Mechanisms underlying helper T-cell plasticity: Implications for immune-mediated disease
2013; Elsevier BV; Volume: 131; Issue: 5 Linguagem: Inglês
10.1016/j.jaci.2013.03.015
ISSN1097-6825
AutoresKiyoshi Hirahara, Amanda C. Poholek, Golnaz Vahedi, Arian Laurence, Yuka Kanno, Joshua D. Milner, John J. O’Shea,
Tópico(s)Mast cells and histamine
ResumoCD4 helper T cells are critical for proper immune cell homeostasis and host defense but are also major contributors to immune and inflammatory disease. Arising from a simple biphasic model of differentiation (ie, TH1 and TH2 cells). A bewildering number of fates seem possible for helper T cells. To what extent different helper cell subsets maintain their characteristic gene expression profiles or exhibit functional plasticity is a hotly debated topic. In this review we will discuss how the expression of “signature cytokines” and “master regulator” transcription factors do not neatly conform to a simple helper T-cell paradigm. Although this might seem confusing, the good news is that the newly recognized complexity fits better with our understanding of immunopathogenesis. Finally, we will discuss factors, including epigenetic regulation and metabolic alterations, that contribute to helper cell specificity and plasticity. CD4 helper T cells are critical for proper immune cell homeostasis and host defense but are also major contributors to immune and inflammatory disease. Arising from a simple biphasic model of differentiation (ie, TH1 and TH2 cells). A bewildering number of fates seem possible for helper T cells. To what extent different helper cell subsets maintain their characteristic gene expression profiles or exhibit functional plasticity is a hotly debated topic. In this review we will discuss how the expression of “signature cytokines” and “master regulator” transcription factors do not neatly conform to a simple helper T-cell paradigm. Although this might seem confusing, the good news is that the newly recognized complexity fits better with our understanding of immunopathogenesis. Finally, we will discuss factors, including epigenetic regulation and metabolic alterations, that contribute to helper cell specificity and plasticity. Discuss this article on the JACI Journal Club blog: www.jaci-online.blogspot.com. GlossaryBlimp1A key transcription factor for the differentiation of B cells into antibody-secreting plasma cells within lymphoid organs.EPIGENETICSThe term was coined by Waddington before the era of modern molecular biology. It has come to denote hereditable changes in phenotype or gene expression without changes in DNA sequence.EPIGENOMEThe term indicates the status of the genome-wide chemical changes to the DNA and histone proteins.GENOME-WIDE ASSOCIATION STUDIESCohorts of patients with and without a given disease are examined across the entire genome for single nucleotide polymorphisms that are overrepresented in patients with the disease. This identifies regions of the genome that contain a variant gene or genes that confer disease susceptibility. Candidate genes are then selected based on how closely they are associated with the disease and whether their biologic function correlates with the disease under study.GERMINAL CENTERAn area within a lymphoid follicle where affinity maturation occurs. B cells activated by antigen and helper T cells migrate into germinal centers. Somatic mutation of V region genes in these B cells generates antibodies with different affinity for antigen. Binding of B cells to antigen presented on follicular dendritic cells rescues these B cells from apoptosis. B cells with the highest affinity for antigen will have a survival advantage, which results in an average increase in the affinity of antibodies for antigen during the immune response.INDUCIBLE COSTIMULATOR (ICOS)ICOS is a member of the CD28 family of costimulatory receptors on T cells. ICOS binds to ICOS ligand on antigen-presenting cells and promotes effector responses. Mutations in the ICOS gene have been reported in patients with common variable immunodeficiency.IMMUNE DYSREGULATION–POLYENDOCRINOPATHY–ENTEROPATHY–X-LINKED SYNDROMEFOXP3 mutations lead to immune system