity

MS is one of the most frequent and serious neurological diseases, mostly affecting younger adults. Its etiology and pathomechanisms are still incompletely understood. Evidence exists for a central involvement of central nervous system (CNS)-autoantigen-specific T-cells in the pathogenesis, which is paralleled by data obtained in its animal model, experimental autoimmune encephalomyelitis (EAE). (43-46) With regard to T-cell cytokines, animal studies in cytokine knockout mice conducted in the last decade were not able to support the role of one single cytokine as the only relevant inflammatory key effector molecule in EAE. Regarding Th1 cytokines, IFNg knockout mice as well as TNF-a knockout mice surprisingly showed more severe EAE than wild-type mice. (47,48) Moreover, the type-I interferon (IFN) induction pathway constrains Th17-mediated CNS autoimmune inflammation in mice. (49) Genetic deficiency of IL-17 or neutralization of IL-17 in mice with EAE leads to amelioration of the clinical disease symptoms, but not to complete reduction (for details see section on neutralization below). (50,51) In the human disease MS, genetic analysis has revealed an important role for IL17 in MS lesions (29) and IL-17 production in CNS-infiltrating T-cells is associated with blood-brain barrier disruption (52) and with disease activity. Hereby, IL-17-producing T-cells are present both in active and chronic disease, and consist of both CD4 and CD8 T-cells. (31)

Kinetics and Organ-specific Dynamics of Th17 Cells in CNS Autoimmunity

The various EAE mouse models offer the possibility to trace the different cytokine-producing effector T-cells at various disease stages in peripheral immune compartments and the target organ CNS. This allows both analysis of the longitudinal kinetics as well as of the anatomical 'cross-section' of the autoimmune process. Regarding their precursor frequencies, CNS-autoantigen-specific Th17 cells are not essentially different from Th1 cells (e.g. IFNg-producing cells). In proteolipid protein peptide (PLPp)-induced EAE and in myelin oligodendrocyte peptide (MOGp)-induced EAE, high frequencies of CNS-autoantigen-specific Th17 cells are present in the immune periphery before onset of clinical disease, but not in the CNS. (50,53) During acute EAE, the highest frequencies of CNS-autoantigen-specific Th17 cells are reached in the inflamed CNS. Yet the vast majority of these cells (concerning their absolute mass) is still present in the immune periphery, i.e. the spleen and draining lymph node. They seem to form a considerable reservoir from which Th17 cells are gradually recruited to the target organ to participate in the actual autoaggressive inflammation. In recovery from an acute EAE flare, high numbers of CNS-autoantigen-specific Th17 cells are still detectable in the immune periphery, but not in the CNS.53 Regarding the mechanisms of chronification of EAE, evidence exists in the relapsing-remitting SJL mouse model that determinant spreading and ongoing priming of new Th17 cells happens in the inflamed CNS itself, and not in the immune periphery. (54,55) This correlates with studies in MS which show that activation of Th17 cells in the CNS in MS happens additionally in the target organ itself. (56,57) Since Th17 cells and regulatory cells have reciprocal developmental pathways and effector functions, (34,35) the number of Th17 cells versus the number of regulatory T-cells might determine whether or not inflammation in the CNS becomes chronic. However, this idea is contrasted by the observation that myelin-specific regulatory T-cells accumulate in the CNS but fail to control autoimmune inflammation. (58)

Microbial Influence and the Generation of Th17 Cells in CNS Autoimmunity

The external factors which activate Th17 cells are so far incompletely understood. In autoimmune diseases, systemic infections and the microbial immune stimuli which they provide are considered to contribute to the initiation or worsening of an organ-specific autoimmune process. (44-46) In type-1 diabetes, viral infection often precedes the clinical beginning of the disease, and in rheumatoid arthritis, bacterial lipopeptides can activate autoantigen-specific Th17 cells. (59) With regard to MS, various viral and bacterial agents have been discussed as disease-initiating factors, although final evidence is lacking.60-64 Moreover, common non-CNS-related infections like an airway or urinary tract infection can directly contribute to an MS relapse, potentially via the systemic presence of the microbial compounds and the inflammatory immune mediators which they trigger. (65) In EAE, pertussis toxin (PTX), which is used as an adjuvant on its own, (66) promotes the generation of CNS-autoantigen-specific T-cells by itself, including Th17 cells. (67) Hereby, the use of TLR4 has been suggested as a main mechanism. (68) The T-cell population which is raised after microbial influence contains high frequencies of Th17 cells (Figure 2a). These Th17 cells are not generated by new differentiation in the thymus, but by altered priming in the immune periphery (Figure 2b). The systemic presence of a microbial compound can therefore alter non-pathogenic local autoimmune recognition by T-cells in a fashion which confers a pathogenic character. Such a mechanism could not only explain the initiation, but also the further augmentation of a Th17-mediated autoimmune disease by an infection with an unrelated pathogen. Infection can, not only impact the activity of mature T-cells, but also of maturing/still uneducated T-cells: the thymus has a central role in maintaining T-cell self-tolerance, and disturbance of thymic self-tolerance is implied in various autoimmune diseases. Thymocytes have been shown to be capable of producing IL-17 under certain stimulation conditions in vitro, their inflammatory response to pathogens being stimulus-specific and qualitatively different from that of mature T-cells in the immune periphery. (69) Given the central role of IL-17-producing T-cells in fighting infections both in human diseases and animal models, (70) this could represent a protective reaction against microbial infection operating already in maturing T-cells. However, in vivo studies are required to further clarify the significance of IL-17 production by thymocytes and to investigate whether this might be a mechanism via which microbes and their components are involved in autoimmune disease pathogenesis.

