Claire L. Langrish

Bio: Claire L. Langrish is an academic researcher from Schering-Plough. The author has contributed to research in topics: Cytokine & Interleukin 17. The author has an hindex of 5, co-authored 8 publications receiving 7174 citations.

IL-23 drives a pathogenic T cell population that induces autoimmune inflammation

Abstract: Interleukin (IL)-23 is a heterodimeric cytokine composed of a unique p19 subunit, and a common p40 subunit shared with IL-12. IL-12 is important for the development of T helper (Th)1 cells that are essential for host defense and tumor suppression. In contrast, IL-23 does not promote the development of interferon-γ–producing Th1 cells, but is one of the essential factors required for the expansion of a pathogenic CD4+ T cell population, which is characterized by the production of IL-17, IL-17F, IL-6, and tumor necrosis factor. Gene expression analysis of IL-23–driven autoreactive T cells identified a unique expression pattern of proinflammatory cytokines and other novel factors, distinguishing them from IL-12–driven T cells. Using passive transfer studies, we confirm that these IL-23–dependent CD4+ T cells are highly pathogenic and essential for the establishment of organ-specific inflammation associated with central nervous system autoimmunity.

Divergent Pro- and Antiinflammatory Roles for IL-23 and IL-12 in Joint Autoimmune Inflammation

Abstract: Interleukin (IL) 23 is a heterodimeric cytokine composed of a p19 subunit and the p40 subunit of IL-12. IL-23 affects memory T cell and inflammatory macrophage function through engagement of a novel receptor (IL-23R) on these cells. Recent analysis of the contribution of IL-12 and IL-23 to central nervous system autoimmune inflammation demonstrated that IL-23 rather than IL-12 was the essential cytokine. Using gene-targeted mice lacking only IL-12 (p35−/−) or IL-23 (p19−/−), we show that the specific absence of IL-23 is protective, whereas loss of IL-12 exacerbates collagen-induced arthritis. IL-23 gene-targeted mice did not develop clinical signs of disease and were completely resistant to the development of joint and bone pathology. Resistance correlated with an absence of IL-17–producing CD4+ T cells despite normal induction of collagen-specific, interferon-γ–producing T helper 1 cells. In contrast, IL-12–deficient p35−/− mice developed more IL-17–producing CD4+ T cells, as well as elevated mRNA expression of proinflammatory tumor necrosis factor, IL-1β, IL-6, and IL-17 in affected tissues of diseased mice. The data presented here indicate that IL-23 is an essential promoter of end-stage joint autoimmune inflammation, whereas IL-12 paradoxically mediates protection from autoimmune inflammation.

IL-12 and IL-23: master regulators of innate and adaptive immunity.

Abstract: Initiation of an effective immune response requires close interactions between innate and adaptive immunity. Recent advances in the field of cytokine biology have led to an increased understanding of how myeloid cell-derived factors regulate the immune system to protect the host from infections and prevent tumor development. In this review, we focus on the function of interleukin (IL)-23, a new member of the IL-12 family of regulatory cytokines produced by activated macrophages and dendritic cells. We propose that IL-12 and IL-23 promote two distinct immunological pathways that have separate but complementary functions. IL-12 is required for antimicrobial responses to intracellular pathogens, whereas IL-23 is likely to be important for the recruitment and activation of a range of inflammatory cells that is required for the induction of chronic inflammation and granuloma formation. These two cytokines work in concert to regulate cellular immune responses critical for host defense and tumor suppression.

Anti–IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis

Abstract: IL-23 is a member of the IL-12 cytokine family that drives a highly pathogenic T cell population involved in the initiation of autoimmune diseases. We have shown that IL-23–dependent, pathogenic T cells produced IL-17A, IL-17F, IL-6, and TNF but not IFN-γ or IL-4. We now show that T-bet and STAT1 transcription factors are not required for the initial production of IL-17. However, optimal IL-17 production in response to IL-23 stimulation appears to require the presence of T-bet. To explore the clinical efficacy of targeting the IL-23 immune pathway, we generated anti–IL-23p19–specific antibodies and tested to determine whether blocking IL-23 function can inhibit EAE, a preclinical animal model of human multiple sclerosis. Anti–IL-23p19 treatment reduced the serum level of IL-17 as well as CNS expression of IFN-γ, IP-10, IL-17, IL-6, and TNF mRNA. In addition, therapeutic treatment with anti–IL-23p19 during active disease inhibited proteolipid protein (PLP) epitope spreading and prevented subsequent disease relapse. Thus, therapeutic targeting of IL-23 effectively inhibited multiple inflammatory pathways that are critical for driving CNS autoimmune inflammation.