dysregulation in this disorder. Features include early-onset diabetes, diarrhea, and failure to thrive. Newborns have an eczematous rash. Serious infections can occur. Laboratory abnormalities include high IgE, normal IgG, normal IgM, and normal IgA levels. T and B subsets are also normal. Autoimmune hemolytic anemia, neutropenia, and thrombocytopenia can occur. Female carriers are usually healthy.LOCUSThe position in a chromosome of a particular gene or allele.MUCOCUTANEOUS CANDIDIASISPersistent superficial candidal infections of the mucous membranes, skin, and nails. Other defects that are associated with mucocutaneous candidiasis include CARD9/Dectin-1 deficiency and AIRE gene defects. Patients have selective anergy to Candida species on delayed-type hypersensitivity testing.NAIVE CD4 T CELLST cells that have completed maturation in the thymus but have not yet encountered foreign antigen. They are characterized by no effector function, no cell cycling, and high expression of CCR7 and CD62 ligand (L-selectin and peripheral lymph node homing receptor). Their major CD45 isoform is CD45RA.RAPAMYCINAn immunosuppressant drug used in renal transplantation as prophylaxis against organ rejection.SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION (STAT)Transcription factors that are a part of the Janus kinase (Jak)–STAT pathway. Many cytokines use Jak-STAT pathways for signaling. There are 7 STATs (1-4, 5a, 5b, and 6). The discovery of the Jak-STAT pathway came from analyses of interferon signaling.The Editors wish to acknowledge Daniel A. Searing, MD, for preparing this glossary. A key transcription factor for the differentiation of B cells into antibody-secreting plasma cells within lymphoid organs. The term was coined by Waddington before the era of modern molecular biology. It has come to denote hereditable changes in phenotype or gene expression without changes in DNA sequence. The term indicates the status of the genome-wide chemical changes to the DNA and histone proteins. Cohorts of patients with and without a given disease are examined across the entire genome for single nucleotide polymorphisms that are overrepresented in patients with the disease. This identifies regions of the genome that contain a variant gene or genes that confer disease susceptibility. Candidate genes are then selected based on how closely they are associated with the disease and whether their biologic function correlates with the disease under study. An area within a lymphoid follicle where affinity maturation occurs. B cells activated by antigen and helper T cells migrate into germinal centers. Somatic mutation of V region genes in these B cells generates antibodies with different affinity for antigen. Binding of B cells to antigen presented on follicular dendritic cells rescues these B cells from apoptosis. B cells with the highest affinity for antigen will have a survival advantage, which results in an average increase in the affinity of antibodies for antigen during the immune response. ICOS is a member of the CD28 family of costimulatory receptors on T cells. ICOS binds to ICOS ligand on antigen-presenting cells and promotes effector responses. Mutations in the ICOS gene have been reported in patients with common variable immunodeficiency. FOXP3 mutations lead to immune system dysregulation in this disorder. Features include early-onset diabetes, diarrhea, and failure to thrive. Newborns have an eczematous rash. Serious infections can occur. Laboratory abnormalities include high IgE, normal IgG, normal IgM, and normal IgA levels. T and B subsets are also normal. Autoimmune hemolytic anemia, neutropenia, and thrombocytopenia can occur. Female carriers are usually healthy. The position in a chromosome of a particular gene or allele. Persistent superficial candidal infections of the mucous membranes, skin, and nails. Other defects that are associated with mucocutaneous candidiasis include CARD9/Dectin-1 deficiency and AIRE gene defects. Patients have selective anergy to Candida species on delayed-type hypersensitivity testing. T cells that have completed maturation in the thymus but have not yet encountered foreign antigen. They