[FIGURE 2a OMITTED]

Therapeutic Potential of IL-17 Neutralization

It has been demonstrated that IL-17A knockout (KO) mice display a reduced severity of EAE. (51) In addition, studies in IL-23-KO mice and IL-6 KO mice demonstrated reduced EAE severity in these animals together with strongly reduced frequencies of CNS-autoantigen-specific Th17 cells. (7,35) In contrast, it was reported that IL-17F knockout mice showed no reduction of EAE severity, with only a mild additional effect of simultaneous IL-17A neutralization and that T-cell-specific IL-17A overexpression did not enhance EAE. (71) However, every genetically manipulated organism represents a condition of overall reactive responses, characterized by fundamental physiological differences resulting from an altered organism development which not only affects the molecule of interest and its direct regulation but entire cellular, organ and supra-organ networks. For this reason, neutralization strategies directed at IL-17 in genetically unaltered mice represent valuable additional evidence. Neutralization of IL-17A in EAE in wild-type mice with a monoclonal antibody (Figure 3) as well as with an Fc-Receptor fusion protein (which neutralizes both IL17A and IL-17F) showed therapeutic efficacy, (50) but no complete reduction of disease symptoms. Moreover, studies with vaccination against IL-17 could demonstrate suppression of EAE as well as other organ-specific autoimmune diseases. (72,73) However, in experimental autoimmune uveitis, genetic deficiency of IL-17 did not abrogate disease susceptibility and an IL-17 response by itself was not sufficient to cause autoimmune pathology. (74) Similarly, induction of Th1/Th17 autoimmunity in newborn mice did not lead to clinical autoimmune disease and could even protect the adult organism against it later. (75) All these observations indicate that further studies are necessary to clarify the correlation between IL-17-producing T-cells and actual autoimmune pathology. In the human disease MS, IL-17 neutralization studies have so far not been conducted. However, in a recent trial, treatment with anti-IL-12/23 p40 antibody in relapsing-remitting MS patients did not show therapeutic efficacy. (76)

[FIGURE 2B OMITTED]

[FIGURE 3 OMITTED]

Conclusion

Evidence has accumulated in recent years that Th17 cells might be a relevant effector T-cell population in CNS autoimmune disease. IL-17-producing T-cells are a distinct effector cell lineage different from the IFN-producing 'Th1' cells. They are characterized by different activation and expansion requirements and preferentially enrich in the inflamed CNS during the inflammatory process. Further studies are warranted to shed more light on the pluripotent role of Th17 cells (and other IL-17 producing immune cells) in organ-specific autoimmune diseases in general, and EAE and MS in particular. Certain therapeutic strategies aiming at neutralizing IL-17 or blocking CNS-autoantigen-specific Th17 cells appear to be promising. However, too simplistic new paradigms only focusing on IL-17 as the relevant effector cytokine have to be avoided. It will be relevant to monitor IL-17 levels and frequencies of CNS-autoantigen-specific Th17 cells in treatment studies with other (already established) therapeutic agents. It is also vital to obtain more information on the pathogenicity of the various cellular fractions of the Th17 compartment and in particular to investigate cytotoxic IL-17-producing T-cells. In regard of the close link between infections and T-cell mediated autoimmune diseases, it will be important to extend our knowledge on the influence of microorganisms and their compounds on the generation and activation of autoreactive Th17 cells.

Conflicts of Interest

No conflicts of interest were declared in relation to this article.

Key Points

* Interleukin 17 (IL-17) is secreted by activated T-cells (Th17 cells), and has an important function as an inflammatory mediator * Th17 cells are implied in the pathogenesis of a number of human autoimmune disease conditions and their animal models, including multiple sclerosis and experimental autoimmune encephalomyelitis * Th17 cells strongly accumulate in the inflamed central nervous system (CNS) during the autoimmune reaction * Genetic deficiency in IL-17 or pharmacological neutralization of IL-17 leads to amelioration of clinical disease symptoms, but not to their complete abrogation * Short-term systemic presence of microbial stimuli can lead to priming of CNS-autoantigen-specific Th17 cells and subsequent clinical autoimmune disease

Received: 24 July 2008

Accepted: 12 November 2008

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HH Hofstetter [1], R Gold [2], H-P Hartung [1]

[1] Department of Neurology, Heinrich Heine University, Dusseldorf, Germany

[2] Department of Neurology, St. Josef's Hospital, Ruhr-University, Bochum, Germany

Address for Correspondence

Harald H Hofstetter, Department of Neurology, Heinrich Heine University, Moorenstr. 5, 40225 Dusseldorf, Germany.

E-mail: harald.hofstetter@uni-duesseldorf.de
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