IL-25 regulates Th17 function in autoimmune inflammation

Abstract: Interleukin (IL)-25 is a member of the IL-17 family of cytokines. However, unlike the other members of this family, IL-25 promotes T helper (Th) 2 responses. We now show that IL-25 also regulates the development of autoimmune inflammation mediated by IL-17–producing T cells. We have generated IL-25–deficient (il25−/−) mice and found that they are highly susceptible to experimental autoimmune encephalomyelitis (EAE). The accelerated disease in the il25−/− mice is associated with an increase of IL-23 in the periphery and a subsequent increase in the number of inflammatory IL-17–, IFNγ-, and TNF-producing T cells that invade the central nervous system. Neutralization of IL-17 but not IFNγ in il25−/− mice prevented EAE, suggesting that IL-17 is a major disease-promoting factor. IL-25 treatment at several time points during a relapse-remitting model or chronic model of EAE completely suppressed disease. IL-25 treatment induced elevated production of IL-13, which is required for suppression of Th17 responses by direct inhibition of IL-23, IL-1β, and IL-6 expression in activated dendritic cells. Thus, IL-25 and IL-17, being members of the same cytokine family, play opposing roles in the pathogenesis of organ-specific autoimmunity.

Exploring the full spectrum of macrophage activation.

Abstract: Macrophages display remarkable plasticity and can change their physiology in response to environmental cues. These changes can give rise to different populations of cells with distinct functions. In this Review we suggest a new grouping of macrophage populations based on three different homeostatic activities - host defence, wound healing and immune regulation. We propose that similarly to primary colours, these three basic macrophage populations can blend into various other 'shades' of activation. We characterize each population and provide examples of macrophages from specific disease states that have the characteristics of one or more of these populations.

Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.

Abstract: On activation, T cells undergo distinct developmental pathways, attaining specialized properties and effector functions. T-helper (T(H)) cells are traditionally thought to differentiate into T(H)1 and T(H)2 cell subsets. T(H)1 cells are necessary to clear intracellular pathogens and T(H)2 cells are important for clearing extracellular organisms. Recently, a subset of interleukin (IL)-17-producing T (T(H)17) cells distinct from T(H)1 or T(H)2 cells has been described and shown to have a crucial role in the induction of autoimmune tissue injury. In contrast, CD4+CD25+Foxp3+ regulatory T (T(reg)) cells inhibit autoimmunity and protect against tissue injury. Transforming growth factor-beta (TGF-beta) is a critical differentiation factor for the generation of T(reg) cells. Here we show, using mice with a reporter introduced into the endogenous Foxp3 locus, that IL-6, an acute phase protein induced during inflammation, completely inhibits the generation of Foxp3+ T(reg) cells induced by TGF-beta. We also demonstrate that IL-23 is not the differentiation factor for the generation of T(H)17 cells. Instead, IL-6 and TGF-beta together induce the differentiation of pathogenic T(H)17 cells from naive T cells. Our data demonstrate a dichotomy in the generation of pathogenic (T(H)17) T cells that induce autoimmunity and regulatory (Foxp3+) T cells that inhibit autoimmune tissue injury.

Interleukin 17–producing CD4 + effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages

Abstract: CD4(+) T cells producing interleukin 17 (IL-17) are associated with autoimmunity, although the precise mechanisms that control their development are undefined. Here we present data that challenge the idea of a shared developmental pathway with T helper type 1 (T(H)1) or T(H)2 lineages and instead favor the idea of a distinct effector lineage we call 'T(H)-17'. The development of T(H)-17 cells from naive precursor cells was potently inhibited by interferon-gamma (IFN-gamma) and IL-4, whereas committed T(H)-17 cells were resistant to suppression by T(H)1 or T(H)2 cytokines. In the absence of IFN-gamma and IL-4, IL-23 induced naive precursor cells to differentiate into T(H)-17 cells independently of the transcription factors STAT1, T-bet, STAT4 and STAT6. These findings provide a basis for understanding how inhibition of IFN-gamma signaling enhances development of pathogenic T(H)-17 effector cells that can exacerbate autoimmunity.

IL-17 and Th17 Cells.

Abstract: CD4+ T cells, upon activation and expansion, develop into different T helper cell subsets with different cytokine profiles and distinct effector functions. Until recently, T cells were divided into Th1 or Th2 cells, depending on the cytokines they produce. A third subset of IL-17-producing effector T helper cells, called Th17 cells, has now been discovered and characterized. Here, we summarize the current information on the differentiation and effector functions of the Th17 lineage. Th17 cells produce IL-17, IL-17F, and IL-22, thereby inducing a massive tissue reaction owing to the broad distribution of the IL-17 and IL-22 receptors. Th17 cells also secrete IL-21 to communicate with the cells of the immune system. The differentiation factors (TGF-β plus IL-6 or IL-21), the growth and stabilization factor (IL-23), and the transcription factors (STAT3, RORγt, and RORα) involved in the development of Th17 cells have just been identified. The participation of TGF-β in the differentiation of Th17 cells places ...