are characterized by no effector function, no cell cycling, and high expression of CCR7 and CD62 ligand (L-selectin and peripheral lymph node homing receptor). Their major CD45 isoform is CD45RA. An immunosuppressant drug used in renal transplantation as prophylaxis against organ rejection. Transcription factors that are a part of the Janus kinase (Jak)–STAT pathway. Many cytokines use Jak-STAT pathways for signaling. There are 7 STATs (1-4, 5a, 5b, and 6). The discovery of the Jak-STAT pathway came from analyses of interferon signaling. The Editors wish to acknowledge Daniel A. Searing, MD, for preparing this glossary. CD4 T cells are critical for host defense, but in addition to their key role as helper cells, they can also be troublemakers, driving autoimmune diseases, asthma, and allergies.1Robinson D.S. The role of the T cell in asthma.J Allergy Clin Immunol. 2010; 126: 1081-1093Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar, 2Akdis M. Palomares O. van de Veen W. van Splunter M. Akdis C.A. TH17 and TH22 cells: a confusion of antimicrobial response with tissue inflammation versus protection.J Allergy Clin Immunol. 2012; 129: 1438-1451Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar Classically, we viewed helper T cells as having 2 major fates, TH1 and TH2 cells (Fig 1, A), but we now know that the opportunities for helper diversity are far greater than just these 2 outcomes. The new diversity includes TH17, TH9, and TH22 cells; follicular helper T (TFH) cells; and different types of regulatory T (Treg) cells (Fig 1, B).2Akdis M. Palomares O. van de Veen W. van Splunter M. Akdis C.A. TH17 and TH22 cells: a confusion of antimicrobial response with tissue inflammation versus protection.J Allergy Clin Immunol. 2012; 129: 1438-1451Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar, 3Korn T. Bettelli E. Oukka M. Kuchroo V.K. IL-17 and Th17 Cells.Annu Rev Immunol. 2009; 27: 485-517Crossref PubMed Scopus (3878) Google Scholar, 4Crotty S. Follicular helper CD4 T cells (TFH).Annu Rev Immunol. 2011; 29: 621-663Crossref PubMed Scopus (2083) Google Scholar, 5Tan C. Gery I. The unique features of Th9 cells and their products.Crit Rev Immunol. 2012; 32: 1-10Crossref PubMed Google Scholar, 6Sakaguchi S. Yamaguchi T. Nomura T. Ono M. Regulatory T cells and immune tolerance.Cell. 2008; 133: 775-787Abstract Full Text Full Text PDF PubMed Scopus (3770) Google Scholar In addition, the emerging data point to the increased flexibility of these subsets. Fortunately, we are also beginning to understand the molecular basis of this complexity. This newer appreciation is not just pertinent for understanding the basic aspects of T-cell biology; on the contrary, the new insights provide a more sophisticated understanding of immune-mediated disease and new opportunities for therapy. In this review we discuss helper cell differentiation decisions and how the regulation of helper cell specificity pertains to susceptibility to immune and inflammatory disease. We will consider the intrinsic and extrinsic factors that drive specification and the mechanisms that influence flexibility. Of particular interest with respect to the issue of plasticity are advances in epigenetic technologies as they pertain to T-cell biology. The insights provided are especially relevant for immunologically mediated diseases, in which both genetic and environmental factors play key roles in susceptibility. For more than 2 decades, it has been recognized that CD4 T cells specialize in response to microbial challenges. The first subsets recognized were denoted TH1 and TH2 cells based on the selective production of 2 cytokines, IFN-γ and IL-4, respectively.7Mosmann T.R. Coffman R.L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties.Annu Rev Immunol. 1989; 7: 145-173Crossref PubMed Google Scholar This TH1/TH2 paradigm was reasonably useful for initial categorization of mechanisms involving elimination of microbial pathogens. For instance, TH1 cells are critical for the clearance of many intracellular pathogens, such as Leishmania major and Mycobacterium tuberculosis.8Reiner S.L. Locksley R.M. The regulation of immunity to Leishmania major.Annu Rev Immunol. 1995; 13: 151-177Crossref PubMed Google Scholar, 9North R.J. Jung Y.J. Immunity to tuberculosis.Annu Rev Immunol. 2004; 22: 599-623Crossref PubMed Scopus (555) Google Scholar Similarly, TH2 cells were found to be important for elimination of helminthic parasites, such as Nippostrongylus brasiliensis and Schistosoma mansoni.10Pulendran B. Artis D. New paradigms in type 2 immunity.Science. 2012; 337: 431-435Crossref PubMed Scopus (336) Google Scholar At first, the pathogenesis of immune-mediated disease also seemed to fit within this paradigm. Human asthma, as well as animal models of allergic airway inflammation, revealed the importance of cytokines produced by TH2 cells, namely IL-4, IL-5, and IL-1311Wills-Karp M. Interleukin-13 in asthma pathogenesis.Immunol Rev. 2004; 202: 175-190Crossref PubMed Scopus (551) Google Scholar, 12Cohn L. Elias J.A. Chupp G.L. Asthma: mechanisms of disease persistence and progression.Annu Rev Immunol. 2004; 22: 789-815Crossref PubMed Scopus (716) Google Scholar, 13Umetsu D.T. DeKruyff R.H. The regulation of allergy and asthma.Immunol Rev. 2006; 212: 238-255Crossref PubMed Scopus (209) Google Scholar, 14Hirahara K. Yamashita M. Iwamura C. Shinoda K. Hasegawa A. Yoshizawa H. et al.Repressor of GATA regulates TH2-driven allergic airway inflammation and airway hyperresponsiveness.J Allergy Clin Immunol. 2008; 122: 512-520.e11Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar; the contribution of these various cytokines to the pathophysiology of airway inflammation, eosinophilia, fibrosis, and other responses is well recognized.15Finkelman F.D. Hogan S.P. Hershey G.K. Rothenberg M.E. Wills-Karp M. Importance of cytokines in murine allergic airway disease and human asthma.J Immunol. 2010; 184: 1663-1674Crossref PubMed Scopus (238) Google Scholar, 16Rothenberg M.E. Hogan S.P. The eosinophil.Annu Rev Immunol. 2006; 24: 147-174Crossref PubMed Scopus (1254) Google Scholar, 17Wills-Karp M. Luyimbazi J. Xu X. Schofield B. Neben T.Y. Karp C.L. et al.Interleukin-13: central mediator of allergic asthma.Science. 1998; 282: 2258-2261Crossref PubMed Scopus (2404) Google Scholar Moreover, genome-wide association studies of asthmatic patients have revealed the association of DNA variants in the TH2 cytokine locus and the IL4R gene with susceptibility to asthma.18Li X. Howard T.D. Zheng S.L. Haselkorn T. Peters S.P. Meyers D.A. et al.Genome-wide association study of asthma identifies RAD50-IL13 and HLA-DR/DQ regions.J Allergy Clin Immunol. 2010; 125: 328-335.e11Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar, 19Hirota T. Takahashi A. Kubo M. Tsunoda T. Tomita K. Doi S. et al.Genome-wide association study identifies three new susceptibility loci for adult asthma in the Japanese population.Nat Genet. 2011; 43: 893-896Crossref PubMed Scopus (266) Google Scholar, 20Torgerson D.G. Ampleford E.J. Chiu G.Y. Gauderman W.J. Gignoux C.R. Graves P.E. et al.Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations.Nat Genet. 2011; 43: 887-892Crossref PubMed Scopus (635) Google Scholar Equally important has been the successful use of therapeutic mAbs directed against IL-5 (mepolizumab) and IL-13 (lebrikizumab).21Nair P. Pizzichini M.M. Kjarsgaard M. Inman M.D. Efthimiadis A. Pizzichini E. et al.Mepolizumab for prednisone-dependent asthma with sputum eosinophilia.N Engl J Med. 2009; 360: 985-993Crossref PubMed Scopus (1196) Google Scholar, 22Haldar P. Brightling C.E. Hargadon B. Gupta S. Monteiro W. Sousa A. et al.Mepolizumab and exacerbations of refractory eosinophilic asthma.N Engl J Med. 2009; 360: 973-984Crossref PubMed Scopus (1570) Google Scholar, 23Corren J. Lemanske R.F. Hanania N.A. Korenblat P.E. Parsey M.V. Arron J.R. et al.Lebrikizumab treatment in adults with asthma.N Engl J Med. 2011; 365: 1088-1098Crossref PubMed Scopus (1364) Google Scholar, 24Strunk R.C. Bloomberg G.R. Omalizumab for asthma.N Engl J Med. 2006; 354: 2689-2695Crossref PubMed Scopus (207) Google Scholar Such discoveries clearly point to the pathophysiologic role of these cytokines, although it is also clear that not all patients respond to these agents. Such findings clearly point to the additional complexity of these diseases. Initially viewed as one of the products of TH2 cells, IL-9 is an important factor that promotes mucus production; its expression is increased in the airways of asthmatic patients.25Shimbara A. Christodoulopoulos P. Soussi-Gounni A. Olivenstein R. Nakamura Y. Levitt R.C. et al.IL-9 and its receptor in allergic and nonallergic lung disease: increased expression in asthma.J Allergy Clin Immunol. 2000; 105: 108-115Abstract Full Text Full Text PDF PubMed Google Scholar, 26Vermeer P.D. Harson R. Einwalter L.A. Moninger T. Zabner J. Interleukin-9 induces goblet cell hyperplasia during repair of human airway epithelia.Am J Respir Cell Mol Biol. 2003; 28: 286-295Crossref PubMed Scopus (93) Google Scholar, 27Ciprandi G. De Amici M. Giunta V. Marseglia A. Marseglia G. Serum interleukin-9 levels are associated with clinical severity in children with atopic dermatitis.Pediatr Dermatol. 2013; 30: 222-225Crossref PubMed Scopus (40) Google Scholar Recently, however, IL-9 has been found to be produced in a subset of cells that is distinct from classical TH2 cells.5Tan C. Gery I. The unique features of Th9 cells and their products.Crit Rev Immunol. 2012; 32: 1-10Crossref PubMed Google Scholar, 28Schmitt E. Bopp T. Amazing IL-9: revealing a new function for an “old” cytokine.J Clin Invest. 2012; 122: 3857-3859Crossref PubMed Scopus (0) Google Scholar These cells are dubbed TH9 cells, but precisely how they relate to other subsets and the extent to which they constitute a stable subset remain to be determined. It is also well appreciated that IgE is a central player in the pathophysiology of allergies and asthma.24Strunk R.C. Bloomberg G.R. Omalizumab for asthma.N Engl J Med. 2006; 354: 2689-2695Crossref PubMed Scopus (207) Google Scholar, 29Busse W.W. Morgan W.J. Gergen P.J. Mitchell H.E. Gern J.E. Liu A.H. et al.Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children.N Engl J Med. 2011; 364: 1005-1015Crossref PubMed Scopus (711) Google Scholar Although the generation of IgE-producing B cells is a well-accepted action of IL-4, it is also becoming clear that a specific population of CD4 T cells are important for providing B-cell help. These cells are designated as TFH cells and are identified based on their location in germinal centers and surface expression of the molecules CXCR5 and programmed cell death 1 (PD-1).4Crotty S. Follicular helper CD4 T cells (TFH).Annu Rev Immunol. 2011; 29: 621-663Crossref PubMed Scopus (2083) Google Scholar, 30Johnston R.J. Poholek A.C. DiToro D. Yusuf I. Eto D. Barnett B. et al.Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation.Science. 2009; 325: 1006-1010Crossref PubMed Scopus (1180) Google Scholar, 31Yu D. Rao S. Tsai L.M. Lee S.K. He Y. Sutcliffe E.L. et al.The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment.Immunity. 2009; 31: 457-468Abstract Full Text Full Text PDF PubMed Scopus (901) Google Scholar, 32Nurieva R.I. Chung Y. Martinez G.J. Yang X.O. Tanaka S. Matskevitch T.D. et al.Bcl6 mediates the development of T follicular helper cells.Science. 2009; 325: 1001-1005Crossref PubMed Scopus (1118) Google Scholar IL-21 has been referred to as the signature cytokine for TFH cells, but IL-21 is also produced by TH1 and TH17 cells.33Nakayamada S. Kanno Y. Takahashi H. Jankovic D. Lu K.T. Johnson T.A. et al.Early Th1 cell differentiation is marked by a Tfh cell-like transition.Immunity. 2011; 35: 919-931Abstract Full Text Full Text PDF PubMed Scopus (329) Google Scholar, 34Wei L. Laurence A. Elias K.M. O'Shea J.J. IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner.J Biol Chem. 2007; 282: 34605-34610Abstract Full Text Full Text PDF PubMed Scopus (519) Google Scholar In addition, TFH cells can produce cytokines made by other subsets, including IFN-γ, IL-4, IL-17, and IL-10.4Crotty S. Follicular helper CD4 T cells (TFH).Annu Rev Immunol. 2011; 29: 621-663Crossref PubMed Scopus (2083) Google Scholar, 35Reinhardt R.L. Liang H.E. Locksley R.M. Cytokine-secreting follicular T cells shape the antibody repertoire.Nat Immunol. 2009; 10: 385-393Crossref PubMed Scopus (606) Google Scholar, 36Hsu H.C. Yang P. Wang J. Wu Q. Myers R. Chen J. et al.Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice.Nat Immunol. 2008; 9: 166-175Crossref PubMed Scopus (583) Google Scholar Therefore TFH cells might have both overlapping and distinct contributions to disease because they can make TH1 and TH2 cytokines but also contribute specifically to antibody formation. Because they do not localize to tissues, the direct effects of their cytokine production are unlikely to be with regard to tissue inflammation but rather with regard to isotype-specific antibody production. Accordingly, genetic mutations in inducible costimulator (ICOS) or SLAM-associated protein (SAP), genes expressed by TFH cells that are necessary for interaction with B cells, result in a loss of TFH cell development and thus antibody production.37Akiba H. Takeda K. Kojima Y. Usui Y. Harada N. Yamazaki T. et al.The role of ICOS in the CXCR5+ follicular B helper T cell maintenance in vivo.J Immunol. 2005; 175: 2340-2348Crossref PubMed Scopus (311) Google Scholar, 38Qi H. Cannons J.L. Klauschen F. Schwartzberg P.L. Germain R.N. SAP-controlled T-B cell interactions underlie germinal centre formation.Nature. 2008; 455: 764-769Crossref PubMed Scopus (493) Google Scholar, 39Cannons J.L. Qi H. Lu K.T. Dutta M. Gomez-Rodriguez J. Cheng J. et al.Optimal germinal center responses require a multistage T cell:B cell adhesion process involving integrins, SLAM-associated protein, and CD84.Immunity. 2010; 32: 253-265Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar In addition, patients with mutations in signal transducer and activator of transcription (STAT) 3 have reduced TFH cell numbers, which might contribute to the altered antibody repertoire they display.40Ma C.S. Avery D.T. Chan A. Batten M. Bustamante J. Boisson-Dupuis S. et al.Functional STAT3 deficiency compromises the generation of human T follicular helper cells.Blood. 2012; 119: 3997-4008Crossref PubMed Scopus (244) Google Scholar The attempt to link common autoimmune diseases with a simple TH1/TH2 paradigm has been even more problematic.41Gor D.O. Rose N.R. Greenspan N.S. TH1-TH2: a procrustean paradigm.Nat Immunol. 2003; 4: 503-505Crossref PubMed Scopus (198) Google Scholar Certainly, there is evidence that excessive activation of TH1 cells contributes to organ-specific autoimmune diseases.42Szabo S.J. Sullivan B.M. Peng S.L. Glimcher L.H. Molecular mechanisms regulating Th1 immune responses.Annu Rev Immunol. 2003; 21: 713-758Crossref PubMed Scopus (783) Google Scholar However, a number of lines of evidence suggest that autoimmune mechanisms cannot be reduced to the action of TH1 cells alone. In particular, the discovery of a new cytokine, IL-23, led to the recognition of a new subset of helper T cells and their importance in autoimmunity.43Cua D.J. Sherlock J. Chen Y. Murphy C.A. Joyce B. Seymour B. et al.Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain.Nature. 2003; 421: 744-748Crossref PubMed Scopus (2397) Google Scholar The discovery of an IL-17–producing population of CD4 T cells, termed TH17 cells, helped clarify contrasting findings in experimental autoimmune encephalitis, a mouse model of multiple sclerosis. IL-23 was found to have a critical role in experimental autoimmune encephalitis pathogenicity, and selective production of IL-17 by helper T cells was linked to IL-23. Although pathogenicity of the cytokine IL-17 in patients with arthritis has been recognized since the late 1990s, the discovery of IL-23 led to the appreciation of TH17 cells as a distinct subset.43Cua D.J. Sherlock J. Chen Y. Murphy C.A. Joyce B. Seymour B. et al.Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain.Nature. 2003; 421: 744-748Crossref PubMed Scopus (2397) Google Scholar, 44Miossec P, Korn T. Kuchroo V.K. Interleukin-17 and type 17 helper T cells.N Engl J Med. 2009; 361: 888-898Crossref Scopus (0) Google Scholar, 45Veldhoen M. Hocking R.J. Atkins C.J. Locksley R.M. Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.Immunity. 2006; 24: 179-189Abstract Full Text Full Text PDF PubMed Scopus (3055) Google Scholar, 46Bettelli E. Carrier Y. Gao W. Korn T. Strom T.B. Oukka M. et al.Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.Nature. 2006; 441: 235-238Crossref PubMed Scopus (5663) Google Scholar, 47Ivanov I.I. McKenzie B.S. Zhou L. Tadokoro C.E. Lepelley A. Lafaille J.J. et al.The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells.Cell. 2006; 126: 1121-1133Abstract Full Text Full Text PDF PubMed Scopus (4058) Google Scholar Accordingly, mAbs that interfere with the action of IL-17, such as ixekizumab and secukinumab, appear to be useful in patients with diseases such as rheumatoid arthritis and psoriasis.48Leonardi C. Matheson R. Zachariae C. Cameron G. Li L. Edson-Heredia E. et al.Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis.N Engl J Med. 2012; 366: 1190-1199Crossref PubMed Scopus (811) Google Scholar, 49Genovese M.C. Van den Bosch F. Roberson S.A. Bojin S. Biagini I.M. Ryan P. et al.LY2439821, a humanized anti-interleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase I randomized, double-blind, placebo-controlled, proof-of-concept study.Arthritis Rheum. 2010; 62: 929-939Crossref PubMed Scopus (390) Google Scholar, 50Hueber W. Patel D.D. Dryja T. Wright A.M. Koroleva I. Bruin G. et al.Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis.Sci Transl Med. 2010; 2: 52ra72Crossref PubMed Scopus (750) Google Scholar, 51Genovese M.C. Durez P. Richards H.B. Supronik J. Dokoupilova E. Mazurov V. et al.Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, double-blind, randomised, placebo controlled study.Ann Rheum Dis. 2012; ([Epub ahead of print])Google Scholar In addition to pathogenic roles in human autoimmunity and a variety of mouse models of disease, TH17 cells contribute to host defense against extracellular bacteria, such as Staphylococcus aureus and Klebsiella pneumonia, as well as fungi.52Stockinger B. Veldhoen M. Martin B. Th17 T cells: linking innate and adaptive immunity.Semin Immunol. 2007; 19: 353-361Crossref PubMed Scopus (221) Google Scholar, 53Ma C.S. Chew G.Y. Simpson N. Priyadarshi A. Wong M. Grimbacher B. et al.Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3.J Exp Med. 2008; 205: 1551-1557Crossref PubMed Scopus (560) Google Scholar, 54Ye P. Rodriguez F.H. Kanaly S. Stocking K.L. Schurr J. Schwarzenberger P. et al.Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense.J Exp Med. 2001; 194: 519-527Crossref PubMed Scopus (1240) Google Scholar The importance of IL-17 applies not only to autoimmune disease but is also relevant to the pathophysiology of asthma.55Molet S. Hamid Q. Davoine F. Nutku E. Taha R. Page N. et al.IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines.J Allergy Clin Immunol. 2001; 108: 430-438Abstract Full Text Full Text PDF PubMed Scopus (791) Google Scholar, 56Chakir J. Shannon J. Molet S. Fukakusa M. Elias J. Laviolette M. et al.Airway remodeling-associated mediators in moderate to severe asthma: effect of steroids on TGF-beta, IL-11, IL-17, and type I and type III collagen expression.J Allergy Clin Immunol. 2003; 111: 1293-1298Abstract Full Text Full Text PDF PubMed Scopus (564) Google Scholar, 57Laan M. Palmberg L. Larsson K. Linden A. Free, soluble interleukin-17 protein during severe inflammation in human airways.Eur Respir J. 2002; 19: 534-537Crossref PubMed Scopus (85) Google Scholar One important action of IL-17 is the recruitment of neutrophils to the lung during airway inflammation and likely plays a role in steroid-resistant asthma.55Molet S. Hamid Q. Davoine F. Nutku E. Taha R. Page N. et al.IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines.J Allergy Clin Immunol. 2001; 108: 430-438Abstract Full Text Full Text PDF PubMed Scopus (791) Google Scholar, 56Chakir J. Shannon J. Molet S. Fukakusa M. Elias J. Laviolette M. et al.Airway remodeling-associated mediators in moderate to severe asthma: effect of steroids on TGF-beta, IL-11, IL-17, and type I and type III collagen expression.J Allergy Clin Immunol. 2003; 111: 1293-1298Abstract Full Text Full Text PDF PubMed Scopus (564) Google Scholar, 57Laan M. Palmberg L. Larsson K. Linden A. Free, soluble interleukin-17 protein during severe inflammation in human airways.Eur Respir J. 2002; 19: 534-537Crossref PubMed Scopus (85) Google Scholar, 58Wenzel S.E. Schwartz L.B. Langmack E.L. Halliday J.L. Trud
Referência(s)